Although there is debate surrounding the definition of metabolic X syndrome in pediatrics and there are few long-term studies of outcomes in children with metabolic syndrome, pediatric metabolic syndrome needs to be on the radar of all pediatricians interested in ensuring a healthy adult life for their patients.
Cardiovascular disease was nearly 15 times more common among children and adolescents with metabolic syndrome traits in the Lipid Research Clinics study compared with those without the traits. More than two-thirds of patients with metabolic syndrome traits as children went on to develop metabolic syndrome as adults.1 Metabolic syndrome is truly a multisystem disease that requires the pediatrician provide screening, counseling, assessment, and treatment for a wide variety of metabolic problems.
Despite numerous attempts to define metabolic syndrome in the pediatric population, no consensus definition currently exists. There are number of reasons why, including2:
· Some adolescents have transient insulin resistance during adolescence.
· Normal lipid levels vary by age, sex, race.
· There is a lack of standardization for diagnosis of central obesity.
· Metabolic abnormalities in children with metabolic syndrome are relatively moderate.
Whereas different criteria for diagnosing metabolic syndrome exist,3-5 all the definitions generally include assessment and presence of some combination of the following parameters (Table 1 and 2):
1. Elevated triglyceride levels;
2. Reduced high-density lipoprotein (HDL);
3. Elevated blood pressure (BP);
4. Impaired fasting glucose concentration; and
5. Increased waist circumference.
Although the pathogenesis of pediatric metabolic syndrome is not fully elucidated, interactions between insulin resistance, obesity, increased lipids, and inflammation are all involved. Free fatty acid accumulation in hepatic tissue, muscle, and adipose tissue along with lipid partitioning of fat to areas that are more insulin resistant (eg, visceral abdomen) results in limiting insulin sensitivity. Accumulation of free fatty acids in the liver increases both insulin and triglyceride levels. The process also impacts endothelial cell function that further limits sensitivity of tissues to insulin, resulting in decreased uptake of glucose and inflammation. As the body accumulates more fat in adipocytes, an inflammatory response ensues that stimulates more inflammatory activity. Although not fully understood, obesity, inflammation, and insulin resistance are important concepts in the development of pediatric metabolic syndrome.2,5
There are a number of risk factors for development of the metabolic syndrome, including family history, ethnicity, physical activity, and tobacco exposure. Children of parents with early heart disease are more likely to be overweight and have glucose impairment, insulin resistance, central obesity, and abnormal lipid levels.6,7 African American and Hispanic children experience higher rates of the components of metabolic syndrome compared with white children.4 Physical inactivity is associated with development of cardiovascular disease and the individual components of the metabolic syndrome, but increasing activity mediates these risk factors.8-11 Tobacco exposure also may predispose adolescents to the development of insulin resistance.12
The pediatrician needs to focus on identifying obese and overweight children and then aggressively manage risk factors. There are no specific guidelines, but it is prudent to look for elevated BP, hepatomegaly, and acanthosis nigricans in addition to assessing smoking status and family history, as all are associated with components of metabolic syndrome.
Abdominal obesity is associated with increased risk of cardiovascular disease. Although body mass index (BMI) is routinely calculated in pediatric practices, increased BMI does not always indicate increased waist circumference and accumulation of visceral fat. Increased waist circumference is associated with insulin resistance, hypertension, and dyslipidemia in pediatric patients.4 Measuring waist circumference will help the pediatrician identify patients that are at risk for pediatric metabolic syndrome. In the National Heart, Lung, and Blood Institute (NHLBI) Growth and Health Study, every 1-cm increase in waist circumference was associated with a 7.4% increase in risk of metabolic syndrome.13-15
Free fatty acid accumulation in the liver leads to insulin resistance and abnormalities in lipid levels. Elevated triglycerides and low HDL)levels are associated with insulin resistance. The American Academy of Pediatrics (AAP) recommends screening all pediatric patients aged between 9 and 11 years and again between 17 and 21 years, with earlier screening for children with risk factors for cardiovascular disease.16 In the NHLBI Growth and Health study, increasing triglycerides also increased risk of development of metabolic syndrome.
