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Evaluation of a Child for Secondary Causes of Obesity and
Comorbidities CME
Robert E. Kramer, MD Stephen R. Daniels, MD, P...
The patient was born after a 36-week, uncomplicated pregnancy and was delivered vaginally with a
birthweight of 3.8 kg (36...
With a BMI of 52.3 kg/m2
, the patient satisfied adult criteria for morbid obesity. Furthermore, on the
basis of his incre...
shaped palpebral fissures. Feeding problems and growth delay might be prominent during infancy,
and obesity develops betwe...
nonalcoholic fatty liver disease.
Treatment and Management
The lifestyle-modification program chosen for this patient targ...
Written consent for publication was obtained from the patient's mother.
Reprint Address
RE Kramer, Section of P...
1. Spear, B. A. et al. Recommendations for treatment of child and adolescent overweight and
obesity. Pediatrics...
15. Holterman, A. X. et al. Short-term outcome in the first 10 morbidly obese adolescent patients
in the Fda.approved tria...
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Evaluation of a Child for Secondary Causes of Obesity and ...

  1. 1. Evaluation of a Child for Secondary Causes of Obesity and Comorbidities CME Robert E. Kramer, MD Stephen R. Daniels, MD, PhD Nat Clin Pract Endocrinol Metab 5(4):, 2009. © 2009 Nature Publishing Group Abstract and The Case Abstract Background: A 15-year-old boy who had been overweight since the age of 6 months was referred to an adolescent obesity clinic for further assessment of his comorbidities and management of his obesity. The patient had no history of developmental delay or abnormal growth velocity. He had previously tested negative for Prader-Willi syndrome and the melanocortin-4 receptor gene mutation. The patient had made numerous attempts at weight loss in the past, but any weight loss he achieved had been temporary. At presentation, the patient had a BMI of 52.3 kg/m2 , a waist circumference of 156 cm, blood pressure of 130/85 mmHg and severe acanthosis nigricans in the cervical and axillary skin folds. Investigations: Measurement of height, weight, waist circumference and blood pressure; screening tests, including a fasting glucose test, 2 h glucose-tolerance test, measurements of blood lipids and liver function tests. Diagnosis: Morbid obesity, metabolic syndrome, nonalcoholic fatty liver disease, impaired glucose tolerance and dyslipidemia. Management: The patient was assigned to an extensive lifestyle-modification and behavior- modification program, with clinic-based follow-up every 4 weeks. The Case A 15-year-old African American boy presented to a tertiary, adolescent obesity clinic because of continued concerns from the primary-care physician and the patient's family about his rapid, uncontrolled weight gain—approximately 17 kg over the previous 12-month period. The patient had not had any surgery, was not taking any medication and had no allergies. On physical examination, the patient was morbidly obese, with a central distribution of adiposity; he breathed comfortably at rest. His blood pressure, obtained with an appropriately sized upper-extremity cuff, was 130/85 mmHg. His pulse was 76 beats per minute, temperature 36.7 ºC, weight 158.3 kg (>99th percentile) and height 174 cm (65th percentile), which resulted in a BMI of 52.3 kg/m2 (99th percentile). His waist circumference was 156 cm (>95th percentile). A complete, 14-system review, performed at the initial interview, returned significant results for three-pillow orthopnea and daily complaints of heartburn. He slept 7 h per night and snored mildly, although frank apneic episodes were denied. The patient had prominent acanthosis nigricans in the skin folds of the neck and the axillae (Figure 1), no dysmorphic features and no palpable enlargement or nodules of the thyroid gland on examination. His tonsils were not enlarged significantly. He had moderate gynecomastia and numerous, deep striae in the lateral aspects of the abdomen. Examination of the patient's abdomen revealed no enlarged organs, or abnormal tenderness or masses. He was tanner stage 4 for physical development, which was normal for his age. He had normal digits on both upper and lower extremities. Figure 1. (click image to zoom) Acanthosis nigricans, in the skin folds of the neck of the patient described in this article.
