Alison G. Hoppin

Best practice updates for pediatric/adolescent weight loss surgery.

The objective of this study is to update evidence‐based best practice guidelines for pediatric/adolescent weight loss surgery (WLS). We performed a systematic search of English‐language literature on WLS and pediatric, adolescent, gastric bypass, laparoscopic gastric banding, and extreme obesity published between April 2004 and May 2007 in PubMed, MEDLINE, and the Cochrane Library. Keywords were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence‐based models. In light of evidence on the natural history of obesity and on outcomes of WLS in adolescents, guidelines for surgical treatment of obesity in this age group need to be updated. We recommend modification of selection criteria to include adolescents with BMI ≥ 35 and specific obesity‐related comorbidities for which there is clear evidence of important short‐term morbidity (i.e., type 2 diabetes, severe steatohepatitis, pseudotumor cerebri, and moderate‐to‐severe obstructive sleep apnea). In addition, WLS should be considered for adolescents with extreme obesity (BMI ≥ 40) and other comorbidities associated with long‐term risks. We identified >1,085 papers; 186 of the most relevant were reviewed in detail. Regular updates of evidence‐based recommendations for best practices in pediatric/adolescent WLS are required to address advances in technology and the growing evidence base in pediatric WLS. Key considerations in patient safety include carefully designed criteria for patient selection, multidisciplinary evaluation, choice of appropriate procedure, thorough screening and management of comorbidities, optimization of long‐term compliance, and age‐appropriate fully informed consent.

