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Increased adiposity in childhood and adolescence is not always the result of a genetic predisposition toward weight gain superimposed on a calorie-rich environment. Other conditions can also lead to obesity in children (Tables 9-9 and 9-10). Although endocrine disorders and syndromes associated with obesity are found in fewer than 5% of children referred for evaluation of obesity, it is important to consider these etiologies in the evaluation of the overweight child. Hypothyroidism, GH deficiency, and glucocorticoid excess all may result in an increase in adiposity. In addition, some boys with hypogonadism and low testosterone levels have a body composition that favors fat deposition over development of lean body mass. In contrast to most children with obesity who tend to be tall with advanced bone ages, children with the above hormone deficiencies or with glucocorticoid excess tend to have significantly decreased height velocities and delayed bone ages.
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A number of genetic syndromes are also associated with increased weight gain. PWS, most commonly resulting from either a deletion of the paternal allele at the chromosomal region 15q11-13 or uniparental disomy of the maternal allele, is characterized by obesity, hypogonadism, developmental delay, short stature, and hypotonia. Affected children frequently fail to thrive in the first years of life because of early difficulties with swallowing but rapidly gain weight thereafter. Bardet-Biedl syndrome is characterized by obesity, postaxial polydactyly, retinitis pigmentosa, hypogonadism, developmental delay, and short stature. This is an autosomal recessive disorder that is caused by at least three separate mutations that have been mapped to genes on chromosomes 3, 15, and 16. Other genetic disorders, including Carpenter, Cohen, Alström, and Down syndromes, along with Albright hereditary osteodystrophy, are associated with excessive weight gain. As with endocrine disorders leading to obesity, these syndromes are generally associated with short stature. Many are also characterized by developmental delay.
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Hypothalamic injury may also result in rapid weight gain and obesity. Lesions involving the arcuate nucleus and/or the paraventricular nucleus of the hypothalamus can disrupt the ability of the brain to detect peripheral adiposity signals. Individuals with the hypothalamic obesity syndrome develop increased food-seeking behavior with lack of satiety. Furthermore, they still tend to gain weight even with “normal” caloric intake, suggesting a decrease in energy expenditure. Craniopharyngiomas are the most common lesions associated with the hypothalamic obesity syndrome. Although occasionally the tumor itself directly damages the circuits that control hunger, satiety, and energy expenditure, surgical removal of these tumors, with resultant iatrogenic hypothalamic damage, more commonly results in obesity. Other forms of traumatic brain damage, including anoxic brain injury, meningitis, and severe head trauma, can, on occasion, result in varying degrees of obesity. The hypothalamic obesity syndrome may be seen without trauma to the CNS as in the ROHHAD/ROHADDNET syndrome described earlier.
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The majority of cases of obesity, however, have an “idiopathic” basis, although it is clear that there are major genetic influences that determine body size. The tendency toward developing “idiopathic” or “familial” obesity is polygenic. Despite the fact that many of the genes that regulate weight and energy homeostasis are known, at present it is unclear how often defects in these genes contribute to common obesity. Only a minority of single gene mutations has been found in the coding regions of the known weight regulatory genes that could account for obesity. Genome scans looking for obesity genes, however, have uncovered a number of genetic loci that may contribute to the obesity tendency. There is a strong association between body fat and specific DNA markers on chromosomes 1p, 2p, 3p, 6p, 7q, and 11q.48 If human syntenic regions corresponding to mouse quantitative train locus (QTL) maps are included, all human chromosomes, except 9, 18, 21, and Y, have at least one candidate locus for genes regulating weight homeostasis. The large number of obesity loci in the human genome emphasizes the fact that the cause of most human obesity is likely to be polygenic.
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At present, single gene mutations account for fewer than 10% of all cases of obesity. By far the most common of these single gene mutations are defects in the melanocortin-4 receptor (MC4R) gene, accounting for approximately 6% of cases of severe obesity with early onset during childhood.49 While all individuals with homozygous defects have severe obesity, detailed family studies of heterozygous individuals indicate a variable penetrance of the MC4R gene mutation. In one study, only 68% of individuals with heterozygous mutations were classified as obese,50 indicating a large effect of other genetic and environmental modifiers on the actual degree of adiposity in heterozygous individuals.
