Preclinical manifestations of organ damage associated with the metabolic syndrome and its factors in outpatient children

Preclinical manifestations of organ damage associated with the metabolic syndrome and its factors in outpatient children
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  Atherosclerosis 213 (2010) 611–615 Contents lists available at ScienceDirect Atherosclerosis  journal homepage: www.elsevier.com/locate/atherosclerosis Preclinical manifestations of organ damage associated with the metabolicsyndrome and its factors in outpatient children Procolo Di Bonito a , ∗ , Nicola Moio b , Carolina Scilla b , Luigi Cavuto b , Girolamo Sibilio b , Claudia Forziato c ,Eduardo Sanguigno c , Francesco Saitta c , Maria Rosaria Iardino d , Brunella Capaldo e a Department of Internal Medicine, Pozzuoli Hospital, via Domitiana Loc. La Schiana, 80078 Pozzuoli, Napoli, Italy b Department of Cardiology, “S. Maria delle Grazie”, Pozzuoli Hospital, Italy c Department of Pediatrics, “S. Maria delle Grazie”, Pozzuoli Hospital, Italy d Department of Clinical Pathology, “S. Maria delle Grazie”, Pozzuoli Hospital, Italy e Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy a r t i c l e i n f o  Article history: Received 7 July 2010Received in revised form 1 September 2010Accepted 16 September 2010 Available online 23 October 2010 Keywords: Pediatric metabolic syndromeLeft ventricular massAlanine aminotransferaseGlomerular filtration rateMicroalbuminuriaCardiometabolic risk factors a b s t r a c t Background:  To evaluate whether the pediatric metabolic syndrome (MetS) or its factors are useful todetect subclinical abnormalities of cardiac, liver, and glomerular damage in an outpatient population. Methods:  The population study included 799 children (age 10 ± 3 years, mean ± SD), 24% of whomwere normalweight, 25% overweight, and 51% obese. Alanine-aminotransferase (ALT) levels, estimatedglomerularfiltrationrate(eGFR)andHOMA-IRwereanalyzedinallchildren.Microalbuminuria(MA)andleft ventricular (LV) geometry and function were evaluated in 501 and 247 children, respectively. MetSwas defined using Cook’s criteria. Results:  MetS was diagnosed in 131 children (16%). Children with MetS+ and MetS −  were similar forage, gender and Tanner stage distribution. Children with MetS+ showed higher ALT levels (31 ± 19vs 21 ± 11IU/L,  p <0.0001), LV mass (39 ± 10 vs 34 ± 10g/h 2.7 ,  p <0.001) and relative wall thickness(0.37 ± 0.06vs0.35 ± 0.05,  p <0.01)thanMetS − .ThetwogroupsweresimilarforMAandeGFR.Atmultiplelogistic regression analysis, children MetS+ showed a higher risk (OR, 95% Cl) adjusted for confoundingfactors, of high ALT levels (1.71, 1.12–2.59,  p =0.012) and concentric LV hypertrophy (2.17, 1.01–4.66,  p =0.047)thanchildrenMetS − .TheriskofpreclinicalliverandcardiacdamageassociatedwiththeMetSphenotype was not higher than predicted by its single components. Conclusions:  Children with MetS show a 2-fold greater risk of having high ALT levels and concentric LVhypertrophy.However,theriskofsubclinicalmanifestationsofliverandcardiacdamagecanbepredictedequally well by the single components of the syndrome. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The epidemic expansion of childhood obesity is raising greatconcernintermsofpublichealthandsocio-economicimpact,sinceit is a well established risk factor for the development of obesity,diabetes,hypertensionandthemetabolicsyndrome(MetS)inadultlife [1]. In addition, obese children often have MetS, although its prevalence is quite variable depending on ethnicity and diagnos-ticcriteriaadopted.Collectively,clinicalandepidemiologicstudiesreport a prevalence of pediatric MetS ranging from 2 to 12% inschool-children cohorts, which increases by 2–3 fold in obese chil-dren [2].Metabolic syndrome in adults is associated with increased riskto develop diabetes [3] and cardiovascular disease as well as ∗ Corresponding author. Tel.: +39 81 8552281. E-mail