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Multiple definitions of the metabolic syndrome (MS) have been proposed for children, adolescents and adults. The aim of this study was to analyse the variations in the MS prevalence using different definitions and to examine which factors influence the frequency of the MS in childhood and adolescence.
The prevalence of the MS according to eight proposed definitions was studied in 1205 Caucasian overweight children and adolescents aged 4–16 years (mean body mass index (BMI) 27.3 kg/m2, mean age 11.8 years, 46% males, 39% prepubertal). Blood pressure, waist circumference and fasting triglycerides, HDL‐cholesterol, total cholesterol, insulin and glucose concentrations were determined. Overweight was defined according to the International Task Force of Obesity in Childhood. Degree of overweight was calculated as standard deviation score of BMI (SDS‐BMI). Insulin resistance was estimated based on the HOMA model.
The prevalence of the MS varied significantly (p<0.001), being between 6% and 39% depending on the different definitions. Only 2% of the children fulfilled the criteria of the MS in all definitions. Insulin resistance and degree of overweight were associated with the MS. In most definitions, pubertal stage did not influence the occurrence of the MS. In a principal component analysis, total cholesterol, triglycerides and waist circumference showed high final communality estimates.
Since the prevalence of the MS varied widely in overweight children and adolescents depending on the proposed definition used, an internationally accepted uniform definition of the MS is necessary to compare different populations and studies.
Obesity in childhood is an increasing phenomenon.1 Childhood obesity is associated with a wide range of serious complications and increases the risk of early illness and death in later life.1 As in adulthood, obesity in childhood contributes to an increased prevalence of cardiovascular risk factors, such as hypertension, hypertriglyceridaemia, low HDL‐cholesterol and impaired glucose metabolism.2,3 The clustering of these risk factors, which is associated with insulin resistance and occurs in overweight humans more often than might be expected by chance, is called the metabolic syndrome (MS), also known as syndrome X, the insulin resistance syndrome and the deadly quartet.4 Studies reported an increased risk of cardiovascular diseases (CVD) in adults when glucose intolerance, insulin resistance, central obesity, dyslipidaemia and hypertension group together.5,6
Multiple definitions of the MS have been proposed for adults by the WHO,7 the National Cholesterol Education Program's Adult Treatment Panel III,8 the European Group for the Study of Insulin Resistance9 and the International Diabetes Federation,10 which all agreed on the essential components (glucose intolerance, central obesity, hypertension and dyslipidaemia) but differed in the detail.4,11 These definitions were adapted for children and adolescents by different authors, who also used widely varying criteria (table 11).12,13,14,15 Conversely, a uniform internationally accepted definition of the MS in childhood and adolescence would allow comparison of the prevalence data in different studies and populations.
Paediatricians have “diagnosed” the MS increasingly in recent years to describe the cardiovascular risk.12,13,14,15 Furthermore, the MS seems to affect the management of the overweight child,16 since the MS is based on the concept that the clustering of risk factors is predictive for CVD above and beyond the risk associated with its individual components.4,11 Conversely, the concept of the MS has never been proven in childhood and adolescence.
There are very limited data on the variation in the MS prevalence in overweight children and adolescents using different proposed definitions. Furthermore, little is known concerning the factors influencing the frequency of the MS in childhood. Therefore, the aims of this study were to compare the prevalence of the MS according to the different existing definitions in a large sample of overweight children and adolescents, and to analyse the impact of degree of overweight, insulin resistance and pubertal stage on the frequency of the MS.
We collected the clinical data and information on cardiovascular risk factors of all Caucasian non‐syndromally overweight children aged 4–16 years who presented consecutively at the outpatient obesity clinic for children and adolescents at Vestische Hospital, Datteln, Germany, between 1 October 1999 and 31 December 2005. Children with endocrine, genetic or metabolic disorders including type 2 diabetes mellitus were excluded from the study. The control group consisted of 84 normal weight healthy children of the same age, gender and pubertal stage.
Overweight was defined according the International Task Force of Obesity in Childhood (IOTF).17 The degree of overweight was quantified using Cole's least mean square method, which normalised the body mass index (BMI) skewed distribution in childhood and expressed BMI as a standard deviation score (SDS‐BMI).18 Reference data for German children were used since the IOTF percentiles did not allow us to calculate SDS‐BMI.17,19
The pubic hair stage was determined according to Marshall and Tanner. The pubertal developmental stage was categorised into three groups based on pubic hair and genital stages (prepubertal: boys with pubic hair stage I and gonadal stage I, girls with pubic hair stage I and breast stage I; pubertal: boys with pubic hair stage II or gonadal stage II and girls with pubic hair stage II or breast stage II; late/postpubertal: girls with menarche and boys with change of voice).
