P trontiers in Endocrin OPEN ACCESS rer des Sua & nrario ‘Che Pescara tay vest f Sao, tay Stato Unverty ef Marg, rat lant Mae Speciaty section ‘Accepted: 27 Soptenost 2018 Caton: Fema nd Mates ©2019) Treamet eee Syndrome Treatment of Metabolic Syndrome in Children Elena Fornari and Claudio Matfeis* Grecsiay, Unversty of Vora, Verna ay it, Department of Surge Scones, De The Metabolic Synckome may be tentatively defined asthe clustering of several metabolic, Fisk factors in the samo individual. A progressively higher number of children and adolescents is affected by this syndrome worldwide, mainly as a consequence of the constant increase of the prevalence of obesity and sedentary habits. As obesity, the ‘chance thatthe metabolic syndrome traks into adithoods high, Moreover, the evidence ‘of an association between the duration of the expostion to metabolic risk factors and morbidity and mortality justifies early treatment and prevention of the metabolic syndrome in both chien and adolescents, Treatment includes behavioral interventions, adequate nutrition and physical activity, and, i necessary, pharmacological treatments aimed at reducing excessive weight, dysiipcemia, hypertension, and glucose impairments. A mutidisciplinary and staged approach to treatment, which includes pediatrician, mental health practitioner, cletician, and nurses, is crucial. Usually, the reduction of fat mass promotes an overall improvement of all the components of the metabolic syndrome. Noverthotess, every single component of the metabolic syndrome should be treatod as quickly as possible, by using the best curent practice. Drugs may be necessary for treating hypertension, type 2 diabetes melitus and dyslipidemia. In selected cases of ‘gross obesity resistant to treatment, surgical therapy may be also performed Keywords: cbosity treatment hildron, lescents, metabolic symdrome INTRODUCTION [Regardless of the many different definitions of the Metabolic Syndrome (MetS) in child and adolescent (1-4), eatly screening and treating the single components, which contribute to its development, have a pivotal role in reducing cardiometabolic risk (5). There is no uniform agreement in how to treat the individual risk factors other than excessive weight management. Hovever, the set of MetS component risk factors share their pathophysiologic origins and many ‘common treatment approaches grounded in lifestyle modifications (Figure 1) (5). The Bogalusa Heart Study demonstrated that every single risk factor increases the development and severity of atherosclerotic lesions (5).'The American Academy of Pediatrics (AAP) underlines the importance to treat each risk factor individually, independently from the definition of MetS, with the ultimate goal of reducing cardiometabolic risk (5). In fact, the concept of CVR has to be considered continuum and not the sum of the overcoming of cut-off points forthe single rsk factors (5). Treatment of MetS includes behavioral interventions and, if necessary, pharmacological lueatments aimed at reducing excessive weight, dyslipidemia, hypertension, and glucose impairments (Table 1) (7,8). Once every single rsk factor is identified, it should be treated by using the best current practice as quickly as possible. The Princeton Prevalence and Follow-up Studies erin Enoarnaagy Lvenveniersn.o@ + ‘etooer 2018 | Vane 10 tle 702“Team of Metal Syren Chin Genetic and Epigenetic features Dyslipidemia ovesty ‘Insulin esitance 4 visceral adiposity ae 1 lipolysis EF arto Prosinflammatory ‘mechanisms Atherosclerosis Diet and lifestyle + Glucose impairments ‘and T20M f Endothelial disfunction Le eaten DIET AND LIFESTYLE MODIFICATIONS 4 ‘Omega’ fatty acids, | { Plantsterols probioticsand or Vitamin D stanol esters supplementation 2 angiotensin receptor blocker, longacting calcium channel blocker or thiazide diuretic FIGURE 1 | sh Mets patorecnaisms and earespancing tts. aporach and wearer: 4 ‘ACE inhibitor, 4 20M: Metformin and/orinsulin demonstrated that pediatric MetS predicted adults MetS with an ‘OR of 9.4 (9). Considering that the maintenance ofthe pathologic conditions until adulthood inexeases the risk, early treatment is essential (9) ‘There is common agreement that obesity prevention and ‘treatment in children and adolescents is “the first-line approach’ to reduce the cardiovascular risk (CVR) (8, 10). In fact, prevalence of metabolic syndrome in childhood is increasing in parallel with the increasing tends in obesity rates (11, 12), Im addition, although the pathogenesis of MetS is not completely understood, good evidence suggest that interactions between obesity, insulin resistance and pro-inflammatory state, certainly phy a key role in its development and raintenance (13). ‘Treatment of obesity and other MetS“Team of Metal Syren