There is a strong relationship between elevated BP and insulin resistance. Insulin resistance impacts endothelial function, increases sympathetic tone, and inhibits the vasodilatory function of blood vessels. Elevated levels of free fatty acids also inhibit vasodilation. In fact, it is the cluster of insulin resistance and elevated lipid tests rather than any component alone that is most associated with elevated BP.4
As a result, the pediatrician needs to treat the entire cluster rather than just the individual components.
Whereas nonalcoholic fatty liver disease (NAFLD) is not part of the diagnostic criteria for metabolic syndrome, it commonly coexists and increases risk of significant liver pathology such as fibrosis, cirrhosis, and hepatic cellular carcinoma. In addition to its association with metabolic syndrome, NAFLD increases risk for cardiovascular disease, type 2 diabetes mellitus (T2DM), and chronic kidney disease through the same mechanisms of insulin resistance, inflammation, and dyslipidemia.17
Insulin resistance and T2DM
Insulin resistance leads to impaired fasting glucose and subsequent diagnosis of T2DM. Risk of developing diabetes increases 3- to 5-fold when metabolic syndrome components are present.4,18-20
Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) occurs when women have 2 of the following: 1) oligomenorrhea/anovulation; 2) hyperandrogenism, either clinical or biochemical: 3) polycystic ovaries on ultrasound.21
Hyperandrogenism independently increases risk of metabolic syndrome, and PCOS increases risk of metabolic syndrome by a factor of 4, necessitating screening for other components of metabolic syndrome in affected patients.
Elevated C-reactive protein is also noted in obese children, and obesity is increasingly recognized as a proinflammatory state. Despite its link with negative cardiovascular outcomes, inflammatory markers have not been conclusively linked to metabolic syndrome or insulin resistance.4 There are no current recommendations for assessing inflammatory markers as part of screening or treatment.
Care for children with metabolic syndrome involves the following treatments:
Weight reduction and/or weight maintenance
Even small reductions in weight are beneficial. Calculated BMI is standard practice in pediatric practices. Calorie restriction to decrease weight or BMI percentile is the goal without impacting growth. In general, more intensive programs are more successful. Although waist circumference is not currently recommended as part of an obesity assessment because of a lack of pediatric-specific data, waist-to-height ratio of greater than 0.6 predicts a future risk of metabolic syndrome and cardiovascular disease. The pediatrician must also be mindful that the prevalence of depression and mood disorders is increased among obese children. Consider referral to a nutritionist, intensive weight management program, and useful websites such as www.choosemyplate.gov.5
Increased physical activity
Few children get recommended amounts of exercise. Tell parents to think of physical activity like a medication: Children need regular doses to get a benefit. Children both with and without glucose impairment are advised to exercise for 60 minutes daily.22,23
There are a number of simple recommendations the pediatrician can make to patients to help improve diet and decrease calories (Table 3). These include:
1. Drink more water. Sugary drinks have few benefits for the pediatric patient and can significantly increase calories. Zero-calorie or low-calorie drinks and skim milk are excellent options when the child wants to consume something other than water.24
2. Eat more whole grains. Whole grain intake is inversely associated with BMI and waist circumference, and both the Physicians’ Health Study and the Nurses’ Health Study demonstrated consumption of more whole grain foods was associated with lower weight.25
3. Eat breakfast daily. Breakfast eaters are less likely to be overweight or obese.26 If children are already overweight or obese, beginning the day with a good breakfast can help their weight control plan.
4. Eat fewer processed foods. Processed foods are more energy dense and often contain extra sugars. A fresh banana is better than banana pudding or a dehydrated banana chips.
5. Avoid junk foods. If parents buy healthier options, their children simply will not have as many opportunities to consume calorie-rich, low-nutrition foods. Small incremental changes in purchasing decisions lead to changes in eating habits that may lead to big differences in the nutritional state of children and adolescents.