address:  procolodibonito@alice.it (P. Di Bonito). increased mortality from cardiovascular disease and all causes[4]. Furthermore, adults with MetS are more likely to have targetorgan damage, namely non alcoholic fatty liver disease (NAFLD)[5], microalbuminuria (MA) [6], chronic kidney disease [7], altered left ventricular (LV) geometry and function [8], as well as arte- rial stiffness [9]. In recent years, the concept of pediatric MetS has become a subject of increasing debate [10]. Besides the controver- sies over diagnostic criteria, an important question relates to itsclinical and prognostic significance, given the paucity of longitu-dinal data linking children with MetS with adult morbidity andmortality.OnecluetoaddressthisissuecouldbetoseewhethertheMetS is associated with preclinical manifestations of organ injuryalreadyinchildren[11],asitisinadults[5–9].Inaddition,whether inCaucasianchildrenMetSphenotypeismoreusefulthanitssinglecomponents in identifying subjects with preclinical cardiac, liverand glomerular abnormalities is at present unknown. Against thisbackground, in the present cross-sectional study we investigatedwhetherpediatricMetSoritscardio-metabolicriskfactors,defined 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.09.017  612  P. Di Bonito et al. / Atherosclerosis  213 (2010) 611–615 by age- and gender related cut-off, are associated with preclinicalmanifestationsoforgandamage.Inparticular,weexaminedcardiacphenotype, liver and glomerular function in a large population of outpatient Caucasian children. 2. Methods  2.1. Study population Thecross-sectionalstudyincluded799childrenaged6–16years(393 boys and 406 girls) consecutively referred to the outpatientunitofthePediatricDepartmentofPozzuoliHospitalbetween2004and 2009. Our sample consisted of 180 (25%) normal weight, 171(24%) overweight, and 373 (51%) obese children. All subjects hadbeen referred to our unit by their general practitioners because of allergy problems, overweight, and obesity. They were apparentlyhealthy and had no history of diabetes, hypertension, or alcoholconsumption, nor any evidence of liver disease. Children with gas-trointestinal, cardiac, renal, urinary and infectious diseases wereexcluded.Anthropometric measurements were obtained with standardmethods as elsewhere described [12]. Children’s degree of sexual maturity was evaluated by Tanner’s staging for pubic hair (I–V).Blood pressure was measured according to standard criteria at theright arm in the supine position after a five-minute rest, using amercurysphygmomanometerwithanappropriatelysizedcuff,anda stethoscope placed over the brachial artery pulse; three read-ings were taken 2min apart and the average of the two last valueswas used in the analyses. Diagnosis of high blood pressure wasconfirmed in a subsequent visit, performed within 2 weeks fromthe previous one, before starting the nutritional intervention, asreported elsewhere [13].  2.2. Measurements Fasting blood samples were taken from all participants, for thedetermination of biochemical parameters, in the centralized labo-ratory of Pozzuoli Hospital. Fasting plasma glucose, fasting plasmainsulin, total cholesterol, triglycerides, high density lipopro-tein (HDL)–cholesterol, alanine aminotransferase (ALT), aspartateaminotransferase(AST)andcreatinineweredeterminedaccordingtostandardproceduresusingaROCHEanalyzer(ModularAnalyticsSerumWorkArea,68298Mannheim,Germany).Insulinsensitivitywas evaluated by the Homeostasis Model Assessment (HOMA-IR) index using a standard formula: fasting insulin (U/L) × fastingglucose (mmol/L) divided by 22.5. Estimated glomerular filtra-tion rate (eGFR) was calculated using updated Schwartz formula:0.413 × height (cm)/serum creatinine (mg/dl) [14]. Twenty-four hour urine was collected for the determination of urinary albuminexcretion by the kinetic nephelometric method (IMAGE system,Beckman Coulter Inc., Fullerton, CA, USA).  