METABOLIC SYNDROME

2.1.1 A brief history of metabolic syndrome in adults and children

In the 18th century, an Italian anatomist Giovanni Battista Morgagni (25 Feb 1682 – 6 Dec 1771) discovered a link between abdominal obesity, hypertension,

hyperuricemia, atherosclerosis, and obstructive sleep apnea (28). Later in the 20th century during the First World War, two Austrian physicians Karl Hitzenberger and Martin Richter-Quittnerr made an observation dealing with metabolic

abnormalities among their patients but could not publish their results until the end of the war. At about the same time, a Swedish physician Eskil Kylin and a Spaniard physician Gregorio Marañon published papers about the common coexistence of hypertension and diabetes mellitus in adults. During the next decades, many researchers reported observations on the clustering of cardiovascular and metabolic disorders. (29)

In the late 20th century in 1988, Gerald M. Reaven made MetS generally known and named it as “syndrome X”. According to his findings, Professor Reaven formed a hypothesis on a cluster of metabolic abnormalities that was associated with a greatly increased risk of cardiovascular diseases (30). One year later Doctor Norman Kaplan added an important factor, central adiposity, into the cluster of metabolic abnormalities proposed by Reaven. Kaplan summarized four typical characteristics, i.e. central adiposity, impaired glucose tolerance,

hypertriglyceridemia, and hypertension, in his formula of the MetS and named it

“the deadly quartet” (31). The identification of “the deadly quartet” led to the appreciation that the accumulation of these cardiometabolic risk factors could significantly increase the risk of developing several different cardiometabolic diseases (32,33). Therefore, early prevention and identification of these cardiometabolic risk factors were also understood to be of great clinical significance.

There was no unified definition for MetS until the end of the 20th century when WHO published a report on the definition and classification of diabetes mellitus and its complications. The definition of MetS by WHO includes impaired glucose regulation or diabetes and/or insulin resistance together with two or more of the following risk factors: raised arterial pressure (≥ 140/90 mmHg), increased plasma

triglycerides (≥ 1.7 mmol l^-1) and/or low plasma high-density lipoprotein (HDL) cholesterol (men: ≤ 0.9 mmol l^-1; women: ≤ 1.0 mmol l^-1), central obesity (men:

waist to hip ratio > 0.90; women > 0.85; and/or BMI > 30 kg/m^-2), and microalbuminuria (urinary albumin excretion rate > 20 μg min^-1 or

albumin:creatinine ratio ≥ 30 mg g^-1) (34,35). About one year later, the European Group for the study of Insulin Resistance (EGIR) published their own definition for MetS. The definition issued by EGIR was similar to that of WHO and included insulin resistance plus two or more of central obesity, dyslipidemia, hypertension, and increased fasting plasma glucose, but this was never widely used

internationally (36). Many other organizations also published their definitions of MetS after WHO and EGIR.

The IDF finally released a universal consensus workshop-based definition for MetS in 2005. The purpose was to harmonize several existing MetS criteria, and the IDF largely succeeded in achieving that goal. One other major reason for publishing the IDF definition was that the earlier definitions never provided exact and clear clinical criteria for MetS and the comparison between data used in earlier definitions was difficult because of the different characteristics used to identify MetS (14,37). IDF defined MetS in adults as a cluster of the most

dangerous risk factors for type 2 diabetes and cardiovascular disease, including abdominal obesity, increased plasma cholesterol, elevated blood pressure, increased fasting plasma glucose level, and diabetes if not already diagnosed (38).

After IDF published its definition of adult MetS, the next step was a demand for children’s definitions due to the growing epidemic of pediatric obesity (20). Similar to adults, there was no unified definition to assess the risk or existence for MetS in youngsters, and the existing adults’ definitions were not felt appropriate for children and adolescents. In 2007, IDF published a definition of MetS for children and adolescents that was based on data from previous studies using modified adult criteria. In the definition of pediatric MetS, IDF suggested that the syndrome should not be diagnosed among children under 10 years of age. For children 10-16 years of age, the definition included abdominal obesity and two or more of

increased plasma triglycerides, decreased plasma HDL cholesterol, raised blood pressure, and elevated plasma glucose. For adolescents older than 16 years, IDF recommended the use of adult criteria but mentioned that more research would be needed to find an optimum definition. (20) Despite the IDF definition, there is still no international consensus for children’s and adolescents’ MetS. For example, the American Heart Association refused to define pediatric MetS (39). However,

the IDF definition for pediatric MetS is still most widely used and is the closest to having gained an international consensus.

