Case 31-2006 — A 15-Year-Old Girl with Severe Obesity
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《新英格兰医药杂志》
Presentation of Case
A 15 1/2-year-old girl was seen in the outpatient Weight Center of this hospital for the evaluation of severe obesity. She had had a normal gestation without complications and had been adopted during the first month of life. She weighed 3.9 kg at birth and 4.8 kg at 1 month of age. At the age of 1 year, her weight-to-length ratio was in the 75th percentile. At 3 years of age, her body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was above the 97th percentile. She was referred to a nutritionist. Her appetite remained steady, and she ate most foods. Although her food intake appeared to be similar to that of the other children in the family, her BMI continued to increase (Figure 1A).
Figure 1. Changes in BMI over Time (Panel A) and Their Association with Specific Weight-Loss Treatments (Panel B).
Panel A shows a comparison of the patient's BMI (indicated by X) with standard percentiles, according to age and sex. At all ages shown, the patient's BMI is well above the 97th percentile for her age. Over the course of 3 years, various approaches were used to help the patient lose weight (Panel B). After the discontinuation of sertraline, sibutramine was added, which was associated with a modest weight loss and no side effects. Over a period of 15 months, in conjunction with moderate-to-high levels of physical activity, the patient lost 3.2 kg. As is typical with pharmacotherapy for obesity, she regained the weight after stopping the drug. Metformin was begun for the treatment of diabetes, in conjunction with dietary counseling. Treatment with orlistat was attempted but was discontinued after only a few doses because of steatorrhea. At the age of 17 years, she participated in a group-based program at the Weight Center, consisting of behavioral and nutritional interventions with a group of adolescents, with the parents meeting separately. The patient lost 3.2 kg during the 3-month course of the program and maintained the weight loss in the subsequent 6 months.
Snoring and restless sleep began at approximately 5 to 6 years of age. At the age of 7 years, she was enrolled in a monthly weight-control program, and a year later, she was evaluated by a nutrition specialist. Physical examination revealed an overweight child with mild acanthosis nigricans of the neck with no other abnormalities. The next year, her parents noted that she was eating secretly; hyperpigmentation of the thighs was noted on physical examination. Between the ages of 10 and 11 years, her weight increased approximately 15 kg, and she began a program for weight control at her pediatrician's practice. At 12 years of age, she was seen by a psychiatrist, who noted dysthymia and poor motivation and prescribed sertraline and psychotherapy.
When the patient was 13 years old, her parents noticed nocturnal somnambulation and an increased intake of food. At 13 years 3 months, the patient was referred to an endocrinologist because she had not lost weight and had chronic daytime fatigue. Her height was 162.4 cm, her weight 106.9 kg, her blood pressure 132/73 mm Hg, and her pulse 76 beats per minute. Breast development was Tanner stage 3, and pubertal development was Tanner stage 5 (with 1 representing immature development and 5 maturity); acanthosis nigricans was present around the neck and groin. The remainder of the examination was normal; there was no hirsutism. Results of laboratory tests are shown in Table 1.
Table 1. Laboratory Values.
Snoring and insomnia worsened during adolescence. Menarche occurred at the age of 14 years, and her menstrual cycles were irregular. Daytime sleepiness worsened, including falling asleep at school, and morning headaches developed. A combination of dextroamphetamine sulfate and amphetamine aspartate was prescribed to enhance alertness. During an evaluation by a sleep specialist at the age of 14 years, physical examination revealed a blood pressure of 120/90 mm Hg; the tonsils were enlarged, but there was no marked crowding. A series of overnight polysomnograms obtained between the ages of 13 and 15 years showed progressive worsening of obstructive sleep apnea, including intermittent oxygen desaturation, hypercapnia, periodic leg movements, and sleep disruption. Bilevel ventilation therapy was started when the patient was 13 years old, but compliance with the therapy was poor. Pulmonary-function testing revealed normal spirometric values and lung volumes. The results of electrocardiography, chest radiography, and echocardiography were normal.
At the age of 14 years (17 months before this evaluation), the patient attended a summer camp and lost approximately 20 kg; she promptly regained the weight after returning home and gained an additional 12 kg during the subsequent year. Three months before presentation, she participated in a home-administered weight-loss plan on the basis of a point system, but her weight continued to increase.
At the time of the evaluation in the Weight Center, she had daytime somnolence but no headaches. She drank low-calorie soft drinks and two glasses of juice daily. She snacked twice during the night on sandwiches or other carbohydrate-containing foods. She exercised with a personal trainer three to five times per week and watched television approximately 6 hours per day on weekends. She typically slept 7 hours on school nights and 12 hours per night on the weekends. She had no difficulty initiating sleep, but she was hard to arouse in the morning.
The patient's early development had been normal; she walked at 12 months of age and spoke in short sentences at 15 months. Her depression had improved after a change in schools during the year preceding her presentation at the Weight Center, and the psychotherapy was discontinued. She was a good student in the 10th grade. A grandmother in her birth family was known to have been overweight; no other biologic-family history was known. Members of her adoptive family, including her parents and two younger siblings, were of normal weight. Her only medication was sertraline, and she had no known allergies.
Her height was 164.5 cm, her weight 126.6 kg, and her BMI 46.7. The blood pressure was 124/95 mm Hg. Severe acanthosis nigricans was present on the neck and axillae, and there was moderate acne on the face; a slightly android pattern of hair growth was evident on the abdomen, and there were moderate striae on the lower abdomen. There was no hair growth on the face, no rash in the skin folds, and no edema. The remainder of the physical examination was normal.
Additional laboratory testing was performed (Table 1), and a plan for management was developed.
