US Pharm. 2010;35(6):HS-2-HS-6.
There has been a renewed interest in metabolic syndrome in children in recent years in association with increasing childhood obesity, and the origins of metabolic syndrome have been traced back to childhood.1 This article attempts to collate the information available so far and to describe the challenges currently faced in diagnosing and treating metabolic syndrome in children.
Metabolic syndrome is a group of risk factors that increase a patient’s chance of developing heart disease and diabetes, including abdominal obesity, dyslipidemia, glucose intolerance, and hypertension.2 However, health care providers do not commonly recognize that these components may coexist in children and may lead to future atherosclerotic cardiovascular disease in young adults.3
Various attempts have been made to define metabolic syndrome in adults. Ford and Li describe metabolic syndrome as “a cluster of anthropometric, physiological, and biochemical abnormalities tied together by incompletely understood underlying mechanisms that predisposes those affected to development of diabetes and cardiovascular disease.”3 Washington defines metabolic syndrome as “a cluster of a variable number of risk factors that exceed criterion values. These risk factors include an increased waist circumference (central adiposity), systemic hypertension, elevated fasting plasma triglyceride, and an elevated fasting glucose or insulin resistance.”3 Metabolic syndrome is described by Zimmet et al as a “cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which include abdominal obesity, dyslipidaemia, glucose intolerance, and hypertension.”4 According to the Third Report of the National Cholesterol Education Program Adult Treatment Panel (ATP III), metabolic (or insulin resistance) syndrome is “the presence in an individual of at least three of the following five risk factors: central or abdominal obesity, hypertriglyceridemia, hypertension, low HDL cholesterol, and high fasting glucose levels.”5
There is currently no uniform definition for metabolic syndrome in children. This poses a challenge for measuring prevalence, setting up screening measures, and establishing treatment protocols.6,7 Furthermore, it is not possible to accurately compare the results of different studies measuring prevalence in children since the studies’ threshold values vary. What is known so far is that the prevalence of metabolic syndrome in children is much lower than in adults.8
Data from the National Health and Nutrition Examination Survey (NHANES) for 1999 to 2002 (NHANES 99-02) showed that the rate of metabolic syndrome in children varies widely depending upon a number of factors, such as ethnicity, weight, age, and sex.9 More factors need to be identified and further studied. NHANES III (1988-1994) demonstrated that the prevalence of metabolic syndrome increases proportionally to body-mass index (BMI). The number of overweight children and adolescents aged 6 to 19 years was 4% higher in NHANES 99-02, compared with NHANES III.8 Considering that there is a gradual rise in childhood overweight in Western society, obesity is becoming the most important contributing risk factor for metabolic syndrome. The prevalence of metabolic syndrome in U.S. youths has been shown to be highest among Hispanic adolescents (5.6%), followed by white adolescents (4.8%); prevalence is lowest among African American adolescents (2.0%), even though African Americans have a higher overall body weight than white Americans.8 This indicates that the patient’s ethnicity also affects prevalence.
While the prevalence of metabolic syndrome seems to vary with age, further evidence is needed to support this claim, since the different threshold values used in the various studies hamper direct comparison. In NHANES III, Cook et al calculated a prevalence rate of 4.2% in children and adolescents aged 12 to 19 years, and the Bogalusa Heart Study found a prevalence of 3.6% in youths aged 8 to 17 years.5 Evidence to support the influence of the patient’s sex on prevalence is conflicting, and further research is required in this field.5
In order to gain an understanding of the pathophysiology of metabolic syndrome in children, the focus of recent studies has been narrowed to insulin resistance and obesity.8 Most features of metabolic syndrome can be attributed to insulin resistance, and weight loss seems to play an indirect role by increasing insulin sensitivity.4,8,10 It has been found that individuals with high insulin levels over a long period of time are 36 times more overweight, have 2.5 times more hypertension, and have 3 times more dyslipidemia than those with low insulin levels.5 A similar study demonstrated that children with BMI and waist-circumference values that classify them as overweight or obese are at increased risk for adult metabolic syndrome.11 The relationship between elements of metabolic syndrome and excess adiposity has been shown even in children as young as 2 to 5 years.12
In obese patients, insulin sensitivity is reduced as a result of the detrimental effect of inflammatory molecules on the insulin signaling pathways.13 The white adipose tissue is infiltrated by macrophages that produce proinflammatory cytokines, which are responsible for breaking down the response to insulin.13
Particular attention needs to be paid to children going through puberty, since insulin sensitivity is reduced during this period in both diabetic and nondiabetic individuals.5 Furthermore, body fat, blood pressure, and lipids are all affected by the hormonal changes that occur during puberty.5
While there is no consensus regarding the diagnosis of metabolic syndrome in children and adolescents, it is evident that each component of the syndrome must be identified as early as possible in order to prevent definitive lesions and chronic disease during childhood and in later life.5 The next challenge is how to identify the syndrome and determine which criteria should be used for diagnosis.14 In an attempt to develop diagnostic criteria, researchers in one study used the International Diabetes Federation definition with clear cutoff points. They suggested that, while this definition may exclude some patients who normally would be considered according to other definitions, it will be more widely accepted because of its convenience.14 TABLE 1 lists some measurements that health care professionals should consider when developing a protocol to diagnose metabolic syndrome.5,8
Recently, a close association was established between metabolic syndrome and nonalcoholic fatty liver disease in children.15 Based upon this finding, the authors of this study strongly suggested screening for other comorbidities associated with metabolic syndrome and treating the patient appropriately.15
In addition to helping patients and caregivers identify metabolic syndrome and understand the complex matrix of underlying issues, pharmacists can provide support and training for appropriate management. A number of approaches have been used to manage metabolic syndrome in children and reduce risks later in life; however, the primary focus is on lifestyle intervention. Specifically, lifestyle changes involving diet and physical activity are recommended by several expert authors as first-line therapy for overweight, hypertension, insulin resistance, and dyslipidemia.5 One paper proposes that focusing treatment strategies on improving insulin sensitivity may be more beneficial than focusing on obesity reduction for preventing or delaying the onset of cardiovascular disease and type 2 diabetes in high-risk youths.8 TABLE 2 lists American Academy of Pediatrics (AAP)–recommended target BMIs for determining which children need to reduce weight to be healthy.5
Since there is increasing evidence to support insulin resistance as the underlying cause of metabolic syndrome, treatment strategies are being developed to improve insulin sensitivity.4 The cornerstones of treatment are diet and exercise intervention, nutritional intervention, and pharmacologic intervention.
