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12. Risk Factor Clustering and the Metabolic Syndrome

INTRODUCTION

This section of the Guidelines provides recommendations to pediatric care providers on an approach to the metabolic syndrome in children and adolescents.  The evidence review and the development process for the Guidelines are outlined in Section I.  Introduction and are described in detail in Appendix A.  Methodology.  This section begins with background information on the prevalence of the risk factor cluster known as the metabolic syndrome.  This is followed by the Expert Panel's summary of the evidence review on the metabolic syndrome cluster and its recommendations for management in pediatric practice. The complete evidence tables will be available at http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm.  Because of the paucity of the evidence, recommendations are a consensus of the Expert Panel.  References are listed sequentially at the end of the section, with references from the evidence review identified by unique PubMed identifier (PMID) number in bold text.  Additional references do not include the PMID number.

BACKGROUND

As in adults, traditional cardiovascular (CV) risk factors—such as obesity, hypertension, and dyslipidemia—demonstrate clustering in youth.[1]  Behavioral risk factors—such as smoking, inadequate diet, and sedentary behavior—also demonstrate clustering, as do an advantageous diet and optimal exercise habits.[2],[3],[4],[5],[6]  Becoming obese increases the prevalence of the risk factor cluster called the metabolic syndrome in adults.[7],[8]  In the United States, metabolic syndrome is said to affect 34–39 percent of adults,[9] including 7 percent of men and 6 percent of women in the 20- to 30-year-old age group.[10]  There are varying definitions of the metabolic syndrome, and the prevalence changes depending on the specific definition used.[11]  The National Heart, Lung, and Blood Institute and the American Heart Association recently examined the various approaches and published a recommended definition of metabolic syndrome in adults, which includes elevated waist circumference, triglyceride (TG), blood pressure (BP), fasting glucose, and reduced high-density lipoprotein cholesterol (HDL–C).[12]

OVERVIEW OF THE EVIDENCE FOR RISK FACTOR CLUSTERING AND THE METABOLIC SYNDROME

There is a lack of consensus on how to define metabolic syndrome in youth, which has led to widely varying estimates of its frequency.[13],[14],[15],[16]  A recent analysis of National Health and Nutrition Examination Survey data from 1999 to 2002 yielded prevalence estimates of 2.0–9.4 percent for all teens and 12.4–44.2 percent for obese teens.[17]  Regardless of the definition used, the prevalence of the metabolic syndrome risk factor cluster is higher in older children (12 to 14 years old) compared with younger children (8 to 11 years old).  A recent consensus statement suggests limiting the definition to youth older than age 10 years.[18]  Age-related changes in body size, lipid levels, and BP make it difficult to set rigid pediatric cut points to define metabolic syndrome.[19]  Complicating matters further are the observed racial and gender differences in postpubertal lipid and insulin levels, laboratory variation in fasting insulin levels, and the biologic variability in TG levels and BP.[20],[21]  These factors at least partially explain why one longitudinal school-based study found that nearly half of adolescents designated as having metabolic syndrome failed to retain the diagnosis at 3-year followup, regardless of the definition used.[22]

The specific etiology for metabolic syndrome is unknown; however, it is most likely caused by the expression of various genotypes modified by environmental interactions and mediated through abdominal obesity and insulin resistance.[23]  Data pointing to genetic influences include the observation that the metabolic syndrome cluster of risk factors is more common in children with a parental history of type 2 diabetes mellitus (T2DM)[24] or metabolic syndrome[25] and that African Americans have a significantly higher prevalence of the metabolic syndrome components, beginning at puberty.[26],[27]  The importance of lifestyle is demonstrated in a recent study showing a significant dose-response relationship between sedentary behavior, measured in hours of screen time per day, and increased odds for the presence of the metabolic syndrome risk factor cluster.[28]

The pathophysiology by which genetic and environmental influences result in the metabolic syndrome is poorly understood.  The association of elevated BP with metabolic syndrome may be mediated by a different route than that for dyslipidemia.[29],[30]  Factor analyses suggest that a metabolic entity (dyslipidemia, obesity) and a hemodynamic factor (elevated BP) may contribute separately to characterization of a given individual as having the full metabolic syndrome phenotype through a shared correlation with hyperinsulinemia/insulin resistance.[31],[32]  Despite disagreement on a definition, there is evidence that the high population prevalence of obesity in children and adolescents has led to an increased prevalence of clustering of metabolic syndrome risk factors over the past decade.[33]  More research is needed in understanding the biologic processes that result in the cluster of risk factors identified as metabolic syndrome in adults.

Data are emerging on the utility of diagnosing the metabolic syndrome in youth as a predictor of future CV disease (CVD).  Longitudinal studies of cohorts in which the metabolic syndrome cluster was present in childhood identify an increased incidence of both T2DM and clinical CV events over a followup of 25 years.[34]  Many observational studies have focused on the metabolic syndrome and have demonstrated a strong association between obesity in early childhood and subsequent development of the metabolic syndrome constellation in adulthood.  Obesity associated with elevated insulin levels from early childhood and the combination of obesity and elevated insulin strongly predicted future metabolic syndrome.[35]  When obesity is associated with hypertension in childhood, the risk of future metabolic syndrome is also significantly increased.[36]  Waist circumference as a measure of abdominal obesity and BMI in children and adolescents both predict future development of the metabolic syndrome.[37]  Emerging data suggest that use of the metabolic syndrome as a diagnosis in children and adolescents may increase the ability to predict subclinical target organ damage in adulthood.[38],[39]  Cross-sectional studies of the relationship between metabolic syndrome risk factors and vascular dysfunction in youth are less clear.[40],[41],[42]  Additional longitudinal studies are needed to determine whether metabolic syndrome in childhood predicts CV outcomes beyond that associated with individual risk components.