  2. 2. The patient was born after a 36-week, uncomplicated pregnancy and was delivered vaginally with a birthweight of 3.8 kg (36th percentile). He was breastfed for the first month of life. The patient had normal physical and language development. He began walking at age 11 months and his height had always tracked along the 50th to 75th percentiles. The patient had been home-schooled since the age of 11 years, owing to his anxiety and difficulties that arose from being bullied by peers. In the state where the patient's family lived, the law required only written notice on the part of the parent of their intent to home-school a child and maintenance of current immunization records. No requirement for routine physical examination or health screening existed for home-schooled children, although this patient did have regular check-ups with his primary- care physician. The patient lived at home with his parents, who were both medically disabled—the father from complications of a meningioma and the mother from debilitating arthritis. In addition, both parents had a history of obesity, hypertension and type 2 diabetes mellitus. His mother had undergone gastric-bypass surgery 2 years before the patient's presentation at the adolescent obesity clinic. The patient had in the past participated in numerous diet and exercise programs under the guidance and direction of his primary-care physician, including meal-replacement products, over-the-counter dietary supplements, nutritional counseling and a prescribed exercise program with a personal trainer. Despite initial success with these interventions, any weight loss he achieved was temporary, with return to baseline weight, plus 4.5–9.0 kg of additional weight. Dietary recall of the previous 24 h was undertaken at the time of the patient's initial interview at the adolescent obesity clinic. The recall test revealed that the portion sizes of the patient's meals were excessive. He ate multiple courses at each sitting, snacked frequently, consumed approximately 450 kcals daily from sweetened beverages and ate fast food on average three times per week. Meals at home were served 'restaurant-style', with plates prepared in the kitchen and then brought to the table, and consumed while watching television. An assessment of the patient's physical activity, also undertaken at the initial interview, revealed that the total time he spent in front of a screen was around 6 h per day, with an average of 4 h spent watching television, 1 h of playing video games and 1 h of computer time per day; these times increased on weekends. He had not performed any regular physical activity since he left regular school. Before his referral to the adolescent obesity clinic, the patient's primary-care physician had undertaken a genetic evaluation, in which they looked for a potential etiology for his obesity. This included high-resolution chromosomal analysis, which showed the patient to be a normal male with a 46,XY karyotype, who had no consistent, detectable abnormalities of chromosome number or structure. In addition, southern blot analysis demonstrated a normal methylation pattern of the Prader–Willi loci on the long arm of chromosome 15, which indicated that the patient was unlikely to have either Prader–Willi or Angelman syndrome. Finally, single-gene tests for defects in the melanocortin-4 receptor (MCR4) were performed, which showed no sequence variants to indicate the presence of an MCR4 mutation. After the patient's initial evaluation in the adolescent obesity clinic, further tests were performed after an overnight fast. These tests revealed a total cholesterol level of 5.13 mmol/l (standard range <5.18 mmol/l), HDL cholesterol level of 0.65 mmol/l (standard range 0.88–1.53 mmol/l), LDL cholesterol level of 3.70 mmol/l (standard range <2.59 mmol/l) and a triglyceride level of 2.49 mmol/l (standard range 0.36–1.51 mmol/l). Liver-function tests revealed an aspartate aminotransferase level of 0.90 µkat/l (standard range 0.25–0.66 µkat/l), alanine aminotransferase level of 1.85 µkat/l (standard range 0.50–1.09 µkat/l), γ-glutamyltransferase level of 1.23 µkat/l (standard range 0.08–0.91 µkat/l), and total bilirubin level of 6.8 µmol/l (standard range 3.4–20.5 µmol/l). Insulin level was 1,069.5 pmol/l (standard range 13.8–201.6 pmol/l) and serum glucose level was 5.5 mmol/l (standard range 3.3–5.8 mmol/l). Results at 2 h after administration of an oral glucose tolerance test revealed a serum glucose level of 8.3 mmol/l (normal range <7.8 mmol/l). Hepatic ultrasonography showed no evidence of biliary stones or dilation of the biliary tree, but rather generalized, increased echogenicity of the liver, which is consistent with fatty infiltration.
