Introduction

The prevalence of childhood and adolescent obesity has reached dramatic dimensions globally and still remains one of the most challenging problems in the western civilization.

Many affected children already present with one or more cardiovascular risk factors or metabolic disturbances such as dyslipidemia, disturbed glucose tolerance and even type 2 diabetes, hyperuricemia, arterial hypertension, and others [1]. As associated comorbidities increase with severity of obesity already at a young age, a significant number of obese children and adolescents already suffer from elevated transaminases and nonalcoholic fatty liver disease (NAFLD), orthopedic problems, psychological comorbidity (depression or attention deficit disorders), and sleep disorders. In addition, there is significantly increased risk for malignancies later in life [2,3,4].

The Global Burden of Disease Study has presented data that prevalence of childhood obesity has doubled in more than 70 countries since 1980. It is estimated that up to 115.1 million children are obese, accounting to a global prevalence of 5% [5, 6••]. Overall prevalence of overweight and obesity was as high as 23% in 2015, corresponding to 603.7 million adults. This is the more alarming since obesity has been made responsible for about 4 million deaths worldwide in 2015 which were mainly attributable to cardiovascular disease (nearly 70% of the deaths) [5].

Therapeutic interventions to treat childhood obesity (i.e., to reduce BMI or standard deviation score of body mass index, BMI-SDS) have only shown modest success to date, with an achievable reduction in BMI-SDS between 0.05 and 0.42 [7]. However, results of therapeutic interventions are the better the earlier they are initiated and show the best effects in younger children (kindergarten- or early school age), whereas effects are limited during puberty [8]. A recent study has shown that obesity that has started before the onset of puberty is associated with a significantly increased risk to develop type 2 diabetes and cardiovascular disease in midlife [9]. All these aspects underline the importance to identify children at increased risk for cardiometabolic comorbidity as early in life as possible. Consistent and internationally validated criteria should be applied so that preventive or therapeutic measures can be initiated before concomitant disease has manifested. The aim of this review is to give a concise and critical overview regarding our current understanding of the metabolic syndrome in childhood and adolescence and to discuss available therapeutic options.

Definition of Metabolic Syndrome in Children and Adolescents

There is no international consensus how to define the metabolic syndrome (MetS) in children and adolescents so far. Since 2003, several definitions have been proposed by several groups, and most authors have adapted criteria from the adult population. However, definitions differ in terms of cut-off values. There is common agreement that four main components should be included: (1) hyperinsulinemia/disturbed glucose metabolism/insulin resistance, (2) arterial hypertension, (3) dyslipidemia, and (4) abdominal obesity. According to the most commonly used MetS definitions for the pediatric population, as suggested by Cook et al. [10] as well as the International Diabetes Federation (IDF) [11], MetS can be diagnosed with abdominal obesity and the presence of two or more other clinical features. Abdominal obesity is defined as elevated waist circumference (WC), based on age- and gender-specific percentile curves. Additional anthropometric, clinical, and metabolic parameters to define MetS in children and adolescents should also be based on age- and sex-specific reference curves or values.

An overview of proposed definitions is presented in Table 1.

Table 1 Comparison of suggested diagnostic criteria for the MetS in childhood and adolescence. Definition of MetS in the pediatric population as proposed by different groups. MetS can be diagnosed if ≥ 3 criteria are fulfilled
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Available definitions for the MetS in children and adolescents have several limitations: (1) Additional parameters that are significantly associated with increased cardiometabolic risk, such as steatosis hepatis/NAFDL or hyperuricemia, have not been considered so far. (2) There is ongoing discussion about which criteria are to use. Among these criterions are some marked differences to the setting of cut-off values, which may lead to underestimation of affected children [16]. And, (3) available definitions only refer to peri- or postpubertal children, and criteria or cut-offs for prepubertal children are lacking so far. Therefore, Ahrens et al. proposed a new definition of MetS, which also includes criteria for prepubertal children [17]. The German Leibnitz Institute for Prevention Research and Epidemiology (BIPS) has established an online tool to assist pediatricians and general practitioners in assessing the risk of MetS in children aged 3–10 years. Data from the IDEFICS study were applied to validate and implement this tool [18]. First analyses have shown that this tool has led to a higher number of children/adolescents that are considered “at risk to develop MetS” and are therefore under observation.

