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0021-7557/07/83-05-Suppl/S204
Jornal de Pediatria
Copyright 2007 by Sociedade Brasileira de Pediatria
REVIEW ARTICLE
Metabolic syndrome: identifying the risk factors
Simão Augusto Lottenberg,1 Andrea Glezer,2 Luiz Alberto Turatti2
Abstract
Objectives: To discuss the metabolic syndrome and identify its risk factors, including in the pediatric age group.
Sources: Indexed review articles.
Summary of the findings: The metabolic syndrome is characterized by insulin resistance and the presence of
risk factors for cardiovascular diseases and diabetes mellitus type 2. Consensus has not yet been reached on itsdiagnostic criteria. This review presents diagnostic criteria defined by the American Heart Association (US NationalCholesterol Education Program), the American Association of Clinical Endocrinologists, the World Health Organizationand the International Diabetes Federation and discusses the possibilities of applying them to children. Pathophysi-ologic features of the syndrome are also covered, principally those related to the perinatal period and childhood.
Conclusions: The metabolic syndrome is being diagnosed with ever greater frequency, principally during
adolescence. Lifestyle changes, such as to diet and level of physical activity are fundamental to prevention. Treatmentwith medication and, in extreme cases, with surgery should also be considered, depending on severity and age.
J Pediatr (Rio J). 2007;83(5 Suppl):S204-208: Metabolic syndrome, diabetes mellitus, cardiovascular risk, dyslipidemia.
Metabolic syndrome: definitions
Cook et al.3 adapted the NCEP criteria and proposed a defini- Metabolic syndrome is characterized by insulin resistance tion of pediatric metabolic syndrome based on the presence and the presence of risk factors for cardiovascular diseases of three out of the following criteria: waist circumference and diabetes mellitus type 2.1 During the 1980s, Reaven,2 greater than or equal to the 90th percentile, fasting glycemia observed that dyslipidemia, arterial hypertension and hyper- greater than or equal to 110 mg/dL, triglycerides greater than glycemia were very often found in combination in a single or equal to 110 mg/dL, HDL-cholesterol less than 40 mg/dL patient and that they indicated increased cardiovascular risk; and arterial blood pressure greater than or equal to the 90th a condition he named Syndrome X. Since then, many differ- percentile. Furthermore, measurement of waist circumfer- ent definitions of metabolic syndrome have emerged. Con- ence in children is not standardized. Some authors have stan- sensus has not yet been reached on the diagnostic criteria for dardized measurements by age and define measurements metabolic syndrome. Table 1 below compares the criteria from the leading institutions that have released publications on the Pathophysiology
Epidemiological studies suggest that there is a relation- In addition to these criteria, which are used to diagnose ship between low birth weight, especially in small for gesta- the metabolic syndrome, other metabolic abnormalities, such tional age infants, and developing metabolic syndrome in as increased fibrinogen and plasminogen activity factor, hype- adulthood. According to the World Health Organization,5 low ruricemia, increased C-reactive protein, hyperhomocysteine- birth weight is the term that should be used to describe infants mia, increased TNF-α expression and reduced adiponectin born weighing less than 2,500 grams. The definition of small for gestational age (SGA), has greater scope and takes into There is no definition of the metabolic syndrome in child- consideration weight and length, according to sex and gesta- hood that is accepted by the entire scientific community.1 tional age.6 Infants born below -2 standard deviations are 1. Doutor, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP, Brazil. Médico assistente, Disciplina de Endocrinologia, Faculdade de Medicina, USP, São Paulo, SP, Brazil. Coordenador, Liga de Diabetes, Hospital das Clínicas, Faculdade de Medicina, USP, São Paulo, SP, Brazil.
2. Doutor, Faculdade de Medicina, USP, São Paulo, SP, Brazil. Liga de Diabetes, Hospital das Clínicas, Faculdade de Medicina, USP, São Paulo, SP, Brazil.