  3. 3. With a BMI of 52.3 kg/m2 , the patient satisfied adult criteria for morbid obesity. Furthermore, on the basis of his increased waist circumference, elevated blood pressure, elevated triglyceride levels, and low HDL cholesterol level, he satisfied adult criteria for the metabolic syndrome. In addition, on the basis of his mild to moderate elevation in aminotransferase levels, morbid obesity, evidence of insulin resistance and increased echogenicity on hepatic ultrasonography, a presumptive diagnosis of nonalcoholic fatty liver disease was made. This patient's total cholesterol and HDL cholesterol levels were both above the 95th percentile for his age, which further supported the diagnosis of dyslipidemia that had been established by the low HDL cholesterol and high triglyceride levels. His elevated 2 h glucose level on a oral glucose test demonstrated impaired glucose tolerance, but not type 2 diabetes mellitus. For the treatment of morbid obesity and associated comorbidities, the patient started to attend a lifestyle-modification program. The program included a nutrition plan that limited his intake of fat to no more than 30%, saturated fat to no more than 7% and trans-fatty acids to no more than 1% of total calories. He has been followed up on a monthly basis in the obesity clinic, with rotating visits to a physician, dietitian, nurse practitioner and exercise physiologist. In the first month of treatment, the patient achieved his goal of weight maintenance, and by the fourth month, he had lost 8.0 kg, which decreased his BMI by 2.7 kg/m2 to 49.6 kg/m2 . The typical treatment goal is a 5% reduction in weight in the first 6 months of therapy, which this patient had already achieved within 4 months. Repeat laboratory analysis of his lipid levels, insulin, glucose and aminotransferases will also be performed after 6 months of therapy. Discussion of Diagnosis For adults, morbid obesity is generally defined as a BMI of greater than 35 kg/m2 with documented comorbid conditions, or a BMI of 40 kg/m2 with or without comorbidities; this patient had a BMI of 52.3 kg/m2 . Children with BMI values between the 85th and 95th percentiles for their age and sex are considered overweight, those with BMI values above the 95th percentile are considered obese, and those whose BMI values over the 99th percentile, such as in the patient we describe, are considered severely obese.[1] Adult criteria for the metabolic syndrome include increased waist circumference, elevated blood pressure, elevated triglyceride levels, and low HDL cholesterol level.[2] All these criteria were met by this patient. No universally accepted definition of the metabolic syndrome in children exists, although many criteria have been proposed.[3] Worldwide prevalence of pediatric obesity has increased at an alarming rate over the past three decades, which has prompted tremendous concern in the medical, as well as in the lay communities. US data from the national Health and nutrition examination survey over this time period has demonstrated an increase in the prevalence of adolescent obesity (BMI >95th percentile) from 5% in 1963 to 17.4% in the years between 1999 and 2004.[4] Data for 2003–2006, however, indicate a prevalence of 16.3%, which seems to indicate that the trend is stabilizing.[5] Although the vast majority of obese children and adolescents do not have an underlying, organic etiology for their condition, a variety of genetic syndromes are commonly associated with morbid obesity. Most of these syndromes, however, are characterized by substantial developmental delay that limits the patients' awareness of their orexigenic behavior and decreases their adherence to lifestyle modification. In addition to these behavioral factors, the propensity toward increased BMI in many of these syndromes is compounded by short stature. In some syndromes, neurologic factors exist that promote excessive eating or limit satiety, as do metabolic factors that decrease energy expenditure. In the case described here, the patient was screened for two of these conditions, Prader–Willi syndrome and MC4R gene mutations, before being referred to the adolescent obesity clinic. Prader–Willi syndrome is the prototypical syndromic form of obesity and is caused by a deletion in the long arm of chromosome 15 at q11q13. This deletion either occurs in the paternal chromosome or results from maternal disomy, in which two copies of the maternal chromosome exist, but no paternal chromosome is present. Characteristic features of this syndrome include hypotonia, mild to moderate mental retardation, small hands and feet, hypogonadotropic hypogonadism, fair skin and almond-
  4. 4. shaped palpebral fissures. Feeding problems and growth delay might be prominent during infancy, and obesity develops between 6 months and 6 years of age. Prader–Willi syndrome causes hyperphagia as well as impaired satiety and decreased energy expenditure.[6] The disease can be diagnosed by performing either high-resolution chromosome analysis or fluorescent in situ hybridization with specific probes. The product of the MC4R gene is a 333 kD protein that is primarily expressed in the brain and encoded by a single exon on 18q22. Mutations in this gene are associated with obesity in an autosomal-dominant fashion, and in one study researchers found anomalies in this gene in 5.8% of the 500 morbidly obese children who participated.[7] Unlike almost all other inherited forms of obesity, MC4R mutations are not associated with mental retardation or growth delay. The role of genetic screening in obese patients remains to be defined, as increasing numbers of genes are being identified that are involved in the regulation of energy homeostasis. The vast majority of these genetic syndromes, however, are characterized by developmental delay and short stature, as well as by a variety of specific phenotypic characteristics (Table 1). This fact should help caregivers to weigh the benefit of performing such screens in obese children with normal development and growth velocity. In addition, knowledge of other defining features of these syndromes can help guide physical examination and indicate whether further screening for the genetic syndrome is necessary. By contrast, the usefulness of genetic screening for single-gene mutations that affect specific proteins important in energy homeostasis, such as those in the MC4R gene, is difficult to ascertain. Unlike mutations in many of the specific syndromes, these single-gene mutations, as illustrated by those of MC4R, might not be associated with other phenotypic features. The caregiver's ability to determine the diagnostic yield of specific genetic testing on the basis of the patient's history and their physical examination findings is, therefore, limited. Moreover, until specific therapies are developed for patients with mutations, the clinical usefulness of identification of these conditions might be restricted to genetic counseling. Given the normal develop mental and growth history in the patient we describe, in conjunction with the lack of characteristic, phenotypic features on physical examination, detailed genetic screening would not have been indicated. Screening for the common comorbidities of obesity, such as dyslipidemia, nonalcoholic fatty liver disease, hypertension, insulin resistance or diabetes mellitus, is indicated in morbidly obese adolescents, as outlined in the recent review by the American Academy of Pediatrics Expert Committee on Childhood Obesity.