Serum fasting triglyceride, HDL‐cholesterol, total cholesterol and glucose concentrations were measured using commercially available test kits (HDL‐C Plus, Roche Diagnostics, Mannheim, Germany; Vitros analyser, Ortho Clinical Diagnostics, Neckargemuend, Germany; MEIA, Abbott, Wiesbaden, Germany). Fasting insulin concentrations were measured by high‐specific microparticle enhanced immunometric assay (MEIA Abbott, Wiesbaden, Germany). Intra‐ and interassay variations were less than 5% in all methods. Homeostasis model assessment (HOMA) was used to detect the degree of insulin resistance.20 The resistance can be assessed from the fasting glucose and insulin concentrations by the formula: resistance (HOMA)=(insulin (mU/l)×glucose (mmol/l))/22.5.
An oral glucose tolerance test (oGTT) was performed in obese children and adolescents with at least two risk factors (first degree relatives with type 2 diabetes mellitus, dyslipidaemia, hypertension, acanthosis nigricans) according to the recommendations of the American Diabetes Association.21
Blood pressure was measured according to the guidelines of the National High Blood Pressure Education Program (NHBPEP).22 Systolic and diastolic blood pressure were measured twice at the right arm after a 10 min rest in the supine position using a calibrated sphygmomanometer and averaged. The cuff size, which was based on the length and circumference of the upper arm, was chosen to be as large as possible without having the elbow skin crease obstruct the stethoscope.22
The MS was defined according to the criteria of Weiss,12 Viner,14 De Ferranti,15 Cook,13 WHO,7 EGIR,9 ATPIII8 and IDF.10 Following the German guidelines for overweight children,23 we used BMI percentiles of German children19 to define the 95th and 97th BMI percentiles in the definition of Viner and Weiss, the age‐ and height‐related percentiles of NHBPEP for blood pressure,22 the cut‐off points of lipids for German children23 in the definition of Weiss, and the percentiles of Dutch children for waist circumferences.24 Impaired fasting glucose was defined as fasting serum glucose 100 mg/dl according to the new WHO definition.25 Impaired glucose tolerance was defined as 2 h serum glucose >140 mg/dl in the oGTT. Since oGTT was not performed in every child but impaired glucose tolerance was part of the definition in some proposed definitions for the MS, we alternatively used the following definition for disturbed glucose metabolism based on the proposal of Viner.14 Disturbed glucose metabolism was defined as impaired fasting glucose, hyperinsulinaemia (15 mU/l for prepubertal children, 30 mU/l for pubertal children, 20 mU/l for postpubertal children) or impaired glucose tolerance.
Data were presented as median and interquartile range. Significance was tested by χ2 test. A random error of α=0.05 was considered as level of significance. Correlation analyses and principal component analysis (PCA)26 were used to show patterns of the variables considered to define the MS. First, correlation matrices (Pearson's coefficients) of puberty specific criteria were constructed. These matrices were further studied by PCA, an exploratory factor analysis method that allows identification of unobservable latent factors that underlie or structure a set of variables. Only factors with eigenvalues >1 were considered. The cumulative variance explained by these factors was estimated and factor loadings with correlations >0.75 were classified as high. Additionally, final communality estimates were estimated.
In order to assess the impact of degree of overweight (SDS‐BMI) and insulin resistance (HOMA) on the occurrence of the MS according to different definitions, we calculated multivariate logistic regression models adjusted for age and sex. Non‐significant (p>0.05) interaction terms between SDS‐BMI and HOMA were removed in respective models.
All analyses were performed using Winstat and SAS 9.1 (SAS Institute, Cary, NC, USA). The local ethics committee of the University of Witten/Herdecke approved this study. Informed consent was obtained from all subjects and their parents.
A total of 1205 overweight, including 965 (80%) obese children, and 84 normal weight children were included in the study (table 11).). The overweight and normal weight children did not differ in age, gender or pubertal stage.
Among the normal weight children, six (7%) demonstrated fasting insulin levels above the threshold suggested by Viner.14 None of the normal weight children had glucose levels >100 mg/dl. Two (2%) children had blood pressure values >90th percentile, but none were >97th percentile. One child (1%) demonstrated HDL‐cholesterol below 40 mg/dl, but none had cholesterol levels >95th percentile. Nine children (11%) had triglycerides >110 mg/dl and four (5%) >150 mg/dl. None of the 84 normal weight children fulfilled any of the proposed definitions of the MS. Regardless of the type of definition, the MS was observed significantly (p<0.001) more frequently in overweight children as compared with normal weight children.
