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Context: Obesity is associated with nonalcoholic fatty liver disease (NAFLD). Sleeve gastrectomy (SG) is an effective means of weight loss and improvement of NAFLD in adults; however, data regarding the efficacy of SG in the early stages of pediatric NAFLD are sparse. Objective: To assess the impact of SG on hepatic fat content 1 year after SG in youth with obesity compared with nonsurgical controls with obesity (NS). Design: A 12-month prospective study in 52 participants (mean age, 18.2 ± .36 years) with obesity, comprising 25 subjects who underwent SG (84% female; median body mass index [BMI], 44.6 [42.1-47.9] kg/m²) and 27 who were NS (70% female; median BMI, 42.2 [38.7-47.0] kg/m²). Main outcome measures: Hepatic fat content by computed tomography (liver/spleen ratio), abdominal fat by magnetic resonance imaging. Results: Mean 12-month decrease in BMI was greater in SG vs NS (-12.5 ± .8 vs -.2 ± .5 kg/m², P< .0001). There was a within-group increase in the liver-to-spleen (L/S) ratio in SG (.13 ± .05, P = .014) but not NS with a trend for a difference between groups (P = .055). All SG participants with an L/S ratio <1.0 (threshold for the diagnosis of NAFLD) before surgery had a ratio of >1.0 a year after surgery, consistent with resolution of NAFLD. Within SG, the 12-month change in L/S ratio was negatively associated with 12-month change in visceral fat (p = -.51 P = .016). Conclusions: Hepatic fat content as assessed by noncontrast computed tomography improved after SG over 1 year in youth with obesity with resolution of NAFLD in all subjects. This was associated with decreases in visceral adiposity. [ABSTRACT FROM AUTHOR]

Context: Female athletes, particularly runners, with insufficient caloric intake for their energy expenditure [low energy availability (EA) or relative energy deficiency] are at risk for impaired skeletal integrity. Data are lacking in male runners. Objective: To determine whether male runners at risk for energy deficit have impaired bone mineral density (BMD), microarchitecture, and estimated strength. Design: Cross-sectional. Setting: Clinical research center. Participants: 39 men (20 runners, 19 controls), ages 16–30 years. Main Outcome Measures: Areal BMD (dual-energy x-ray absorptiometry); tibia and radius volumetric BMD and microarchitecture (high)resolution peripheral quantitative computed tomography); failure load (microfinite element analysis); serum testosterone, estradiol, leptin; energy availability. Results: Mean age (24.5 ± 3.8 y), lean mass, testosterone, and estradiol levels were similar; body mass index, percent fat mass, leptin, and lumbar spine BMD Z-score (−1.4 ± 0.8 vs −0.8 ± 0.8) lower (P < .05); and calcium intake and running mileage higher (P ≤ .01) in runners vs controls. Runners with EA

We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as acetylcarnitine deficiency. A 9-year-old girl initially diagnosed with and treated for acetylcarnitine deficiency at an outside hospital presented with recurrent hypoglycemia, failure to thrive, poor weight gain, and short stature. She had discontinued levocarnitine therapy because of lack of response, and testing with us demonstrated a normal carnitine and acyl carnitine panel and hyperinsulinemic hypoglycemia during a diagnostic fast. Oral diazoxide and hydrochlorothiazide were initiated with resolution of hypoglycemia. She had iron deficiency anemia, but an upper gastrointestinal evaluation was normal. Genetic testing confirmed a diagnosis of CDG 1b caused by deficiency of mannose phosphate isomerase. Oral mannose was started with gradual reduction in and eventual discontinuation of the diazoxide dose. Hypoglycemia in the pediatric age group needs a systematic approach. It is important to raise awareness of CDG 1b, which can present as persistent hyperinsulinemic hypoglycemia. Mannose supplementation can ameliorate clinical symptoms and biochemical abnormalities. [ABSTRACT FROM AUTHOR]

