Metabolic Syndrome

Abstract

The metabolic complications associated with obesity, such as insulin resistance, hypertension, hyperlipidemia, and the potential for arteriosclerotic heart disease, are on the rise in the pediatric population. Definition of the metabolic syndrome and determination of its significance is a changing process in which resolution has not yet been achieved, and its constellation of signs may have clinical significance beyond that of the individual risk factors.After completing this article, readers should be able to:With the burgeoning global epidemic of childhood obesity, there is growing concern that the metabolic complications associated with obesity, such as insulin resistance, hypertension, and hyperlipidemia, historically encountered primarily in adults, are now on the rise in the pediatric population also. The metabolic syndrome (MetS) is characterized by a constellation of metabolic risk factors and is associated with the development of atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) in adults. Efforts to identify children and adolescents at risk of developing MetS to prevent or mitigate its associated outcomes have been active areas of research within this population. However, several questions remain with regard to establishing a consensus definition of pediatric MetS and its long-term clinical implications. Does the constellation of signs have clinical significance beyond that of the individual risk factors?Although the term “metabolic syndrome” was first used by Hanefeld and Leonhardt in the early 1980s, (1)(2) the observation that certain metabolic disturbances appeared to cluster together has been noted since the beginning of the past century, when Swedish and Spanish physicians Kylin and Marañon independently described the frequent copresentation of diabetes mellitus (DM) and hypertension. (1)(3) The MetS has since been variously labeled as the deadly quartet, Syndrome X, and the insulin resistance syndrome, and its definition has evolved as more is known about the pathophysiology of the syndrome and its associated clinical features.Gerald Reaven introduced the concept of insulin resistance as a common etiologic factor for the group of metabolic disturbances and disorders he collectively called Syndrome X. In addition to hypertension, Reaven’s definition included impaired glucose tolerance (IGT), hyperinsulinemia, high levels of very-low-density lipoprotein (VLDL) triglycerides (TGs), and low levels of high-density lipoprotein (HDL) cholesterol. (4) Central adiposity was added subsequently as a clinical feature of MetS by Norman Kaplan, (5) and current definitions of MetS now include the following key characteristics: hyperinsulinemia or insulin resistance, dyslipidemia, hypertension, and obesity, with a particular emphasis on central adiposity.Over the past 15 years, several organizations, including the World Health Organization, the International Diabetes Foundation (IDF), the American Heart Association (AHA), and the National Heart, Lung, and Blood Institute (NHLBI), have proposed diagnostic criteria to better define MetS in adults. (6) In 2009, representative members from the AHA, NHLBI, IDF, and several other major organizations released a joint interim statement proposing a unified set of common criteria for the clinical diagnosis of adult MetS in an effort to reconcile the different clinical definitions that existed. (7) As a result, each of the 5 clinical measures (body weight, TGs, HDL, blood pressure [BP], and glucose) was given a single set of categorical cut points; an exception was waist circumference (WC), which was defined by population and country-specific definitions.In light of the challenges of defining MetS in adults, defining clinical criteria for pediatric MetS is complicated further by the physiologic changes that occur during growth and development throughout childhood and puberty. For example, insulin resistance increases in early puberty, but stabilizes in mid-adolescence and may vary also between genders. (8) Lipid profiles also have been noted to vary across ages. (9)Additionally, there are several other challenges to defining pediatric MetS and to understanding its clinical significance in children. These barriers include the frequently subtle abnormalities that manifest in most children who have suspected metabolic disturbances; the lack of definitive normal ranges of insulin levels throughout childhood and puberty; and the absence of WC parameters to define central obesity associated with morbidity related to MetS in the pediatric population. (10) As a result, there are currently no consensus guidelines providing specific diagnostic criteria for pediatric MetS. Instead, criteria frequently have been adapted from adult standards of the National Cholesterol Education Program Adult Treatment Panel III (ATPIII) criteria, or other definitions by using gender- and age-specific normal values appropriate for children and adolescents.In 2007, the IDF published a proposed set of criteria specific to children and adolescents to provide guidance on establishing a unified definition for pediatric MetS. (11) Table 1 demonstrates the wide range of diagnostic parameters that have been used in research studies frequently cited in the literature along with the diagnostic criteria proposed by the IDF.Given the varying definitions available for pediatric MetS, determining its prevalence in children and adolescents is problematic. An analysis of the NHANES 1999–2002 data by Cook et al (12) compared the prevalence of pediatric MetS by using four previously published definitions