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Introduction
Metabolic syndrome (MetS) is characterized by a cluster of cardiovascular risk
factors (hypertension, altered glucose metabolism, dyslipidemia, and abdominal
obesity) that occur in obese adults and children [1]. MetS risk is rising in children and adolescents as childhood obesity
continues to rise [2,3]. In order to better manage MetS in childhood, we must
understand its pathophysiology, risk factors, and management methods.
MetS affects >30% of the adult population >30 years of age in South
Korea [4]. According to the Korea National
Health and Nutrition Examination Survey, its prevalence has been increasing
gradually in young adults since 1998 [5].
Controversy exists regarding the various definitions of the syndrome and its ability
to predict future adverse cardiometabolic events in a manner surpassing other
well-described risk factors. Despite this, there can be little controversy regarding
the current national and worldwide epidemic of obesity, and the links between risk
factors in youth and subsequent adult cardiovascular disease (CVD) [6]. Also, the rise in the prevalence of
pediatric obesity is one of the most alarming public health issues facing the world,
including Korea, today [7].
MetS is associated with many clinical conditions besides CVD and type 2 diabetes
(T2DM), including chronic low-grade inflammation, oxidative stress, hyperuricemia,
hypertension, dyslipidemia, hyperandrogenism and polycystic ovarian syndrome (PCOS),
hepatic steatosis and non-alcoholic fatty liver disease (NAFLD), impaired glucose
tolerance, obstructive sleep apnea, hypogonadism, vascular dementia and
Alzheimer’ disease, and certain forms of cancer [8,9].
Despite the risks and associated conditions, several factors contribute to the
controversy surrounding pediatric MetS. First of all, it is difficult to define MetS
in pediatric populations. MetS in adults is predictive of CVD and T2DM; however,
several definitions of MetS have been proposed for children and adolescents, and
there is no clear consensus on which one should be applied [10,11]. Moreover,
regardless of the definition used, there is no uniform way to treat MetS other than
weight management.
Our purpose in this review article is to provide an overview of MetS in the pediatric
population, focusing on its definition, pathophysiology, screening, prevention, and
treatment.
Definition of Metabolic Syndrome in Childhood
MetS among adults has been defined clinically by at least five health organizations,
including the World Health Organization (WHO); the U.S. National Cholesterol
Education Program (NCEP) Adult Treatment Panel (ATP) III; the American Association
of Clinical Endocrinologists/American College of Endocrinology; the International
Diabetes Federation (IDF); and the American Heart Association (AHA) in conjunction
with the National Heart, Lung, and Blood Institute (NHLBI) of the U.S. National
Institutes of Health. In 2001, the NCEP developed the first risk criteria definition
for atherosclerosis and cardiovascular disease based on the "any three of
five" risk criteria. NCEP ATP III defines five risks: (I) hyperglycemia, (II)
hypertriglyceridemia, (III) low high-density lipoprotein cholesterol (HDL-C) level,
(IV) hypertension, and (V) an increase in waist circumference. In 2005, the
AHA/NHLBI modified this definition of MetS by reducing glucose cut points, and the
IDF introduced its “worldwide” definition of MetS, placing greater
emphasis on abdominal obesity by making it a necessary criterion for MetS diagnosis.
Although the AHA/NHLBI and IDF definitions have many similarities, there are
important differences between them with respect to cut points of the various
component risks. However, most commonly used definitions agree that the following
components are relevant: central obesity, impaired glucose tolerance, dyslipidemia,
and hypertension.
Among children and adolescents, MetS definitions differ even more than among adults.
MetS was first studied among adolescents in a pediatric population; however, the
prevalence varied by more than 2-fold in the same database. In 2007, the IDF
assembled an international group of experts to develop a consensus
definition. Specifically, the IDF recommended pediatric MetS should only be
applied to children ≥10 years of age with three or more of following risk
factors: high waist circumference, high blood pressure, IR, and dyslipidemia [10]. Among those 10–15 years of age,
those in the >90th percentile for waist circumference or with a
systolic blood pressure>130 mmHg or diastolic blood pressure>85 mmHg,
triglycerides>150 mg/dL, or HDL-C<40 mg/dL would be defined as having
MetS. For adolescents>15 years of age, the adult criteria should be used for
diagnosis (Table 1).