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The onset of obesity in subjects with MC4R mutations occurs in early childhood. Affected individuals tend to have increased lean body mass and increased bone density. Increased linear growth is also observed although no changes in GH secretion have been noted. Thyroid function is normal. Unlike what is seen in leptin deficiency, puberty is not affected and fertility is preserved.
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Severe hyperinsulinemia occurs in all obese individuals with MC4R defects.50 In addition, subjects with MC4R deficiency appear to be hyperphagic when compared to unaffected siblings.49, 50 Many of these individuals exhibit food-seeking behaviors. Unlike the MC4R knockout mouse, humans with MC4R gene mutations exhibit no deficits in energy expenditure.50 However, it remains possible that differences in energy expenditure are either too small to detect or would only be apparent after caloric restriction and a decrease in percent body fat to normal.
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The obesity and hyperinsulinemia phenotype in MC4R deficiency appears to improve with age.50 The decrease in insulin levels parallels an improvement in the hyperphagia. The effect of the MC4R gene defect on long-term obesity-associated morbidity and mortality is presently unknown.
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Single gene mutations other than MC4R that are known to result in obesity are collectively quite rare. Mutations have been described in leptin and in the leptin receptor, resulting in early-onset obesity, hyperphagia, hyperinsulinemia, delayed puberty, and short stature.49 POMC gene mutations result in childhood-onset obesity, adrenal insufficiency, and red hair.49 Finally, prohormone convertase gene mutations have been shown to result in extreme childhood obesity, abnormal glucose homeostasis with very low insulin levels, hypogonadotropic hypogonadism, and adrenal insufficiency.51
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Treatment of overweight and obese children and adolescents remains a challenging proposition. Inherited weight set points resist efforts to change body composition. Loss of adipose tissue brings about compensatory decreases in metabolic rate and increases in appetite. Nevertheless, the primary focus of treatment in obese children is decreased caloric intake in combination with increased energy expenditure through increased activity (Figure 9-9). In children who are still growing, it is important that any limit in caloric intake be carefully determined to allow enough calories for adequate growth. Treatment should begin early before the development of severe obesity. The treatment plan should involve the entire family and progress in a stepwise manner as habits are changed and skills are learned.
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There remains considerable debate regarding whether fats or carbohydrates should be the primary nutritional component limited in the diet to achieve decreased caloric intake. Energy expenditure and body composition do not appear to change with isoenergetic constant protein meals even with extreme changes in the fat-to-carbohydrate ratio. When limiting caloric intake to induce weight loss, however, some studies suggest a benefit of limiting carbohydrate instead of limiting fat to achieve target calorie goals. Although reported weight loss between low-carbohydrate and low-fat diets is similar, paradoxically the low-fat diet results in a less favorable result on lipid profiles.52 Diets high in carbohydrate result in increased hepatic lipogenesis and increased triglycerides.53 There may also be a shift to smaller more atherogenic LDL particles with low-fat diets.
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Alternatively, low-fat diets may have some advantages over low-carbohydrate diets. Fat consumption may be less satiating than carbohydrate, and a high fat-to-carbohydrate ratio in the diet may promote overconsumption. This would result in a positive energy balance and weight gain in susceptible individuals. Fat is more easily absorbed from the intestine than is carbohydrate and fecal energy loss is lower in diets with a higher percentage of dietary fat. Fatty foods are calorically denser with a greater amount of calories per gram than are carbohydrates. Thus, more calories can be consumed over a short period with fatty foods than with high-carbohydrate foods. These findings would suggest a benefit of low-fat diets.
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More recently, there has been growing debate over whether high-protein diets might have some advantage for weight reduction. A 2012 meta-analysis of 74 randomized controlled trials suggests slightly greater weight loss, BMI reduction, and decrease in waist circumference in adults consuming higher-protein diets. However, the magnitude of these differences was small, at least in the short term, with an effect size of only 1.2 kg for weight loss over a 3-month interval. This is not likely of clinical significance unless the effect is cumulative over longer periods, and such data are not available at present.54 In a prospective study of energy-restricted high protein versus high carbohydrate, low-fat diets combined with1 year of cognitive behavioral therapy in adults, there was no difference in weight loss between the groups.55 This highlights the fact that, regardless of the actual composition of the diet, any decrease in caloric intake should be of some benefit to the overweight patient provided adequate protein is supplied to allow for growth. Conflicting results of various studies make it difficult to recommend one method of decreased caloric intake over another.