Differential Diagnosis
Dr. Alison G. Hoppin: This patient presented with uncommon manifestations of a common disease. Obesity is common: 17.4% of adolescents in the United States are considered overweight by the standards of the Centers for Disease Control and Prevention.1 However, this patient's degree of obesity was very unusual: with a BMI of 46.7, she had adiposity levels that constituted class 3 obesity (on a scale of 1 to 3, with class 1 indicating a BMI of 30.0 to 34.9, class 2 a BMI of 35.0 to 39.9, and class 3 a BMI of 40.0 or more) in an adult. In addition, she had most of the important medical complications of obesity in children and adolescents (Table 2).
Table 2. Important Health Effects of Obesity in Children and Adolescents.
This patient's most acute health issues at presentation were symptoms suggestive of sleep apnea and diabetes mellitus. Because the symptoms of sleep apnea are somewhat subjective and there are no clear screening criteria, the problem is probably underdiagnosed in children and adolescents with obesity.2,3,4,5 This patient was referred to Dr. Eliot Katz, a specialist in sleep disorders in children, who will discuss the evaluation and management of her sleep apnea.
Obstructive Sleep Apnea
Dr. Eliot S. Katz: Testing of this patient by overnight polysomnography at 15 years of age (Figure 2) indicated that her sleep latency was less than 4 minutes (normal, 9 to 33), suggesting objective sleepiness. She had recurrent episodes of partial or complete upper-airway obstruction associated with intermittent hypoxemia (minimum oxygen saturation, 86%; normal value, 92 to 96), hypercapnia (awake, 52 mm Hg, and asleep, 64 mm Hg; normal carbon dioxide peak during sleep, 53 mm Hg), and electroencephalographic arousal (Figure 2). Her apnea–hypopnea index was markedly elevated at 21 events per hour (normal value, 1). Despite these findings, she had normal sleep architecture and sleep efficiency. Children with severe obstructive sleep apnea often have normal distribution of sleep states, despite frequent episodes of obstruction and brief electrocortical arousal.
Figure 2. Sleep Study at 15 Years of Age.
A 90-second portion of an overnight polysomnogram obtained while the patient was in stage 2 sleep shows a series of episodes of obstructive apnea and hypopnea (arrows), characterized by a marked reduction in airflow despite ongoing respiratory efforts. Accompanying the obstructive events are cyclic reductions in oxygen saturation of 5 to 10%. At the end of each obstruction is an arousal consisting of augmentation of electromyographic tone and a frequency shift in the electroencephalogram. EOG denotes electrooculogram, and O2-A1 right occipital lead referenced to the left mastoid lead.
Obesity poses both an obstructive load to the upper airway and an elastic load to the entire pulmonary system. Although pulmonary function, as measured by spirometry, is often normal in obese children during wakefulness at rest, as it was in this child, there are often measurable deficits during exercise and sleep. Obese children are 4.5 times as likely to have obstructive sleep apnea as are children who are not obese.19 The severity of the condition is related to the degree of visceral adiposity, rather than to the amount of total body fat. This patient had a central pattern of obesity, which has the strongest correlation with the metabolic syndrome.20 More than 90% of children with both obesity and habitual snoring have obstructive sleep apnea.21 Thus, this patient probably had obstructive sleep apnea during her 8-to-10-year history of snoring before her initial polysomnography. Androgens affect ventilatory control and increase visceral fat; thus, obstructive sleep apnea is more commonly seen in boys after puberty (rather than before puberty) and in women who have excessive levels of androgen associated with the polycystic ovary syndrome, which was suspected in this patient.22
Sequelae
The consequences of obstructive sleep apnea include cardiovascular abnormalities, neurocognitive impairment, daytime sleepiness, and metabolic disturbances — several of which were seen in this patient. Her hypertension was probably a consequence of both obstructive sleep apnea and obesity. In extreme cases, biventricular dysfunction and pulmonary hypertension may develop, and screening for pulmonary hypertension with echocardiography is indicated for children with severe obstructive sleep apnea. The 8-to-10-year history of probable obstructive sleep apnea during a vulnerable period of brain growth places this patient at risk for neurocognitive impairment, including mood disturbance, which she had. The disease has a minimal effect on intelligence but may impair executive functioning and attention span and has been associated with poor school performance in adolescents.23
In contrast to adults with sleep apnea, most children do not have clinical or objective sleepiness.24 Sleepiness in adolescents is frequently multifactorial and includes an insufficient amount of sleep, poor sleep hygiene, increased sleep requirements and circadian-rhythm disturbances, and disrupted sleep related to obstructive sleep apnea, sleepwalking, and nocturnal eating. Thus, this patient had many reasons for sleepiness.
Both obstructive sleep apnea and obesity are associated with increased levels of inflammatory markers,20,25 which are believed to be involved in the normal homeostatic regulation of sleep. Thus, increased levels of circulating cytokines may contribute to the sleepiness that is characteristic of both obstructive sleep apnea and obesity. Obstructive sleep apnea can increase insulin resistance and leptin levels, independent of obesity,20,25 and treatment with continuous positive airway pressure can reduce insulin resistance and levels of leptin and inflammatory markers.
Treatment
In contrast to children of normal weight, obese children with adenotonsillar hypertrophy typically do not have complete resolution of obstructive sleep apnea after adenotonsillectomy, although their condition typically improves.26 In this patient, nasopharyngoscopy demonstrated only mild adenotonsillar hypertrophy that was not considered to warrant surgical removal. Weight loss can lessen the severity of obstructive sleep apnea, but residual obstruction is frequently present.27
Continuous positive airway pressure and bilevel ventilation are both effective therapies for obstructive sleep apnea.28 However, 15 to 20% of patients will not comply with the use of nasal positive-pressure ventilation at all; for the remainder of patients, the average duration of use is approximately 5 hours per night. Although this patient acknowledged improvements in daytime functioning after receiving nocturnal bilevel ventilation, she complied poorly with therapy. Thus, her case illustrates both the consequences of sleep apnea and the difficulties in managing it.
