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.
Jornal de Pediatria - Vol. 83, No. 5(Suppl), 2007 S205 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
Metabolic syndrome - Lottenberg SA et al. 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.
Jornal de Pediatria - Vol. 83, No. 5(Suppl), 2007 S207
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. S208 Jornal de Pediatria - Vol. 83, No. 5(Suppl), 2007
Metabolic syndrome - Lottenberg SA et al. References
16. Boney CM, Verma A, Tucker R, Vohr BR.
17. Heptulla R, Smitten A, Teague B, Tamborlane WV, Ma YZ,
3. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz
Arch Pediatr Adolesc Med. 2003;157:821-7.
4. Taylor RW, Jones IE, Williams SM, Goulding A.
19. Daskalopoulou SS, Mikhailidis DP, Elisaf M.
20. Kolovou GD, Anagnostopoulou KK, Salpea KD, Mikhailidis DP.
5. World Health Organization. World Health Statistics 2005.
22. Tresaco B, Bueno G, Pineda I, Moreno LA, Garagorri JM, Bueno
7. Murphy VE, Smith R, Giles WB, Clifton VL.
23. Sinha R, Fisch G, Taegue B, Tamborlane WV, Banyas B, Allen K,
10. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM.
25. Orio F Jr., Palomba S, Cascella T, Savastano S, Lombardi G,
27. Serra JD, Franch MA, Gómez López L, Martinez Costa C, Sierra
An Pediatr (Barc). 2007;66:284-304.
28. Inge TH, Krebs NF, Garcia VF, Skelton JA, Guice KS, Strauss RS,
14. Luo ZC, Fraser WD, Julien P, Deal CL, Audibert F, Smith GN, et
CEP 01416-001 – São Paulo, SP – Brazil
Cystic Fibrosis Goals of this session : To review the pathophysiology of Cystic Fibrosis To review the relevant physical findings of CF To place the pathophysiology of CF into a clinical context through a case presentation Pathophysiology review : Mutation in CFTR transmembrane receptor (on chromosome 7) ATP Binding Cassette protein that acts as regulated chloride channel Phe
The first thing we need to solve this question is to determine the relative length of amicrosecond. A quick search on the web determines the conversions we need:• 1 day = 24 hours × 60 minutes × 60 seconds = 8.64 ×1010 microseconds• 1 year = 365.25 days ≈ 3.16 × 1013 microsecondsNow if each function takes f (n) microseconds to complete and we wish to find the largestn such that the fu