[8] Current guidelines for laboratory screening of children with a BMI that falls above the 95th percentile seen in the primary-care setting include serum measurements of fasting glucose, lipids, aspartate aminotransferase and alanine aminotransferase levels. Indications for further screening might include a family history of any of the above mentioned comorbidities or increased clinical suspicion for a specific comorbidity (Figure 2). If a patient's blood pressure is consistently elevated above the 95th percentile for age, sex and height, use of an appropriately sized cuff to undertake 24 h ambulatory blood-pressure monitoring would be appropriate, followed by screening for renal hyper tension by ultrasonography, serum blood urea nitrogen and creatinine levels, urinalysis and urine culture.[9] If sleep apnea is suspected on the basis of snoring, pauses in respiration during sleep, daytime somnolence, secondary enuresis or falling performance in school, poly somnography might be considered. If nonalcoholic fatty liver disease is suspected, hepatic ultrasonography is indicated, in addition to laboratory screening for alternative causes of chronic liver disease, such as α1-antitrypsin deficiency, autoimmune hepatitis, Wilson disease and viral hepatitis. If type 2 diabetes mellitus is suspected, a 2 h glucose-tolerance test should be performed. If the patient has goiter or hypothyroidism is clinically suspected, serum levels of TSH, free T4, antibodies to thyroid peroxidase and to thyroglobulin should be measured. Figure 2. (click image to zoom) Screening algorithm for obese children with BMI in the 95th percentile or above. abbreviations: aLt, alanine aminotransferase; ast, aspartate aminotransferase; BP, blood pressure; FISH, fluorescence in situ hybridization, NAFLD,
  5. 5. nonalcoholic fatty liver disease. Treatment and Management The lifestyle-modification program chosen for this patient targeted specific behaviors identified in his history that had contributed to his increased total caloric and saturated fat intake, as well as his decreased levels of physical activity. Motivational interviewing techniques, such as empathy, reflective listening, setting of agendas and shared decision-making, were incorporated into the initial interview as well as follow-up visits.[10] He was asked to keep a log of his daily physical activity for review at follow-up visits and for the purpose of self-monitoring—a well-validated behavior-modification technique in obesity treatment.[11] He is scheduled to attend the adolescent obesity clinic once a month. At these visits, adherence to recommendations are assessed, continued education in nutrition and activity is provided, medical comorbidities are reassessed, and additional recommendations and goals are agreed upon. This form of lifestyle modification is individualized to the specific characteristics of the patient and, therefore, does not lend itself to a standardized, formulaic approach. Rather, it is based on identification and modification of behaviors that are strongly linked to the development of obesity in children, such as consumption of sweetened beverages, portion control and limitation of sedentary behavior (Box 1). Assessment of the patient's self-efficacy and readiness for change, while these modifiable behaviors are targeted, is the approach to therapy favored in the American Academy of Pediatrics Expert Committee guidelines, which contains a comprehensive review of the evidence base behind each of these behaviors.[8] After 6 months of behavior and lifestyle modification, the patient's progress and comorbidity status will be re assessed. If the initial goal of 5% reduction in weight is not achieved, or if the severity of the patient's comorbidities demands more-aggressive management, pharmacologic or surgical therapies might be considered. Currently, two medications are approved for the treatment of obesity in adolescents: sibutramine and orlistat. Pediatric trials have been performed on both medications,[12,13] but their clinical use has been limited by a high out-of-pocket cost to patients. Bariatric surgery— either gastric bypass[14] or laparoscopic, adjustable gastric banding[15] —is increasingly used for the treatment of adolescent obesity. The patient described here is currently awaiting his 6-month re- evaluation to determine whether these alternative therapies should be considered, although his excellent response to lifestyle modification so far argues for continuation of this approach. Conclusions As the epidemic of pediatric obesity continues, primary-care physicians are increasingly called upon to assess and treat this condition and its comorbidities. Achievement of meaningful weight loss through lifestyle modification is difficult and frustrating for parents and physicians alike, and might raise suspicion of an underlying genetic condition that results in impaired metabolic homeostasis. Careful consideration of the family history and developmental history of the child, paired with close attention to growth parameters and specific phenotypic features revealed during the physical examination, can reliably exclude the need for specific screenings for genetic obesity in the majority of obese pediatric patients. Routine screening for common comorbidities of obesity should be performed and, if any are identified, the patient should be considered for specific treatment of these comorbidities if he or she fails to respond to dietary and lifestyle modifications. Acknowledgements Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.