Dr. Hoppin: This patient had features of the metabolic syndrome, a constellation of findings associated with an increased risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus.10
Insulin Resistance and Type 2 Diabetes Mellitus
This patient had evidence of insulin resistance, with severe acanthosis nigricans, an elevated insulin level after an overnight fast, and a glycated hemoglobin value of 6.7%. Subsequent testing revealed a blood glucose level of 141 mg per deciliter (7.8 mmol per liter) 2 hours after an oral glucose load (Table 1), documenting impaired glucose tolerance.29 Insulin resistance is independently associated with both obesity and puberty, so this patient is at risk for both reasons.6,7,8 In a longitudinal study of obese adolescents, progression from normal to impaired glucose tolerance occurred in 10% during a 2-year period, and 25% of these patients had progression to type 2 diabetes.30
Six months after the first visit, treatment with metformin was begun, in consultation with an endocrinologist. During the next 2 years, the patient had a slight improvement in glycemic control, with glycated hemoglobin values ranging from 6.5 to 7% and fasting blood glucose levels between 90 and 95 mg per deciliter (5.0 to 5.3 mmol per liter). However, during a period of noncompliance with the metformin, her fasting blood glucose levels rose to a range of 244 to 275 mg per deciliter (13.5 to 15.3 mmol per liter), diagnostic of diabetes mellitus.
Hypertension and Dyslipidemia
The patient had mild hypertension at her first visit, which gradually worsened during the next 18 months. Pharmacologic intervention is recommended for hypertension that persists despite a modification in diet and for patients with diabetes mellitus.9 Angiotensin-converting–enzyme inhibitors are recommended preferentially in children with diabetes. Treatment with lisinopril was initiated 18 months after her first visit. Her fasting total cholesterol and triglyceride levels were high, whereas the level of low-density lipoprotein cholesterol was in the borderline range. Our dietary counseling included recommendations for a reduction in dietary fat.31
Polycystic Ovary Syndrome
The patient also had findings that suggested the polycystic ovary syndrome and nonalcoholic fatty liver disease, both of which are associated with the metabolic syndrome phenotype. The classic clinical features of the polycystic ovary syndrome include menstrual disturbance, hirsutism, and polycystic ovaries. However, on the basis of broader diagnostic criteria, the disorder is thought to affect 5 to 10% of women of reproductive age.11 Although the patient had menarche and menstrual patterns that could be considered normal and she did not have marked hirsutism, she had an elevated level of free testosterone at 13 years of age, suggesting the presence of hyperandrogenism. Two years after her first visit here, she presented with acute right ovarian torsion due to a cyst. During surgery to remove the cyst, the contralateral ovary was polycystic on gross examination, confirming the diagnosis of the polycystic ovary syndrome. After the operation, treatment with ethinyl estradiol and drospirenone was begun.
About 30% of adolescent girls with the polycystic ovary syndrome have glucose intolerance or diabetes mellitus.32 Hyperinsulinemia seems to be the common mechanism: insulin acts synergistically with luteinizing hormone to increase the production of androgen by the ovarian theca cells while also decreasing the level of sex hormone–binding globulin.12,33 Treatment with metformin can lead to clinical improvement, even in adolescents without overt diabetes mellitus.34
Nonalcoholic Fatty Liver Disease
On initial evaluation, mild elevations of serum aminotransferase levels were present, without hyperbilirubinemia. Nonalcoholic fatty liver disease is the most common cause of mild aminotransferase elevations in children and is strongly associated with obesity and the metabolic syndrome.13,14 It is important to exclude other causes of liver disease, so when the finding persisted, we did laboratory testing to rule out viral hepatitis, autoimmune hepatitis, and Wilson's disease; all the test results were negative. No specific treatments have been established for fatty liver disease in children or adults, but weight loss is almost certainly helpful.
Causes of Obesity
We have discussed the consequences of the patient's obesity, but what can be said about the causes of it? Because she was adopted in early infancy, her case illustrates better than most how biologic determinants of obesity can dominate over lifestyle or environmental exposures, as Dr. Kaplan will discuss.
Dr. Lee M. Kaplan: In obesity, a combination of genetic, developmental, and environmental determinants alters the body's normal system for the regulation of weight. The prevalence of obesity has increased in the past 50 years, with a disproportionate increase in severe obesity. Between 1986 and 2000, the prevalence of obesity (BMI >30) increased by a factor of 2, the prevalence of class 3 obesity (BMI >40) increased by a factor of 4, and the prevalence of the most severe forms of obesity (BMI >50) increased by a factor of 6.35,36
Most people are genetically susceptible to abnormal weight gain under the right conditions. The availability of highly processed, calorie-dense foods and a decreasing level of physical activity are important environmental contributors to obesity, but they are not the only ones. Disrupted meal patterns, disordered and inadequate sleep, disturbances in normal circadian rhythms, high levels of stress, social isolation, and the use of medications that promote weight gain may be equally important. Several of these factors may have affected the patient, including sleep deprivation and the stresses of adolescence. In contrast, the contribution of her diet or pattern of eating to the obesity appears to be limited.
The early onset of obesity and the striking difference in weight between the patient and her adoptive siblings despite similar eating habits suggest an important contribution of genetics to her obesity.37,38 There is strong evidence that genetic background plays an important role in determining the predisposition to obesity. Obesity often runs in families, and the correlation of BMI among siblings is little affected by whether they were raised together or apart and is often independent of the type or pattern of food intake or physical activity. Studies of twins suggest that genetic factors determine about 50 to 70% of the predisposition to the development of obesity.39
We have little information about the biologic relatives of the patient, other than that her grandmother was overweight. Although the onset of her obesity was very early, most of the known monogenetic or oligogenetic causes of obesity are unlikely.40 These rare disorders reflect alterations in genes that encode central nervous system regulators of body weight, such as leptin, the leptin receptor, melanocyte-stimulating hormone, and the melanocortin 4 receptor (MC4R). Genetic testing through a research protocol revealed no evidence of an abnormal MC4R in the patient. The plasma leptin level was 47 ng per milliliter (normal range, 3.3 to 18.3); the elevated level was appropriate to her obesity, thereby excluding genetic deficiency in leptin or its receptor. Symptoms of the most common, well-defined obesity syndromes — including the Prader–Willi syndrome, the Bardet–Biedl syndrome, and a deficiency in single-minded homologue 1 (SIM-1) — were absent.