In summary, cardiometabolic disease is a major health risk already in young children with obesity. Prevalence of MetS in childhood and adolescence has been estimated to differ between 6 and 39%, depending on which diagnostic criteria are applied [19].

Diagnostic Criteria

To define cardiometabolic risk in obese children and adolescents, a detailed clinical examination is essential. Anthropometric measures should include standardized determination of body height, weight, waist, and hip circumferences, applying age- and gender-specific centiles. The degree of overweight or obesity should be determined, applying age-and gender-specific BMI-centiles. The clinical examination should also include the determination of pubertal stage according to Tanner, clinical signs for cardiometabolic risk factors such as acanthosis nigricans, hirsutism, or striae distensae. To exclude rare syndromal diseases associated with obesity, it is proposed to investigate for syndromic symptoms like dysmorphia, mental retardation, and growth retardation [20].

Although the BMI does not allow to distinguish between fat and muscle mass, it is the most useful marker and the “gold standard” to define obesity in childhood and adolescence. In addition, it shows strong correlations to different cardiometabolic risk factors such as dyslipidemia, hyperinsulinemia, or elevated blood pressure [13, 21].

As abdominal obesity is significantly associated to cardiometabolic risk, the anthropometric index waist-to-height-ratio (WHtR) has been established and provides a useful tool to define abdominal obesity in childhood. A WHtR < 0.5 is regarded as normal in both, children and adults. The clustering of BMI and WHtR could identify more patients with cardiometabolic risk factors [22]. The index WHtR reflects the degree of abdominal obesity or visceral fat depots and may thus define cardiometabolic risk associated with obesity [23].

Blood pressure in the daily routine is mostly accessed by point of care measurements. This can lead to misinterpreting of the obtained values. Thus, blood pressure should be measured at rest and in the lying position, and the mean value of three measurements should be documented. The risk of arterial hypertension is still underestimated and underdiagnosed in children. To assess a potential risk for arterial hypertensions, age- and sex-specific centile curves should be applied in children and adolescents. A systolic or diastolic blood pressure higher than the 95 percentile suggests arterial hypertension in children. To confirm the diagnosis, a 24-h blood pressure measurement should be performed [24].

When cardiometabolic complications or the presence of MetS are suspected, a fasting blood sample should be obtained and a basal checkup should be performed, including fasting glucose and insulin, transaminases, lipids, uric acid, and additional parameters if appropriate (see Table 2).

Table 2 Suggested diagnostic workup in overweight/obese children and adolescents if MetS is suspected
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In addition to fasting glucose and fasting insulin, the HOMA-IR (homeostatic model assessment of insulin resistance) should be assessed [15]. It has to been emphasized that the HOMA-IR could not be strictly transferred from adulthood to adolescents: A marked increase in insulin concentrations and in HOMA-IR values was observed in 13- and 16-year-olds compared with 9-year-olds, which is attributable to decreased insulin sensitivity associated with the onset of puberty [25].

Uric acid is a product of the purine metabolism. The uric acid plays an important role in the pathophysiology of arterial hypertension, kidney function, congestive heart failure, and the development of type 2 diabetes. This could be explained through the fact that a high purine intake (animal protein, meat, and seafood) and fructose (processed food) intake lead to elevated uric acid levels [26]. Many obese children already present with marked hyperuricemia.

Steatosis hepatis or non-alcoholic fatty liver disease (NAFLD) has meanwhile been regarded as the hepatic manifestation of MetS. It presents the most common form of chronic hepatic disease in childhood, and it is estimated that up to 20% of obese children already suffer from steatosis hepatis or NAFDL. Alanine-aminotransferase (ALAT) and gamma-glutamyl-transferase (GGT) are two liver function parameters that are strongly associated with an elevated waist circumference or BMI [21, 27].