Effects of Sibutramine Treatment in Obese Adolescents: A Randomized Trial

Context Few trials have evaluated drugs for obesity in adolescents. Contribution This 12-month randomized, double-blind trial evaluated behavioral therapy plus either sibutramine or placebo in 498 very obese adolescents who were 12 to 16 years of age. Sibutramine reduced mean body mass index (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 8.4 kg) more than placebo. Sibutramine also improved some lipid and glycemic measures and was associated with tachycardia. Cautions Only 76% and 62% of the sibutramine and placebo recipients, respectively, completed the trial. Implications Sibutramine plus behavioral therapy for 1 year can reduce weight and improve metabolic risk factors in some very obese adolescents. The Editors Adolescent obesity is a major public health problem, with 15.5% of U.S. adolescents 12 to 19 years of age defined as overweight (>95th percentile for age- and sex-specific measures for body mass index [BMI]) (1, 2). Overweight often leads to serious health consequences during childhood, such as hypertension, depression, and social exclusion (3). Recently, the incidence of type 2 diabetes, typically an adult disease, has dramatically increased in the pediatric population (46). Cardiovascular risk factors, such as dyslipidemia, insulin sensitivity, and hypertension, are also more prevalent in adolescents with a BMI greater than the 95th percentile than in those with a BMI less than the 85th percentile (7). Management of adult obesity relies on a range of options, including diet, physical activity, behavior modification, pharmacotherapy, and surgery (8, 9). The serotonin and norepinephrine reuptake inhibitor sibutramine facilitates weight loss and weight maintenance in obese adults with commensurate improvements in metabolic variables for up to 2 years of treatment (1012). Prevention is the optimal approach; however, effective treatment in children with a BMI greater than the 95th percentile is needed. Comprehensive behavioral methods have shown weight loss benefit in younger children (13). In most studies, adolescents typically remain overweight after therapy (14). In an earlier single-center, 6-month controlled trial, sibutramine and a comprehensive behavioral program induced statistically significantly more weight loss in obese adolescents than the behavioral program alone (15). Overall, sibutramine is well tolerated; however, increases in mean blood pressure and pulse rate have been reported in some adults (10, 16) and adolescents (15). Our large multicenter study examined the longer-term effects on weight loss by adding sibutramine to behavior therapy in obese adolescents. Methods Design Overview The protocol-designated objective of our 12-month, double-blind study was to evaluate the efficacy and safety of sibutramine in addition to behavior therapy in obese adolescents. At baseline, we randomly assigned participants (3:1 randomization ratio) to sibutramine or placebo (Figure 1). The randomization schedule was stratified by center and baseline BMI (37 kg/m2 or >37 kg/m2) and was computer-generated in blocks of 4 by the sponsor. Each site was responsible for assigning sequential treatments within each stratum. The sponsor kept allocation codes sealed and secure until the database was locked before analysis. Participants, their parents, and study personnel were blinded to treatment. All participants received a behavior therapy program that included lifestyle modification instructions to improve nutrition and increase physical activity. We conducted the study from July 2000 to February 2002 at 33 U.S. weight loss clinics. Individual sites were responsible for recruitment, and we selected eligible participants from the sites clinical database or from responses to advertisements of the study. We obtained approval from individual institutional review boards. Figure 1. Study flow diagram. P P P Participants We included adolescents 12 to 16 years of age with a BMI (calculated as weight [kg] divided by height [m2]) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex (17) and was not more than 44 kg/m2. Contraindications included cardiovascular disease (including arrhythmias), type 1 or 2 diabetes mellitus, major psychiatric disorders, pregnancy, use of a weight loss medication or participation in structured weight loss programs for more than 2 weeks, medication use promoting weight gain or contraindicated with sibutramine (16), or cigarette smoking. We excluded candidates with systolic blood pressure greater than 130 mm Hg, diastolic blood pressure greater than 85 mm Hg, or pulse rate greater than 95 beats/min. We included candidates with stable hypertension who were receiving therapy. Participants completed behavioral assessments conducted by a staff psychologist or psychiatrist. We obtained written, informed consent from the parent and assent from the adolescent. Interventions Behavioral Protocol Participants received instruction in a center-specific behavior therapy program. Individual centers implemented flexible lifestyle modification approaches that were specific to the participants needs. This included self-monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, contingency management, cognitive restructuring, and social support. Counseling at each visit promoted increased physical activity and reduced sedentary behavior. Nutritional counseling encouraged development of healthy eating habits and promoted dietary consumption based on a 500-kcal/d deficit. Medication Protocol At baseline, we randomly assigned participants (3:1 randomization ratio) to receive 10 mg of sibutramine or placebo daily. At month 6, doses of all participants who had not lost more than 10% of their initial BMI were uptitrated (blinded) to 15 mg of sibutramine or placebo. Abbott (previously Knoll Pharmaceuticals) manufactured and provided all capsules. Placebo and sibutramine capsules appeared identical and were dispensed similarly. We discontinued therapy for or closely monitored the participants with systolic blood pressure, diastolic blood pressure, or pulse rate that increased at a single visit to more than 150 mm Hg or by more than 20 mm Hg, to 95 mm Hg or by more than 15 mm Hg, or to 110 beats/min or by more than 20 beats/min, respectively, until acceptable values returned. We used a protocol-driven algorithm for repeating visits or withdrawing participants whose values did not return to specified limits. In the case of intolerance, participants were to be withdrawn from the study. Measurements and Follow-up Procedures The primary efficacy measure was absolute change from baseline in BMI. Secondary outcomes included percentage change in BMI, proportion of patients achieving reductions in BMI of 5% or more or 10% or more, absolute and percentage changes in body weight and lipid and glycemic variables, and absolute change in waist circumference. Participants had weekly visits for the first 2 weeks, visits every 2 weeks until week 12, and monthly visits thereafter. At each visit, we recorded weight to the nearest 0.1 kg, with the participant in light clothing and without shoes, and height to the nearest 0.5 cm. We measured waist circumference monthly. We evaluated medication adherence by capsule count. We assessed growth by using a pediatric growth chart (18) and performed full physical examinations at screening and at months 3, 6, and 12 (or at discontinuation). We assessed sexual maturation by self-reported changes in Tanner staging (19). We determined fasting lipid and glycemic variables at major assessments (Clinical Reference Laboratory, Lenexa, Kansas). We performed electrocardiography before treatment and at month 12 or at discontinuation. We obtained blood pressure (manually) and pulse rate (by palpation of the radial or brachial artery) at all visits. We withheld study medication until blood samples were obtained for laboratory assessments at months 3, 6, and 12. The investigator recorded all adverse events, both observed and volunteered, on the appropriate case report form, as well as in the participants clinic, office, or hospital chart. For each event, the investigator provided information on severity, start and stop dates, relationship to study drug, actions taken, and outcome. The investigator also recorded adverse events resulting from concomitant illnesses, reactions to concomitant medications, or progression of disease states. Statistical Analysis The planned sample size was approximately 400 participants with a 3:1 randomization ratio of sibutramine to placebo. On the basis of previous 12-month adult trials, we determined that 300 participants in the sibutramine group would be adequate to assess safety and exposure, allowing an overall dropout rate of approximately 50% and a probability that approximately 50% of participants receiving 10 mg of sibutramine would lose 10% or more of initial BMI at 6 months. The inflated sample size ensured enough participants with echocardiograms, ambulatory blood pressure monitoring, and dual-energy x-ray absorptiometry measurements (minimum of 120, 80, and 100 participants, respectively, at baseline) since these assessments would be performed in subsets. Although the protocol did not document a formal sample size calculation for efficacy, approximately 132 adolescents (99 in the sibutramine group and 33 in the placebo group) would allow a between-group difference in BMI of 2 kg/m2, with 90% power (2-sided level of 0.05) to be statistically significant, assuming a common SD of 3 kg/m2. We documented the prespecified statistical analysis methods while all study and sponsor personnel, including the statistician, were blinded to treatment. The primary efficacy variable was the absolute change from baseline in BMI. Secondary efficacy variables determined from baseline included percentage change in BMI, proportions of participants achieving 5%