and found that the prevalence of pediatric MetS ranged from 2% to 9% in the general population and from 12% to 44% in obese children, depending on the definitions used. Goodman examined prevalence rates in a school-based study comparing the National Cholesterol Education Program/ATPIII and World Health Organization criteria and reported overall prevalence rates of 4% and 8%, respectively. In the same study, the prevalence of MetS in obese patients increased substantially to 20% and 39%, respectively. (13) By using modified ATPIII criteria, de Ferranti et al (14) found an overall prevalence of 9% in a sample of US adolescents from the NHANES 1988–2004 data and also showed racial and ethnic distributions similar to adults, with Mexican-Americans and non-Hispanic white individuals having greater prevalence than non-Hispanic black people.There is concern, however, that existing criteria underestimate the MetS prevalence in certain high-risk populations, such as non-Hispanic black individuals. (15) Although prevalence may vary because of inconsistent criteria, the variations in prevalence across different populations suggest a need to define diagnostic parameters appropriate for these populations. Not surprisingly, these studies consistently demonstrate a significant increase in prevalence of pediatric MetS in obese children compared with the general population.The clinical utility of diagnosing pediatric MetS is also complicated by the instability of the diagnosis throughout childhood and adolescence. In a convenience sample of children ages 6 to 12 years at risk for developing adult obesity, 46% of those diagnosed as having MetS at baseline did not meet the diagnostic criteria for MetS at long-term follow-up (mean 5.6 ± 1.9 years). (16) Goodman et al (17) reported both loss (49%–56% of participants depending on criteria used) and gain (4%–5%) of a MetS diagnosis at 3-year follow-up in a school-based study of 1,098 adolescents.The lack of stability in the diagnosis of pediatric MetS raises several questions regarding the optimal approach for screening, in particular, when and how to screen children at risk for MetS. In addition, this diagnostic uncertainty affects the ability to devise appropriate strategies for the management of MetS in the clinical setting.Although studies in adults show strong evidence that those who have MetS are at increased risk of developing both T2DM and atherosclerotic cardiovascular disease, (18) as well as other obesity-related conditions such as nonalcoholic fatty liver disease (NAFLD), (19) polycystic ovarian syndrome, (20) and obstructive sleep apnea, (21) the long-term outcomes of children and adolescents who have or are at risk for pediatric MetS are not well established. Studies do suggest that pediatric MetS predicts adult MetS, (22)(23) and that obesity, particularly central obesity, correlates strongly with cardiovascular risk among youth; (24)(25)(26) but limited data exist to support the direct relationship between pediatric MetS and subsequent progression to adult cardiovascular outcomes such as atherosclerotic cardiovascular disease and T2DM.Recognizing pediatric MetS as a unique cardiovascular risk predictor compared with its individual components remains controversial. Analysis of data from the Bogalusa Heart and Cardiovascular Risk in Young Finns studies reveals that the categorical definition of MetS is no better than screening with high BMI to identify youth at risk of developing long-term outcomes such as adult MetS, subclinical atherosclerosis, and T2DM. (27) However, in another analysis from the Bogalusa Heart Study, the authors report a stronger correlation of pediatric MetS with the persistence of multiple cardiovascular risk clustering over an 8-year period, compared with individual risk factors alone (systolic BP, insulin level, and total-to-HDL cholesterol ratio), suggesting that these risk factors may reinforce each other and track together as a group. (22) Studies also appear to indicate an association between pediatric MetS with both subclinical cardiovascular disease in young adults (23)(28) and T2DM. (29) More longitudinal studies are needed to clarify these relationships and evaluate the effectiveness of preventive and therapeutic interventions for pediatric MetS.The etiology of MetS is incompletely understood; however, insulin resistance and hyperinsulinemia are thought to be central to the development of MetS and may play a role in the pathogenesis of its individual metabolic components. Peripheral effects of insulin resistance on various organ systems is thought to explain some of the differences in the expression of MetS and its associated conditions such polycystic ovary syndrome (PCOS), NAFLD, and obstructive sleep apnea. (10)(30) Although insulin resistance appears to have an important role in the underlying mechanism of MetS, not all individuals who have insulin resistance proceed to develop MetS, (31) suggesting that other factors may be contributing to the pathogenesis of MetS. Obesity, particularly abdominal or visceral obesity, inflammatory mediators, adipocytokines, cortisol, oxidative stress, genetic predisposition, and lifestyle characteristics such as physical activity and diet are all thought to be involved in the pathophysiologic framework for MetS. (10)(32)(33)Genetic and environmental factors appear to influence an individual’s risk of developing MetS. Familial clustering for MetS risk factors is seen in several studies, suggesting that genetic effects or shared environments may contribute to development of MetS. (34)(35)(36) Children of parents who have