Table 1.
Pediatric definition of MetS (IDF definition)
In its scientific statement published two years later, the AHA stressed the
importance of identifying pediatric cardiometabolic risks and noted that only some
of them could be identified by the current MetS criteria. The AHA did not include a
definition of MetS for pediatric populations and noted that adapting adult
definitions to pediatric populations had limitations. To date, there is no clear
consensus on whether MetS should be defined in pediatric populations and, if
defined, which definition should be used. However, this definition also
stated that children <10 years of age should not be diagnosed with MetS. This
was explained by the absence of age-specific reference values for MetS components
for this age group [10]. In 2014, Ahrens et
al. proposed a quantitative MetS score using age- and gender-specific anthropometric
and metabolic parameters in children 2–11 years of age [11]. To help physicians identify children at risk, the scoring
system recommends strict monitoring of children in the ≥90th
percentile of body mass index (BMI), and for those in the ≥95th
percentile, urgent intervention is recommended [11].
MetS' utility in pediatrics is contested beyond its definition. The presence
of MetS predicts the presence of CVD and diabetes in adulthood. As compared to
patients without MetS risk factors, Malik et al. found that a person with MetS and
diabetes had an increased hazard ratio for coronary heart disease mortality by 1.75
times [12]. However, there has been some
concern that the syndrome is ineffective in adolescents, given that there is some
instability in the definition of the syndrome as adolescent’s transition from
adolescence to adulthood.
Most children defined as having MetS at childhood fail to meet diagnostic criteria
three to six years later during follow-up. Even though the prevalence of MetS has
increased at the population level, within-person variation in the presence or
absence of MetS has been large in observational longitudinal studies. Many studies
have shown that 50% of MetS-positive subjects become MetS-negative over time, either
during short-term follow-up (~3 weeks) or long-term (9 years) [13]. There was no correlation between this instability and a
change in weight [13]. As a result,
MetS remains highly unstable throughout childhood. In a child, the criteria can be
met at one point in time and not at another, and it is unclear whether this
represents an improvement or a deterioration in health.
Given the absence of a consensus on the definition of MetS, the unstable nature of
MetS, and the lack of clarity about the predictive value of MetS for future health
in pediatric populations, pediatricians are rightly confused about MetS. Thus,
rather than focusing on defining MetS in youth, the American Academy of Pediatrics
(AAP) recommends that pediatricians focus on the concept of cardiovascular risk
factor clustering and associated risk factor screening. This concept is especially
important because the Bogalusa Heart Study demonstrated that increased clustering of
atherosclerotic CVD risk factors was associated with increased severity of
atherosclerotic lesions [14]. In addition,
the AAP recommends pediatricians avoid using cut points based on MetS definitions.
MetS identifies multiple components that cluster together and are associated with
insulin resistance and adipose tissue pathology. Disparities in these thresholds are
a major reason for discrepancy between definitions. In addition, there is a
continuum of risk associated with many risk factors. A continuous variable may be
more reliable in predicting the future risk of young adults from early adolescence
[15]. Risk factor screening and
the identification of youth with MetS risk factor abnormalities allow providers to
allocate scarce resources to children who are at a higher cardiometabolic risk,
specifically those with multiple components. The screening and associated treatment
of MetS is an important component of preventive pediatric care.
Pathogenesis of Metabolic Syndrome
Despite the lack of clarity about MetS pathogenesis, recent research suggests that
obesity, insulin resistance, and inflammation play a key role in the development of
MetS.
1. Insulin resistance
Insulin resistance is the opposite of insulin sensitivity and is defined as a
decreased response to insulin-mediated cellular actions. The phrase
“insulin resistance,” as generally applied, refers to whole-body
reduced glucose uptake in response to physiologic insulin levels and its
consequent effects on glucose and insulin metabolism. However, it is now clear
that not all insulin-responsive tissues are equally sensitive to insulin.
Generalized insulin resistance would result in global metabolic dysfunction,
such as leprechaunism or Rabson–Mendenhall syndrome. Thus, the insulin
resistance in obesity inevitably affects different tissues quantitatively.