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The type of carbohydrate consumed may also be an important mediator of increased weight gain. Added sugars, generally mono- and disaccharides added to food by the manufacturer or the consumer, have been implicated in many studies as a factor in increasing adiposity both in adults and children. A large proportion of the added sugars consumed by children and adolescents are consumed in the form of sugar-sweetened beverages. Because liquid intake does not reliably trigger satiety signals, caloric intake via sugar-sweetened beverages is often not offset by a reduction in caloric intake at later meals. This results in an overall positive energy balance that quite often leads to weight gain.56 Reducing or eliminating the intake of sugar-sweetened beverages is an essential component of lifestyle change for the overweight child and his/her family.
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The metabolism of mono- and disaccharides may also account for their role in promoting obesity. High intake of fructose has been implicated in mediating obesity and numerous obesity-related complications in children and adults.57 Most of the soft drinks on the market today contain high-fructose corn syrup. Both fructose and glucose are metabolized via glycolysis and the Krebs cycle to form energy. Alternatively, these compounds can form substrate for lipogenesis and, therefore, energy storage as adipose tissue. Glucokinase, the rate-limiting enzyme for glycolysis, is inhibited by increased adenosine triphosphate (ATP) generation. Inhibition of glucokinase tends to limit the entry of glucose into the cell when energy stores are sufficient and, therefore, less substrate is available for lipogenesis. Fructokinase, however, is not limited by increased energy stores. Therefore, fructose is available to be used and easily converted into triglycerides regardless of the energy state of the cell.
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The actual recommended daily caloric intake will vary from patient to patient depending on age and degree of adiposity. Furthermore, total daily energy expenditure required for normal growth and development in each child varies. Depending on the severity of the obese condition, the daily recommended caloric intake in an overweight child should allow for either weight maintenance or a rate of weight gain less than normal for age. This allows the child to gradually approach a healthier weight without the adverse effects on height growth that can be seen with severe caloric restriction. In general, actual weight loss is not recommended in growing children unless life-threatening comorbid conditions exist.
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One approach to calculating daily recommended caloric intake is to estimate the total average daily caloric intake in excess of that needed for normal growth and development. This can be estimated using the equation that, for every 3500 kcal of food consumed and not used for growth and development, 1 lb of fat is stored. If a child has gained more weight during a period than would have been expected using standard growth charts, that child has likely consumed excessive calories and converted the calories into adipose tissue. The excessive calories consumed can be calculated by determining the total excess weight gained over a defined number of days (in pounds), multiply by 3500, and divide by the number of days. This daily caloric excess can be subtracted from the patient’s current daily caloric intake as estimated by a nutritionist using dietary recall. In theory, a diet based on these calculations should provide caloric intake equal to that required for normal growth and development. In practice, these calorie calculations serve only as a starting point and often overestimate caloric needs and energy expenditure. Assuming adherence to treatment recommendations, only weekly at-home and monthly clinic weight measurements will provide information regarding whether or not a particular caloric intake is leading to weight maintenance or weight loss in any obese child.