The different prevalences of the MS and the frequencies of the used criteria in the 1205 overweight children according to the different definitions for children and adolescents are shown in table 22.. In table 33,, the frequencies of the MS based on the definition for adults are shown. The frequency of the MS varied significantly (p<0.001) between the different definitions. A total of 114 (9%) children fulfilled the criteria of the MS in all proposed definitions for children and 22 (2%) fulfilled the criteria of the MS in all proposed definition including the definition for adults. A total of 1170 (97%) children demonstrated at least one criterion and 990 (82%) had at least two of the criteria used to define the MS.
We performed an oGTT in 194 obese children and detected impaired glucose tolerance in 27 (14%) of these children. If only impaired glucose tolerance was used as the criterion and not the alternative definition of disturbed glucose metabolism, 13% of the children fulfilled the definition of Weiss and 1% of the children fulfilled the definition of the WHO for the MS.
Degree of overweight and insulin resistance were significantly associated with occurrence of the MS regardless of the definition and after adjustment for age and sex (table 44).
The frequencies of the MS based on definitions for children and adolescents separated into gender and pubertal stage are shown in fig 11.. In each proposed definition, the differences in the frequency of the MS between the prepubertal, pubertal and late/postpubertal girls were not significant. In the definitions of Cook and De Ferranti but not in the definitions of Viner and Weiss, the MS was detected significantly more frequently in pubertal than in prepubertal boys (fig 11).). Analysing prepubertal, pubertal and late/postpubertal children separately, the frequency of the MS varied significantly (p<0.001) between the different definitions.
The correlation matrix between the criteria systolic blood pressure, waist circumference, BMI and levels of fasting glucose, total cholesterol, HDL‐cholesterol, triglycerides and insulin showed high correlation coefficients (r>0.4) only for BMI and insulin levels with r=0.49.
PCA by pubertal stage yielded four, three and three factors explaining 70%, 56% and 58% of variance for pre‐pubertal, pubertal and post‐pubertal children, respectively. The final communality estimates showed three components as main explanatory variables for the variation between overweight children. Among pre‐pubertal children high final communality estimates (>0.75) were observed for cholesterol level and waist circumference, while among pubertal and post‐pubertal children a high communality estimate was only observed for triglycerides.
Our study demonstrated that the prevalence of the MS was associated with degree of overweight and the insulin resistance index HOMA, and had a wide range (6–39%) using the different proposed definitions. Only 9% of the children fulfilled all the definitions of the MS for children and adolescents, pointing to a low degree of overlap between the different proposed definitions for the MS. These findings are in concordance with one small study in childhood.16 Therefore, a comparison between studies using different definitions of the MS is not meaningful in childhood. To compare different populations and studies, an internationally accepted practical uniform definition of the MS has to be established for children and adolescents.
Not only did the prevalence of the MS vary widely between the different definitions, but also the impact of puberty on the prevalence of the MS varied widely as well. De Ferranti and Cook reported a 3–5‐fold higher prevalence of the MS in pubertal adolescents compared with prepubertal children.13,15 Using their definition, we also found a higher prevalence of the MS in pubertal adolescents but only in boys and not in girls. Conversely, the other definitions of the MS proposed for childhood and adolescence demonstrated no influence of pubertal stage on the MS. The proposed definitions of the MS for children and adolescents differed widely in their criteria and the thresholds of their components. These facts likely explained the difference in frequencies of the MS and the different effect of pubertal stage on the MS.
PCA demonstrated that total cholesterol, triglycerides and waist circumference explained most of the variance between the analysed children and adolescents. Therefore, inclusion of these criteria in the definition of the MS helps to differentiate the children.