1) Hepatic insulin resistance
In addition to being a primary target of insulin action, the liver plays a
critical role in substrate metabolism. After insulin is released from
β-cells following a glucose loading, it travels directly to the liver
via the portal vein, where it binds to insulin receptors and elicits two key
actions at the level of gene transcription. First, insulin stimulates the
phosphorylation of FoxO1, preventing it from entering cell nuclei and
decreasing the expression of genes required for gluconeogenesis, which are
principally phosphoenolpyruvate carboxykinase and glucose 6-phosphatase
[16]. This process leads to
decreased hepatic glucose production. A second effect of insulin is that it
activates the transcription factor sterol regulatory element–binding
protein (SREBP)-1c. This increases the transcription of genes required for
fatty acid and TG biosynthesis, particularly adenosine triphosphate citrate
lyase, acetyl-coenzyme A carboxylase, and fatty acid synthase, which
together promote the process of de novo lipogenesis (DNL). TGs synthesized
by DNL are then packaged with apoliprotein B into very-low-density
lipoproteins (VLDLs), which are then exported to the periphery to be stored.
The use of VLDLs is then enabled by the reciprocal activation of lipoprotein
lipase on the surface of endothelial cells within the adipose tissue or the
muscle tissue [17]. For reasons that
remain unclear, in insulin-resistant individuals, hepatic insulin resistance
is usually selective or dissociated; that is, they have impaired
insulin-mediated glucose homeostasis (mediated by the FoxO1 pathway) but
enhanced insulin-mediated hepatic DNL (mediated by the SREBP-1c pathway)
[18]. The increase in free fatty
acid (FFA) flux within the liver, either by DNL or FFA delivery via the
portal vein, impairs hepatic insulin action, which, in turn, leads to
increases in hepatic glucose output, the synthesis of pro-inflammatory
cytokines; excess TG; low HDL-C secretion by the liver; and an elevated
number of relatively cholesterol-depleted, small, dense LDL particles. As a
result of these intrahepatic accumulations of FFA and lipids, liver insulin
sensitivity is also negatively affected [19].
2) Adipose tissue insulin resistance
The expanded adipose tissue mass attributable to obesity often increases
lipolysis and FFA turnover. Normally, insulin inhibits adipose tissue
lipolysis; however, in the insulin-resistant state, the process is
accelerated, increasing the release of FFA into the circulation.
Furthermore, visceral adipocytes are more sensitive to
catecholamine-stimulated lipolysis than subcutaneous adipocytes, which
increases the FFA flux [20]. Adipose
tissue also receives macrophage infiltration, which leads to the hypertrophy
of adipocytes and the release of cytokines [21]. These circulating cytokines also affect insulin action in
liver and muscle tissues.
3) Muscle insulin resistance
The increased plasma FFA levels from insulin-resistant livers disrupt the
glucose-fatty acid or Randle cycle, facilitating hyperglycemia by impairing
insulin-mediated glucose transport to skeletal muscle [22]. The ectopic deposition in skeletal muscle of fat
as intramyocellular lipid may also play a direct role in the pathogenesis of
insulin resistance and MetS via lipid metabolite-induced activation of
protein PKCε with subsequent impairment of insulin signaling [23]. In childhood, ethnicity and
puberty are the two most important biological factors influencing insulin
resistance.
2. Lipid partitioning
The phrase “lipid partitioning” refers to the distribution of body
fat in various organs and compartments. The majority of excess fat is stored in
its conventional subcutaneous depot, yet other potential storage sites exist as
well, such as the intraabdominal (visceral) fat compartment and
insulin-responsive tissues like muscle and the liver. Although still under
debate, a potential etiology of MetS involves a pattern of lipid partitioning
(i.e., the specific depots in which excess fat is stored). This pattern of lipid
storage determines the secretion profile of adipocytokines and its effect on
circulating levels of inflammatory cytokines and FFA flux. Through their
combined effects, these factors impact insulin-mediated pathways in target
organs (such as muscle and the liver) and vascular system by influencing
endothelial function.
3. Adipocytokines
1) Leptin
Adipocytes secrete several proteins that act as regulators of glucose and
lipid metabolism. Because they share structural similarities with cytokines,
these proteins are collectively termed adipocytokines. The level of
circulating leptin serves as an adiposity sensor to prevent starvation and
correlates with the degree of obesity in the body. Leptin probably has a
permissive role in high-energy metabolic processes such as puberty,
ovulation, and pregnancy, but its role in states of energy excess is less
known. In obesity, the development of leptin resistance may lead to abnormal
partitioning of surplus lipids within adipocytes [24].