  6. 6. Disclaimer Written consent for publication was obtained from the patient's mother. Reprint Address RE Kramer, Section of Pediatric Gastroenterology, Hepatology and Nutrition, the Children's Hospital, University of Colorado Denver, 13123 E. 16th avenue, B-290, Aurora, CO 80045, USA. Email: Tables Table 1. Genetic Causes of Obesity Box 1. Behavioral Targets for Lifestyle Modification
  7. 7. References 1. Spear, B. A. et al. Recommendations for treatment of child and adolescent overweight and obesity. Pediatrics 120 (Suppl. 4), s254-s288 (2007). 2. Alberti, K. G., Zimmet, P. & Shaw, J. Metabolic syndrome.a new worldwide definition. a consensus statement from the International diabetes Federation. Diabet. Med. 23, 469-480 (2006). 3. Jolliffe, C. J. & Janssen, I. Development of age-specific adolescent metabolic syndrome criteria that are linked to the adult treatment Panel III and International diabetes Federation criteria. J. Am. Coll. Cardiol. 49, 891-898 (2007). 4. Ogden, C. L. et al. Prevalence of overweight and obesity in the united states, 1999-2004. JAMA 295, 1549-1555 (2006). 5. Ogden, C. L., Carroll, M. d. & Flegal, K. M. High body-mass index for age among us children and adolescents, 2003.2006. JAMA 299, 2401-2405 (2008). 6. Butler, M. G., Theodoro, M. F., Bittel, D. C. & Donnelly, J. E. Energy expenditure and physical activity in Prader-Willi syndrome: comparison with obese subjects. Am. J. Med. Genet. 143, 449-459 (2007). 7. Farooqi, I. S. et al. Clinical spectrum of obesity and mutations in the melanocortin-4 receptor gene. N. Engl. J. Med. 348, 1085-1095 (2003). 8. Krebs, N. F. et al. Assessment of child and adolescent overweight and obesity. Pediatrics 120 (Suppl. 4), s193-s228 (2007). 9. Falkner, B. & Daniels, S. R. Summary of the fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Hypertension 44, 387-388 (2004). 10. Resnicow, K., Davis, R. & Rollnick, S. Motivational interviewing for pediatric obesity: conceptual issues and evidence review. J. Am. Diet. Assoc. 106, 2024-2033 (2006). 11. Helsel, D. L., Jakicic, J. M. & Otto, A. D. Comparison of techniques for self-monitoring eating and exercise behaviors on weight loss in a correspondence-based intervention. J. Am. Diet. Assoc. 107, 1807-1810 (2007). 12. Berkowitz, R. I. et al. Effects of sibutramine treatment in obese adolescents: a randomized trial. Ann. Intern. Med. 145, 81-90 (2006). 13. Ozkan, B., Bereket, A., Turan, S. & Keskin, S. Addition of orlistat to conventional treatment in adolescents with severe obesity. Eur. J. Pediatr. 163, 738-741 (2004). 14. Lawson, M. L. et al. One-year outcomes of Roux-en-y gastric bypass for morbidly obese adolescents: a multicenter study from the Pediatric Bariatric study Group. J. Pediatr. Surg. 41, 137-143 (2006).
  8. 8. 15. Holterman, A. X. et al. Short-term outcome in the first 10 morbidly obese adolescent patients in the Fda.approved trial for laparoscopic, adjustable gastric banding. J. Pediatr. Gastroenterol. Nutr. 45, 465-473 (2007).