The adipose tissue is meanwhile regarded an endocrine organ that secretes a variety of different factors such as pro-inflammatory cytokines (e.g., TNF-α, IL-6) and adipokines (e.g., adiponectin, leptin, chemerin). These factors are significantly correlated to metabolic and cardiovascular risk factors [28]. Most of these adipokines are not yet implemented into a routine laboratory checkup [29]. Although Reinehr et al. [30] did not find an association between markers of MetS (i.e., triglycerides, HDL-cholesterol, LDL-cholesterol, blood pressure, HOMA-IR) and several adipocytokines, it has been suggested by several groups to include the measurement of distinct adipokines and pro-inflammatory markers into the basal checkup of obese children and adolescents to evaluate the risk for cardiometabolic comorbidities.

According to the current recommendations of the American Diabetes Association (ADA), an oral glucose tolerance test with 1.75 g glucose per kilo/maximum to 75 g should be performed in obese children older than 10 years with a first- or second-degree relative with type 2 diabetes [31].

Suggested diagnostic workup is summarized and presented in Table 2.

Therapeutic Options for MetS in Childhood and Adolescence

Many studies have shown that the weight status in early childhood is a significant predictor for the weight status and associated cardiometabolic comorbidities later in life. Thus, prevention or treatment of childhood obesity should start as early in life as possible. If any possible, it should start with preventive measures already in kindergarten- or young school age.

As far as therapeutic options are concerned, a recent systemic review has confirmed what we have known before: A multidisciplinary lifestyle intervention provides the strongest evidence of effectiveness [32]. Some studies have suggested that a more personalized intervention may be beneficial for an effective therapy [8, 33].

The hallmarks to treat obesity in childhood and adolescence are presented as follows:

Lifestyle Intervention

Lifestyle intervention provides the basis for obesity therapy in children and adolescents and is to date the “gold standard” or major therapeutic option for the majority of pediatric patients. It should include a balanced diet with reduction in energy-dense, sugar-, and fat-rich products, an increase in daily physical activity, as well as behavioral treatment [2].

According to Foster et al., lifestyle intervention can be divided into four stages: (1) “prevention plus” which focusses on healthy eating and activity habits; (2) “structured weight management” which is based on monthly visits to provide structured approaches to diet counselling and regular physical activity; (3) “comprehensive multidisciplinary intervention” which is similar to stage 2 but includes weekly visits and additional structured behavioral intervention; and stage (4) “tertiary care intervention” which includes a structured program addressing all modules of stage 3, but which is in addition considering concomitant disease, medications, severe dietary restrictions, or surgical intervention [8].

As pharmacotherapy and bariatric surgery are treatment options only for an absolute minority of adolescent patients (see below), lifestyle intervention is the “gold standard” and the basis for the majority of obese children and adolescents to date.

The four stages of lifestyle intervention suggested by Foster and colleagues are widely accepted and applied to prevent or treat childhood obesity and cardiometabolic comorbidities: While most programs are based on stage 2 or 3, most of the available and validated programs differ in duration, frequency of consultation, type and intensity of intervention, and after-care programs. Most of the programs have a duration between 6 and 18 months. To guarantee short- as well as long-term success, the multidisciplinary team should consist of pediatricians, nutrition counselors, psychologists, and exercise physiologists. However, the average achievable reduction in BMI-SDS is rather low after 18–24 months of follow-up (mean reduction in BMI-SDS (z-score) of − 0.34, see above) [32].

Although these effects may be regarded as very small, a decrease in BMI-SDS of − 0.125 is capable of reducing multiple cardiovascular risk factors (CRF) such as systolic/diastolic blood pressure, triglycerides, insulin resistance measured by HOMA-Index, and increasing HDL cholesterol. In addition, a decrease in BMI-SDS of more than − 0.25 was significantly associated with an improvement of all CRFs except fasting glucose and LDL [34•]. In general, an intervention may be regarded as successful if BMI-SDS is reduced by ≥ 0.2 which is almost equivalent to 1 kg/m2 [35]. In accordance with all these studies presented above, Weiss and colleagues have shown that a reduction in BMI-SDS (z-score) of greater than 0.09 is already associated with improvements of almost all cardiovascular risk factors [36]. Even weight stabilization in obese children may be regarded as success: a stabilization of body weight in a child growing 5 cm/year equals to a reduction of BMI-SDS of − 0.5 [34•].