Roux-en-Y Gastric Bypass Enhances Energy Expenditure and Extends Lifespan in Diet-induced Obese Rats

Gastrointestinal weight‐loss surgery (GIWLS) is currently the most effective treatment for severe obesity, with Roux en‐Y gastric bypass (RYGB) among the best of the available surgical options. Despite its widespread clinical use, the mechanisms by which RYGB induces its profound weight loss remain largely unknown. This procedure effects weight loss by altering the physiology of weight regulation and eating behavior rather than by simple mechanical restriction and/or malabsorption as previously thought. To study how RYGB affects the physiology of energy balance, we developed a rat model of this procedure. In this report, we demonstrate that RYGB in diet‐induced obese (DIO) rats induces a 25% weight loss, prolongs mean survival by 45%, and normalizes glucose homeostasis and lipid metabolism. RYGB induced a 19% increase in total and a 31% increase in resting energy expenditure (REE). These effects, along with a 17% decrease in food intake and a 4% decrease in nutrient absorption account for the normalization of body weight after this procedure. These effects indicate that surgery acts by altering the physiology of weight regulation and help to explain the effectiveness of RYGB in comparison to restrictive dieting and other forms of dietary and pharmacological therapies for obesity. The clinical effectiveness of RYGB and its physiological effects on body weight regulation and energy expenditure (EE) suggest that this operation provides a unique opportunity to explore the mechanisms of energy homeostasis and to identify novel therapies for obesity and related metabolic diseases.

Unconjugated Bilirubin Exhibits Spontaneous Diffusion through Model Lipid Bilayers and Native Hepatocyte Membranes

The liver is responsible for the clearance and metabolism of unconjugated bilirubin, the hydrophobic end-product of heme catabolism. Although several putative bilirubin transporters have been described, it has been alternatively proposed that bilirubin enters the hepatocyte by passive diffusion through the plasma membrane. In order to elucidate the mechanism of bilirubin uptake, we measured the rate of bilirubin transmembrane diffusion (flip-flop) using stopped-flow fluorescence techniques. Unconjugated bilirubin rapidly diffuses through model phosphatidylcholine vesicles, with a first-order rate constant of 5.3 s−1 (t 1 2 = 130 ms). The flip-flop rate is independent of membrane cholesterol content, phospholipid acyl saturation, and lipid packing, consistent with thermodynamic analyses demonstrating minimal steric constraint to bilirubin transmembrane diffusion. The coincident decrease in pH of the entrapped vesicle volume supports a mechanism whereby the bilirubin molecule crosses the lipid bilayer as the uncharged diacid. Transport of bilirubin by native rat hepatocyte membranes exhibits kinetics comparable with that in model vesicles, suggesting that unconjugated bilirubin crosses cellular membranes by passive diffusion through the hydrophobic lipid core. In contrast, there is no demonstrable flip-flop of bilirubin diglucuronide or bilirubin ditaurate in phospholipid vesicles, yet these compounds rapidly traverse isolated rat hepatocyte membranes, confirming the presence of a facilitated uptake system(s) for hydrophilic bilirubin conjugates.

Relationship between sleep apnea, fat distribution, and insulin resistance in obese children.