Many genes contribute to the regulation of body weight, and a genetic predisposition to obesity, which the patient and other children with early-onset obesity almost certainly have, probably results from the influence of multiple genes, which combine to support an energy-thrifty phenotype.41
Discussion of Management
Weight-Loss Strategies
Dr. Hoppin: Despite the likelihood of a strong biologic basis for the patient's obesity, there is no specific physiological target that we can address to facilitate her weight management. The patient had lost approximately 20 kg in weight while attending a summer weight-loss camp 17 months before presentation to the Weight Center; she rapidly regained this weight after returning home. Such rebounds after acute weight loss from dietary restriction are very common and probably speak to the resilience of weight-regulatory mechanisms rather than to bad habits or a failure of willpower. Thus, we believed that the lifestyle habits of the patient and family were not the primary cause of her obesity. Nonetheless, our first approach was to work with her and her family to optimize these habits.
This patient embarked on a new series of weight-control attempts, with limited success (Figure 1B). She continued to work with a personal trainer, engaging in aerobic and strength training 3 days a week, and received dietary supervision from the trainer, supplemented by individual nutritional counseling from a registered dietitian. She was able to stabilize her eating patterns to some degree, and the frequency of nocturnal eating decreased. After her first visit, sertraline was tapered and then discontinued, and a trial of sibutramine was begun 2 months later. Metformin was added 4 months later for glycemic control. With these combined therapies, her weight gain stopped, but she lost only 3.2 kg during the first year, and sibutramine was ultimately withdrawn.
When she was 17 years old, she participated in a group-based program at our center with weekly meetings for 3 months. The group consisted of adolescent girls with obesity and was led by a dietitian. Specific goals were to improve food choices and planning and included both nutritional education and behavioral techniques. Dietary guidelines included modest caloric restriction and a relatively low intake of simple carbohydrates. The parents of the girls met concurrently with a psychologist to address family dynamics related to weight control. The patient participated actively and enthusiastically in the group program; she reduced her weight by another 3.2 kg and maintained the weight loss during the subsequent 6 months.
Three years after her first evaluation, the patient had maintained a 6.8-kg weight loss for about a year. However, her BMI of 44 remained in the range of severe obesity, and she continued to have sleep apnea, diabetes mellitus, hypertension, and dyslipidemia.
Bariatric Surgery
When the patient was 18 years old, we began to consider the possibility of weight-reduction surgery. Gastric bypass is clearly the most consistently effective treatment for severe obesity in adults42,43; although less is known about outcomes in adolescents, a few published case series suggest that they are similar to those in adults.44 An expert panel45 has recommended that weight-reduction surgery be considered for adolescents with a BMI of more than 40 who have severe medical complications of obesity (such as sleep apnea or diabetes, as in this patient) or with a BMI of more than 50 who have any medical complications and in whom efforts to control weight through other measures have been unsuccessful. In adolescents, medical follow-up to monitor for and treat potential micronutrient deficiencies is essential.46
The patient was an appropriate candidate for bariatric surgery. Her weight and coexisting illnesses were appropriate indications according to criteria for both adults and adolescents. She had made a variety of sustained efforts to control her weight by other measures, and she had an excellent record of compliance with long-term medical follow-up.
At the age of 19 years, the patient underwent a laparoscopic Roux-en-Y gastric bypass. Her initial postoperative recovery was uncomplicated. A wedge biopsy of the liver was performed during the operation.
Dr. Gregory Y. Lauwers: The liver biopsy showed histologic evidence of nonalcoholic steatohepatitis (Figure 3). The condition is characterized by inflammation and fibrosis, indicating damage to hepatocytes, and is considered to be a progressive form of nonalcoholic fatty liver disease. It has the potential to progress to cirrhosis and hepatocellular carcinoma, but the magnitude of the risk is not known.47
Figure 3. Liver-Biopsy Specimen Obtained during Gastric Bypass Procedure.
Panel A shows marked diffuse macrovesicular steatosis with inflammation (arrows) and ballooning degeneration of hepatocytes (inset, arrow) (hematoxylin and eosin). Panel B (trichrome stain) shows extensive fibrosis with bridging between portal areas; fine pericellular fibrosis is seen at a higher magnification (inset). In the absence of a history of alcohol use or other liver disease, the presence of fat is characteristic of nonalcoholic fatty liver disease. The presence of inflammation and fibrosis indicates progression to nonalcoholic steatohepatitis.
Dr. Lynne L. Levitsky (Pediatric Endocrinology): At her most recent follow-up, 1 month after surgery, the patient's weight had decreased from 122.5 kg to 109.6 kg, with a BMI of 39.8. Metformin and lisinopril had been discontinued at the time of the surgery. The blood pressure was 138/79 mm Hg, and her morning blood glucose levels by finger-stick measurement had been normal on all but two occasions. On physical examination, acanthosis nigricans that had developed on the wrists and ankles had resolved but persisted on the neck.
Anatomical Diagnosis
Severe childhood obesity with obstructive sleep apnea, hypertension, impaired glucose tolerance progressing to type 2 diabetes mellitus, the polycystic ovary syndrome, and nonalcoholic steatohepatitis.
Dr. Hoppin reports having received grant support from the Massachusetts Vitamin Litigation Fund. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Pediatrics (A.G.H., E.S.K.), the Gastrointestinal Unit (L.M.K.), and the Department of Pathology (G.Y.L.), Massachusetts General Hospital; and the Departments of Pediatrics (A.G.H., E.S.K.), Medicine (L.M.K.), and Pathology (G.Y.L.), Harvard Medical School.