Suggested citation: Lottenberg SA, Glezer A, Turatti LA. Metabolic syndrome: identifying the risk factors. J Pediatr (Rio J). 2007;83(5 Suppl):S204-208.
Metabolic syndrome - Lottenberg SA et al.
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Table 1 - Definitions of metabolic syndrome
AACE = American College of Endocrinology/American Association of Clinical Endocrinologists; BMI = Body mass index; BP = arterial blood pressure; DM2= diabetes mellitus type 2; GTT = oral glucose tolerance test; HOMA = homeostasis model assessment; HWR = hip:waist ratio; IDF = InternationalDiabetes Federation; M = men; NCEP = US National Cholesterol Education Program; SAH = systemic arterial hypertension; Tg = triglycerides; W =women; WC = waist circumference; WHO = World Health Organization.
defined as SGA, which makes it easier to identify in newborns gestational age, it is possible that some individuals classified who have been affected by some degree of fetal suffering. It as low weight were merely premature, and not SGA. Other is estimated that 2.3% to 10% of newborn infants are SGA.
authors have been unable to reproduce Barker's results and, The majority of these children manage to attain normal growth therefore, further studies are needed.7 It is imperative that within the first 2 years of life, known as catch-up growth. Being these studies employ standardized methods to assess gesta- SGA brings with it a risk of metabolic syndrome in adulthood, tional age, such as ultrasound.7 Figure 1 summarizes these especially for those children who recover rapidly soon after birth. In contrast, absence of catch-up growth is a cause ofshort stature and many psychological consequences during Size at birth is fundamentally dependent on placental func- tion and duration of pregnancy. The placenta is the point ofinterchange between the maternal and fetal metabolisms and The causative mechanisms of the relationship between regulates fetal growth by means of the secretion and metabo- SGA and the metabolic syndrome remain obscure, but, cur- lism of growth hormones, such as IGF (insulin growth factor), rently, the hypothesis of fetal programming, by which fetal adaptation to exposure to nutrient scarcity results in a failureto adapt to exposure to an abundance of nutrients, is widely A variety of situations, such as malnutrition, infection, accepted.8,9 This hypothesis, also known as the Barker maternal arterial hypertension, gestation or diabetes, inflam- Hypothesis,10 postulates that certain structures of the organs mation and hypoxia are responsible for exposing the fetus to have their functions programmed during embryonic and fetal adipokines, cytokines and growth factors and to hypersecre- life. This programming will determine the balance (set point) tion of corticoids, hyperinsulinemia, hyperleptinemia and IGF- of adult physiological and metabolic responses.8 Barker et al.
axis abnormalities.13 This environment causes changes to found that the prevalence of insulin resistance at 50 years of metabolism, the immune system, the vascular system, hemo- age was 10 times greater among individuals who had been dynamics, the renal system and growth. Some authors believe that increased oxidative stress suffered in these situations is In contrast, Neel11 and Hattersley & Tooke,12 have offered directly related to modulation of genes related to the action a different hypothesis for the emergence of metabolic syn- of insulin and modulation of arterial blood pressure, and, drome in adulthood. For these authors, insulin resistance is therefore, may be one of the mechanisms behind the emer- determined genetically and the insulin resistant genotype is gence of the metabolic syndrome in adulthood.14 Infants born the factor that determines low birth weight, glucose intoler- at high weights are also at increased risk of metabolic syn- ance and arterial hypertension. The criticism that some drome, although for low birth weight babies the risk is much authors7 have made of the work by Barker et al. is that the greater. There are currently several ongoing prospective and weight assessed was that achieved by 1 year of age and not randomized studies attempting to prevent oxidative stress at birth. Furthermore, since ultrasound was not used to assess S206 Jornal de Pediatria - Vol. 83, No. 5(Suppl), 2007
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Figure 1 - Hypotheses to explain the relationship between SGA and