Objective: To determine mechanisms contributing to impaired bone health in youth 24 months following sleeve gastrectomy (SG). Design: Twenty-four-month longitudinal observational study. Methods: Participants included 23 youth undergoing SG and 30 non-surgical controls (NS) 13-25 years old with moderate-to-severe obesity. Subjects underwent fasting labs for bone turnover markers (N-terminal propeptide of type 1 procollagen, C-telopeptide (CTX)), sex hormones, sex hormone binding globulin (SHBG), and enteric peptides, DXA for areal bone mineral density (aBMD) and body composition, high-resolution peripheral quantitative CT for volumetric BMD (vBMD) at the distal radius and tibia, and microfinite element analysis for strength estimates. Results: Groups did not differ for mean age or BMI z-scores. Over 24 months, compared to NS, SG had greater reductions in BMI z-scores, and spine, hip, and femoral neck aBMD Z-scores (P ≤ .012), greater increases in serum CTX and SHBG (P ≤ .039), and greater decreases in estrone and ghrelin (P ≤ .021). Among females, estrone and free androgen index (FAI) decreased (P ≤ .022) in SG vs NS groups. After controlling for age and sex, decreases in BMI and lean mass were associated with decreases in total hip and femoral neck aBMD Z-scores, and decreases in radial total and trabecular vBMD and failure load, and tibial total and trabecular vBMD. Among females, after controlling for age, decreases in estrone were associated with decreases in spine aBMD Z-scores and radial total and trabecular vBMD, and decrease in FAI with decreases in radial failure load. Conclusion: Reductions in BMI, lean mass, and sex steroids over 24 months post-SG are associated with bone loss and could be targeted for preventative or therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective: To investigate the response of anorexigenic oxytocin to food intake among adolescents and young adults with avoidant/restrictive food intake disorder (ARFID), a restrictive eating disorder characterized by lack of interest in food or eating, sensory sensitivity to food, and/or fear of aversive consequences of eating, compared with healthy controls (HC). Design: Cross-sectional. Methods: A total of 109 participants (54 with ARFID spectrum and 55 HC) were instructed to eat a ~400-kcal standardized mixed meal. We sampled serum oxytocin at fasting and at 30-, 60-, and 120-min postmeal. We tested the hypothesis that ARFID would show higher mean oxytocin levels across time points compared with HC using a mixed model ANOVA. We then used multivariate regression analysis to identify the impact of clinical characteristics (sex, age, and body mass index [BMI] percentile) on oxytocin levels in individuals with ARFID. Results: Participants with ARFID exhibited greater mean oxytocin levels at all time points compared with HC, and these differences remained significant even after controlling for sex and BMI percentile (P = .004). Clinical variables (sex, age, and BMI percentile) did not show any impact on fasting and postprandial oxytocin levels among individuals with ARFID. Conclusions: Consistently high oxytocin levels might be involved in low appetite and sensory aversions to food, contributing to food avoidance in individuals with ARFID. [ABSTRACT FROM AUTHOR]

Context: Vertical sleeve gastrectomy (VSG) is an increasingly common tool to achieve weight loss and improve metabolic health in adolescents and young adults with obesity, although it may adversely affect bone health. Objective: This work aimed to evaluate the effect of VSG on bone health in youth. Methods: An observational 2-year study was conducted at a tertiary care center of 66 patients aged 13 to 24 years with moderate-to-severe obesity meeting criteria for VSG. The patients underwent VSG (n= 30) or nonsurgical (n=36) management per the decision of patient and clinical team. Main outcome measures included dual-energy x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of bone mineral density (BMD), geometry, and microarchitecture. Results: VSG patients achieved 25.3±2.0% weight loss at 2 years (P<.001) while control subjects gained 4.0±2.0% (P= .026). Total hip BMD declined 8.5±1.0% following VSG compared with 0.1±1.0% gain in controls (P< .001), with similar results at the femoral neck (P<.001). Total volumetric BMD (vBMD) decreased both at the distal radius and tibia following VSG (P<.001) driven primarily by trabecular vBMD loss (P< .001). Two-year changes in cortical vBMD did not differ between groups, though cortical porosity decreased following VSG both at the radius and tibia (P=.048 and P< .001). Cortical thickness increased in controls but not in VSG (P=.022 and P= .002 for between-group comparisons at the radius and tibia, respectively). Following VSG, estimated failure load decreased at the radius and did not demonstrate the physiologic increases at the tibia observed in controls. Conclusion: VSG leads to progressive changes in bone health over 2 years, and may lead to increased skeletal fragility in adolescents and young adults. [ABSTRACT FROM AUTHOR]