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A 15 1/2-year-old girl was seen in the outpatient Weight Center of this hospital for the evaluation of severe obesity. She had had a normal gestation without complications and had been adopted during the first month of life. She weighed 3.9 kg at birth and 4.8 kg at 1 month of age. At the age of 1 year, her weight-to-length ratio was in the 75th percentile. At 3 years of age, her body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was above the 97th percentile. She was referred to a nutritionist. Her appetite remained steady, and she ate most foods. Although her food intake appeared to be similar to that of the other children in the family, her BMI continued to increase (Figure 1A).
Figure 1. Changes in BMI over Time (Panel A) and Their Association with Specific Weight-Loss Treatments (Panel B).
Panel A shows a comparison of the patient's BMI (indicated by X) with standard percentiles, according to age and sex. At all ages shown, the patient's BMI is well above the 97th percentile for her age. Over the course of 3 years, various approaches were used to help the patient lose weight (Panel B). After the discontinuation of sertraline, sibutramine was added, which was associated with a modest weight loss and no side effects. Over a period of 15 months, in conjunction with moderate-to-high levels of physical activity, the patient lost 3.2 kg. As is typical with pharmacotherapy for obesity, she regained the weight after stopping the drug. Metformin was begun for the treatment of diabetes, in conjunction with dietary counseling. Treatment with orlistat was attempted but was discontinued after only a few doses because of steatorrhea. At the age of 17 years, she participated in a group-based program at the Weight Center, consisting of behavioral and nutritional interventions with a group of adolescents, with the parents meeting separately. The patient lost 3.2 kg during the 3-month course of the program and maintained the weight loss in the subsequent 6 months.
Snoring and restless sleep began at approximately 5 to 6 years of age. At the age of 7 years, she was enrolled in a monthly weight-control program, and a year later, she was evaluated by a nutrition specialist. Physical examination revealed an overweight child with mild acanthosis nigricans of the neck with no other abnormalities. The next year, her parents noted that she was eating secretly; hyperpigmentation of the thighs was noted on physical examination. Between the ages of 10 and 11 years, her weight increased approximately 15 kg, and she began a program for weight control at her pediatrician's practice. At 12 years of age, she was seen by a psychiatrist, who noted dysthymia and poor motivation and prescribed sertraline and psychotherapy.
When the patient was 13 years old, her parents noticed nocturnal somnambulation and an increased intake of food. At 13 years 3 months, the patient was referred to an endocrinologist because she had not lost weight and had chronic daytime fatigue. Her height was 162.4 cm, her weight 106.9 kg, her blood pressure 132/73 mm Hg, and her pulse 76 beats per minute. Breast development was Tanner stage 3, and pubertal development was Tanner stage 5 (with 1 representing immature development and 5 maturity); acanthosis nigricans was present around the neck and groin. The remainder of the examination was normal; there was no hirsutism. Results of laboratory tests are shown in Table 1.
Table 1. Laboratory Values.
Snoring and insomnia worsened during adolescence. Menarche occurred at the age of 14 years, and her menstrual cycles were irregular. Daytime sleepiness worsened, including falling asleep at school, and morning headaches developed. A combination of dextroamphetamine sulfate and amphetamine aspartate was prescribed to enhance alertness. During an evaluation by a sleep specialist at the age of 14 years, physical examination revealed a blood pressure of 120/90 mm Hg; the tonsils were enlarged, but there was no marked crowding. A series of overnight polysomnograms obtained between the ages of 13 and 15 years showed progressive worsening of obstructive sleep apnea, including intermittent oxygen desaturation, hypercapnia, periodic leg movements, and sleep disruption. Bilevel ventilation therapy was started when the patient was 13 years old, but compliance with the therapy was poor. Pulmonary-function testing revealed normal spirometric values and lung volumes. The results of electrocardiography, chest radiography, and echocardiography were normal.
At the age of 14 years (17 months before this evaluation), the patient attended a summer camp and lost approximately 20 kg; she promptly regained the weight after returning home and gained an additional 12 kg during the subsequent year. Three months before presentation, she participated in a home-administered weight-loss plan on the basis of a point system, but her weight continued to increase.
At the time of the evaluation in the Weight Center, she had daytime somnolence but no headaches. She drank low-calorie soft drinks and two glasses of juice daily. She snacked twice during the night on sandwiches or other carbohydrate-containing foods. She exercised with a personal trainer three to five times per week and watched television approximately 6 hours per day on weekends. She typically slept 7 hours on school nights and 12 hours per night on the weekends. She had no difficulty initiating sleep, but she was hard to arouse in the morning.
The patient's early development had been normal; she walked at 12 months of age and spoke in short sentences at 15 months. Her depression had improved after a change in schools during the year preceding her presentation at the Weight Center, and the psychotherapy was discontinued. She was a good student in the 10th grade. A grandmother in her birth family was known to have been overweight; no other biologic-family history was known. Members of her adoptive family, including her parents and two younger siblings, were of normal weight. Her only medication was sertraline, and she had no known allergies.
Her height was 164.5 cm, her weight 126.6 kg, and her BMI 46.7. The blood pressure was 124/95 mm Hg. Severe acanthosis nigricans was present on the neck and axillae, and there was moderate acne on the face; a slightly android pattern of hair growth was evident on the abdomen, and there were moderate striae on the lower abdomen. There was no hair growth on the face, no rash in the skin folds, and no edema. The remainder of the physical examination was normal.
Additional laboratory testing was performed (Table 1), and a plan for management was developed.
Differential Diagnosis
Dr. Alison G. Hoppin: This patient presented with uncommon manifestations of a common disease. Obesity is common: 17.4% of adolescents in the United States are considered overweight by the standards of the Centers for Disease Control and Prevention.1 However, this patient's degree of obesity was very unusual: with a BMI of 46.7, she had adiposity levels that constituted class 3 obesity (on a scale of 1 to 3, with class 1 indicating a BMI of 30.0 to 34.9, class 2 a BMI of 35.0 to 39.9, and class 3 a BMI of 40.0 or more) in an adult. In addition, she had most of the important medical complications of obesity in children and adolescents (Table 2).
