Evaluate the effects of metabolic syndrome in adolescents and children

The interest of metabolic syndrome (MS) has been increased since the last century. This concept was first exposed in the 1920s and the publication indicated that MS was associated with hypertension, gout, and diabetes. Following, in the 1940s, some ground-breaking research by Vague were conducted on the correlation between central body fat distribution and several risk factors of cardiovascular disease (CVD). Later, in the 1990s, the lecture of Reaven's Banting started the modern era of MS. He drew new attention to the correlation between insulin resistance and many metabolic abnormalities linked to MS also named as “syndrome X.”¹ Recently, the definition of MS is a cluster of risk factors for atherosclerotic CVD and type 2 diabetes mellitus (T2DM) which consist of obesity, glucose intolerance, abnormal lipid profile, and hypertension.² In the Ozanne and Hales’ study, the possible mechanisms of developing T2DM and MS in regard to fetal development were reviewed.³ It indicated that MS development may be associated with early growth restriction in utero which might lead to onset of the pathological processes of T2DM in early childhood. Childhood MS might raise the risk of T2DM, CVD, and other related diseases, for instance, nonalcoholic fatty liver disease and polycystic ovary syndrome in life.⁴ Additionally, MS in childhood may likely track into adulthood, but the evidence is limited, owing to limited studies that track participants during childhood to adulthood period and always use secondary data that may not be strong enough to reveal such tracking. Until at present, little has been known how well MS in children can predict adult disease.⁵

Recently, the common recognitions about the components of pediatric MS and its important predictability in the risk of T2DM and CVD development have been made during the accumulation of research evidence. This article aims to discuss those two diseases as the consequence of MS through MS definition and the major underlying pathophysiology.

The definition of MS in children and adolescents has not been unified, and it is usually based on the adult standards (such as the International Diabetes Federation (IDF) guidelines) and varies with different ethnic populations by different criteria and cutoff points.⁶ Five similar studies were chosen and examined their MS definition, among which some criteria for defining MS were used in later studies. Those studies were conducted among the American adolescents to predict the prevalence of MS. Four of them used the modified adults version to define MS (the National Cholesterol Education Programme—Adult Treatment Panel III) (NCEP-ATP III) (see Table 1 for specific criteria of NCEP-ATP III).^{7, 8, 9, 10, 11} Another study used MS definition derived from the 2007 child IDF.^11,12 Findings showed that several cutoff points of variables are different and ambiguous, even using the same resource to classify MS.

Specifically, for defining variables with varied levels, fasting triglyceride (TG) was defined as ≥150 mg/dL by Park et al.⁸; however, defined as ≥100 mg/dL by de Ferranti et al.⁷ and Cook et al.9; and defined as ≥110 mg/dL by Duncan et al.¹⁰ For defining variables whether considering gender's difference, waist circumference (WC) was defined as >75th percentile by de Ferranti et al.⁷ and defined as ≥90th percentile by Cook et al.,⁹ Duncan et al.,¹⁰ and Ford et al.,11 but defined separately in genders: >102 cm for male and >88 cm for female in Park et al.⁸

Furthermore, some studies defined MS by using specific ethnic or race criteria. However, which level should be selected as criteria for MS in children does not have a universal agreement.⁵ Different thresholds for some of the essential variables are used by studies, which may lead to the difficulty of diagnosing MS, estimating MS prevalence and the clinical consequences. According to those studies, a standardized definition of children may be needed even though they had a common disadvantage that was measured body mass index (BMI) instead of WC. Tables 2 and 3 show the specific range of characteristics and measures used commonly for diagnosing MS in children.

However, a single MS definition to adolescents and children might not be proper to show problems in this age, owing to the unique physical development during childhood.¹⁰ Endocrine levels may be influenced by pubertal development and genders. A typical previous study indicated that the adverse association existed among puberty, body fat, age, insulin resistance, and adiponectin. Compared with prepubertal children, pubertal children had apparently lower adiponectin level (P < 0.001). Especially, adiponectin was shown to be at lower level in pubertal girls, and no difference of adiponectin had been found between prepubertal girls and boys. The negative association had been observed among body fat (r = 0.44; P = 0.002), age (r = 0.41; P = 0.003), insulin resistance (r = 0.33; P = 0.016), and adiponectin.¹³ Hence, for adolescents and children, to define abnormalities by using single cutoff point might not be suitable. A recent study combined clinical indicators and diseases as criteria. Specifically, five criteria were: TG serum concentration ≥150 mg/dL/treating TG; in male high-density lipoprotein cholesterol (HDL-C) <40 mg/dL/in female <50 mg/dL/treating HDL-C; BMI > age and 95th percentile; glucose concentration ≥100 mg/dL/treating hyperglycemia; systolic blood pressure (SBP) ≥130 mmHg or/and diastolic blood pressure (DBP) ≥85 mmHg/treating hypertension.¹²

Additionally, there are also some other difficulties in determining a standardized definition of MS in children. For example, ethnic differences exist in developing MS.¹⁴ MS criteria may need consider ethnic variations and immigrant population.

MS is defined as a cluster of high TGs, obesity, low HDL cholesterol, high blood pressure, and insulin resistance which associate with the early progress of coronary atherosclerosis and T2DM.^2,3 In the pediatric literature, lot of effort has been made to explore the relationship among CVD, T2DM, and MS. MS in children may be an indicator of CVD and T2DM in their adult period, but limited data directly explore the impact of MS on disease outcomes in adolescents and children. The consistent finding was that there is a strong positive relationship between children with MS and the development of CVD in their later life. Youth with MS were at two- to three- fold risk of having subclinical atherosclerosis (carotid intima–media thickness) and T2DM compared with healthy youth.¹⁵

However, the correlation between the severity of MS and the level of adiponectin and fasting insulin has been not clear enough. One recent study pointed that childhood MS Z-scores had a positive association with insulin levels in adult (P < 0.001) and a negative association with levels of adiponectin (P = 0.01). For individual analyses, greater levels of insulin and MS Z-score during adulthood were significantly related to greater odds of occurrence CVD and diabetes over the following 11.2 years (P < 0.001).

Therefore, MS severity had a long-term link to the level of adiponectin and insulin, and it independently and consistently correlated with T2DM and CVD, which may be owing to the potential, environmental, and genetic influence over time. So, in the future, MS severity may be used as a risk predictor of these diseases.¹⁶

The correlation among MS, T2DM, and CVD varied with ethnicity and race. The black population with MS has a greater risk of CVD than the white population with MS. The reason may be that MS induces some nontraditional risk factors of CVD including C-reactive protein, high level of low-density homocysteine, lipo-protein oxidation, adiponectin, lipoprotein a, and plasminogen activator inhibitor-1, and so on. Therefore, to predict and examine CVD and T2DM caused by MS should consider ethnicity/race and also nontraditional and traditional risk factors. Researchers suggested that nontraditional risk factors need to be added in the definition of MS.¹⁷

There are several points that may need to be emphasized for the future study. First, the definition of MS may need to be standardized. Number of studies have been attempted to characterize MS in children. However, to date, there has been no universally accepted MS definition in children, which may lead to the situation where it is hard to diagnose MS and to estimate its clinical consequences, and subsequently hard to take early treatment. To define the standardized concept of MS may need complete understanding of the underlying pathophysiology and consideration of variations concerning related factors including age, ethnicity, sex, family history, and lifestyle behaviors. Second, the true picture of diabetic and cardiometabolic risk may be due to over-weight/obesity and insulin resistance, but that may not mean that other traditional components of MS, pathological and metabolic factors, and genetic factors can be ignored to predict CVD and T2DM.