2) Adiponectin
Adiponectin is distinctive in obesity because, in contrast to the other
adipocytokines, its level is decreased in obese people. The adiponectin gene
is found on chromosome 3q27, which has previously been associated with the
emergence of T2DM and MetS. Numerous single-nucleotide polymorphisms in the
adiponectin gene have been linked to the emergence of T2DM in people all
over the world, indicating that adiponectin is crucial for the regulation of
glucose and lipid metabolism [25].
Two adiponectin receptors, ADIPOR1 and ADIPOR2, have been identified.
ADIPOR1 is expressed in numerous tissues, including muscle, while ADIPOR2 is
mostly restricted expression in the liver. Both ADIPOR1 and ADIPOR2 are
receptors for the globular head of adiponectin and operate as start-up
molecules for signal transduction pathways that result in elevated
peroxisome proliferator–activated receptor (PPAR)-α and
adenosine monophosphate kinase activity, which encourages the absorption of
glucose and the oxidation of fatty acids. Additionally, it has been
demonstrated that adiponectin has strong anti-atherogenic properties because
it accumulates in the subendothelial region of damaged vascular walls and
inhibits the development of adhesion molecules and the attraction of
macrophages [26].
Studies in obese children and adolescents have revealed that adiponectin
levels are inversely associated to the degree of obesity, insulin
resistance, visceral adiposity, IHCL, and IMCL, while weight loss increases
adiponectin concentrations.
3) Inflammatory cytokines
It is becoming increasingly clear that obesity contributes to chronic
inflammation in a subclinical manner [27]. Thus, adipose tissue functions not only as an energy
reservoir but also as an active secretory organ, releasing peptides into the
circulation, such as inflammatory cytokines. As obesity progresses, the
balance between these peptides is altered, and large adipocytes and
macrophages embedded within them produce more inflammation-inducing
cytokines (i.e., tumor necrosis factor–α and interleukin-6)
and fewer anti-inflammatory peptides such as adiponectin. One hypothesis
posits that, as adipocytes store energy, the perilipin borders of the fat
vacuoles break down, leading to the adipocyte’s dismiss. Cell death
then recruits macrophages in the adipose tissue, especially the visceral
compartment, which also secrete inflammatory cytokines in the process of
clearing debris, initiating a pro-inflammatory cascade that anticipates and
possibly drives the development of systemic insulin resistance, diabetes,
and endothelial dysfunction [28].
Elevated levels of CRP also correlate with other components of MetS in obese
children [29]. Thus, inflammation may
be one of the links between obesity and insulin resistance, and it may also
promote endothelial dysfunction and early atherogenesis.
Most of the aforementioned molecules have been associated with elements of
MetS and its characteristic pattern of lipid partitioning. Specifically, low
adiponectin levels have been associated with insulin resistance, low-grade
inflammation, and increased intramuscular fat [30]. Moreover, component analyses of plasma leptin
concentrations and the variables that are considered relevant to MetS
revealed that plasma leptin concentrations were clustered with insulin
resistance and hyperinsulinemia [31].
Screening
Clinicians should recognize children who are obese and overweight and at risk for
T2DM and CVD. It is important to screen these children for behavioral and medical
risks, including persistent obesity, as well as its associated co-morbidities [32]. A significant risk factor for childhood
obesity that needs to be considered during the screening evaluation is the presence
of obese parents [32]. The history and
physical examination are the first steps in the comorbidity screening process.
Clinicians should request information about the signs and symptoms for associated
comorbidities that may be present, such as PCOS, liver disease, and obstructive
sleep apnea, which can be confirmed as a comorbidity with polysomnography [32]. Serum alanine aminotransferase and
aspartate aminotransferase levels are respectably effective screening tests for
fatty liver disease. When values are double the upper limit of normal, a pediatric
hepatologist should be consulted [32].