6. Add vitamin D. Research indicates that low vitamin D levels are associated with a number of the changes associated with metabolic syndrome. Other research has indicated that there also may be an independent association with cardiovascular and cancer risk. The National Academy of Medicine, the Endocrine Society, and the AAP recommend 600 international units of vitamin D daily.27-29
Limit screen time
Reducing sedentary behaviors provides more time for physical activity among busy children. The AAP recommends no more than 1 hour of screen time daily for children aged 2 to 5,30 and for children and adolescents aged 5 through 18 years, says families need to develop an appropriate balance for traditional and social media time that does not interfere with physical activity and sleep.31 Limiting screen time is an intervention as screen time is associated with eating.23
First-line therapy for children with lipid abnormalities is generally lifestyle changes and modifications to diet and exercise regimens. Pharmacotherapy with statins is usually not indicated in patients aged younger than 10 years and is started for those children aged older than 10 years and after a 6-month trial of lifestyle modification based on low-density lipoprotein (LDL) levels.16 Whereas adverse effects are rare and patients generally tolerate them,32 patients need to be mindful of them. Adverse effects of statins include myopathy, elevation of liver function tests, and new onset T2DM. Adolescent females on statins also need to use appropriate contraception during sexual activity because of potential teratogenic effects.
Nonemergent treatment of hypertension follows a stepwise approach initially with nonpharmacologic measures such as weight reduction, exercise, and dietary modification. Pharmacologic management is beyond the scope of this article, but the 2004 National High Blood Pressure Education Program Working Group (NHBPEP) and the 2016 European Society of Hypertension are guidelines that can help guide the pediatrician’s management.33,34
Much is known and even more is left to be discovered related to pediatric metabolic syndrome. Pediatricians need to familiarize themselves with the risks, screening, and treatment of all its components to ensure a healthy transition to adult life for their patients.
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11. Schmitz KH, Jacobs DR Jr, Hong CP, Steinberger J, Moran A, Sinaiko AR. Association of physical activity with insulin sensitivity in children. Int J Obes Relat Metab Disord. 2002;26(10):1310-1316.
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15. Morrison JA, Friedman LA, Harlan WR, et al. Development of the metabolic syndrome in black and white adolescent girls: a longitudinal assessment. Pediatrics. 2005;116(5):1178-1182.
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17. El Tawil D. Non-alcoholic fatty liver disease-a multisystem disease. Presented at: Grand Rounds, Department of Pediatrics, Lehigh Valley Health Network; March 15, 2016; Allentown, PA.
18. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care. 2008;31(9):1898-1904.
19. Dolan LM, Bean J, D'Alessio D, et al. Frequency of abnormal carbohydrate metabolism and diabetes in a population-based screening of adolescents. J Pediatr. 2005;146(6):751-758.
20. Weiss R, Dufour S, Taksali SE, et al. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet. 2003;362(9388):951-957.
21. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-47.
22. Physical Activity Guidelines for Americans Midcourse Report Subcommittee of the President’s Council on Fitness, Sports and Nutrition. Physical Activity Guidelines for Americans Midcourse Report: Strategies to Increase Physical Activity Among Youth. Washington, DC: US Department of Health and Human Services; 2012. Available at: https://health.gov/paguidelines/midcourse/pag-mid-course-report-final.pdf. Accessed January 24, 2017.
23. Copeland KC, Silverstein J, Moore KR, et al; American Academy of Pediatrics. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131(2):364-382. Erratum in: Pediatrics. 2013;131(5):1014.
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27. American Academy of Pediatrics. Dietary reference intakes for calcium and vitamin D. Pediatrics. 2012;130(5):e1424.
28. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011:1132.
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31. Council on Communications and Media. Policy statement: Media use in school-aged children and adolescents. Pediatrics. 2016;138(5):e20162592.
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33. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34(10):1887-1920.
34. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 suppl 4th report):555-576.