Treatment of CV risk factor clustering in youth has not been thoroughly evaluated.  Maintenance of low levels of CV risk factors starting in childhood is associated with a lower prevalence of end organ damage as assessed by carotid intima-media thickness in adults.[43]  Several nonrandomized, single-arm diet and exercise intervention trials show improvement in metabolic syndrome-associated CV risk factors, although all involve small numbers of subjects and limited followup.[44],[45],[46]  A small number of randomized controlled trials (RCTs) address treatment of the metabolic syndrome cluster with medication in obese adolescents with insulin resistance.[47],[48],[49]  All of these RCTs used metformin as an insulin-sensitizing agent, and in each, metformin was associated with greater weight loss, an improvement in endocrine-metabolic measures and some decrease in abdominal fat mass compared with the control group.  An additional study was conducted in an entirely Asian population, which limited generalizability, and another was a retrospective chart review.  Additional large RCTs with long-term followup in children are needed before insulin-sensitizing agents can be routinely recommended for either treatment of obesity or prevention of diabetes in youth with metabolic syndrome.

RECOMMENDATIONS FOR MANAGEMENT OF RISK FACTOR CLUSTERING AND THE METABOLIC SYNDROME

The metabolic syndrome concept is important because it identifies a common multiple CV risk phenotype in pediatrics.  However, the absence of a defined etiology, lack of consensus on definition, and paucity of high-level evidence addressing management in childhood led the Expert Panel to conclude that the metabolic syndrome should not be considered as a separate risk factor in childhood and adolescence.  Prevention of the development of obesity is the most important strategy to lower the prevalence of metabolic syndrome in adults, and this appears strongly applicable in childhood.  Given the strong relationship of obesity and physical inactivity to the metabolic syndrome and insulin resistance, the Expert Panel makes the following recommendations.  Due to the paucity of evidence available, the recommendations are a consensus of the Expert Panel (Grade D).

  • Presence of any combination of multiple risk factors should prompt intensification of therapy, with an emphasis on lifestyle modification, which may improve individual metabolic syndrome risk factor levels.
  • Presence of obesity should prompt specific evaluation of all other CV risk factors, including family history of premature CVD (Section IV), high BP (Section VIII), dyslipidemia (Section IX), diabetes (Section XI), and tobacco exposure (Section VII).
  • Coexistence of obesity with any other major CV risk factor should be recognized by clinicians as a setting in which:
    • Intensive weight reduction should be initiated per the recommendations in Section X.  Overweight and Obesity, along with specific risk factor management, including pharmacologic therapy, as needed, per the risk factor-specific sections in these Guidelines (Section VIII.  High Blood Pressure;Section IX.  Lipids and Lipoproteins;Section XI.  Diabetes Mellitus and Other Conditions Predisposing to the Development of Accelerated Atherosclerosis; Section VII.  Tobacco Exposure).
    • Prompt evaluation for diabetes mellitus, liver function abnormalities, left ventricular hypertrophy, and sleep apnea should be undertaken.

These recommendations are supported by knowledge that CV morbidity has a continuous relationship across the risk distribution spectrum and that youths with multiple borderline risk factors may, in fact, have risk equivalent to an individual with extreme abnormality of a single major risk factor.  A patient's presentation like this should lead to intense nutrition and exercise management with close followup, and if lifestyle intervention is unsuccessful, consideration should be given to referral to an endocrine specialist.  Table 12–1 provides definitions for levels of metabolic syndrome-associated variables which, when combined, represent significantly increased CV risk.

Table 12–1. Metabolic Syndrome Component Levels for Evaluation of Children with Multiple Risk Factors

Risk Factor

Cutpoint

Reference

Obesity - Body mass index

≥85 to <95th%ile

Centers for Disease Control and Prevention growth charts[50]

Obesity - Waist circumference

≥90 to < 95th%ile

National Health and Nutrition Examination Survey[51]

Blood Pressure

≥90 to <95th%ile

The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents[52]

Dyslipidemia - High-density lipoprotein cholesterol (HDL-C)

≥ 40 to ≤45 mg/dL

See Section IX. Lipids and Lipoproteins in these Guidelines for normative values

Dyslipidemia - Triglycerides, Age 0-9 years

≥ 75 to <100 mg/dL

See Section IX. Lipids and Lipoproteins in these Guidelines for normative values

Dyslipidemia - Triglycerides, Age ≥10 years

≥ 90 to <130 mg/dL

See Section IX. Lipids and Lipoproteins in these Guidelines for normative values

Dyslipidemia - Non-HDL-C

≥ 120 to < 144 mg/dL

See Section IX. Lipids and Lipoproteins in these Guidelines for normative values

Glycemia - Fasting glucose

≥ 100 to <126 mg/dL

American Diabetes Association screening recommendations[53]

Glycemia - Fasting insulin

Elevated fasting insulin level, above normal for gender, race and pubertal status is considered evidence of insulin resistance

Elevated FI level-above normal for gender, race, and pubertal status-is considered evidence of insulin resistance.



REFERENCES

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