Table 2. Important Health Effects of Obesity in Children and Adolescents.
This patient's most acute health issues at presentation were symptoms suggestive of sleep apnea and diabetes mellitus. Because the symptoms of sleep apnea are somewhat subjective and there are no clear screening criteria, the problem is probably underdiagnosed in children and adolescents with obesity.2,3,4,5 This patient was referred to Dr. Eliot Katz, a specialist in sleep disorders in children, who will discuss the evaluation and management of her sleep apnea.
Obstructive Sleep Apnea
Dr. Eliot S. Katz: Testing of this patient by overnight polysomnography at 15 years of age (Figure 2) indicated that her sleep latency was less than 4 minutes (normal, 9 to 33), suggesting objective sleepiness. She had recurrent episodes of partial or complete upper-airway obstruction associated with intermittent hypoxemia (minimum oxygen saturation, 86%; normal value, 92 to 96), hypercapnia (awake, 52 mm Hg, and asleep, 64 mm Hg; normal carbon dioxide peak during sleep, 53 mm Hg), and electroencephalographic arousal (Figure 2). Her apnea–hypopnea index was markedly elevated at 21 events per hour (normal value, 1). Despite these findings, she had normal sleep architecture and sleep efficiency. Children with severe obstructive sleep apnea often have normal distribution of sleep states, despite frequent episodes of obstruction and brief electrocortical arousal.
Figure 2. Sleep Study at 15 Years of Age.
A 90-second portion of an overnight polysomnogram obtained while the patient was in stage 2 sleep shows a series of episodes of obstructive apnea and hypopnea (arrows), characterized by a marked reduction in airflow despite ongoing respiratory efforts. Accompanying the obstructive events are cyclic reductions in oxygen saturation of 5 to 10%. At the end of each obstruction is an arousal consisting of augmentation of electromyographic tone and a frequency shift in the electroencephalogram. EOG denotes electrooculogram, and O2-A1 right occipital lead referenced to the left mastoid lead.
Obesity poses both an obstructive load to the upper airway and an elastic load to the entire pulmonary system. Although pulmonary function, as measured by spirometry, is often normal in obese children during wakefulness at rest, as it was in this child, there are often measurable deficits during exercise and sleep. Obese children are 4.5 times as likely to have obstructive sleep apnea as are children who are not obese.19 The severity of the condition is related to the degree of visceral adiposity, rather than to the amount of total body fat. This patient had a central pattern of obesity, which has the strongest correlation with the metabolic syndrome.20 More than 90% of children with both obesity and habitual snoring have obstructive sleep apnea.21 Thus, this patient probably had obstructive sleep apnea during her 8-to-10-year history of snoring before her initial polysomnography. Androgens affect ventilatory control and increase visceral fat; thus, obstructive sleep apnea is more commonly seen in boys after puberty (rather than before puberty) and in women who have excessive levels of androgen associated with the polycystic ovary syndrome, which was suspected in this patient.22
Sequelae
The consequences of obstructive sleep apnea include cardiovascular abnormalities, neurocognitive impairment, daytime sleepiness, and metabolic disturbances — several of which were seen in this patient. Her hypertension was probably a consequence of both obstructive sleep apnea and obesity. In extreme cases, biventricular dysfunction and pulmonary hypertension may develop, and screening for pulmonary hypertension with echocardiography is indicated for children with severe obstructive sleep apnea. The 8-to-10-year history of probable obstructive sleep apnea during a vulnerable period of brain growth places this patient at risk for neurocognitive impairment, including mood disturbance, which she had. The disease has a minimal effect on intelligence but may impair executive functioning and attention span and has been associated with poor school performance in adolescents.23
In contrast to adults with sleep apnea, most children do not have clinical or objective sleepiness.24 Sleepiness in adolescents is frequently multifactorial and includes an insufficient amount of sleep, poor sleep hygiene, increased sleep requirements and circadian-rhythm disturbances, and disrupted sleep related to obstructive sleep apnea, sleepwalking, and nocturnal eating. Thus, this patient had many reasons for sleepiness.
Both obstructive sleep apnea and obesity are associated with increased levels of inflammatory markers,20,25 which are believed to be involved in the normal homeostatic regulation of sleep. Thus, increased levels of circulating cytokines may contribute to the sleepiness that is characteristic of both obstructive sleep apnea and obesity. Obstructive sleep apnea can increase insulin resistance and leptin levels, independent of obesity,20,25 and treatment with continuous positive airway pressure can reduce insulin resistance and levels of leptin and inflammatory markers.
Treatment
In contrast to children of normal weight, obese children with adenotonsillar hypertrophy typically do not have complete resolution of obstructive sleep apnea after adenotonsillectomy, although their condition typically improves.26 In this patient, nasopharyngoscopy demonstrated only mild adenotonsillar hypertrophy that was not considered to warrant surgical removal. Weight loss can lessen the severity of obstructive sleep apnea, but residual obstruction is frequently present.27
Continuous positive airway pressure and bilevel ventilation are both effective therapies for obstructive sleep apnea.28 However, 15 to 20% of patients will not comply with the use of nasal positive-pressure ventilation at all; for the remainder of patients, the average duration of use is approximately 5 hours per night. Although this patient acknowledged improvements in daytime functioning after receiving nocturnal bilevel ventilation, she complied poorly with therapy. Thus, her case illustrates both the consequences of sleep apnea and the difficulties in managing it.
