DOES METABOLIC SYNDROME EXIST IN CHILDREN?

OBJECTIF NUTRITION 77 (SEPTEMBER 2005)
by Dr Béatrice DUBERN, Hôpital Armand-Trousseau (AP-HP, Paris.)

In adults, the presence of metabolic syndrome is associated with a clear increase in cardiovascular accidents. The recent rise in the prevalence of obesity in children makes it necessary to identify and manage vascular risk factors in pediatrics. It is therefore indispensable to be able to detect these factors in three particularly exposed populations of children: obese children, children with low birth weight and children of a diabetic mother, born with high birth weight.

The prevalence of metabolic syndrome varies depending on the populations under study.
It affects nearly 25% of adults in the United States while in France, a mere 10%  are concerned. This suggests the role of the environment as well as genetic factors.
For children, no simple definition of metabolic syndrome exists to date due to variations in standards according to age and size, the absence of waistline growth curves and cohort studies.
However, it is essential to be able to detect vascular risk factors for the metabolic syndrome in three high-risk populations: obese children, children with low birth weight and children of diabetic mothers with high birth weight.

OBESE CHILDREN

To date, there is no epidemiological data for obese children linking the presence of metabolic syndrome to cardiovascular risk.

However, by using the definition of NCEP ATP III adapted to pediatrics, the prevalence of metabolic syndrome in American teenagers was observed to be nearing 5%.  In cases of obesity, it rose to 20%, and with severe obesity even 50%. By using the same definition and adapting it to French reference values, the prevalence of metabolic syndrome was nearly 14% among two hundred children aged 11.8 ± 2.2, monitored for severe obesity (Z-score of the body mass index above + 3 standard deviations) at the Armand-Trousseau Hospital. In this group, the most frequently encountered anomalies were android distribution of fat mass, measured by biphotonic absorptiometry, and HDL-cholesterol below the 5th percentile (figure 1).
The variations of the prevelance of metabolic syndrome from one country to another reveal not only the necessity to establish standards and a definition for children in line with vascular risk, but also the probable role of other factors (genetic and/or environmental) in adult populations.

CHILDREN WITH LOW BIRTH WEIGHT

Among children born with low birth weight (below the 3rd percentile for the term), the risk of metabolic syndrome, particularly in adult years, exists with a clearly established relation between low birth rate and subsequent vascular risk.
Indeed, many studies have demonstrated a link between intra-uterine growth retardation and a significantly higher risk of metabolic syndrome, cardio-vascular disease, type 2 diabetes and obesity in adulthood. As a result, the risk of developing metabolic syndrome is ten times higher among subjects with a birth weight below 2.5 kg, as compared to those with normal birth weight. Finally, among children born with intra-uterine growth retardation, probable genetic determinants are also involved. Early insulin-resistance was demonstrated in children born with intra-uterine growth retardation among certain ethnic minorities including Indian (4 to 8 year-old children) and African-American (4 to 14 year-old children).

CHILDREN OF DIABETIC MOTHERS, WITH HIGH BIRTH WEIGHT

Among children with high birth weight, born from diabetic mothers, recent studies have also demonstrated an increased risk of metabolic syndrome in the course of childhood, independently of obesity. One longitudinal study in the United States showed that these children were three times more at risk of developing metabolic syndrome at the age of 11, whether they were obese or not, by comparison to children born to diabetic mothers, but with normal birth weight. In the same study, maternal obesity appeared as an additional risk factor for metabolic syndrome during childhood, suggesting the role of in utero hyperinsulinemia. This data must, however, be confirmed by other studies.

THE PHYSIOPATHOLOGY OF METABOLIC SYNDROME

Insulin-resistance is at the heart of the physiopathological mechanisms causing metabolic syndrome. The increase in the fat mass, and particularly in visceral fat mass, is highly correlated with insulin-resistance. Indeed, perivisceral adipose tissue has very high metabolic activity while the release of free fatty acids leads to deficient glucose capture in peripheral tissue (skeletal muscles, liver) with hyperinsulinemia, hypertriglyceridemia and hypo-HDL-cholesterolemia. Clinical studies have shown that abdominal distribution of fat mass was positively correlated to insulinemia on an empty stomach and to triglyceridemia, and inversely correlated to HDL-cholesterol (independently of corpulence). In addition, the factors produced by adipose tissue such as TNF (Tumor Necrosis Factor), interleukine-6 and adiponectin also play a primordial role in the physiopathology of insulin-resistance (figure 2).

Among children born with intra-uterine growth retardation, in utero malnutrition induces changes in the development of adipose tissue: hypotrophic newborns have a reduced fat mass at birth. However, a majority of children born with intra-uterine growth retardation develop, in their first months of life, exaggerated height and weight growth dynamics, referred to as “catch-up” growth. It helps them regain their genetically programmed growth curve, before the age of 2. These dynamics imply the development of adipose tissue.  Two theories link intra-uterine growth retardation and metabolic syndrome with insulin-resistance. This association is either the result of the “thrifty” genotype whose selection is favored during energy deficiency, or of persistent metabolic and hormonal consequences of in utero malnutrition on foetal growth and the development of the pancreas (thrifty phenotype). “Foetal programming”, i.e. fetal adaptation to an altered intra-uterine environment, could play a central role in the association between intra-uterine growth retardation and diseases developed in adulthood.

LONG-TERM RISK OF METABOLIC SYNDROME IN CHILDREN

Among adults, the presence of a metabolic syndrome multiplies the risk of cardiovascular accidents by four. Among obese children, the quantification of such a risk remains difficult due to the absence of epidemiological studies on the occurrence of major cardiovascular events.
However, the relationship has now been established between childhood obesity and cardiovascular risk during adulthood, independently of changes in weight.
Indeed, longitudinal studies have shown that obesity in adolescence multiplies the risk of coronary disease by two and the risk of atherosclerosis in adulthood by seven, independently of changes in weight at this age. In addition, recent studies have shown the presence of arterial mechanics and endothelial function disorders in obese children that could be the first signs of vascular disease that will be encountered during adulthood. These arterial anomalies are correlated with hyperinsulinemia on an empty stomach and insulin-resistance and are inversely correlated with HDL-cholesterol.
Data show that the presence, since childhood, of metabolic syndrome components could largely determine cardiovascular risk associated with obesity.
In children born with intra-uterine growth retardation, the relation between low birth weight and vascular risk has been established. Indeed, in utero malnutrition and induced hormonal responses are responsible for early vascular anomalies.  For example, the increase of plasmatic cortisol described in a foetus with intra-uterine growth retardation could be partly responsible for high blood pressure during adulthood, due to the role of cortisol in the regulation of foetal blood pressure (increased vascular sensitivity to angiotensin II). Similarly, changes in the IGF1 growth hormone line with growth hormone resistance- are believed to play a role, particularly in cardiovascular function.

Conclusion

A direct link has now been established between insulin-resistance in children, on the one hand, and vascular risk in adult life, on the other hand: numerous studies have confirmed the role of insulin-resistance in early vascular lesions and the risk of mortality during adulthood, particularly among children born with intra-uterine growth retardation.
Increased prevalence of infant obesity may forebode an outbreak of cardiovascular diseases in the next decades. It is therefore necessary to have a specific child-appropriate definition for metabolic syndrome detection and consider appropriate therapy as a complement to dietary management and the promotion of exercise.


Dr. Béatrice DUBERN
Hôpital Armand-Trousseau, (AP-HP, Paris.)

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