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Physical activity increases energy expenditure and is critical to successful weight loss or weight maintenance.58 In fact, physical activity accounts for 15% to 30% of total daily energy expenditure, more than any other single component that is amenable to modification. In addition, increased activity may result in increased muscle mass, which increases resting energy expenditure. Exercise has numerous other metabolic benefits in children, including reductions in blood pressure, triglycerides, and insulin levels, all of which decrease cardiovascular risk. Overweight children need to be encouraged to become more active. Current recommendations (eg, CDC and the American Heart Association) suggest that children and adolescents should engage in ≥60 minutes of physical activity daily. Targeting sedentary behaviors (eg, decreasing television viewing and video game playing), rather than enforcing physical activity, results in an improvement in body composition.59 Recommendations for exercise should emphasize activities that are fun. If the activities are uncomfortable or uninteresting to the child, they are unlikely to be sustained. Behavioral modification is necessary to achieve and maintain long-term weight loss (Table 9-11). Habits that encourage a sedentary lifestyle need to be changed. In addition, behaviors that result in increased consumption of calories should be altered. Behavioral interventions aimed at the child alone are unlikely to achieve long-term success. Indeed, the only intervention studies that demonstrate long-term success in maintaining weight loss are those targeted to changing behaviors of the entire family.59
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Weight-loss medications and bariatric surgery
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Intensive intervention, either medical or surgical, should be discouraged except in very limited situations. In patients with documented serious comorbid conditions who have failed prolonged attempts at nutritional management and behavioral counseling, weight loss medications might be considered. Orlistat, a lipase inhibitor, is the only FDA-approved weight loss drug for children aged 12 years and older. It has a modest effect on weight, and compliance is limited by gastrointestinal side effects. In children and adolescents, the glucagon-like peptide-1 receptor agonist, exenatide, may have some benefit in the treatment of profound pediatric obesity (BMI ≥ 1.2 times the 95th percentile for age or BMI ≥ 35 kg/m2) but is not FDA-approved for this indication. Exenatide appears to work by increasing satiety and decreasing appetite and, over the short term, reducing BMI, body weight, and fasting insulin levels, with only modest short-term side effects, primarily mild nausea.60 There is increasing concern, however, that exenatide may increase the risk of pancreatitis, pancreatic cancer, and thyroid cancers. Overall, there are minimal data regarding the safety and efficacy of other anorectic medications in pediatric patients. The short-term effects on growth and the long-term effects on general health of these medications in children are unknown. Weight loss induced by medications may require lifelong administration of these drugs for weight maintenance, because adults tend to regain previously lost weight when drugs such as orlistat and exenatide are stopped or replaced with placebo.61 Therefore, long-term potential side effects need to be considered and balanced against current health problems resulting from the overweight condition of the patient.
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Bariatric surgery has been performed on a limited number of obese adolescent patients and has yielded some success. Studies have shown postoperative weight loss of 20 to 60 lb and BMI loss of up to 35% following laparoscopic gastric banding and gastric bypass surgeries.62 Gastric bypass appears to be more effective, with weight loss almost double that seen with banding procedures.62 Guidelines were published in 2009 to assist in selecting appropriate adolescent patients for bariatric surgical intervention. These guidelines state that adolescents with a BMI greater than 35 kg/m2 and severe comorbidities or a BMI greater than 40 kg/m2 and mild comorbidities could be considered for bariatric surgery if a number of other criteria are met, including pubertal development to Tanner stage 4 or beyond, achievement of 95% of predicted adult height, commitment to psychological evaluation before surgery, anticipated good compliance with postoperative recommendations, and failure of organized preoperative attempts at weight reduction.62 Surgery should be performed only at centers experienced in adolescent bariatric surgery. Close follow-up with a weight loss team is essential for long-term success. As with anorectic medications, the long-term consequences of these procedures in adolescents are unknown, and therefore bariatric surgery should be cautiously considered only in cases in which significant comorbid conditions exist and diet and exercise have failed.
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Treatment of Metabolic Syndrome
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True therapeutic lifestyle intervention, delivered in a multidisciplinary setting and based on cognitive behavioral therapy, has been shown to reduce the frequency of clinical findings consistent with the metabolic syndrome in obese adolescents.63 Although there is evidence for improvement in features of the metabolic syndrome in adults with the use of metformin, a biguanide drug that improves insulin sensitivity, there is debate in the pediatric literature regarding to what extent metformin adds value to therapeutic lifestyle change in the management of metabolic syndrome during adolescence. Many, but not all, of the retrospective studies that have been conducted support greater BMI reductions when metformin is added to therapeutic lifestyle interventions.64 One double-blind, placebo-controlled prospective study, however, demonstrated a 1.3% reduction in BMI, 11% reduction in fasting glucose, and 38% reduction in fasting insulin levels following 6 months of modest-dose metformin therapy in adolescents aged 12 to 19 years with hyperinsulinemia and a family history of T2DM. None of the adolescents in this study had glucose intolerance or PCOS.65 Another study demonstrated a significant decrease in triglycerides and total cholesterol with metformin and a low-calorie diet with only 8 weeks of intervention.66 Metformin may be prescribed at a total daily dose of up to 2000 mg, divided twice daily. The most common side effects include gastrointestinal, including nausea, bloating, diarrhea, and sometimes emesis. These may be mitigated by starting at a low dose (500 mg daily) and working up by 500 mg every 1 to2 weeks. Taking the medication with food is also helpful.
