Vibha Singhal

Treatment of Pediatric Obesity: A Systematic Review and Meta-Analysis of Randomized Trials

CONTEXT The efficacy of treatments for pediatric obesity remains unclear. OBJECTIVE We performed a systematic review of randomized trials to estimate the efficacy of nonsurgical interventions for pediatric obesity. DATA SOURCES Librarian-designed search strategies of nine electronic databases from inception until February 2006, review of reference lists from published reviews, and content expert advice provided potentially eligible studies. STUDY SELECTION Eligible studies were randomized trials of overweight children and adolescents assessing the effect of nonsurgical interventions on obesity outcomes. DATA EXTRACTION Independently and in duplicate, reviewers assessed the quality of each trial and collected data on interventions and outcomes. DATA SYNTHESIS Of 76 eligible trials, 61 had complete data for meta-analysis. Short-term medications were effective, including sibutramine [random-effects pooled estimate of body mass index (BMI) loss of 2.4 kg/m(2) with a 95% confidence interval (CI) of 1.8-3.1; proportion of between-study inconsistency not due to chance (I(2)) = 30%] and orlistat (BMI loss = 0.7 kg/m(2); CI = 0.3-1.2; I(2) = 0%). Trials that measured the effect of physical activity on adiposity (i.e. percent body fat and fat-free mass) found a moderate treatment effect (effect size = -0.52; CI = -0.73 to -0.30; I(2) = 0%), whereas trials measuring the effect on BMI found no significant effect (effect size = -0.02; CI = -0.21 to 0.18; I(2) = 0%), but reporting bias may explain this finding. Combined lifestyle interventions (24 trials) led to small changes in BMI. CONCLUSIONS Limited evidence supports the short-term efficacy of medications and lifestyle interventions. The long-term efficacy and safety of pediatric obesity treatments remain unclear.

Behavioral interventions to prevent childhood obesity: A systematic review and metaanalyses of randomized trials

CONTEXT The efficacy of lifestyle interventions to encourage healthy lifestyle behaviors to prevent pediatric obesity remains unclear. OBJECTIVE Our objective was to summarize evidence on the efficacy of interventions aimed at changing lifestyle behaviors (increased physical activity, decreased sedentary activity, increased healthy dietary habits, and decreased unhealthy dietary habits) to prevent obesity. DATA SOURCES Data sources included librarian-designed searches of nine electronic databases, references from included studies and reviews (from inception until February 2006), and content expert recommendations. STUDY SELECTION Eligible studies were randomized trials enrolling children and adolescents assessing the impact of interventions on both lifestyle behaviors and body mass index (BMI). DATA EXTRACTION Two reviewers independently abstracted data on methodological quality, study characteristics, intervention components, and treatment effects. DATA ANALYSIS We conducted random-effects metaanalyses, quantified inconsistency using I(2), and conducted planned subgroup analyses for each examined outcome. DATA SYNTHESIS Regarding target behaviors, the pooled effect size for physical activity (22 comparisons; n = 9891 participants) was 0.12 [95% confidence interval (CI) = 0.04-0.20; I(2) = 63%], for sedentary activity (14 comparisons; n = 3003) was -0.29, (CI = -0.35 to -0.22; I(2) = 0%), for healthy dietary habits (14 comparisons, n = 5468) was 0.00 (CI = -0.20; 0.20; I(2) = 83%), and for unhealthy dietary habits (23 comparisons, n = 9578) was -0.20 (CI = -0.31 to -0.09; I(2) = 34%). The effect of these interventions on BMI (43 comparisons, n = 32,003) was trivial (-0.02; CI = -0.06-0.02; I(2) = 17%) compared with control. Trials with interventions lasting more than 6 months (vs. shorter trials) and trials with postintervention outcomes (vs. in-treatment outcomes) yielded marginally larger effects. CONCLUSION Pediatric obesity prevention programs caused small changes in target behaviors and no significant effect on BMI compared with control. Trials evaluating promising interventions applied over a long period, using responsive outcomes, with longer measurement timeframes are urgently needed.

