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.
|
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