2.3. Echocardiography Two hundred forty-seven children were selected to undergoechocardiography. This sample did not differ from the remain-der for age and gender distribution. Standard echocardiogramswere obtained by a commercially available echocardiographicsystem with tissue Doppler imaging (TDI) capabilities (PowerVision 8000, Toshiba-Corp.). All measurements were analyzedaccording to the recommendations of the American Society of Echocardiography [15]. LV mass was calculated according to the Penn convention and indexed for height 2.7 (LVM). Relative wallthickness (RWT) was calculated from posterior wall thickness(PWT), interventricular septum thickness (IVST) and left ven-tricular diastolic diameter (LVDD) using the following formula:(PWT+IVST)/(LVDD).RWTwasnormalizedforagebythefollowingequation: (RWT − 0.005) × (age − 10) [16]. Increased LV mass and RWT were defined by values >38g/height 2.7 and >0.375, respec-tively [17]. Left ventricular geometry was subdivided on the basis of LV mass and RWT into: normal geometry (normal LV mass andnormal RWT), eccentric hypertrophy (increased LV mass and nor-mal RWT), concentric remodeling (normal LV mass and increasedRWT), concentric LV hypertrophy (LVH) (increased LV mass andincreased RWT) [18]. LV function was analyzed by conventional andTDIechocardiographyaselsewheredescribed[13].Transmitral peakrapidfillingvelocity( E  ),peakatrialfillingvelocity(  A ), E  /  A ratioandisovolumicrelaxationtime(IRT)wereobtainedasmeasuresof diastolicfunction.ForTDIechocardiography,threemajorvelocitieswere recorded at the annular site: peak positive systolic velocity( S  a ),andtwopeaknegativevelocitiesduringtheearly( E  a )andlate(  A a )phasesofdiastole. E  a /  A a  ratiowerealsocalculated.Allechocar-diographic readings were made online by the same investigatorwho was blinded to the metabolic status of the children.  2.4. Definitions Overweight and obesity were defined using Italian growthcharts, according to individual BMI  ≥ 85th and  ≥ 95th percentilefor age and gender, respectively [19]. In the absence of Italian criteria for the definition of pediatric MetS, we used the cut-points generated by Cook et al. according to the growth curvesfor cardio-metabolic risk factors derived from children and ado-lescentanalyzedintheNationalHealthandNutritionExaminationSurvey from 1988 to 1994 (NHANES III) and the current nationalseries (NHANES 1999–2006) [20]. High blood pressure levels were definedbysystolicbloodpressure>90thpercentileforgender,age,andheight[21].Sincethethresholdtodefineimpairedfastingglu- coseisgenerallyconsidered ≥ 100mg/dl,weadoptedthiscut-point.The presence of MetS was defined by 3 or more factors between:high waist circumference, high blood pressure, high triglycerides,low HDL and high glucose. High ALT levels, as surrogate of NAFLD,were defined using a cut-point >25.8IU/L in boys and 22.1IU/L ingirls,correspondingtothe95thpercentilelevelforALTinahealthy,normal weight pediatric population [22]. This cut-point was strik- ingly similar to that observed in our population, corresponding tothe 93th percentile of our normal weight subjects.Since few children showed glomerular filtration ratebelow 90mL/min/1.73m 2 , we defined low eGFR by a value<100mL/min/1.73m 2 corresponding to the 25th of our distribu-tioninnonobesechildren.Microalbuminuria,whichwasanalyzedin 501 (63%) out of 799 children similar for age, gender and BMIto the remainders, was defined as an albumin excretion rate ≥ 30mg/24h [23].The study was approved by the Local Ethics Committee andinformedconsentwasobtainedfromtheparentsofallparticipants.  