Bi-annual liver disease screening is recommended starting at the age of 10 years for
children with obesity or those who are overweight with other risk factors [33]. Screening for T2DM is recommended in
overweight (≥85th percentile) or obese (≥95th
percentile) children and adolescents with ≥1 of the following risk factors:
(I) Family history of T2DM in first- or second-degree relatives; (II) at risk race
or ethnicity (Native American, African American, Latino, Asian American, and Pacific
Islander); (III) signs of insulin resistance or associated conditions, such as
acanthosis nigricans, hypertension, dyslipidemia, PCOS, or a history of being born
small for gestational age; and (IV) maternal history of diabetes or gestational
diabetes during the child’s gestation [34]. The ADA recommends starting screening at the age of 10 years or at
the onset of puberty, whichever arrives earlier, and be repeated every three years
[34]. Generally, fasting plasma glucose,
2-hour plasma glucose measured during the 75-gram oral glucose tolerance test, and
the glycated hemoglobin test are equally appropriate for diagnostic screening [34]. Starting at age 3 years, blood pressure
should be obtained annually at all regular health check-ups, and results should be
compared to reference ranges from tables issued by the NHLBI [35]. Finally, children should be routinely screened for
dyslipidemia with universal lipid screening between 9–11 years of age with a
non-fasting, non-HDL lipid profile. Screening children 2–8 years of age with
fasting lipid profiles is recommended for obese children since obesity is considered
a moderate- to high-risk factor [35]. The
NHLBI recommends repeating lipid profiling in overweight adolescents at 12–16
years of age. The level of abnormality, the presence of additional known risk
factors, and the presence of high-risk diseases should determine whether to pursue
dietary or medicinal intervention [35].
Prevention and Treatment of Metabolic Syndrome
1. Prevention
Pediatric obesity prevention involves promoting healthy diet and increasing
physical activity as the primary prevention strategies in order to avoid MetS in
children. Lifestyle modifications to achieve a healthy diet include increasing
consumption of vegetables and fruits; increasing fiber intake while reducing
dietary fat; and avoiding carbonated beverages, refined carbohydrates,
high-fructose corn syrup, high sodium, and processed foods [36]. Fruit juice should be replaced with
whole fruits for additional nutritional value. Physical activity is also
recommended 3–5 days per week with ≥20 min of vigorous short
bursts to improve metabolic measures in children and adolescents, which may
prevent obesity [36]. A meta-analysis
conducted by Kamath et al. found that lifestyle modification had a positive
effect on reducing sedentary behavior in long-term trials and reduced unhealthy
dietary habits. In comparison to adolescents, those adjustments were more
successful with children [37]. Adopting
healthy sleep habits, limiting non-academic screen time, involving the entire
family and community in prevention efforts, and using school-based programs and
community engagement for the prevention of pediatric obesity are additional
lifestyle changes that can lower the risk of developing obesity [36].
2. Treatment
In general, childhood MetS is treated through weight reduction by lifestyle
modifications, including dietary intervention, increased physical activity, and
the management of various disease-specific factors. Pharmacological treatments
and bariatric surgery are other alternatives for managing obesity.
1) Lifestyle modifications and behavioral treatment
For the first step to change, clinicians should assess patients and families.
In this way, family and patient interventions will be more easily
incorporated. When compared to programs focused solely on the child, those
that involved the entire family in lifestyle change were found to have
favorable outcomes for lowering BMI [37]. Comprehensive weight reduction programs, including
nutritional, physical activity, education, and behavioral therapy, have been
linked to improvements in a number of metabolic parameters, including blood
pressure and lipid profile indices in obese children and adolescents [38]. Obese children and adolescents
should be screened for mental health, including eating disorders,
depression, and other mood disorders. Support and referral to available
behavioral health resources for those disorders are essential.
(1) Dietary intervention
Basic dietary recommendations are mostly based on low-fat diets and,
recently, low-carbohydrate diets are gaining popularity [39]. Recent Endocrine Society
guidelines recommended avoiding beverages sweetened with sugar,
elimination of fructose-rich corn syrup, and decreased consumption of
processed foods high in salt and saturated dietary fat in children over
2 years of age and adolescents. Furthermore, consumption of dietary
fibers, vegetables, and whole fruits other than fruit juice or
carbonated drinks is encouraged. Additionally advocated for nutritional
intervention are education about portion control, improved product
labeling, and the consumption of frequent meals to prevent snacking
[36]. In addition, because
eating fast and the risk of developing T2DM are highly associated, slow
eating should be taught as an important eating habit [40]. According to a systematic
review of 107 trials, low-carbohydrate diets had weight reduction
outcomes proportional to those of low-fat diets and had no particularly
negative impact on blood pressure, insulin, fasting serum glucose, or
cholesterol levels [39].