In pregnancies where uterine growth is restricted, there 95th percentile by age and HDL-cholesterol below the 5th per- is increased placental vascular resistance, which in turn centile by age. The prevalence of more than two components increases afterload on the fetal heart, which may impact on of the metabolic syndrome at any given time was 50% for LGA fetal programming for cardiovascular disease. A deficiency in group/mothers with gestational DM, 29% for LGA group/ the action of the placental enzyme 11βHSD 2 (hydroxys- control mothers, 21% for AGA group/mothers with gesta- teroid dehydrogenase type 2) provokes increased exposure tional DM and 18% for AGA group/control mothers. The status to maternal cortisol, which may program the fetus for arterial of LGA and maternal obesity, individually, doubled the risk of hypertension and metabolic diseases. The placenta functions developing metabolic syndrome. The risk of developing meta- as a sensor of nutritional status, regulating nutrient trans- bolic syndrome did not differ between the LGA and AGA port in accordance with supply. This is why the placenta plays groups, but was increased in the LGA group with mothers with a fundamental role in fetal programming. Changes to the maternal compartment can cause mitigation of placental More recently, some authors hypothesize that one impor- genes, increasing oxidative stress and modifying placental tant determinant of the emergence of metabolic syndrome in adulthood is rapid weight gain, especially fat, during the post-natal period, which is very common among SGAs with Newborn infants subjected to a hyperinsulinemic uterine catch-up growth. From this fact it can be concluded that the environment also exhibit an increased risk of developing Barker hypothesis could be applied to the postnatal period.6 metabolic syndrome in adulthood. Boney et al.16 assessed thedevelopment of metabolic syndrome in individuals who were Accumulation of adipose tissues, particularly in the large for gestational age (LGA) and appropriate for gesta- abdominal region, is fundamental to triggering off the meta- tional age (AGA). The study followed-up 84 children in the LGA bolic syndrome. There is an association between adipose tis- group and 95 in the AGA group, at ages 6, 7, 9 and 11 years, sue and the principal inflammatory cells, leading to an the mothers of whom did or did not have a history of gesta- increase in production of inflammatory mediators and tional diabetes. The children were subdivided into four groups: increased liberation of free fatty acids, the effects of which LGA with control mothers, LGA with mothers with gestational are felt both in the Langerhans beta islet cells and their recep- DM, AGA with control mothers and AGA with mothers with ges- tors and also in the vascular wall. Studies with children and tational DM. Anthropometric and biometric measurements adolescents have confirmed that these phenomena begin were taken at 6, 7, 9 and 11 years. Metabolic syndrome was defined based on presence of obesity (BMI > 85th percen- Metabolic syndrome in the pediatric age group
tile), systolic or diastolic arterial blood pressure above the95th percentile, fasting glycemia above 110 mg/dL and post- According to the NCEP diagnostic criteria, the prevalence prandial glycemia above 140 mg/dL, triglycerides above the of metabolic syndrome among American adults was 6.7% for Metabolic syndrome - Lottenberg SA et al.
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the age group from 20 to 29 years, 43.5% for 60 to 69 years It is of fundamental importance to treat childhood obe- and 42% among those more than 70 years old.18 Although it sity, and, in order that this treatment is successful, it is fun- is more common among the elderly, the incidence rate of damental to involve the child/adolescent, their family and metabolic syndrome at earlier ages has been increasing, espe- their social environment, in order to encourage lifestyle cially due to lifestyle changes and the increase in obesity.19 The prevalence of metabolic syndrome among American ado-lescents is 4.8%, varying depending on age, sex, ethnic ori- Changes aimed at achieving healthy diet must be gin, social strata and presence of obesity.20 embarked on by the entire family, with the intention ofincreasing the consumption of fruit, vegetables, skimmed milk Insulin resistance is the pathophysiologic basis for the products and water, two fraction feeding and reduce consump- emergence of the metabolic syndrome. Some prospective tion of fried food, pastries, sweets and processed meat prod- studies, like the Cardiovascular Risk in Young Finns Study and the Bogalusa Heart Study have demonstrated that hyperin-sulinemia and, in particular, childhood obesity, are risk fac- Promotion of physical activity, whether programmed or tors for the metabolic syndrome and that early not, reducing the child's idle time, especially in front of the hyperinsulinemia precedes the emergence of the metabolic television and computer, is another crucial point. The entire syndrome, even in childhood. Childhood obesity, defined as a family should also be involved in this process.