2.5. Statistical analysis Data are expressed as mean ± SD, or number. Given the skeweddistributionofHOMA-IR,triglycerides,plasmacreatinine,UAE,ALT,AST,thestatisticalanalysisofthesevariableswasappliedafterlog-transformation and back transformation to natural units, to allowpresentationintextandtables.MeanswerecomparedbyunpairedStudent’s  t  -test. Chi-square or Fisher’s exact test, as appropriate,were used to compare proportions.Theoddsratio(OR)ofmarkersofsubclinicalorgandamage(highALT, concentric LVH, low eGFR and MA) associated with the MetSwasfirstanalyzedbyunivariateanalysis(unadjusted)fromtwo-by-twotables.Further,multiplelogisticregressionanalyseswereusedto evaluate the association of MetS and its factors with markers of organ damage, adjusted for age, gender, Tanner stage and BMI. A  P. Di Bonito et al. / Atherosclerosis  213 (2010) 611–615 613  Table 1 Anthropometric and biochemical features of children according to MetS status.All subjects No MetS MetS  p -value n  799 668 131Boys (%) 393 (49) 331 (50) 62 (47) NSAge (years) 10 ± 3 10 ± 3 10 ± 3 NSPubertal stage (%) 399 (50) 342 (51) 57 (44) NSNormal weight (%) 199 (25) 198 (30) 1 (1) 0.0001Overweight (%) 179 (22) 159 (24) 20 (15) NSObesity (%) 421 (53) 311 (47) 110 (84) 0.0001BMI (kg/m 2 ) 25 ± 6 24 ± 6 29 ± 5 0.0001Waist circumference (cm) 87 ± 14 80 ± 17 92 ± 12 0.0001FPG (mg/dl) 85 ± 7 85 ± 7 87 ± 9 0.025HOMA-IR 2.7 ± 2.3 2.4 ± 1.8 4.4 ± 3.5 0.0001Cholesterol (mg/dl) 162 ± 31 161 ± 30 165 ± 36 NSHDL-cholesterol (mg/dl) 51 ± 11 54 ± 11 41 ± 7 0.0001Triglycerides (mg/dl) 87 ± 43 77 ± 31 130 ± 57 0.0001SBP (mmHg) 106 ± 12 104 ± 11 116 ± 12 0.0001DBP (mmHg) 61 ± 9 60 ± 9 65 ± 11 0.0001ALT (IU/L) 24 ± 14 22 ± 12 34 ± 27 0.0001AST (IU/L) 25 ± 8 25 ± 7 28 ± 11 0.001Creatinine (mg/dl) 0.54 ± 0.11 0.54 ± 0.10 0.55 ± 0.11 NSeGFR (mL/min/1.73m 2 ) 111 ± 18 111 ± 17 110 ± 18 NSUAE (mg/24h) 5.0 (3.0–8.0) 5.0 (3.0–8.0) 5.0 (2.0–9.0) NSDataareexpressedasmean ± SD,numbers(%),medianandinterquartilerange.FPG:fastingplasmaglucose;SBP:systolicbloodpressure;DBP:diastolicbloodpressure;ALT: alanine aminotransferase, AST: aspartate aminotransferase; eGFR: estimatedglomerular filtration rate; UAE: urinary albumin excretion rate. two-sided  p value<0.05wasconsideredstatisticallysignificant.Thestatistical analysis was performed with SPSS for Windows, version13.0 (SPSS Inc., Chicago, USA). 3. Results The main features of the population studied are reported inTable 1. Pediatric MetS was identified in 131 children (16.4%),the great majority of whom were obese (84%). Children with theMetS were similar for age (10 ± 3 vs 10 ± 3 years), gender dis-tribution (males 47% vs 50%) and pubertal stage (44% vs 51%)to children without the MetS. As expected, children with MetS,as compared to children without MetS, showed higher levels of BMI, waist circumference (  p <0.0001, for both), fasting plasmaglucose (  p <0.025), HOMA-IR, triglycerides, systolic and diastolicblood pressure (  p <0.0001 for all) and lower levels of HDL choles-terol(  p <0.0001).Inaddition,MetSphenotypewasassociatedwithhigher levels of ALT (34 ± 27 vs 22 ± 12IU/L,  p <0.0001), and AST(28 ± 11 vs 25 ± 7,  p <0.001). More than half of children with MetSshowed a higher level of ALT (>25.8IU/L in boys and >22.1IU/L ingirls, 56% vs 29%,  p <0.0001), as compared to the children withoutMetS.  Table 2 Cardiac features of children according to MetS status.Echocardiographic variables No MetS MetS  p -value N   187 60Boys (%) 98 (52) 27 (45) NSAge (years) 10 ± 3 10 ± 3 NSBody mass index (kg/m 2 ) 26 ± 5 30 ± 5 0.0001Heart rate (b/min) 83 ± 12 88 ± 12 0.005LV end-diastolic dimension (mm) 41 ± 5 42 ± 5 NSLV posterior wall thickness (mm) 7 ± 1 8 ± 1 0.025Interventricular septum thickness (mm) 7 ± 1 8 ± 1 0.0001Relative wall thickness (mm) 0.35 ± 0.05 0.37 ± 0.06 0.004Left ventricular mass (g) 91 ± 35 102 ± 30 0.026Left ventricular mass (g/h 2.7 ) 35 ± 10 38 ± 10 0.017Ejection fraction (%) 63 ± 6 65 ± 6 NSIsovolumic relaxation time (ms) 65 ± 10 66 ± 10 NS E  /  A  ratio 2.1 ± 0.7 2.2 ± 0.7 NS E  a /  A a  ratio 2.3 ± 0.7 2.3 ± 0.7 NS S  a  velocity (cm/s) 10 ± 2 10 ± 2 NS E  /  A ratio:early/atrialvelocityratio; E  a /  A a  ratio:earlyannular/atrialannularvelocityratio;  S  a : systolic annular velocity. No difference was observed for eGFR and MA between the twogroups.Children