(2) Physical activity
The second-most important behavioral intervention is physical activity.
The AAP and the European Society for Pediatric Endocrinology advise
engaging in physical activity regardless of weight status, aiming for at
least 30 minutes of daily moderate to vigorous activity, and keeping
non-academic screen time to no more than one to two hours per day [36,41]. It is recognized that inactivity can decrease insulin
sensitivity in skeletal muscle, which can be reversed by increasing
physical activity. Physical activity is also helpful in improving the
lipid profile by lowering LDL and triglyceride concentrations and
increasing the HDL concentration [42]. Regular physical activity increases cardiorespiratory
fitness by reducing blood pressure, arterial stiffness, and abdominal
fat [43]. Most children,
including children with obesity, do not achieve these recommendations.
Exercise physiologists and physical therapists can help these children
by developing individual exercise plans, especially when movement is
limited by gross motor delay or musculoskeletal pain [44].
2) Pharmacological therapies
As previously stated, lifestyle modification therapy is the primary form of
treatment for MetS. When patients are unable to achieve their weight loss
objectives with lifestyle modification therapy alone, pharmacotherapy is the
next logical treatment option to consider (Table 2) [45-49]. The indication for pharmacotherapy
to treat pediatric obesity includes an age of ≥10 years and a BMI in
the ≥95th percentile with weight-related co-morbidities or
a BMI that is ≥120% of the 95th percentile, regardless of
comorbidities, without an appropriate response to lifestyle modification
[36]. Intense lifestyle
modification programs should be considered along with pharmacotherapy [32].
Table 2.
Medications for weight loss in the pediatric population
| Drug name | Mechanism of action | FDA indication | Off-label drug use | Side effects |
|---|---|---|---|---|
| Orlistat [45] | Pancreatic and gastric lipase inhibitor | Obesity≥12 years of age | Not indicated | Flatulence, oily spotty stools, diarrhea, vitamin/mineral deficiency |
| Exenatide [46] | GLP-1 agonist | T2DM in adults | <18 years of age for obesity (polygenic with the presence of diabetes, hypothalamic, syndromic) | Bloating, diarrhea, flatulence |
| Liraglutide [47,48] | GLP-1 agonist | 3.0 mg of liraglutide approved for obesity in adolescents (12–17 years) with a reduced-calorie diet and increased physical activity | Not indicated | Bloating, nausea/vomiting, abdominal pain, the elevation of pancreatic amylase and lipase |
| Metformin [49] | Activation of protein kinase pathway | ≥10 years of age, T2DM | PCOS, insulin resistance, prediabetes, metabolic syndrome, anti-psychotic medication–induced weight gain, stress eating/emotional eating | Bloating, diarrhea, flatulence, contraindicated with risk of lactic acidosis |
Options for pharmacotherapy to treat pediatric obesity are limited. Orlistat,
a lipase inhibitor that blocks the absorption of fats from the human diet,
is the only medicine recognized by the American Food and Drug Administration
(FDA) for long-term use in the treatment of pediatric obesity (≥12
years of age). However, due to its modest efficacy (2.61-kg weight loss
after one year of treatment), its therapeutic application is somewhat
limited, and many adolescents may find its side effects unpleasant
(flatulence; oily, spotty stools; and diarrhea) [45].
Glucagon-like peptide-1 receptor (GLP-1) agonists include exenatide and
liraglutide. Exenatide has FDA approval for adult T2DM, and a liraglutide
3.0-mg injection has FDA approval for adult obesity. Recently, a liraglutide
3.0-mg injection received FDA approval for the treatment of obesity in
adolescents (aged 12–17 years) with a body weight>60 kg and an
initial BMI≥30 kg/m2 combined with a reduced-calorie diet
and increased physical activity. GLP-1 agonist–associated weight
reduction appears to be related to decreased gastric emptying and increased
satiety and appetite suppression. Recently, a randomized controlled trial of
adolescent obesity with a 56-week liraglutide treatment period reported that
the use of a liraglutide 3.0-mg injection combined with lifestyle
modification led to significant reduction in BMI z-score [46]. In patients with syndromic and
hypothalamic obesity with hyperphagia, GLP-1 agonist therapy has the
potential for weight reduction and weight stabilization [47,48].