Diet and Exercise Intervention: It is well established that lifestyle changes, such as diet and level of physical activity, are fundamental to prevention. Regular exercise not only improves response to a 2-hour glucose tolerance test, but also improves insulin sensitivity, even without weight loss.5 It is thought that this action occurs through the activation of cellular glucose uptake independent of insulin.5 Additionally, exercise is associated with lower blood pressure.
A recent study examining the effect of diet and exercise intervention on metabolic syndrome in overweight children indicated that metabolic syndrome can be reversed even with short-term lifestyle intervention.16 The 16 study participants, aged 10 to 17 years, were given a complete physical examination and then underwent a 14-day diet and exercise program. In addition to attending daily cooking classes and talks about nutrition, exercise, and general wellness, the subjects consumed a healthy, balanced diet containing less than 100 mg cholesterol and less than 1,600 mg sodium per day. Caffeinated beverages were not permitted. To meet the goal of increased physical activity and energy expenditure, the subjects engaged in 2 to 2.5 hours of supervised activity, including tennis, beach games, and gym-based exercises, each day. Before the intervention, seven subjects had metabolic syndrome based on parameters of insulin level, insulin resistance, body weight, cholesterol, and triglycerides, as well as blood pressure. In all subjects, all values except body weight were reduced postintervention.
In an earlier study, high-intensity physical training for 8 months in overweight adolescents resulted in improvements in fasting plasma triglycerides, LDL particle size, and diastolic blood pressure, despite little change in body weight.17 Non–weight-bearing activities, in particular, have been shown to be more acceptable to overweight children and to promote long-term health. Therefore, youthful patients should be directed to concentrate on cardiovascular training activities that are more enjoyable for children and adolescents.18
Similarly, a 12-week program based on the Kids N Fitness lifestyle intervention program had a positive effect on reducing risk factors for metabolic syndrome and insulin resistance in overweight children.19 Parents and caregivers attended educational sessions about the comorbidities of obesity, and the children took part in an exercise program. The exercise sessions included cardiovascular training activities such as dodgeball, volleyball, jump rope, and running.19 This was followed by family-centered educational sessions for both children and caregivers. Statistically significant improvements in BMI, systolic blood pressure, cholesterol and triglycerides, postprandial glucose, and leptin levels were seen in all children who completed the program.19
The CASPIAN study discovered an association between physical activity and metabolic syndrome in children that was independent of BMI and age.1 The researchers used questionnaires to collect data regarding the children’s level of physical activity.1 The level of physical activity was assessed and categorized, and the measurements for metabolic syndrome were based on the criteria set forth by ATP III.1
In addition to providing advice on healthy eating and exercise, pharmacists can assist children and adolescents who need to lose weight by discouraging them from spending long periods of time in front of the television, supporting physical-education programs in schools, and helping create safe neighborhoods that promote physical activity.
Different authorities have proposed guidelines for healthy eating habits. The U.S. Department of Health and Human Services recommends that children and adolescents consume at least five fruits and vegetables a day and that no more than 30% of total calories per day comes from dietary fat. This program encourages increased consumption of whole grains and advises the avoidance of sweets, sodas, and other empty-calorie foods.5
The “stoplight diet,” created by Epstein and Squires, divides foods into three categories: green (foods that can be eaten at any time), yellow (foods that are eaten within limits), and red (foods that should be avoided).5 The AAP takes a slightly different approach, guiding parents and families to make lifestyle changes by teaching them strategies to promote and maintain healthy eating habits and physical activity.20 While the majority of patients should be referred to a dietitian when making drastic changes to their diet, pharmacists should have a basic understanding of healthy eating habits to better guide their patients.