with MetS showed higher levels of heart rate(  p <0.005),PWT(  p <0.0125),IVST(  p <0.0001),RWT(  p =0.004)andLV mass (  p =0.017) (Table 2). No difference was observed for LV function either at conventional or TDI echocardiography. A higherpercentage of children with MetS showed concentric LVH com-pared to children without (25% vs 11%,  p <0.0025). No differencewasobservedinthepercentageofeccentricLVH(20%vs23%,  p =ns)and concentric remodeling (18% vs 10%,  p =ns) between the twogroups.At univariate analysis, children with MetS showed an increasedrisk of high ALT levels (  p <0.0001) and concentric LVH (  p =0.003)(Table 3). At multivariate analysis, the risk was not influenced by age, gender, and Tanner stage (data not shown). When BMI wasincluded in the model, the independent role of MetS persisted onhigh ALT levels and concentric LVH. In addition, the risk of organdamageassociatedwithMetSwasnothigherthanthatpredictedbysomeofitsfactors.Inparticular,theriskofhighALTwasassociatedwith high waist circumference (  p =0.028) and high triglycerides(  p =0.023), while the risk of concentric LVH was associated withhigh blood pressure (  p =0.001). 4. Discussion This study provides evidence that pediatric MetS is associatedwith some preclinical manifestations of organ damage. ChildrenwithMetSshowsa2-foldgreaterriskofhighALTlevelsandconcen-tric LVH; however, this risk is not higher than that associated with  Table 3 Odd Ratio and 95% Cls of high levels of ALT and concentric left ventricular hypertrophy associated with MetS and its factors.Univariate analysis p-value Multivariate analysis a  p -valueHigh ALT levelsMetabolic syndrome 3.12 (2.13–4.58) 0.0001 1.71 (1.12–2.59) 0.012High waist circumference 10.02 (5.58–18.00) 0.0001 1.81 (1.07–3.08) 0.028High blood pressure 2.07 (1.45–2.94) 0.0001 1.09 (0.74–1.61) NSHigh triglycerides 3.03 (1.94–4.73) 0.0001 1.75 (1.08–2.85) 0.023Low HDL-cholesterol 1.95 (1.44–2.64) 0.0001 1.07 (0.75–1.51) NSConcentric left ventricular hypertrophyMetabolic syndrome 2.82 (1.38–5.74) 0.003 2.17 (1.01–4.66) 0.047High waist circumference 3.02 (1.03–8.89) 0.037 1.54 (0.42–5.61) NSHigh blood pressure 4.60 (2.25–9.39) 0.0001 3.88 (1.80–8.38) 0.001High triglycerides 2.13 (0.94–4.839) NS 1.35 (0.56–3.29) NSLow HDL-cholesterol 2.17 (1.08–4.35) 0.027 1.67 (0.79–3.55) NS a Adjusted for age, gender, BMI and tanner stage.  614  P. Di Bonito et al. / Atherosclerosis  213 (2010) 611–615 someofitscomponents;inparticular,highwaistcircumferenceandtriglycerides are strong predictors of HALT while high blood pres-sure is predictive of concentric LVH. In addition, no impairmentof cardiac and glomerular function was found in these childrencompared to controls.The definition of pediatric MetS is still controversial due to thedifferent criteria used to categorize risk factors, although mostof them are based on 85–95th percentiles of reference popula-tions. A major intrinsic problem with the use of cut-points forcardiometabolicriskfactorsinthepediatricpopulationisthevaria-tionovertime,especiallyduringthetransitionfromprepubertaltoadult status. In this context, it is of interest to recall a recent paperby Cook et al. who have recently generated, for each componentof the syndrome, age- and sex-related cut-points that correspondwith and transition into abnormal adult cut-off values [20]. Using thesecriteria,inourpopulationweobservedanoverallprevalenceofMetSashighas16.4%,whichincreasesto26.1%amongobesechil-dren.AnothercriticalissueistheusefulnessofdiagnosingpediatricMetS in a clinical setting. In particular, since MetS is a constella-tion of several cardiometabolic risk factors linked by a commonsoil, it is difficult to evaluate the impact of MetS versus its indi-vidual components on organ damage. Previous studies conductedin American Indian adolescents have shown that MetS has a pro-found impact on cardiovascular phenotype, evidenced by LVH andreduced LV systolic and diastolic function [24]. Currently, no such data is available in Caucasian pediatric populations. Our childrenwith the MetS showed an increased LV mass of concentric typebut, at variance with the population of the strong heart [24], no impairment of LV function. This discrepancy may be explained bythe different features of the population studied since the subjectsofthestrongheartstudywereolder(meanage17years)thanours,andexhibitedahigherprevalenceofhypertension,cigarettesmok-ingandalcoholconsumption,allfactorspotentiallyresponsibleforLVdysfunction.Itislikelythattheyoungageofourpopulationand,consequently, the shorter exposure to the metabolic milieu of thesyndrome,couldaccountforthelackofcardiacfunctionalchanges,which may take longer to develop. In this light, our observation isthe first one to demonstrate the early appearance of abnormalitiesof LV geometry associated with MetS in a population of Caucasianchildren.Another trait frequently associated with MetS is non alco-holic fatty liver disease (NAFLD). This condition, characterized byfat infiltration of the liver, is known to predict not only steato-hepatitis, and eventually cirrhosis, but also type 2 diabetes [25]and cardiovascular disease [26]. The prevalence of NAFLD in a pediatric population and in children with MetS is difficult to esti-mate because the diagnosis should be confirmed by liver biopsy.However, alanine aminotransferase (ALT) elevation is generallyconsidered a surrogate of NAFLD, to be used for clinical purposes.ElevatedALTlevelshavebeenreportedinahighproportionofobesechildren [27]; in addition, previous studies have shown a strong associationbetweenhighALTlevelsandMetS,althoughthosestud-ies did not employ gender-related cut-offs [28,29]. In the present study,weconfirmedacloseassociationbetweenMetSandelevatedALT using sex specific cut-offs for ALT levels.StudiesontheassociationbetweenmicroalbuminuriaandMetSin children and adolescents are scanty and conflicting. Invitti etal. [30] reported a high prevalence (37%) of microalbuminuria in obese children with MetS compared to those without (20%). Incontrast, in the National Health and Nutrition Examination Sur-vey (1999–2004), Nguyen et al. could not find any associationbetween MetS and microalbuminuria; rather, microalbuminuriawas more prevalent among adolescents without abdominal obe-sity than those with this condition (7.9% vs 1.0%) [31]. Our results are in agreement with the NAHNES study since in our populationthe prevalence of microalbuminuria was low (<4%) and not influ-enced by the presence of MetS. The characteristics of the subjectsstudied, with particular reference to the frequency of high bloodpressure among the components of the MetS may contribute tothese variable results.The present study presents some limitations. Firstly, our sub- jectswerereferredtoanoutpatientclinicmainlyforweight-relatedproblems and, therefore, may not be representative of the generalpediatric population. In addition, the cross-sectional design of thestudy does not allow to establish a causal relation between MetSand manifestations of liver and cardiac damage as well as on theirprogression. Longitudinal monitoring of these children will clar-ify this issue. Secondly, liver damage was expressed in terms of ALT elevation, and no CT scan or magnetic resonance imaging wasperformed. On the other hand, it would not have been justifiedgiven the very young age of the participants and the epidemio-logical nature of our study. The strength of this work lies in thecomprehensive analysis of the association between pediatric MetSand preclinical signs of liver, glomerular and cardiac damage ina large number of Caucasian children. As a matter, this approachallows us to pinpoint the clinical significance of MetS in children. 5. Conclusions In an outpatient population of Caucasian children, pediatricMetS is associated with preclinical manifestations of liver and car-diac damage. 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