One major difference between the proposed criteria for the MS was the definition of insulin resistance. Insulin levels without respect to glucose concentrations are not a good predictor of insulin resistance.27 Furthermore, values of fasting insulin levels are limited by great intra‐ and interindividual variability.27 Accurate assessment of insulin resistance as suggested by the WHO requires a complicated test (eg, the hyperinsulinaemic euglycyaemic clamp technique).7 Its application in children is invasive and impractical, so clinicians prefer simple tools such as fasting glucose. Conversely, only 1% of the overweight children demonstrated impaired fasting glucose even if we used the new WHO definition.25 However, the insulin resistance index HOMA was associated with the MS in all definitions for children and adolescents. Moreover, previous longitudinal studies reported that insulin resistance was more closely related to components of the MS as compared with degree of overweight.4,28
Furthermore, central obesity is one major element in the definition of the MS in adults7,8,9,10 and not the degree of overweight as used in some proposals for children.12,14 However, the cut‐offs of the waist circumference percentiles for European children do not seem to be very specific since the majority of our overweight children had waist circumferences above the proposed thresholds.
Most importantly, the entire concept of the MS is controversial.4,11 A major concern in the definition of the MS refers to the use of cut‐off points for the various risk factors, thus implying that the values above the specified thresholds are associated with an excess risk, yet the rationale for the different cut‐off points has never been delineated.11 Moreover, the dichotomous use of continuous data such as lipids, waist circumference and blood pressure values, seems inaccurate since they are not all‐or‐nothing values. In fact, the relationship is not even linear which makes it all the more difficult and opens up the issue of how risk in this conglomeration of the “syndrome” might be weighted more appropriately.
Finally, the MS is based on the concept that the clustering of risk factors is predictive for CVD above and beyond the risk associated with its individual components. In overweight children, dyslipidaemia, hypertension and disturbed glucose metabolism were related to intima‐media thickness (IMT) of the common carotid artery,29,30 which is predictive and related to the severity of CVD.31,32 Therefore, the integration of these factors in the definition of the MS seems meaningful. However, it has not yet been determined whether the clustering of these risk factors is associated with an increased of CVD in childhood above the risk of the individual components. Without evidence of an increased risk in the MS beyond the sum of its parts, it may be better to pay individual attention to the well documented individual risk factors.
The frequencies of the cardinal factors of the MS (disturbed glucose metabolism, hypertension and dyslipidaemia) were similar to those found in previous studies in Caucasian children.2,3,33,34 Most overweight and obese children had one or two of these cardiovascular risk factors. It was found that 6–14% children and adolescents fulfilled the criteria for the different definitions of the MS used in adulthood, underlining the fact that the components of the MS are already present in some children.
The overall prevalence of the MS was lower in our overweight children and adolescents as compared with the studies of Weiss (39% vs 12%) and Viner (33% vs 18%).12,14 However, in our sample the overall prevalence of the MS was similar to that found in the study of Cook (29% vs 21%) and more frequent than that reported by De Ferranti (10% vs 39%).13,15 Different age ranges, races, degrees of overweight, referral practices, geographical variation in obesity and epigenetic factors might explain these differences. While the subjects in our study and those of Viner and Weiss were recruited in specialised obesity/endocrine clinics, which probably meant the frequency of the MS was overestimated, the cohorts of Cook and De Ferranti originated from general populations and had a tendency to a lower prevalence of the MS. We analysed only Caucasian children, while the studies with the highest prevalence of the MS also included subjects of Hispanic, African and Asian origin, who are suggested to have a higher frequency of the MS.12,14
This study has a few potential important limitations. Data from clinical samples may not be representative of the general population, and selection and referral bias may have influenced our estimate of the prevalence of the MS. Furthermore, oGTT was not performed in every child. Finally, consideration of pubertal stage instead of dividing children into prepubertal, pubertal and late/postpubertal groups would be the ideal way to analyse the effect of puberty on the prevalence of the MS. Conversely, performing such a study needs a very large sample size since children have not only to be divided according to different pubertal stage but also according to gender. Additionally, division into groups according to pubic hair and breast stages partially depends on the investigator.
In summary, definitive criteria for the MS for childhood and adolescence have not yet been determined. The MS was related to insulin resistance and weight status, and was independent of the pubertal stage in most definitions. The prevalence of the MS was quite different depending on the proposed definitions for children and adolescents. An internationally accepted uniform definition of the MS is needed to allow comparisons between different studies and populations. Furthermore, the concept of the MS that the clustering of risk factors is predictive for CVD above and beyond the risk associated with its individual components has to be proven in childhood and adolescence.
We thank Rania Clark for careful proofreading.
BMI - body mass index
CVD - cardiovascular disease
HOMA - homeostasis model assessment
IOTF - International Task Force of Obesity in Childhood
MS - metabolic syndrome
NHBPEP - National High Blood Pressure Education Program
oGTT - oral glucose tolerance test
PCA - principal component analysis
SDS - standard deviation score
Competing interests: None.