Nutritional Intervention: Grains, fiber, and phytoestrogens are the primary nutrients that have beneficial effects on insulin sensitivity.8 Pharmacists and dietitians should encourage patients to regularly consume foods such as soy, flaxseed, whole-grain cereals, fruits, and vegetables, which contain high levels of these nutrients.
Pharmacologic Intervention: Drug therapy with insulin sensitizers, including metformin and thiazolidinediones (TZDs), has shown positive effects. A recent systemic review showed that individually tailored lifestyle interventions, when combined with metformin, demonstrated a reduction in fasting insulin and BMI in children and adolescents with insulin resistance.21 TZDs are useful insulin sensitizers that enhance glucose uptake via their activation of peroxisome proliferator-activated receptor gamma.13 The primary effect of TZDs is on the adipose tissue, where they favorably alter the production of inflammatory molecules that contribute to the many components of metabolic syndrome.4
In addition to the above, some patients may require drug therapy for hypertension and/or hypercholesterolemia, since at present each component of the syndrome is treated separately.4
Since a large percentage of youths with metabolic syndrome probably will develop type 2 diabetes and cardiovascular disorders later in life, it is important that health care providers develop and test primary prevention strategies to manage childhood metabolic syndrome.3 By building close relationships with their patients and opening up communication, pharmacists can help identify candidates for diagnosis, provide support for patients and their families in making lifestyle changes, and advise patients on the correct use of their medications.
1. Kelishadi R, Razaghi EM, Gouya MM, et al. Association of physical activity and the metabolic syndrome in children and adolescents: CASPIAN study. Horm Res. 2007;67:46-52.
2. Zimmet P, Alberti G, Kaufman F, et al. The metabolic syndrome in children and adolescents: the IDF consensus. Diabetes Voice. 2007;52:29-31.
3. Washington RL. Metabolic syndrome—no longer an adult only disease. J Pediatr. 2008;152:A1.
4. Zimmet P, Alberti G, Kaufman F. The metabolic syndrome in children and adolescents. Lancet. 2007;369:2059-2061.
5. Jessup A, Harrell JS. The metabolic syndrome: look for it in children and adolescents, too! Clin Diabetes. 2005;23:26-32.
6. Ford ES, Li C. Defining the metabolic syndrome in children and adolescents: will the real definition please stand up? J Pediatr. 2008;152:160-164.
7. Lee S, Bacha F, Gungor N, Arslanian S. Comparison of different definitions of pediatric metabolic syndrome: relation to abdominal adiposity, insulin resistance, adiponectin, and inflammatory biomarkers. J Pediatr. 2008;152:177-184.
8. Cruz ML, Goran MI. The metabolic syndrome in children and adolescents. Curr Diab Rep. 2004;4:53-62.
9. Cook S, Auinger P, Li C, Ford E. Metabolic syndrome rates in United States adolescents, from the National Health and Nutrition Examination Survey, 1999-2002. J Pediatr. 2008;152:165-170.
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11. Sun SS, Liang R, Huang TT, et al. Childhood obesity predicts adult metabolic syndrome: The Fels Longitudinal Study. J Pediatr. 2008;152:191-200.
12. Rappaport EB. Identifying and evaluating the metabolic syndrome in children and adolescents. Ethn Dis. 2007;17(3 suppl 4):S4-1-6.
13. Quinn CE, Hamilton PK, Lockhart CJ, McVeigh GE. Thiazolidinediones: effects on insulin resistance and the cardiovascular system. Br J Pharmacol. 2008;153:636-645.
14. Mancini MC. Metabolic syndrome in children and adolescents — criteria for diagnosis. Diabetol Metab Syndr. 2009;1:20.
15. Sundaram SS, Zeitler P, Nadeau K. The metabolic syndrome and nonalcoholic fatty liver disease in children. Curr Opin Pediatr. 2009;21:529-535.
16. Chen AK, Roberts CK, Barnard RJ. Effect of a short-term diet and exercise intervention on metabolic syndrome in overweight children. Metabolism. 2006;55:871-878.
17. Kang HS, Gutin B, Barbeau P, et al. Physical training improves insulin resistance syndrome markers in obese adolescents. Med Sci Sports Exerc. 2002;34:1920-1927.
18. Bernhardt DT, Gomez J, Johnson MD, et al. Strength training by children and adolescents. Pediatrics. 2001;107:1470-1472.
19. Monzavi R, Dremaine D, Geffner ME, et al. Improvement in risk factors for metabolic syndrome and insulin resistance in overweight youth who are treated with lifestyle intervention. Pediatrics. 2006;117:e1111-e1118.
20. Barlow SE, Dietz WH. Obesity evaluation and treatment: Expert Committee recommendations. Pediatrics.1998;102:E29.
21. Quinn SM, Baur LA, Garnett SP, Cowell CT. Treatment of clinical insulin resistance in children: a systematic review. Obes Rev. http://dx.doi.org/10.1111/j. 1467-789X.2009.00697.x. Epub ahead of print. Accessed January 29, 2010.
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