Metformin, a biguanide primarily used for glycemic control, has been used
off-label to achieve weight loss in children. Meformin is FDA-approved for
children≥10 years of age for T2DM. Currently, in a systematic review
of randomized controlled trials on children and adolescents, Masarwa et al.
[49] assessed the effectiveness
of metformin. Researchers discovered that metformin reduced BMI z-score
modestly in obese subjects and had the greatest effect on children and
adolescents with NAFLD. Several studies reported improvements in fasting
plasma glucose and insulin resistance, but not in lipid levels. As compared
to a placebo, metformin was associated with double the number of
gastrointestinal adverse effects [49]. By this finding, the question of whether metformin is an
appropriate adjuvant therapy to lifestyle change for the treatment of
pediatric obesity is raised.
3) Surgical therapies
As a standard course of treatment, surgical intervention for childhood and
adolescent obesity is still not approved. In children and adolescents,
research on the effects of surgery on growth and development is limited.
Thus, it should only be considered when growth and puberty are complete.
Also, surgical treatment for children and adolescents in growing process
should be limited to strict standards. Before considering surgical
treatment, evaluation for previous treatment, such as multidisciplinary
treatment and pharmacotherapy, should be conducted. Furthermore, adolescents
and their families should have psychological stability and competence,
availability for appropriate follow-up care, and a demonstrated ability to
comply with healthy dietary and activity routines. It is also very important
that the patient has a reliable caretaker who can provide physical and
psychosocial support through the entire process. Recently, metabolic and
bariatric surgery (MBS) has been shown to be an effective treatment for
severe obesity in adolescences, and studies have reported significant
improvements in co-morbidities associated with obesity [50]. According to the most recent
recommendations issued by the American Society for Metabolic and Bariatric
Surgical Pediatric Committee, MBS could be considered for children
≥10 years of age with a BMI that is ≥120% of the
95th percentile who also have a weight-related co-morbidity,
such as T2DM, hypertension, NAFLD, and/or obstructive sleep apnea, or those
with a BMI that is ≥140% of the 95th percentile regardless
of co-morbidities [50]. According to
the recommendations, treatment should be provided to adolescents who have
previously attempted to reduce weight, have a low Tanner stage, and have
immature bone growth [50]. Lack of
evidence, however, suggests that MBS may have a negative impact on a
child's pubertal status as determined by Tanner staging, linear
development, or height. The impact of MBS on children's pubertal
development should therefore be the subject of additional research. MBS has
the potential to result in both macro- and micronutrient deficit, therefore
lifetime supplemental protein, iron, calcium, and vitamins are necessary to
prevent deficiencies [50].
Gastroesophageal reflux, which has been recorded in >12%–30%
of patients requiring long-term usage of proton pump inhibitors, is another
side effect of MBS [51]. Patients
undergoing any of these surgical procedures are at risk of anastomosis site
leaking, hernia, stricture, and wound infection; however, children are less
likely than adults to experience these consequences [51].
Conclusion
It is known that early diagnosis and successful treatment of MetS are key to reducing
the risk of cardiometabolic disease. Although sometimes the diagnosis is delayed
because MetS is overlooked by families, early identification and management are
crucial and help to attenuate the disease progression. Screening children and
adolescents for overweightness and obesity by considering up-to-date reference
values, age- and sex-related percentiles, and comorbidities using good clinical
judgment is highly recommended. According to the 2017 Korean National Growth Charts
(KNGC2017), BMI for age≥85th percentile and
<95th percentile is defined as overweight and BMI for
age≥95th percentile is defined as indicative of obesity [52]. To provide specialized care, it is crucial
to assemble a knowledgeable multidisciplinary team, which has to be composed of a
pediatrician, mental health professional, nutritionist, nurses, and other referral
specialists for complications [35]. The
health system must, however, confront with the question of how to support such a
multidisciplinary team financially.
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