early coronary artery disease in the Bogalusa Heart Study were more likely to be overweight beginning in childhood and commonly presented with components of MetS, including elevated levels of total cholesterol, low-density lipoprotein (LDL), and plasma glucose. (37) Furthermore, children having at least 1 parent who has MetS have significantly higher levels of central obesity and insulin resistance than children in whom neither parent has MetS. (38)Components of MetS, including obesity, insulin resistance, cardiovascular disease, and T2DM, continue to affect black and Hispanic children disproportionately more than white children; (39)(40)(41) however, the rates of MetS in black youth are lower than in non-Hispanic white or Hispanic children. (42)(43) In contrast, when using lipid thresholds specific to black individuals, the prevalence of MetS among black youth was similar to non-Hispanic white and Hispanic children. (44) These disparities and inconsistencies have prompted a call for developing criteria specific to race and ethnicity in the evaluation of MetS to ensure appropriate identification of youth at risk for MetS and development of future adverse cardiovascular outcomes. (15)In addition to physical activity being beneficial for weight management and obesity prevention, (45) physical activity alone improves several cardiovascular risks. Studies demonstrate that physical activity appears to be associated independently with improved insulin sensitivity; (46) lower LDL and TG and higher HDL concentrations; (47) and improved endothelial function, such as reduced systolic and diastolic BPs, arterial stiffness, and arterial wall remodeling in prepubertal obese children. (48) Additionally, increased physical activity appears to have an anti-inflammatory effect. (49)(50)Tobacco use has long been recognized as a significant risk factor for cardiovascular disease and also may be associated independently as a risk factor for MetS. One observational study reported a dose–response relationship between tobacco smoke and MetS among adolescents and speculated an association between tobacco and insulin resistance. (51)There is strong evidence supporting the association between obesity with insulin resistance, T2DM, and atherosclerotic cardiovascular disease. (52)(53) Specifically, abdominal obesity due to accumulation of visceral fat is associated with increased cardiovascular risk independent of total body fat in adult populations. (54) Although BMI is used widely as a standard measure for obesity, BMI does not always reflect central adiposity and cannot differentiate the contributions made by muscle, bone, and fat. (55)(56) WC and waist-to-hip ratio have been suggested frequently as potential surrogates to determine the degree of visceral fat. (57) WC is an independent predictor of insulin resistance in youth, (58) and is associated with hypertension and dyslipidemia. (59) For these reasons, WC has been suggested as a more reliable measure for predicting MetS than BMI alone.At this time, however, routine use of WC to measure central adiposity in children is not recommended because of insufficient information and lack of specific guidance for clinical application, according to an expert panel of the American Medical Association and the Centers for Disease Control and Prevention Task Force on Assessment, Prevention, and Treatment of Childhood Obesity. (60)Dyslipidemias, especially high TG and low HDL cholesterol levels, are strongly associated with insulin resistance in children and adolescents. (22)(61) In general, the lipid abnormalities associated with insulin resistance are thought to result from an increased flux in free fatty acid delivery to the liver, resulting in hepatic insensitivity to the inhibitory effects of insulin on VLDL secretion and overproduction of TG-rich VLDL particles. (62)(63)(64) This process may be mediated by abnormal levels of inflammatory markers, such as adipokines and cytokines, associated with visceral obesity. (62)HDL cholesterol metabolism also is altered by the increased levels of VLDL through the activation of hepatic lipase, forming small dense HDL and increasing clearance of HDL from the circulation. (63) Small dense LDL, which is believed to have increased atherogenic potential, is associated with abdominal obesity, visceral fat, and insulin resistance in adults and children. (65)(66)The association between insulin resistance and essential hypertension is well established, (67) and several mechanisms appear to be involved in this process. Insulin has vasodilatory effects on the endothelium, resulting from complex pathways that stimulate endothelial production of nitric oxide, a potent vasodilator. (68)(69) However, in individuals who have insulin resistance, even before any evidence of glucose intolerance, endothelial dysfunction and the vasodilatory response frequently are blunted. (35) These effects may occur because of the role of insulin in sodium reabsorption, (70)(71) the increased sympathetic tone due to hyperinsulinemia and obesity, (72)(73) and indirect impairment of vasodilation from the presence of fatty acids. (74)The cluster of metabolic abnormalities associated with MetS may have an effect on BP greater than each of the individual factors alone. In one study examining the relationship between insulin resistance and BP in 11- to 15-year-olds, correlations were found when metabolic factors (fasting insulin, insulin resistance, TG, HDL cholesterol, or LDL cholesterol ) were considered as a group; but no correlations were seen when each factor was considered independently. (75) This clustering