2.1.2 Definitions of pediatric metabolic syndrome

According to IDF’s criteria for MetS, obesity and insulin resistance are the essential components of MetS among children (20). As mentioned earlier, notwithstanding several attempts to define pediatric MetS, researchers have not succeeded in devising a clear unanimous definition or diagnostic criteria that would have been accepted all over the world (Table 1). The challenge among children and

adolescents is that it is complicated to establish the definitions for MetS due to the many physiological and methodological confounding factors. For example,

pubertal status and development, age, sex, and race have an effect on each component of the MetS among children and adolescents. Therefore, it seems to be more appropriate to use a continuous risk score for MetS among children and adolescents than to apply criteria that are based on artificial cut-offs for the individual features of MetS used in adults (40–44). None of the definitions for children’s and adolescents’ MetS has been fully validated among children and adolescents. Therefore, it has been stated that it would be better to focus on the prevention and treatment of the individual cardiometabolic risk factors to avoid clustering of these risk factors rather than the diagnostics of MetS (45,46).

36 Table 1. Definitions for children’s and adolescents’ MetS. Definition Criteria Age (ys) GlucoseBMI Waist circumference Triglycerides HDL cholesterol Blood pressure Cook et al. 2003 (15)≥3 of following 12-19 ≥6.1 mmol/l ≥90th percentile ≥1.2 mmol/l ≤1.03 mmol/l ≥90th percentile of SBP or DBP De Ferranti et al. 2004 (16) ≥3 of following 12-19 ≥6.1 mmol/l ≥75th percentile ≥1.1 mmol/l <1.3 mmol/l (for boys 15-19 years <1.17 mmol/l)

≥90th percentile of SBP or DBP Cruz et al. 2004 (17)≥3 of following 8-13 IGT (ADA criterion)≥90th percentile ≥90th percentile ≤10th percentile ≥90th percentile of SBP or DBP) Weiss et al. 2004 (18)≥3 of following 4-20 IGT (ADA criterion)BMI-Z score ≥2.0≥95th percentile ≤5th percentile≥95th percentile of SBP or DBP) Ford et al. 2005 (19)≥3 of following 12-17 ≥6.1 mmol/l ≥90th percentile ≥1.2 mmol/l ≤1.03 mmol/l ≥90th percentile of SBP or DBP Viner et al. 2005 (47)≥3 of following 2-18≥6.1 mmol/l ≥95th percentile≥1.7 mmol/l ≤0.9 mmol/l ≥95th percentile of SBP IDF definition 2007 (20)Obesity and ≥2 of following

10-15 ≥5.6 mmol/l or family history of MetS or T2D or a related disorder.

≥90th percentile or adult cut-off if lower

≥1.7 mmol/l <1.03 mmol/l SBP ≥130 or DBP ≥85 mm Hg IDF definition 2007 (20)Obesity and 2 of following

≥16 (Use IDF criteria for adults MetS)

≥5.6 mmol/l or family history of MetS or T2D or a related disorder.

≥94 cm for males and ≥80 cm for women

≥1.7 mmol/l <1.03 mmol/l for males and <1.29 mmol/l for women

SBP ≥130 or DBP ≥85 mm Hg (or hypertension treatment) Ahrens et al. 2014 (48)≥3 of following 2-<11 ≥90th percentile (or ≥90th percentile of HOMA-insulin resistance)

≥90th percentile ≥90th percentile (or HDL cholesterol ≤10th percentile)

≤10th percentile (or triglycerides cholesterol ≥90th percentile)

≥90th percentile of SBP or DBP BMI, body mass index; HDL, high-density lipoprotein; IGT, impaired glucose tolerance; SBP, systolic blood pressure; DBP, diastolic blood pressure

2.1.3 Prevalence of metabolic syndrome

It is difficult to estimate the prevalence of children’s and adolescents’ MetS because there are no established criteria for its diagnosis. Nonetheless, several study groups have reported the prevalence of MetS especially among obese children or adolescents when applying their own definitions, commonly used pediatric definitions (Table 1), or modified definitions utilized for adults.

