The notion that cardiovascular risk factors cluster in certain individuals has been known for several decades. However, it was not until the early 1980s that the relationship between obesity, dyslipidemia (particularly hypertriglyceridemia), and hypertension was recognized.1980 In the late 1980s–early 1990s, the central roles of insulin resistance (specifically resistance to insulin-stimulated glucose uptake) and abdominal obesity in the syndrome became apparent.1993 Our current paradigm of metabolic syndrome was established in 1988, when Reaven described the role of insulin resistance in human disease and the interrelation between insulin resistance, hypertension, T2DM, and CVD.1988 Although Reaven used the term Syndrome X to describe the interrelationships of these conditions, many other terms, including the deadly quartet, the cardiometabolic syndrome, and the insulin resistance syndrome have been and continue to be used in the medical literature. Due to the collection of different components, and the reliance of cutoff thresholds of different non-Gaussian distributions, several organizations have established different diagnostic criteria for metabolic syndrome. Nonetheless, the same clustering of CVD risk factors that had been first observed in adults in the early 1920s1923 became evident in obese children by the mid-1990s.1994
Although many attempts have been made to define metabolic syndrome in the pediatric population, to date no consensus definition exists. Indeed, a writing committee of the American Heart Association in 2009 refused to define it (RHL was a committee member).2009 In 2007, the International Diabetes Federation (IDF) attempted a definition of pediatric metabolic syndrome using age-specific diagnostic criteria2007 and proposed that metabolic syndrome be considered in (1) children aged 6–10 years who are obese (defined as waist circumference (WC) ≥90th percentile) and have other relevant risk factors (such as family history of cardiometabolic disease) and in (2) children aged 10–16 years who are obese (defined as WC ≥90th percentile) and meet the adult metabolic syndrome criteria for triglycerides (TGs), HDL-cholesterol (HDL-C), blood pressure (BP), and glucose concentrations. Using the IDF definition in the pediatric population and data from the National Health and Nutrition Examination Survey (NHANES) database, the reported prevalence of metabolic syndrome in U.S. adolescents for the period 1999–2004 was approximately 4.5%; it increased with age, was higher among males (6.7%) than females (2.1%), and was highest among Mexican-American adolescents (7.1%).2008
Several methodological and physiological limitations complicate the establishment of a definition for pediatric metabolic syndrome. For example, children develop transient physiologic insulin resistance during puberty,2006, 2008 and normal lipid levels vary by age, sex, and race.2009 Reliance on a fasting blood sample makes diagnosis and detection simple and cheap yet prevents the utilization of a postglucose load sample to detect impaired glucose tolerance (which is a better marker of peripheral insulin resistance in this age group than is a fasting sample). Other barriers include the lack of standardized central obesity measures in children, the lack of normal ranges for insulin assays and concentrations across childhood, and the fact that disturbances in many of the metabolic perturbations associated with metabolic syndrome in children are usually moderate. Children and adolescents with metabolic syndrome may not have the same degree of laboratory abnormalities as those seen in adults.2009 While laboratory values for some of these phenotypes reflect a risk factor continuum, conventional definitions of metabolic syndrome employ threshold values, creating a false binary system that may obscure important information. One promising approach to overcome this barrier is to use the measurements of metabolic syndrome elements as continuous variables and to sum the z-scores of each component in order to quantify the risk.2008 It has been shown that children of different ethnic backgrounds differ in patterns of lipid partitioning, the major contributor to the development of insulin resistance, and in their metabolic profiles of specific risk markers such as lipids.2007 Thus, youths of African American origin seem to be “protected” from the syndrome when standard definitions are used, in contrast to the overall worse cardiovascular outcome seen in adults of this ethnic background.
As such, the criteria for metabolic syndrome used in most pediatric studies to date have been variably adapted from adult definitions and standards with the use of available sex- and age-dependent normative values. As in the adult definitions of metabolic syndrome, almost all of them include the following five elements: (1) an elevated TG level, (2) a reduced HDL-C level, (3) a raised BP, (4) an elevated fasting plasma glucose concentration, and (5) an increased WC. Furthermore, most definitions allow for a partial combination of the above factors rather than a requirement that all five be present in order to define metabolic syndrome.
The stability of metabolic syndrome definitions in childhood has been questioned, specifically when assessing the less stringent criteria in obese and normal weight children. Indeed, upon testing normal weight children, the signal to noise ratio of these definitions is low and minor changes induced by normal growth may result in a change in the metabolic syndrome status of an individual.2007 In contrast, when such definitions are tested in the population at risk (i.e., obese children), weight reduction may still affect their stability yet weight maintenance or gain leads to a stable and reproducible definition.2009
Currently, 17% of all children and adolescents in the United States are obese,2012 and childhood obesity is associated with insulin resistance,2012, 1996, 1996 abnormal glucose metabolism,2002 elevated BP,2004 dyslipidemia,2003 inflammation,2008 and compromised vascular function2008—all components of metabolic syndrome.2009 Obesity and its metabolic complications also track from childhood to adulthood.2009 So, not only is childhood obesity a strong predictor of subsequent obesity, insulin resistance, and dyslipidemia in adulthood, but weight gain in excess of normal growth during childhood is also a determinant of adult cardiovascular risk.2008
However, the body mass index (BMI), a calculation (kg/m2) based on weight and height that is used to define “overweight” and “obesity,” does not account for all variances in insulin sensitivity and cardiometabolic risk.2002 Furthermore, there is considerable debate as to the metabolic differences between visceral and subcutaneous fat and the role of these fat depots in cardiometabolic disease. As such, obesity does not automatically indicate the presence of metabolic syndrome. Lipid partitioning (i.e., the distribution of fat among its potential depots) is much more related to the metabolic phenotype of obese children and adolescents than the degree of obesity.2004 Thus, lipid partitioning is a major determinant of peripheral insulin sensitivity and is strongly associated with other metabolic biomarkers such as systemic inflammation and free fatty acid fluxes. These elements determine the metabolic milieu and phenotype of the individual much more than the degree of obesity per se. Again, obesity is a marker for metabolic dysfunction, not the cause.
An early marker of cardiovascular disease in childhood is intimal–medial thickness (IMT), a surrogate of early atherogenesis. When the various published definitions of metabolic syndrome were tested in overweight and obese adolescents along with IMT measurements, only the most conservative definitions were significantly correlated with the degree of IMT, and the presence of impaired glucose tolerance had a strong positive predictive value for the top quartile of IMT.2008 These observations suggest that the definition of metabolic syndrome should probably be more conservative (e.g., the extreme 5% vs. 10%) in children than in adults, and that the presence of impaired glucose tolerance—-the early sign of altered glucose metabolism—-should be interpreted as a generalized proatherogenic metabolic state. While some investigators suggest that actual carotid plaques (rather than overall arterial wall thickening) are the true expression of atherosclerosis in this age group, carotid plaques have not been sufficiently studied as outcome variables in children. While standard definitions of metabolic syndrome, along with weight changes, have also been shown to predict the development of prediabetes and type 2 diabetes at the age of 24 years,2011 the presence of impaired glucose tolerance in adolescents (a component of metabolic syndrome in some definitions) is the best predictor of progression to overt diabetes in adolescence.2005