BACKGROUND Obstructive sleep apnea (OSA) is associated with obesity, inflammation, and insulin resistance. The role of fat distribution in OSA pathogenesis has not been established in children. The objective of the study is to examine the relationship between fat distribution, OSA, and insulin resistance in an unselected population of obese children. METHODS All obese (BMI > 95th percentile) children (ages 5-18 y) seen at a pediatric obesity clinic were invited to participate. Subjects underwent polysomnography, and were tested for dyslipidemia, inflammation, and insulin resistance measured by the homeostasis model assessment (HOMA). In a subset of subjects, magnetic resonance (MRI) imaging was used to determine the abdominal visceral and subcutaneous adipose tissue areas and magnetic resonance spectroscopy (MRS) spectroscopy was used to intramyocellular lipids in leg muscles. MEASUREMENTS AND MAIN RESULTS 31 obese subjects enrolled and completed polysomnography and serum testing, and 19 subjects underwent MRI/MRS. The mean age was 12.6 ± 3.0 y and the mean body mass index (BMI) was 39.5 ± 11.2 kg/m(2). Forty-eight percent had OSA (mean apnea hypopnea index [AHI] 6.26 ± 6.77 events/h) Subjects with OSA had significantly increased BMI, log HOMA, triglycerides, and leptin compared to those without OSA. In regression analysis, only BMI z-score was associated with log HOMA. In the subset of patients with imaging data, visceral fat area was strongly predictive of AHI (p = 0.003, r(2) = 0.556). BMI z-score, gender, and age were not predictive. CONCLUSIONS Visceral fat distribution is independently predictive of OSA severity in obese children.

Serum leptin in children and young adults with inflammatory bowel disease.

BACKGROUND Pediatric inflammatory bowel disease is often associated with growth failure and inadequate energy intake. Although several circulating cytokines are known to be elevated in inflammatory bowel disease, the mechanism for the related anorexia has not been described. Leptin is a newly recognized circulating protein that is an important regulator of appetite and energy metabolism; leptin levels are elevated in several animal models of inflammation. This study was conducted to determine whether serum leptin levels are elevated in young patients with inflammatory bowel disease. METHODS One hundred twelve children and young adults with Crohns disease or ulcerative colitis were studied prospectively. Forty-two patients with other gastrointestinal illnesses were used as control subjects. Height, weight, erythrocyte sedimentation rate, serum albumin concentration, and clinical information were collected prospectively, and leptin was measured by radioimmunoassay of stored serum. RESULTS No significant differences in leptin levels were found among disease groups or control subjects. Body mass index and gender were the only independent predictors of serum leptin in all groups examined. Disease activity varied inversely with serum leptin in patients with Crohns disease, but these differences were explained entirely by variations in body mass index. CONCLUSIONS The determinants of serum leptin were the same in young patients with inflammatory bowel disease as in normal populations, indicating that alterations in leptin levels are unlikely to mediate the anorexia and growth failure associated with this disease.

Obesity in children and adolescents: Working group report of the second world congress of pediatric gastroenterology, hepatology, and nutrition

Latin American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (M.F., R.U.); Commonwealth Association of Paediatric Gastroenterology and Nutrition (L.B., T.N.); Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (W.C., D.L.); North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (A.H., R.S.); and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (B.K., L.M.).

Myocardial Tissue Remodeling in Adolescent Obesity

Background Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described. Methods and Results We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum. Conclusions Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function.

Adolescent obesity and bariatric surgery.

Purpose of reviewExamines the effects of bariatric surgery on adolescent obesity. Recent findingsThe risks and outcomes of bariatric surgery in adolescence are presently being defined and may be somewhat different from those in adults. Adolescents may have a greater risk of weight regain, and greater risk of noncompliance to treatment after surgery. However, long-term outcomes are not yet available, and the underlying metabolic benefits appear to be substantial and similar to those of adults. SummaryMorbid obesity in adolescents has severe acute and chronic complications. Bariatric surgery in adolescents seems as well tolerated as in adults when performed in centers with appropriate experience and adequate surgical volume. The pathophysiologic implications of bariatric surgery are profound. A better understanding of the mechanisms leading to postsurgical improvement in insulin resistance and weight loss could lead to the development of other therapies to achieve the same effects with lesser morbidities.

Prevalence and outcome of non-alcoholic fatty liver disease in adolescents and young adults undergoing weight loss surgery

We evaluated the prevalence of non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) in 27 adolescents referred for weight loss surgery (WLS).