In summary, these results underline the importance of weight stabilization or (even small) weight loss induced by lifestyle interventions to reduce or minimize the risk of obesity-associated cardiometabolic comorbidity later in life.

Rehabilitation

To date, it is discussed controversially, which type of rehabilitation is most favorable and most effective in childhood obesity. Inpatient rehabilitation approaches have shown rapid short-term effects to reduce BMI-SDS after an intervention of 26 weeks (− 18%) compared to ambulant rehabilitation (− 10.5%). In addition, nearly all cardiometabolic risk factors improved [37]. However, inpatient rehabilitation is not the most appropriate form of rehabilitation for many obese youngsters due to obligations in schools, fears to be away from the family for several weeks, and other reasons. In addition, many obese children show a rapid rebound in weight gain as soon as they return home. Therefore, the focus for future approaches should be shifted towards ambulant rehabilitation with settings addressing the entire family and which also include aftercare programs.

As the most significant reduction in BMI-SDS can be achieved in prepubertal children compared to obese adolescents, rehabilitation approaches should generally be initiated as soon as possible [38].

Pharmacotherapy

While various drugs for weight reduction have been released to the market during the past years, most of them were withdrawn again due to limited effectiveness and/or severe side effects, and none of them was approved for children and adolescents [39].

To date, there is only one medication that has been approved by the US Food and Drug Administration (FDA) to be used in children and adolescents: metformin. However, this antihyperglycemic drug has only been approved so far to treat type-2 diabetes (and not disturbed glucose tolerance or insulin resistance) in children 10 years or older. While its safety profile is quite favorable and it is capable of improving glucose metabolism and of reducing cardiometabolic risk profile in obese children and adolescents, its effects on weight loss or BMI reduction, respectively, are rather limited [2, 40].

Another group of medications which is under development and is tested in clinical trials to be used in obese children and adolescents is incretin hormones such as glucagon-like peptide 1 (GLP-1). However, none of these medications has been approved for the use in the pediatric population so far. These group of agents are described in more detail in another study [2].

Obese children and adolescents with dyslipidemia should be treated in first line with lifestyle modification (diet counselling and elevated physical activity). If this treatment approach fails and if LDL levels are higher than 160 mg/dl, treatment with statin may be considered [41].

If obese children present with arterial hypertension, first-line treatment again should focus on lifestyle modification and increased physical activity. Only if this has failed, pharmacotherapy might be considered in the second line and should be started with an ACE inhibitor [24, 42]. β-Blockers should, if possible, not be used in the pediatric population because of their negative effect on energy metabolism and other side effects [43].

If obese adolescents have already manifested type 2 diabetes, pharmaceutic intervention will depend on the HbA1c level. If they present HbA1c > 6.5% and an impaired fasting glucose > 7 mmol/l, they should be treated with metformin in the first line, in addition to a lifestyle intervention. Insulin is to be considered if HbA1c levels are higher than 9% [44]. The intake of metformin is also a therapeutic option if a polycystic ovary syndrome (PCOS) has been diagnosed [41]. In summary, there is common agreement that first-line treatment of MetS in children and adolescents should be lifestyle modification. The use of medications should be limited to those who have failed to respond after 6 months.

Bariatric Surgery

Bariatric surgery in (extreme) obese children and adolescents is the last therapeutic option when all other interventions have failed. To date, bariatric surgery has been suggested to be a therapeutic option only for extreme obese adolescents (BMI > 35 kg/m2) with cardiometabolic disease, if all conservative approaches including lifestyle intervention, rehabilitation, and pharmacotherapy have failed [45]. Although a rapid weight loss after surgery can be achieved, it is not a therapeutic option for the majority of adolescent patients due to certain risks like dumping syndrome, difficulties in post-operative care, risk of a poor supply in fat soluble vitamins and electrolytes, and others. In addition, there are only limited data so far for long-term results and long-term safety [7, 40].

Prevention of MetS in Children and Adolescents

Due to the fact that therapeutic approaches often only show modest effects in obese children and adolescents (see above), prevention of childhood obesity should be the primary goal and should include both, behavioral and community-based approaches.