Objective: Anorexia nervosa is complicated by high bone resorption, low bo ne mineral density (BMD), and increased fracture risk. We investigated whether off-label antiresorptive therapy with denosumab increases BMD in women with anorexia nervosa. Design: Twelve-month, randomized, double-blind, placebo-controlled study. Methods: Thirty ambulatory women with anorexia nervosa and areal BMD (aB MD) T-score <-1.0 at =1 sites were randomized to 12 months of denosumab (60 mg subcutaneously q6 m onths)(n = 20) or placebo (n = 10). Primary end point was postero-anterior (PA) lumbar spine aBMD by dual-e nergy x-ray absorptiometry. Secondary end points included femoral neck aBMD, tibia and radius volumetric BMD and bone microarchitecture by high-resolution peripheral quantitative CT, tibia and radius failure load by fin ite element analysis (FEA), and markers of bone turnover. Results: Baseline mean (±s.d.) age (29 ± 8 (denosumab) vs 29 ± 7 years (placebo)), BMI (19.0 ± 1.7 vs 18.0 ± 2.0 kg/m2), and aBMD (PA spine Z-score -1.6±1.1 vs -1.7±1.4) were similar between groups. PA lumbar spine aBMD increase d in the denosumab vs placebo group over 12 months (P = 0.009). The mean (95% CI) increase in PA lumbar spine aBMD was 5.5 (3.8-7.2)% in the denosumab group and 2.2 (-0.3-4.7)% in the placebo group. The change in femoral neck aBMD was similar between groups. Radial trabecular number incre ased, radial trabecular separation decreased, and tibial cortical porosity decreased in the denosumab vs placebo group (P = 0.006). Serum C-terminal telopeptide of type I collagen and procollagen type I N-terminal propeptide decreas ed in the denosumab vs placebo group (P < 0.0001). Denosumab was well tolerated. Conclusions: Twelve months of antiresorptive therapy with denosumab reduced bone turnover and increased spine aBMD, the skeletal site most severely affected in women with ano rexia nervosa. [ABSTRACT FROM AUTHOR]

Context: Sleeve gastrectomy (SG) improves metabolic endpoints but is associated with impaired bone outcomes. Objective: To determine mechanisms contributing to impaired bone health in youth following SG. Methods: 12-month longitudinal observational study in a multidisciplinary tertiary-care hospital, including 64 youth 13-25 years old with moderate-to-severe obesity (51 females); 30 underwent SG and 34 were nonsurgical (NS) controls. SG was undertaken after a combined decision-making process between treatment team and patient. The main outcome measures were fasting blood for enteric peptides, sex steroids, sclerostin, and bone turnover markers (N-terminal propeptide of type 1 procollagen [P1NP] and C-terminal cross-linking telopeptide [CTX]); dual-energy X-ray absorptiometry measures of areal bone mineral density (aBMD) and body composition; high resolution peripheral quantitative computed tomography; measures of volumetric BMD (vBMD); microfinite element analysis of strength estimates (distal radius and tibia). Results: SG had greater reductions in body mass index (BMI) z-scores, serum estrone, and the free androgen index (FAI) (P ≤ .046), and greater increases in sclerostin, P1NP, and CTX (P ≤ .010) than NS controls. Fasting ghrelin decreased in SG vs NS (P < .0001); fasting peptide YY did not change. Most changes were driven by female SG participants. Among females (the majority of study participants), after controlling for baseline age and race, reductions in total hip aBMD Z-scores were positively associated with changes in BMI, lean mass, estrone, FAI, and ghrelin, and inversely with changes in sclerostin.. Decreases in total vBMD of the radius and tibia were associated positively with decreases in BMI. Increases in CTX were associated with decreases in BMI, lean mass, and ghrelin, and increases in sclerostin. Conclusion: Bone loss after SG in youth is associated with changes in body composition, sex steroids, sclerostin, and enteric peptides. These are potential targets for future preventative or therapeutic strategies. [ABSTRACT FROM AUTHOR]