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If the manifestations of the metabolic syndrome include IGT, this may be an indication in itself for the use of metformin. In light of evidence in the adult population that metformin therapy may decrease the progression of IGT to frank DM by as much as one-third,67 many pediatric providers use metformin in children and adolescents with glucose intolerance or simply insulin resistance with normal glucose tolerance (see Figure 9-9).
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Because the use of metformin is sometimes limited by its gastrointestinal side effects, there has been some discussion of whether other insulin-sensitizing agents might also be useful in the obese adolescent population. Thiazolidinediones (TZDs) are known in the adult population to be effective in the management of T2DM and in the prevention of progression from IGT to T2DM. There are very limited data in adolescents on the use of drugs within this class, but one prospective study demonstrated that the use of a TZD resulted in conversion from IGT to normal glucose tolerance in 58% of subjects, as compared to a conversion rate of 44% for placebo-treated subjects.68 While this may present an interesting avenue for future research, TZDs are not currently approved for use in children or adolescents, and they have been associated with rare, but very serious hepatotoxicity and cardiotoxicity. The use of these drugs should be limited at this time to the setting of research protocols.
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Treatment of Dyslipidemia
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The most recent policy statement of the American Academy of Pediatrics recommends 6 months of dietary and lifestyle modification as initial therapy for children found to have dyslipidemia on screening studies (see Figure 9-9). When dietary and lifestyle modifications are insufficient, pharmacologic intervention is recommended for patients 10 years and older with an LDL-C 190 mg/dL or greater, or an LDL-C 160 mg/dL or greater with a family history of early cardiovascular disease or at least two additional risk factors of early cardiovascular disease, or an LDL 130 mg/dL or greater with DM. The most significant change in the most recent expert panel recommendations was the identification of statins as the first line of pharmacologic therapy for patients meeting criteria. Prior to initiating statin therapy, liver function studies should be performed to establish a baseline. Regardless of the absolute value of the LDL-C, if the patient meets criteria for treatment, statin therapy is initiated at a low dose. Laboratory studies are performed at approximately 3-month intervals to assess therapeutic response as well as the effects of therapy on liver function. The initial goal is to lower the LDL-C concentration to less than 160 mg/dL; however, in the presence of high-risk situations such as a family history of cardiovascular disease or a patient history of obesity, diabetes, metabolic syndrome or other factors, the target goal may be as low as 110 mg/dL.43
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For patients with elevated triglycerides and/or decreased HDL-C, lifestyle modifications remain the primary therapeutic approach. While the precise mechanism of action is not established, studies suggest that omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce serumTG levels through decreased hepatic secretion of TG-containing lipoproteins and enhanced clearance of TG-containing lipoproteins.69 A daily dose of 1000 to 2000 mg DHA has been shown to lower TG, raise HDL-C, and it may paradoxically increase LDL-C. Patients with mixed dyslipidemias, including elevated TG and LDL-C, may benefit from the combination of omega-3 fatty acids and a statin.
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An alternative therapy, nicotinic acid (Niacin), is not as effective as statins at decreasing serum LDL-C; however, it offers the advantage of raising HDL-C and lowering triglycerides more effectively than statins. Intense flushing is often experienced by patients taking high-dose niacin and compliance in children, primarily for this reason, is often limited.
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Patients with secondary adiposity-related hypertriglyceridemia (atherogenic dyslipidemia) consisting of hypertriglyceridemia, low HDL-C, and features of the metabolic syndrome benefit most from intensive weight management and appropriate dietary changes. The presence of obesity should prompt specific evaluation of all other cardiovascular risk factors (systemic hypertension, DM, tobacco exposure, and dyslipidemia) and comorbidities (hepatic steatosis, left ventricular hypertrophy, sleep apnea, and right ventricular hypertension).
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If criteria for pharmacological therapy for hypertriglyceridemia are met, the use of LDL-C-lowering medications is recommended as first-line therapy followed by consideration of fibrates.11 The combination of a statin with omega-3 fatty acids has been shown to be effective in improving lipid parameters beyond that of the statin alone.