Irisin Levels Are Lower in Young Amenorrheic Athletes Compared with Eumenorrheic Athletes and Non-Athletes and Are Associated with Bone Density and Strength Estimates

Irisin and FGF21 are novel hormones implicated in the “browning” of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14–21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes.

Endocrinology of anorexia nervosa in young people: recent insights.

Purpose of reviewAnorexia nervosa is among the most prevalent chronic medical conditions in young adults. It has acute as well as long-term consequences, some of which, such as low bone mineral density (BMD), are not completely reversible even after weight restoration. This review discusses our current understanding of endocrine consequences of anorexia nervosa. Recent findingsAnorexia nervosa is characterized by changes in multiple neuroendocrine axes including acquired hypogonadotropic hypogonadism, growth hormone resistance with low insulin-like growth factor-1 (likely mediated by fibroblast growth factor-1), relative hypercortisolemia, alterations in adipokines such as leptin, adiponectin and resistin, and gut peptides including ghrelin, PYY and amylin. These changes in turn contribute to low BMD. Studies in anorexia nervosa have demonstrated abnormalities in bone microarchitecture and strength, and an association between increased marrow fat and decreased BMD. One study in adolescents reported an improvement in BMD following physiologic estrogen replacement, and another in adults demonstrated improved BMD following risedronate administration. Brown adipose tissue is reduced in anorexia nervosa, consistent with an adaptive response to the energy deficit state. SummaryAnorexia nervosa is associated with widespread physiologic adaptations to the underlying state of undernutrition. Hormonal changes in anorexia nervosa affect BMD adversely. Further investigation is underway to optimize therapeutic strategies for low BMD.

Effect of Chronic Athletic Activity on Brown Fat in Young Women

Background The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. Purpose We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. Methods The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross-sectional study of 24 women (16 athletes and8 non-athletes) between 18–25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8).We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. Results Athletes and non-athletes did not differ for age or BMI. Compared with non-athletes, athletes had lower percent body fat (p = 0.002), higher percent lean mass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = -0.46, p = 0.02).BAT volume correlated inversely with lean mass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. Conclusions Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit.

Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited GNAS Deletion.

Proximal tubular resistance to parathyroid hormone (PTH) resulting in hypocalcemia and hyperphosphatemia are preeminent abnormalities in pseudohypoparathyroidism type Ib (PHP1B), but resistance toward other hormones as well as variable features of Albrights Hereditary Osteodystrophy (AHO) can occur also. Genomic DNA from PHP1B patients shows epigenetic changes at one or multiple differentially methylated regions (DMRs) within GNAS, the gene encoding Gαs and splice variants thereof. In the autosomal dominant disease variant, these methylation abnormalities are caused by deletions in STX16 or GNAS on the maternal allele. The molecular defect(s) leading to sporadic PHP1B (sporPHP1B) remains in most cases unknown and we therefore analyzed 60 sporPHP1B patients and available family members by microsatellite markers, single nucleotide polymorphisms (SNPs), multiplex ligation‐dependent probe amplification (MLPA), and methylation‐specific MLPA (MS‐MLPA). All investigated cases revealed broad GNAS methylation changes, but no evidence for inheritance of two paternal chromosome 20q alleles. Some patients with partial epigenetic modifications in DNA from peripheral blood cells showed more complete GNAS methylation changes when testing their immortalized lymphoblastoid cells. Analysis of siblings and children of sporPHP1B patients provided no evidence for an abnormal mineral ion regulation and no changes in GNAS methylation. Only one patient revealed, based on MLPA and microsatellite analyses, evidence for an allelic loss, which resulted in the discovery of two adjacent, maternally inherited deletions (37,597 and 1427 bp, respectively) that remove the area between GNAS antisense exons 3 and 5, including exon NESP. Our findings thus emphasize that the region comprising antisense exons 3 and 4 is required for establishing all maternal GNAS methylation imprints. The genetic defect(s) leading in sporPHP1B to epigenetic GNAS changes and thus PTH‐resistance remains unknown, but it seems unlikely that this disease variant is caused by heterozygous inherited or de novo mutations involving GNAS.