Context: Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency.Objective: To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes.Design: Double-blind, randomized, placebo-controlled 12-month longitudinal study.Participants: Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study.Intervention: Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range.Main Outcome Measures: Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates.Results: Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups.Conclusions: We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN. [ABSTRACT FROM AUTHOR]

Context: Among patients with type 1 diabetes (T1D), the risk of hip fracture is up to 6-fold greater than that of the general population. However, the cause of this skeletal fragility remains poorly understood.Objective: To assess differences in hip geometry and imaging-based estimates of bone strength between youth with and without T1D using dual-energy x-ray absorptiometry (DXA)-based hip structural analysis.Design: Cross-sectional comparison.Participants: Girls ages 10 to 16 years, including n = 62 with T1D and n = 61 controls.Results: The groups had similar age, bone age, pubertal stage, height, lean mass, and physical activity. Bone mineral density at the femoral neck and total hip did not differ in univariate comparisons but was lower at the femoral neck in T1D after adjusting for bone age, height, and lean mass. Subjects with T1D had significantly lower cross-sectional area, cross-sectional moment of inertia, section modulus, and cortical thickness at the narrow neck, with deficits of 5.7% to 10.3%. Cross-sectional area was also lower at the intertrochanteric region in girls with T1D. Among those T1D subjects with HbA1c greater than the cohort median of 8.5%, deficits in hip geometry and strength estimates were more pronounced.Conclusions: DXA-based hip structural analysis revealed that girls with T1D have unfavorable geometry and lower estimates of bone strength at the hip, which may contribute to skeletal fragility and excess hip fracture risk in adulthood. Higher average glycemia may exacerbate effects of T1D on hip geometry. [ABSTRACT FROM AUTHOR]

Context: Sleeve gastrectomy (SG), the most common metabolic and bariatric surgery in adolescents, is associated with bone loss. Marrow adipose tissue (MAT) is a dynamic endocrine organ that responds to changes in nutrition and might serve as a novel biomarker for bone health. Two types of MAT have been described, which differ in anatomic location-proximal regulated MAT vs distal constitutive MAT.Objective: To determine the effects of SG on volumetric bone mineral density (vBMD) and MAT in adolescents with obesity. We hypothesized that SG would lead to a decrease in vBMD and differential changes in MAT.Design: 12-month prospective study in 52 adolescents with moderate-to-severe obesity (38 female; mean age:17.5 ± 2.2 years; mean BMI 45.2 ± 7.0 kg/m2), comprising 26 subjects before and after SG and 26 nonsurgical controls.Main Outcome Measures: Lumbar vBMD by quantitative computed tomography; MAT of the lumbar spine, femur and tibia by proton magnetic resonance spectroscopy; abdominal fat and thigh muscle by magnetic resonance imaging.Results: Adolescents lost 34.1 ± 13.1 kg after SG vs 0.3 ± 8.4 kg in the control group (P < 0.001). Lumbar vBMD decreased in the SG group (P = 0.04) and this change was associated with a reduction in weight and muscle area (P < 0.05) and an increase in lumbar MAT (P = 0.0002). MAT of the femur and tibia decreased after SG vs controls (P < 0.05); however, the differences were no longer significant after controlling for change in weight.Conclusion: SG in adolescents decreased lumbar vBMD associated with an increase in lumbar MAT and decrease in extremity MAT. This demonstrates differential changes of regulated MAT in the lumbar spine and constitutive MAT in the distal skeleton in adolescents in response to SG. [ABSTRACT FROM AUTHOR]