In order to reach this goal, the report of the WHO commission on ending childhood obesity suggests different measures with six key points: (a) promotion of heathy food; (b) promotion of physical activity; (c) focus on preconception and pregnancy care; (d) starting diet and physical activity in early childhood; (e) special care of health, nutrition, and physical activity for school-aged children; and (f) perform a proper weight management. More detailed information is available in the Report of the World Health Organization (WHO) [46••].

There are additional four measures that have been demanded in the Global Action Plan of the WHO in order to prevent and control noncommunicable diseases such as obesity in children and adolescents: These measures include (1) restriction of the advertisement of unhealthy foods to children, (2) improving school meals by development of binding quality standards for the catering offers in kindergartens and schools, (3) implementation of a sugar—or fat tax to reduce consumption of unhealthy foods, and (4) increase in daily physical activity by offering more physical activity/sports in schools and kindergartens [47].

There is common agreement in the scientific community that a shift from individual, behavioral-oriented obesity prevention towards environment- or community-based prevention strategies are mandatory to fight the obesity epidemic.

Summary and Future Perspectives

Obesity still remains one of the global burdens in medicine especially because of its remaining high prevalence in children and adolescents and associated cardiometabolic sequalae of the MetS that often start early in life [5]. Obese children and adolescents often stay obese adults, leading to markedly increased morbidity and mortality. As obesity induces major changes in the cytokine and adipokine profile of the growing organism, there is significantly increased risk for the development of type 2 diabetes, cardiometabolic disease, and different types of cancer [2].

Consistent and internationally validated diagnostic criteria to define MetS in the pediatric population are not available and are urgently needed. Most definitions of the MetS in children are adapted from adults. Common agreement has been made to include abdominal obesity, arterial hypertension, dyslipidemia, and disturbed glucose metabolism as main features. However, there are certain limitations in the clinical use of these proposed definitions due to different criteria applied, heterogeneous cut-off values, and missing values for prepubertal children. In addition, gender and ethnic origin should also be considered and clinically relevant disturbances such as NAFDL or hyperuricemia which may significantly define cardiometabolic risk later in life are not yet considered in available definitions of the MetS.

Many obese children and adolescents already present with two or more features of the MetS, and therapeutic options are mainly based on lifestyle intervention so far. Depending on which definition of the MetS is applied, the percentage of affected children and adolescents as well the number of involved components (low grade vs. high grade MetS) may vary widely. In addition, obese children may also present with a “healthy” phenotype, and underlying factors of the so-called metabolically healthy obesity (MHO) are poorly understood so far and need further investigations [48]. Prevalence for the MHO phenotype has been estimated to be between 4 and 68% in overweight and obese children, depending on criteria applied [48]. In a pediatric cohort from central Europe, prevalence for MHO has been found to be 16% [49]. On the other hand, elevated waist circumference as marker of abdominal obesity and increased cardiometabolic risk profile is commonly seen in the first line in the majority of children affected by MetS, followed by altered lipid profile. In the third line, elevated blood pressure can be frequently found [19]. However, steatosis hepatis/NAFDL and increased liver enzymes affect up to 50% of obese children and adolescents and should thus be included into the diagnostic criteria defining MetS.

Intervention strategies for overweight and obese children and adolescents have been shown only limited effects to date and cannot prevent long-term consequences and cardiometabolic sequalae later in life in the most countries of the world. Thus, prevention of obesity should be the major goal and should start as early in life as possible. Puberty seems to be a critical period for the development of hyperinsulinemia, insulin resistance, and other features of the metabolic syndrome, and hyperinsulinemia and subclinical inflammation are suggested to be key players for the development of concomitant disease of obesity later in life.

Conclusions

Common and internationally validated diagnostic criteria to define MetS in childhood and adolescence are urgently needed. Such criteria should also consider additional factors such as age, gender, pubertal stage, or ethnicity and should also include additional components which may define cardiovascular risk such as NAFDL/elevated liver enzymes or hyperuricemia. To date, treatment of MetS in childhood and adolescence is mainly based on lifestyle intervention, as pharmacotherapy or bariatric surgery is only recommended for a small minority of patients so far.