Dr. Hoppin: This patient had features of the metabolic syndrome, a constellation of findings associated with an increased risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus.10
Insulin Resistance and Type 2 Diabetes Mellitus
This patient had evidence of insulin resistance, with severe acanthosis nigricans, an elevated insulin level after an overnight fast, and a glycated hemoglobin value of 6.7%. Subsequent testing revealed a blood glucose level of 141 mg per deciliter (7.8 mmol per liter) 2 hours after an oral glucose load (Table 1), documenting impaired glucose tolerance.29 Insulin resistance is independently associated with both obesity and puberty, so this patient is at risk for both reasons.6,7,8 In a longitudinal study of obese adolescents, progression from normal to impaired glucose tolerance occurred in 10% during a 2-year period, and 25% of these patients had progression to type 2 diabetes.30
Six months after the first visit, treatment with metformin was begun, in consultation with an endocrinologist. During the next 2 years, the patient had a slight improvement in glycemic control, with glycated hemoglobin values ranging from 6.5 to 7% and fasting blood glucose levels between 90 and 95 mg per deciliter (5.0 to 5.3 mmol per liter). However, during a period of noncompliance with the metformin, her fasting blood glucose levels rose to a range of 244 to 275 mg per deciliter (13.5 to 15.3 mmol per liter), diagnostic of diabetes mellitus.
Hypertension and Dyslipidemia
The patient had mild hypertension at her first visit, which gradually worsened during the next 18 months. Pharmacologic intervention is recommended for hypertension that persists despite a modification in diet and for patients with diabetes mellitus.9 Angiotensin-converting–enzyme inhibitors are recommended preferentially in children with diabetes. Treatment with lisinopril was initiated 18 months after her first visit. Her fasting total cholesterol and triglyceride levels were high, whereas the level of low-density lipoprotein cholesterol was in the borderline range. Our dietary counseling included recommendations for a reduction in dietary fat.31
Polycystic Ovary Syndrome
The patient also had findings that suggested the polycystic ovary syndrome and nonalcoholic fatty liver disease, both of which are associated with the metabolic syndrome phenotype. The classic clinical features of the polycystic ovary syndrome include menstrual disturbance, hirsutism, and polycystic ovaries. However, on the basis of broader diagnostic criteria, the disorder is thought to affect 5 to 10% of women of reproductive age.11 Although the patient had menarche and menstrual patterns that could be considered normal and she did not have marked hirsutism, she had an elevated level of free testosterone at 13 years of age, suggesting the presence of hyperandrogenism. Two years after her first visit here, she presented with acute right ovarian torsion due to a cyst. During surgery to remove the cyst, the contralateral ovary was polycystic on gross examination, confirming the diagnosis of the polycystic ovary syndrome. After the operation, treatment with ethinyl estradiol and drospirenone was begun.
About 30% of adolescent girls with the polycystic ovary syndrome have glucose intolerance or diabetes mellitus.32 Hyperinsulinemia seems to be the common mechanism: insulin acts synergistically with luteinizing hormone to increase the production of androgen by the ovarian theca cells while also decreasing the level of sex hormone–binding globulin.12,33 Treatment with metformin can lead to clinical improvement, even in adolescents without overt diabetes mellitus.34
Nonalcoholic Fatty Liver Disease
On initial evaluation, mild elevations of serum aminotransferase levels were present, without hyperbilirubinemia. Nonalcoholic fatty liver disease is the most common cause of mild aminotransferase elevations in children and is strongly associated with obesity and the metabolic syndrome.13,14 It is important to exclude other causes of liver disease, so when the finding persisted, we did laboratory testing to rule out viral hepatitis, autoimmune hepatitis, and Wilson's disease; all the test results were negative. No specific treatments have been established for fatty liver disease in children or adults, but weight loss is almost certainly helpful.
Causes of Obesity
We have discussed the consequences of the patient's obesity, but what can be said about the causes of it? Because she was adopted in early infancy, her case illustrates better than most how biologic determinants of obesity can dominate over lifestyle or environmental exposures, as Dr. Kaplan will discuss.
Dr. Lee M. Kaplan: In obesity, a combination of genetic, developmental, and environmental determinants alters the body's normal system for the regulation of weight. The prevalence of obesity has increased in the past 50 years, with a disproportionate increase in severe obesity. Between 1986 and 2000, the prevalence of obesity (BMI >30) increased by a factor of 2, the prevalence of class 3 obesity (BMI >40) increased by a factor of 4, and the prevalence of the most severe forms of obesity (BMI >50) increased by a factor of 6.35,36
Most people are genetically susceptible to abnormal weight gain under the right conditions. The availability of highly processed, calorie-dense foods and a decreasing level of physical activity are important environmental contributors to obesity, but they are not the only ones. Disrupted meal patterns, disordered and inadequate sleep, disturbances in normal circadian rhythms, high levels of stress, social isolation, and the use of medications that promote weight gain may be equally important. Several of these factors may have affected the patient, including sleep deprivation and the stresses of adolescence. In contrast, the contribution of her diet or pattern of eating to the obesity appears to be limited.
The early onset of obesity and the striking difference in weight between the patient and her adoptive siblings despite similar eating habits suggest an important contribution of genetics to her obesity.37,38 There is strong evidence that genetic background plays an important role in determining the predisposition to obesity. Obesity often runs in families, and the correlation of BMI among siblings is little affected by whether they were raised together or apart and is often independent of the type or pattern of food intake or physical activity. Studies of twins suggest that genetic factors determine about 50 to 70% of the predisposition to the development of obesity.39
We have little information about the biologic relatives of the patient, other than that her grandmother was overweight. Although the onset of her obesity was very early, most of the known monogenetic or oligogenetic causes of obesity are unlikely.40 These rare disorders reflect alterations in genes that encode central nervous system regulators of body weight, such as leptin, the leptin receptor, melanocyte-stimulating hormone, and the melanocortin 4 receptor (MC4R). Genetic testing through a research protocol revealed no evidence of an abnormal MC4R in the patient. The plasma leptin level was 47 ng per milliliter (normal range, 3.3 to 18.3); the elevated level was appropriate to her obesity, thereby excluding genetic deficiency in leptin or its receptor. Symptoms of the most common, well-defined obesity syndromes — including the Prader–Willi syndrome, the Bardet–Biedl syndrome, and a deficiency in single-minded homologue 1 (SIM-1) — were absent.