Impaired bone strength estimates at the distal tibia and its determinants in adolescents with anorexia nervosa

BACKGROUND Altered bone microarchitecture and higher marrow adipose tissue (MAT) may reduce bone strength. High resolution pQCT (HRpQCT) allows assessment of volumetric BMD (vBMD), and size and microarchitecture parameters of bone, while 1H-magnetic resonance spectroscopy (1H-MRS) allows MAT evaluation. We have reported impaired microarchitecture at the non-weight bearing radius in adolescents with anorexia nervosa (AN) and that these changes may precede aBMD deficits. Data are lacking regarding effects of AN on microarchitecture and strength at the weight-bearing tibia in adolescents and young adults, and the impact of changes in microarchitecture and MAT on strength estimates. OBJECTIVE To compare strength estimates at the distal tibia in adolescents/young adults with AN and controls in relation to vBMD, bone size and microarchitecture, and spine MAT. DESIGN AND METHODS This was a cross-sectional study of 47 adolescents/young adults with AN and 55 controls 14-24years old that assessed aBMD and body composition using DXA, and distal tibia vBMD, size, microarchitecture and strength estimates using HRpQCT, extended cortical analysis, individual trabecular segmentation, and finite element analysis. Lumbar spine MAT (1H-MRS) was assessed in a subset of 19 AN and 22 controls. RESULTS Areal BMD Z-scores were lower in AN than controls. At the tibia, AN had greater cortical porosity, lower total and cortical vBMD, cortical area and thickness, trabecular number, and strength estimates than controls. Within AN, strength estimates were positively associated with lean mass, aBMD, vBMD, bone size and microarchitectural parameters. MAT was higher in AN, and associated inversely with strength estimates. CONCLUSIONS Adolescents/young adults with AN have impaired microarchitecture at the weight-bearing tibia and higher spine MAT, associated with reduced bone strength.

Vertebral Strength and Estimated Fracture Risk Across the BMI Spectrum in Women.

Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor-of-risk (Φ), the ratio of applied load to bone strength, is a biomechanically based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength (linear combination of integral volumetric bone mineral density [Int.vBMD] and cross-sectional area from quantitative computed tomography [QCT]), vertebral compressive loads, and Φ at L4 in 176 women (65 anorexia nervosa, 45 lean controls, and 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from dual-energy X-ray absorptiometry [DXA]) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared with controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p < 0.0001) but were highest in anorexia nervosa for bending (p < 0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p < 0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p < 0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R = 0.28 to 0.45, p ≤ 0.0001) in all groups combined and negatively with VAT (R = -[0.36 to 0.38], p < 0.003) within the obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending because of inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting because of higher applied loads from higher body weight. Examining the load-to-strength ratio helps explain increased fracture risk in both low-weight and obese women.

Comparing Outcomes of Two Types of Bariatric Surgery in an Adolescent Obese Population: Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy

Background Obesity is prevalent among adolescents and is associated with serious health consequences. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) are bariatric procedures that cause significant weight loss in adults and are increasingly being performed in adolescents with morbid obesity. Data comparing outcomes of RYGB vs. SG in this age-group are scarce. This study aims to compare short-term (1–6 months) and longer-term (7–18 months) body mass index (BMI) and biochemical outcomes following RYGB and SG in adolescents/young adults. Methods A retrospective study using data extracted from medical records of patients 16–21 years who underwent RYGB or SG between 2012 and 2014 at a tertiary care academic medical center. Results Forty-six patients were included in this study: 24 underwent RYGB and 22 underwent SG. Groups did not differ for baseline age, sex, race, or BMI. BMI reductions were significant at 1–6 months and 7–18 months within groups (p < 0.0001), but did not differ by surgery type (p = 0.65 and 0.09, for 1–6 months and 7–18 months, respectively). Over 7–18 months, within-group improvement in low-density lipoprotein (LDL) (−24 ± 6 in RYGB, p = 0.003, vs. −7 ± 9 mg/dl in SG, p = 0.50) and non-high-density lipoprotein (non-HDL) cholesterol (−23 ± 8 in RYGB, p = 0.02, vs. −12 ± 7 in SG, p = 0.18) appeared to be of greater magnitude following RYGB. However, differences between groups did not reach statistical significance. When divided by non-alcoholic steatohepatitis stages (NASH), patients with Stage II–III NASH had greater reductions in alanine aminotransferase levels vs. those with Stage 0–I NASH (−45 ± 18 vs. −9 ± 3, p = 0.01) after 7–18 months. RYGB and SG groups did not differ for the magnitude of post-surgical changes in liver enzymes. Conclusion RYGB and SG did not differ for the magnitude of BMI reduction across groups, though changes trended higher following RYGB. Further prospective studies are needed to confirm these findings.