BMI greater than the 95th percentile for age, after 3 years,exhibits an important association with obesity in adulthood, In pediatrics, pharmacological treatment of obesity should and its prevalence has tripled over the last 3 decades. Insulin be restricted to cases that are most resistant to clinical treat- resistance can be assessed in a variety of ways and, in clinical ment and of the greatest severity. In the United States, only practice, insulinemia and the HOMA index (homeostasis model sibutramine and orlistat have been approved, for use with chil- assessment) are widely used. However, these methods have not yet been standardized for children and adolescents. For Metformin is indicated for children with glucose intoler- example, Goran & Gower21 established insulinemia cut-offs, ance or diabetes mellitus type 2. In these patients the drug according to puberty stage: 15 mcU/l for prepubescents, has an anorexigenic effect, reducing glucose and insulin lev- > 30 mcU/l for pubescents and > 20 mcU/l for postpubes- cents. Tresaco et al.22 defined a cutoff of 3 on the HOMA-IRindex, in Spanish children.
Hypertension and dyslipidemia should also be treated with Glucose intolerance and insulin resistance are often found lifestyle changes and drugs, depending on the severity of the among obese children and adolescents. The individuals who are at greatest risk of developing diabetes mellitus type 2 Bariatric surgery for the treatment of adolescent obesity those who are obese and those who have acanthosis nigri- is an extremely invasive procedure and it can only be indi- cans and a family history. In general, after ten years of age, cated in extremely restricted circumstances in this age group.
adolescents develop this type of diabetes, possibly because The American Pediatric Surgical Association Clinical Task Force the hormonal changes of puberty contribute to exacerbation on Bariatric Surgery recommends that adolescents may be of the disease. Sinha et al.23 diagnosed 4% of obese adoles- candidates for the procedure if they have a BMI greater than cents as having diabetes mellitus type 2. In general, diabetic 50, or greater than 40 and associated with comorbidities patients exhibit other cardiovascular risk factors, such as arte- (sleep apnea, diabetes mellitus type 2), are at a minimum Tan- rial hypertension, present in 17 to 32%, hypertriglyceri- ner puberty stage of III, a multidisciplinary team has failed to demia, present in 4 to 32%, and sleep apnea, present in 6% achieve a response after at least 6 months’ treatment, medi- cal and psychological assessments have been completed, Studies like the Bogalusa Heart Study and the Muscatine there are severe problems socializing, there is good family Study have demonstrated that obesity in adolescents is cor- support and if they are over 13 years old and have the capac- related with a proatherogenic dyslipidemic profile, with increased LDL cholesterol, potentiating the cardiovascular In summary, treatment and prevention of childhood obe- risk, itself already elevated due to the obesity.25 sity have become a public health priority. Acquisition of exces- Treatment
sive fat during the postnatal period is related to insulinresistance in adulthood and breastfeeding may prevent this Weight loss has a major impact on the metabolic syn- obesity.7 Appropriate nutrition and increase physical activity, drome. Published data demonstrate that a reduction of 7% to while still in childhood, are, therefore, important elements in 10% of initial weight is enough to provoke improvements in prevention of the metabolic syndrome and, consequently of waist circumference, lipid profile and glycemia.26 cardiovascular diseases in adulthood.
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Metabolic syndrome - Lottenberg SA et al.
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