Objective: Leptin secretory dynamics across the weight spectrum and their relationship with disordered eating psychopathology have not been studied. Our objective was to compare leptin secretory dynamics in 13 anorexia nervosa (AN), 12 overweight/obese (OB) and 12 normal-weight women using deconvolution analysis. Methods: In this cross-sectional study conducted at a tertiary referral center, serum leptin levels were obtained every 20 min from 2000 to 0800 h. Dual energy X-ray absorptiometry was used to measure percent body fat. Disordered eating psychopathology was assessed by the Eating Disorders Examination-Questionnaire (EDE-Q) and the Eating Disorders Inventory-2 (EDI-2). Results: The groups differed for basal leptin secretion (BASAL) (P=0.02). Mean leptin pulse amplitude, pulse mass, total pulsatile secretion (TPS) and area under the curve (AUC) were significantly different between groups before and after adjustment for BASAL (P<0.0001 for all). Leptin AUC correlated strongly with TPS (r=0.97, P<0.0001) and less with BASAL (r=0.35, P=0.03). On multivariate analysis, only TPS was a significant predictor of leptin AUC (P<0.0001). TPS was inversely associated with most EDE-Q and EDI-2 parameters and the associations remained significant for EDE-Q eating concern (P=0.01), and EDI-2 asceticism, ineffectiveness and social insecurity (P<0.05) after adjusting for BASAL. These relationships were not significant when controlled for percent body fat. Conclusion: Secretory dynamics of leptin differ across weight spectrum, with mean pulse amplitude, mean pulse mass and TPS being low in AN and high in OB. Pulsatile, rather than basal secretion, is the major contributor to leptin AUC. Decreased pulsatile leptin is associated with disordered eating psychopathology, possibly reflecting low percent body fat in AN. [ABSTRACT FROM AUTHOR]

Objective: Preclinical data indicate that oxytocin, a hormone produced in the hypothalamus and secreted into the peripheral circulation, is anabolic to bone. Oxytocin knockout mice have severe osteoporosis, and administration of oxytocin improves bone microarchitecture in these mice. Data suggest that exercise may modify oxytocin secretion, but this has not been studied in athletes in relation to bone. We therefore investigated oxytocin secretion and its association with bone microarchitecture and strength in young female athletes. Design: Cross-sectional study of 45 females, 14-21 years (15 amenorrheic athletes (AA), 15 eumenorrheic athletes (EA), and 15 nonathletes (NA)), of comparable bone age and BMI. Methods: We used high-resolution peripheral quantitative CT to assess bone microarchitecture and finite element analysis to estimate bone strength at the weight-bearing distal tibia and non-weightbearing ultradistal radius. Serum samples were obtained every 60 min, 2300-0700 h, and pooled for an integrated measure of nocturnal oxytocin secretion. Midnight and 0700 h samples were used to assess diurnal variation of oxytocin. Results: Nocturnal oxytocin levels were lower in AA and EA than in NA. After controlling for estradiol, the difference in nocturnal oxytocin between AA and NA remained significant. Midnight and 0700 h oxytocin levels did not differ between groups. At the tibia and radius, AA had impaired microarchitecture compared with NA. In AA, nocturnal oxytocin correlated strongly with trabecular and cortical microarchitecture, particularly at the non-weight-bearing radius. In regression models that include known predictors of microarchitecture in AA, oxytocin accounted for a substantial portion of the variability in microarchitectural and strength parameters. Conclusions: Nocturnal oxytocin secretion is low in AA compared with NA and associated with sitedependentmicroarchitectural parameters.Oxytocinmaycontribute tohypoestrogenemic bone loss inAA [ABSTRACT FROM AUTHOR]