Regardless of the inconsistent definitions, some high-quality studies have provided an indication of the prevalence of children’s and adolescents’ MetS. The prevalence of MetS is highest in overweight and obese children and increases with the degree of adiposity. (49–51) In a North American cohort of 3385 adolescents aged 12-19 years, the prevalence of MetS was 19-35% among obese youngsters compared to less than 2% in their normal-weight peers (50). A systematic review from 85 studies examining children and adolescents aged 7-19 years showed that the median prevalence of MetS in the whole study population was 3.3%; this value for the prevalence of MetS among overweight children was higher i.e. 11.9%; and in obese children it was even higher, 29.2% (49). The prevalence of MetS was higher in boys (5.1%) than in girls (3.0%) and in older children (5.6%) than in younger children (2.9%) (49).

In a large Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study among 18 745 European children aged 2-11 years, the researchers estimated the prevalence of pediatric MetS by using reference standards obtained in the study and devised their own definition of MetS and compared it with three commonly used definitions of MetS among children (15,20,47). The prevalence of pediatric MetS varied in the IDEFICS cohort between 0.3% and 1.5% among girls and between 0.4% and 1.3% among boys using these three commonly used definitions (15,20). The researchers also proposed two decision levels for the definition of children’s MetS. The first level was considered to require a close observation and was called as a monitoring level and the second level was considered to require an intervention and was termed as an action level. They observed that the prevalence of MetS was 2.1% in girls and 1.5% in boys based on the action level and 5.9% in girls and 5.1% in boys based on the monitoring level (48).

The prevalence of pediatric MetS is increasing in parallel with the increasing rates of obesity, MetS is relatively uncommon among non-obese children, and the existence of pediatric MetS has often been even questioned regardless of the different definitions (49,52–55). The prevalence of overweight and obesity has

the National Institute for Health and Welfare of Finland initiated a research project with the aim of investigating, monitoring, and reporting the prevalence of

overweight and obesity among children between 2 and 16 years of age. In this project, researchers collect real-time data from the register of Primary Health Care Visits (Avohilmo) (57). According to the latest report of 96 341 Finnish children, about 25% of boys and about 16% of girls were overweight or obese according to the Finnish ISO-BMI criteria (58). Seven percent of the boys and 3% of the girls were classified as obese by applying these criteria. Using the International Obesity Task Force (IOTF) criteria for overweight and obesity (59) about 19% of the girls and the boys were classified as overweight, and 4% of the girls and 5% of the boys were defined as being obese (60).

2.1.4 Pathogenesis of pediatric metabolic syndrome

Understanding some progress has been made in clarifying the pathogenesis of pediatric MetS (Figure 2). According to the current knowledge, insulin resistance, excessive body adiposity, and inflammation are the core factors underlying the pathogenesis of pediatric MetS. Insulin is secreted by the pancreatic β cells from where it is transported via the portal system to the liver and suppresses glucose production in the liver. In a situation of insulin resistance, the suppression of glucose production is impaired which leads to abnormal glucose homeostasis and this manifests as a decreased tissue response to many insulin mediated cellular actions. (61) For example, in the insulin resistant state, not all insulin mediated cellular actions are impaired (62), because hepatic lipogenesis is not impaired resulting in the release of free fatty acids and triglycerides into the circulation, leading to dyslipidemia and ectopic fat accumulation (63). Excessive fat

accumulation promotes the productions of pro-inflammatory cytokines, such as plasminogen activator inhibitor-1, tumor necrosis factor α, and interleukin 6, and acute phase reactants, such as high-sensitivity C-reactive protein and fibrinogen in adults (64). Subsequently, the excessive fat accumulation evokes a systemic low-grade inflammation. Insulin resistance becomes manifest in several organs, including skeletal muscles, the liver, and the intestine, and is thereby associated with several systemic abnormalities, including impaired glucose metabolism, dyslipidemia, and hypertension. Insulin resistance has also been related to endothelial dysfunction and hypertension but the possible causal relationships have remained unclear (64). In addition, there are many determinants of metabolic risk factor clustering. Behavioral factors, such as lack of PA, excessive ST,

insufficient sleep, and an unhealthy diet, have been associated with the clustering

of cardiometabolic risk factors among children and adolescents (65–68). These associations are modified by genetic, epigenetic and environmental factors (Figure 2). The pathogenesis of pediatric MetS is complex and characterized by a cluster of individual risk factors (Figure 2), and it is the interplay of these risk factors that strongly predicts the future risk of type 2 diabetes and cardiovascular disease (Figure 1).

Figure 2. Determinants and mechanism for the clustering of cardiometabolic risk factors.

2.2 INDEPENDENT CARDIOMETABOLIC RISK FACTORS IN