Regional Fat Depots and their Relationship to Bone Density and Microarchitecture in Young Oligo-amenorrheic Athletes

CONTEXT Various fat depots have differential effects on bone. Visceral adipose tissue (VAT) is deleterious to bone, whereas subcutaneous adipose tissue (SAT) has positive effects. Also, marrow adipose tissue (MAT), a relatively newly recognized fat depot is inversely associated with bone mineral density (BMD). Bone mass in athletes depends on many factors including gonadal steroids and muscle mass. Exercise increases muscle mass and BMD, whereas, estrogen deficiency decreases BMD. Thus, the beneficial effects of weight-bearing exercise on areal and volumetric BMD (aBMD and vBMD) in regularly menstruating (eumenorrheic) athletes (EA) are attenuated in oligo-amenorrheic athletes (OA). Of note, data regarding VAT, SAT, MAT and regional muscle mass in OA compared with EA and non-athletes (C), and their impact on bone are lacking. METHODS We used (i) MRI to assess VAT and SAT at the L4 vertebra level, and cross-sectional muscle area (CSA) of the mid-thigh, (ii) 1H-MRS to assess MAT at L4, the proximal femoral metaphysis and mid-diaphysis, (iii) DXA to assess spine and hip aBMD, and (iv) HRpQCT to assess vBMD at the distal radius (non-weight-bearing bone) and tibia (weight-bearing bone) in 41 young women (20 OA, 10 EA and 11 C 18-25 years). All athletes engaged in weight-bearing sports for ≥ 4 h/week or ran ≥ 20 miles/week. MAIN OUTCOME MEASURES VAT, SAT and MAT at L4; CSA of the mid-thigh; MAT at the proximal femoral metaphysis and mid-diaphysis; aBMD, vBMD and bone microarchitecture. RESULTS Groups had comparable age, menarchal age, BMI, VAT, VAT/SAT and spine BMD Z-scores. EA had higher femoral neck BMD Z-scores than OA and C. Fat mass was lowest in OA. SAT was lowest in OA (p = 0.048); L4 MAT was higher in OA than EA (p = 0.03). We found inverse associations of (i) VAT/SAT with spine BMD Z-scores (r = -0.42, p = 0.01), (ii) L4 MAT with spine and hip BMD Z-scores (r = -0.44, p = 0.01; r = -0.36, p = 0.02), and vBMD of the radius and tibia (r = -0.49, p = 0.002; r = -0.41, p = 0.01), and (iii) diaphyseal and metaphyseal MAT with vBMD of the radius (r ≤ -0.42, p ≤ 0.01) and tibia (r ≤ -0.34, p ≤ 0.04). In a multivariate model including VAT/SAT, L4 MAT and thigh CSA, spine and hip BMD Z-scores were predicted inversely by L4 MAT and positively by thigh CSA, and total and cortical radius and total tibial vBMD were predicted inversely by L4 MAT. VAT/SAT did not predict radius or tibia total vBMD in this model, but inversely predicted spine BMD Z-scores. When L4 MAT was replaced with diaphyseal or metaphyseal MAT in the model, diaphyseal and metaphyseal MAT did not predict aBMD Z-scores, but diaphyseal MAT inversely predicted total vBMD of the radius and tibia. These results did not change after adding percent body fat to the model. CONCLUSIONS VAT/SAT is an inverse predictor of lumbar spine aBMD Z-scores, while L4 MAT is an independent inverse predictor of aBMD Z-scores at the spine and hip and vBMD measures at the distal tibia and radius in athletes and non-athletes. Diaphyseal MAT independently predicts vBMD measures of the distal tibia and radius.