Although the metabolic syndrome (MS) was already identified 40 years ago, the agreed definition by World Health Organization (WHO) and National Cholesterol Education Program (NCEP) (Adult Treatment Panel III, ATP III) is very recent. Both definitions focus on dyslipaemia, obesity, hypertension and hyperglycaemia, but critical figures have been defined according to age, sex and sometimes the height of the individual (as described below).
The overall biochemical markers are hypertriglyceridaemia, low high-density lipoprotein-c (HDL-c), hyperglycaemia, hyperuricaemia, increased testosterone, plasminogen activator inhibitor (PAI) and fibrinogen. Associated clinical symptoms are obesity, hypertension, polycystic ovary, non-alcoholic greasy liver, acantosis nigricans, sleep apnoea and the clinical consequences are type 2 diabetes and cardiovascular disease (CVD).
Several epidemiologic studies of prevalence in adulthood have shown a physiopathologic relationship with type 2 diabetes and CVDReference Mokdad, Bowman, Ford, Vinicor, Marks and Koplan1, Reference Calle, Rodriguez, Walker-Thurmond and Thun2. The so-called epidemic of childhood obesity has increased the interest in this syndrome due to the potential projection into adulthood.
A new concept has been defined in relation to the MS, the syndrome of insulin resistance (IR), defined as a failure of the usual levels of insulin to provide glucose to the peripheral tissues and the liver, with failure in the inhibition of very low density lipoprotein synthesis. It would be a combination of peripheral insulin resistance (PIR) and hyperinsulinaemia. Neither all obese children suffer from PIR, nor those with adequate weight are sensitive to insulin. It is likely that the so-called prudent diet, which replaces saturated fat for an excess of carbohydrates, has favourable consequences to develop this syndrome. Type 2 diabetes would start when this syndrome exhausts the possibilities of enough pancreatic insulin secretion so as to compensate for the resistance and maintain the homoeostatic functions of the hormone.
Prevalence of metabolic syndrome in childhood
Diverse prevalence rates have been reported depending on the different definitions of the syndrome and analytical and somatometric cut-off values. Based on the definition by ATP III, prevalence has been estimated to be 6.7% in young adults and 4.2% in adolescents (males 6.1%).
Impact of obesity
Focused on the overweight and obese children and youth population, the figures rise up to 28.7% in the adolescent population (one has to bear in mind that according to NHANES III estimates, 15% of children between 6 and 19 years are overweight).
Ethnic impact
Studies carried out in the USA showed an increase of this syndrome in the Hispanic adolescent population in contrast with the Caucasian and the Afroamerican population. This increment would be associated basically to overweight, which has doubled in the last 10 years (23.4% in contrast with 12.7% in whites). Although the prevalence of obesity in Afroamerican adolescents is also high (23.6%), curiously the incidence of the MS is low. These data suggest that there is an ethnic factor independent of obesity.
Physiopathology of the metabolic syndrome
In spite of the consensus ATP III on the definition of the syndrome, its physiopathology is controversial. Generally, the most widely accepted hypothesis links the syndrome to obesity.
The Finish study about cardiovascular risk factors in childhood and youth explored predictors of the MS and established that a high basal insulin level was the best predictor. In the Bogalusa study, children between 8 and 17 years of age were followed up for a period of 11.6 years. In this study, the best predictors were obesity and also being in the upper quartile of basal insulin levels. However, the reason why some obese children develop this syndrome while others do not is still unknown. In this sense, Cruz and GoranReference Cruz and Goran3 have reported a study on sensitivity to insulin (measured by intravenous tolerance to glucose test) showing that after adjusting for the differences in adiposity (measured by X-ray absorptiometry), obese children with MS were 6.2% lower. It was the sensitivity to insulin and not the fat mass that correlated negatively with triglycerides and blood pressure, and positively with HDL-c. These findings suggest that it is PIR and not adiposity that is the physiopathological inductor of the syndrome. In spite of these findings, the physiopathological binomy obesity-PIR still prevails, especially when there is visceral fat accumulation.
In any case, ethnic and genetic factors play a role in order to explain the syndrome in the non-obese population and the differences of interobesity.
Genetic factors
The aetiology of PIR is multifactorial and the endocrine-metabolic factors of obtaining and expending energy are involved (energy homoeostasis); hypothalamus-hypophysis factors, such as melanocortine, all hormonal factors of adipose tissue (leptin, adiponectin, resistin, TNF-α, PPAR-α, PPAR-γ) and other factors such as ghrelin, serine-protease inhibitors and, of course, insulin are involved as well.
Among the studies on the gene directly involved in PIR, it is worth mentioning: (1) genes that codify the insulin receptor itself: IRS1
Strategies of screening and treatment of MS in childhood
Localisation of risk population
Taking into account the parameters and cut-off values established for the definition of the syndrome in the paediatric age, it can be deduced that the detection of the syndrome focuses mainly on obese and overweight young people. However, other population groups such as newborns with low or high birth weight, infants with accelerated growth, or children of obese or with gestational diabetes mothers are at a higher risk of developing PIRReference Boney, Verma, Tucker and Vohr14. The presence of clinical manifestations very much related with the MS, acantosis nigricans, polycystic ovary, non-alcoholic fatty liver obliges to searching for the syndrome.
The study of a family background (type 2 diabetes, obesity, hypertension, hypertriglyceridaemia) can be an important help in the localisation of a population at risk. The measurement of simple parameters such as abdominal circumference can be a useful tool in the population screening of these patients.
Treatment
Physical exercise is one of the pillars of treatment. It must be quotidian and intenseReference Kang, Gutin and Barbeau15, and adequate to the individual possibilities. It can be adapted to a programme of exercise (for instance walk or swim for 30 min every day). Weight-bearing exercise is also helpful.
Dietetic aspects of treatment imply the restriction of saturated and trans fatty acids. If reducing weight is necessary, it must be emphasized in the reduction of carbohydrate intake, especially for refined sugars.
Dietary fibre improves insulin sensitivity by different mechanisms. It has been reported that the consumption of whole-grain cereals improves insulin sensitivity in adolescentsReference Sinaiko, Jacobs and Steinberg16. Other foods such as soy protein (rich in isoflavones) and lineseed oil also improve insulin sensitivityReference Bhathena and Velasquez17.
Metformin and thiazolidinediones have been used in the pharmacological treatment of the severe forms of PIR, apparently with good resultsReference Freemark and Bursey18, Reference Ghazzi, Perez and Antonucci19.
For the management of dyslipaemia, fenofibrate and statines have been proposed. It is necessary to remember that the combination of both pharmaceuticals has caused occasionally serious episodes of rabdomiolisis.
Paediatric surgical treatment (intestinal bypass) is only recommended if there is risk of death due to complications of the syndrome such as sleep apnoea.
As a complementary treatment, other factors of atherogenic risk must be avoided, such as smoking or the consumption of alcohol.
Acknowledgements
Conflict of interest declaration: The authors had no conflicts of interest to report.
Authorship contributions: All the authors (P.S.C., J.A.P.P., F.A.L., L.A.-E.A.) declare that they participated sufficiently in the work to take full and public responsibility for its content.