effect supports the importance of considering MetS as a unique collective entity rather than just considering independent risk factors to determine cardiovascular risk.The spectrum of diseases related to impairments in glucose metabolism and hyperglycemia results from either defects in insulin action, ineffective secretion or clearance of insulin, or a combination of those pathophysiologic causes. The development of insulin resistance leading to an impaired fasting glucose level or IGT and on to T2DM is documented in both adult (76) and pediatric populations. (77)(78) However, all children who have impaired glucose tolerance are not certain to progress to a diagnosis of T2DM.To examine this question, Weiss et al followed obese youth who have IGT over a 12-month period and illustrated the dynamic variations of their glucose tolerance status: 46% reverted to normal glucose tolerance, 30% continued to have IGT, and 24% progressed to T2DM. (79) On the other hand, the same study demonstrated that all of the children who did eventually develop T2DM had started initially from an IGT state, suggesting that IGT could be considered a “prediabetic” state. With the growing prevalence of childhood obesity and T2DM in adolescents and the risk of accelerated cardiovascular outcomes in youth who have T2DM, (80) early identification of children who have evidence of hyperglycemia who may be asymptomatic and yet have signs of the other components of MetS is an important step in managing those children who may require more aggressive monitoring and interventions.Increasing recognition of obesity as a chronic, and the association of MetS with has been of a that has been in cardiovascular is in obese children but has not been to insulin resistance or MetS. studies have examined other potential inflammatory markers, including adipocytokines, and with some evidence for a direct association with obesity, insulin resistance, and dyslipidemia. Although inflammatory are not a of any current diagnostic criteria the recognition of the role of and its with MetS and cardiovascular disease is important to among the clinical of addition to atherosclerotic cardiovascular disease and T2DM, conditions such as and are associated with MetS and frequently with its individual is a common in primarily characterized by or polycystic is a risk factor for MetS independent of insulin resistance and obesity, and there is a increase in the prevalence of MetS in who have who have should be for other metabolic including high BP, dyslipidemia, and impaired glucose addition, NAFLD, a syndrome from to or of the liver, is associated with dyslipidemia, obesity, and insulin resistance, and is considered a strong predictor of MetS and future cardiovascular disease and T2DM, as is because a liver is however, of and of the liver may indicate the diagnosis in children, the absence of abnormalities in these and results not be to the diagnosis of the challenges and of defining the clinical parameters for pediatric MetS, is that the prevalence of the individual components of MetS, such as obesity, and T2DM, is on the rise among children and adolescents. Although of the of the MetS and its management the with this population in the of to have a screening guidelines do not exist currently for the MetS in the pediatric evaluation and screening should to identify those youth who are at increased risk of developing MetS, particularly children and adolescents who are overweight or from the Bogalusa Heart Study have that the presence of an increasing of cardiovascular risk factors is associated with an increased risk of developing of atherosclerotic cardiovascular disease, such as fatty and in the and coronary screening may to identify children and adolescents who require more aggressive monitoring and to prevent or the progression of developing atherosclerotic cardiovascular in the pediatric population a and approach to cardiovascular In the released Panel on for Cardiovascular Health and Risk in Children and children who are obese should have further evaluation for other specific cardiovascular risk including evaluation of growth and of physical BP, lipid and evidence of insulin resistance and as well as tobacco Table 2 for overweight and physical in the management of obesity. The report also of weight loss in the presence of any combination of multiple individual risk factors for MetS, in addition to management of any associated cardiovascular risk of the MetS with weight and be seen even with small weight including appropriate atherogenic and increasing physical and are the from both the and the and and to is an important step at the of any weight management youth and their through frequent and to identify such as increasing and with may youth and to there are no specific or guidelines on the use of for of MetS. However, for of hypertension, dyslipidemia, and should be considered Although such as have been used for weight and glucose tolerance for children who have T2DM in small studies, there are no existing for the use of in MetS. a also has in normal glucose tolerance in obese children who have IGT in a published studies are to determine there may be a role for in the management of pediatric MetS as an to lifestyle but routine use of in the clinical is not recommended at this to be to and define the MetS in children and adolescents. include identification of better definitions of obesity in children; development of and ranges for the categorical criteria used to define of long-term of children from to better the and outcomes of and of the effectiveness of and the for this article, the at and on the