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Treatment of Comorbidities
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Polycystic ovary syndrome
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As is true for metabolic syndrome, there are multiple proposed sets of diagnostic criteria for PCOS, including those published by the NIH in 1990, the Rotterdam criteria published in 2003, a set of criteria designed by the Androgen Excess and PCOS Society in 2009, and a revised set of Rotterdam criteria published in 2012 with special attention to the diagnostic conundrums associated with PCOS in adolescence (see Chapter 3 for more detail). All these criteria include oligomenorrhea, clinical and/or biochemical hyperandrogenism, + radiographic evidence of polycystic ovaries. Although there is considerable overlap between the populations displaying elements of the metabolic syndrome and those who meet criteria for PCOS, neither obesity nor any of the metabolic derangements of the metabolic syndrome are required to make a diagnosis of PCOS. When PCOS is seen in conjunction with the metabolic syndrome, there is evidence to suggest that metformin is beneficial. A study of obese adolescent girls with evidence of PCOS showed that the addition of metformin to a treatment regimen consisting of lifestyle intervention + oral contraceptives further reduced serum testosterone levels, decreased waist circumference, and increased HDL cholesterol.70 However, metformin does not appear to be adequate as monotherapy to control the hyperandrogenic symptoms in most adolescents with PCOS. Combination oral contraceptives are still felt to be the medical intervention of greatest utility for this purpose. In some cases, antiandrogens such as spironolactone may also have a role.
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Nonalcoholic fatty liver disease
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An open-label pilot study of metformin in children with biopsy-proven nonalcoholic fatty liver disease (NAFLD) showed significant improvement in both serum aminotransferase levels and hepatic fat content assessed by magnetic resonance (MR) spectroscopy, prompting a randomized controlled trial.12 The TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial is a randomized, double-blind, placebo-controlled study comparing the effects of 800 IU vitamin E or 1000 mg metformin against placebo over 96 weeks of treatment in children aged 8 to 17 years with biopsy-confirmed NAFLD. Although neither vitamin E nor metformin was superior to placebo in achieving sustained reductions in aminotransferase levels, 48% of metformin-treated subjects had resolution of NAFLD by histopathology at the end of the 96-week treatment period, versus only 22% of those receiving placebo.71
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Pulmonary comorbidities
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Both reactive airway disease and sleep apnea respond positively to weight loss. Asthma should be aggressively treated with pharmacologic agents, including inhaled glucocorticoids if needed. The lowest possible dose should be used as multiple studies have demonstrated a systemic effect at moderate to high doses. Systemic absorption can increase weight gain and worsen insulin resistance. Sleep apnea should be suspected in individuals with severe snoring, morning headaches, or daytime somnolence. A sleep study should be obtained and treatment with bilevel positive airway pressure (BiPAP) considered in confirmed cases (see Figure 9-9). If sleep apnea is severe, consider performing an ECG and referring to a cardiologist if right-sided cardiac hypertrophy is detected.
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The only therapy that has shown long-term success in the treatment of obese children is family-based behavioral modification therapy. Unfortunately, such programs are not widely available or financially accessible. When attempts to manage pediatric obesity fail in the primary care setting, many children are referred to pediatric endocrinologists. However, in a retrospective study of 587 children referred to pediatric endocrinologists for obesity evaluation and treatment, the mean percentage overweight increased over the follow-up interval of 1.9 years. While 38% of children showed improvement in percentage overweight, only five subjects (< 1%) reduced their BMI to less than 95th percentile.72 As such, referral should be reserved for those likely to have an etiology other than idiopathic familial obesity, and, of course, for those demonstrating obesity-induced comorbidity.
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Referral to endocrinologists. Primary care physicians should consider referral to a pediatric endocrinologist for patients who meet any of the criteria in Box 9-1.
Referral to other subspecialists. Referral to subspecialists other than pediatric endocrinologists is warranted if the initial workup or follow-up of obese patients reveals any of the findings listed in Box 9-2.
Reporting to child protective services. A report of medical neglect is warranted in the setting of life-threatening complications of obesity that are not being adequately addressed in the home environment.73
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Box 9-1. Referral Criteria—Pediatric Endocrinology
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Box 9-2. Findings Warranting NonendocrineSubspecialty Referral