Many genes contribute to the regulation of body weight, and a genetic predisposition to obesity, which the patient and other children with early-onset obesity almost certainly have, probably results from the influence of multiple genes, which combine to support an energy-thrifty phenotype.41
Discussion of Management
Weight-Loss Strategies
Dr. Hoppin: Despite the likelihood of a strong biologic basis for the patient's obesity, there is no specific physiological target that we can address to facilitate her weight management. The patient had lost approximately 20 kg in weight while attending a summer weight-loss camp 17 months before presentation to the Weight Center; she rapidly regained this weight after returning home. Such rebounds after acute weight loss from dietary restriction are very common and probably speak to the resilience of weight-regulatory mechanisms rather than to bad habits or a failure of willpower. Thus, we believed that the lifestyle habits of the patient and family were not the primary cause of her obesity. Nonetheless, our first approach was to work with her and her family to optimize these habits.
This patient embarked on a new series of weight-control attempts, with limited success (Figure 1B). She continued to work with a personal trainer, engaging in aerobic and strength training 3 days a week, and received dietary supervision from the trainer, supplemented by individual nutritional counseling from a registered dietitian. She was able to stabilize her eating patterns to some degree, and the frequency of nocturnal eating decreased. After her first visit, sertraline was tapered and then discontinued, and a trial of sibutramine was begun 2 months later. Metformin was added 4 months later for glycemic control. With these combined therapies, her weight gain stopped, but she lost only 3.2 kg during the first year, and sibutramine was ultimately withdrawn.
When she was 17 years old, she participated in a group-based program at our center with weekly meetings for 3 months. The group consisted of adolescent girls with obesity and was led by a dietitian. Specific goals were to improve food choices and planning and included both nutritional education and behavioral techniques. Dietary guidelines included modest caloric restriction and a relatively low intake of simple carbohydrates. The parents of the girls met concurrently with a psychologist to address family dynamics related to weight control. The patient participated actively and enthusiastically in the group program; she reduced her weight by another 3.2 kg and maintained the weight loss during the subsequent 6 months.
Three years after her first evaluation, the patient had maintained a 6.8-kg weight loss for about a year. However, her BMI of 44 remained in the range of severe obesity, and she continued to have sleep apnea, diabetes mellitus, hypertension, and dyslipidemia.
Bariatric Surgery
When the patient was 18 years old, we began to consider the possibility of weight-reduction surgery. Gastric bypass is clearly the most consistently effective treatment for severe obesity in adults42,43; although less is known about outcomes in adolescents, a few published case series suggest that they are similar to those in adults.44 An expert panel45 has recommended that weight-reduction surgery be considered for adolescents with a BMI of more than 40 who have severe medical complications of obesity (such as sleep apnea or diabetes, as in this patient) or with a BMI of more than 50 who have any medical complications and in whom efforts to control weight through other measures have been unsuccessful. In adolescents, medical follow-up to monitor for and treat potential micronutrient deficiencies is essential.46
The patient was an appropriate candidate for bariatric surgery. Her weight and coexisting illnesses were appropriate indications according to criteria for both adults and adolescents. She had made a variety of sustained efforts to control her weight by other measures, and she had an excellent record of compliance with long-term medical follow-up.
At the age of 19 years, the patient underwent a laparoscopic Roux-en-Y gastric bypass. Her initial postoperative recovery was uncomplicated. A wedge biopsy of the liver was performed during the operation.
Dr. Gregory Y. Lauwers: The liver biopsy showed histologic evidence of nonalcoholic steatohepatitis (Figure 3). The condition is characterized by inflammation and fibrosis, indicating damage to hepatocytes, and is considered to be a progressive form of nonalcoholic fatty liver disease. It has the potential to progress to cirrhosis and hepatocellular carcinoma, but the magnitude of the risk is not known.47
Figure 3. Liver-Biopsy Specimen Obtained during Gastric Bypass Procedure.
Panel A shows marked diffuse macrovesicular steatosis with inflammation (arrows) and ballooning degeneration of hepatocytes (inset, arrow) (hematoxylin and eosin). Panel B (trichrome stain) shows extensive fibrosis with bridging between portal areas; fine pericellular fibrosis is seen at a higher magnification (inset). In the absence of a history of alcohol use or other liver disease, the presence of fat is characteristic of nonalcoholic fatty liver disease. The presence of inflammation and fibrosis indicates progression to nonalcoholic steatohepatitis.
Dr. Lynne L. Levitsky (Pediatric Endocrinology): At her most recent follow-up, 1 month after surgery, the patient's weight had decreased from 122.5 kg to 109.6 kg, with a BMI of 39.8. Metformin and lisinopril had been discontinued at the time of the surgery. The blood pressure was 138/79 mm Hg, and her morning blood glucose levels by finger-stick measurement had been normal on all but two occasions. On physical examination, acanthosis nigricans that had developed on the wrists and ankles had resolved but persisted on the neck.
Anatomical Diagnosis
Severe childhood obesity with obstructive sleep apnea, hypertension, impaired glucose tolerance progressing to type 2 diabetes mellitus, the polycystic ovary syndrome, and nonalcoholic steatohepatitis.
Dr. Hoppin reports having received grant support from the Massachusetts Vitamin Litigation Fund. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Pediatrics (A.G.H., E.S.K.), the Gastrointestinal Unit (L.M.K.), and the Department of Pathology (G.Y.L.), Massachusetts General Hospital; and the Departments of Pediatrics (A.G.H., E.S.K.), Medicine (L.M.K.), and Pathology (G.Y.L.), Harvard Medical School.
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