Chin TABLE 1 [iso es components ae comeeperdng tine aproach an ear Mets components Frattne approach “peatment bey List inenntons 1. PHARWACOLOGI TREATMENT 1. Dt abe restiton specie tagts sugested by tans) ist, when nested 2. PA Bon of mania gorus PA ery hy nang 2. SURGICALTAEATHENT igorwus sty 3 dy per wees Borate suger: when dese bperenson Lith enantio PHARMACOLOGIC TREATMENT 5. Dat ecaengsonum, ereasng ole oplyphonl, Sit win ale mesieaton a he wane osng range. ineesshg rake of rate, and vegeta) ‘Tint een 22 weeks ACE nhbicrargolersn reaper 2. Pato~eoiin af mederatigarus PR al ast 5 aye bots lng ang eaklam cannelbcke aise perwees devel we be tat ches Dystoemia Listy insertions PHARMACOLOGIC TREATMENT 5. Dit ecaong not eneeen 25 ar 0% of dl caloies Sats when neater srl nota tke <200 malay reuing sere boreal nate, 2. Pm Lest enero Nari 1. Liesfeetewentons and weg ss 2 Probiotics ard omega fay porenion {ico imosiment ne T2OM 2. Wain Econ irovehepaloceldar oslo tus fla tr or trol PHARMACOLOGIC TREATMENT fsa aelerae esease i praca acini Bed presse: TAD, pe? alseer mur AAA ran aha ay Wer sare ‘components share many common elements, 50 interventions ‘that improve one condition could consequentiy be useful to ameliorate also the others. For example, weight reduction following non-surgical interventions, including dietary changes, increased physical activity, and behavioral therapy, was found to be associated with improvements in several metabolic parameters such as dyslipidemia and hypertension (14-16). ‘Weight reduction also resutsin decrease of insulin resistance and low-grade inflammation (17), Combining dietary interventions and physical activity is more effective than cither single intervention in reducing BMI (5). In addition, data from a ‘meta-analysis demonstrate tat the postive effect of ameliorating ‘unhealthy diets and reducing sedentary behavior in long-term trials was more pronounced when directed toward children ‘compared to adolescents (18). Therefore, early management and tweatment are crucial in particular in pediatric population. DIETARY INTERVENTION ‘The mechanisms that explain the correlation between diet ‘modification and effects on MetS components ate not fully clear. Lowering intake of simple sugare may reduce pancreatic stimulus for insulin production (5). Caloric restriction reduce ‘mitochondrial substrate availability (19) whereas increased dietary ber intake decreases the glycemic load (20), The primary {goal in dietary intervention programs should focus on reducing total energy intake (21). Tt is essential that a dietician with proved ‘experience in growing children's needs supervise the caloric reduction (20, 22). Specific targets for dietary habits have also demonstrated efficacy in reducing BMI, ie, substittion of sugar- sweetened beverages with water (22), portion control education, increased intake of fruits and vegetables, reduction of dietary fats, sodium, and processed foads, increased intake of fiber (8, 20,24). ‘The AAP Guidelines report the appropriate recommendations about diet and nutrition in the prevention and first-line therapy. approach of obesity and other risk factors (8). Specific nutritional interventions for the therapy of each single MetS component will be treated in the respective paragraph of the text. The intervention of an expert multidisciplinary team, which includes dietician, psychologist, and providers with proven experience ‘with pediatric obesity, is much more effective to oblain 2 ‘modification of cating habits than other approaches (20, 25). PHYSICAL ACTIVITY Physical activity is any body movement produced by contraction fof skeletal muscle, which results in an increate in energy ‘expenditure above the basal level (8), Strong evidences prove the beneficial metabolic effects of reducing sedentary behavior, Le. increasing walking and physical activity on the overall heath of children and adolescents (8, 25-28). In addition, physical inactivity as been identified as an independent risk factor for ‘coronary heart disease in adults (29). Time apent in moderate to vigorous physical exercise is inversely associated with continuous risk score of MetS (30), Therefore, an increase in physical activity, also independently form a change in weight status, represents an ‘important treatment strategy for childhood MetS and results in improving of metabolic parameters and subclinical measures of atherosclerosis (8, Physical activity increases hepatic mitochondrial substrate ‘metabolism, reducing the availability of substrate for lipogenesis and mitigating insulin resistance (31,32) and causes“Team of Metal Syren Chin TABLE 2|Gusetnesorpreschoc-aged clan and for ereahaged een and adbecent mrevcrcorage ieee ough 8 yee) a sey ty ect ae shoul chen shod be physcay ace rough dlvebpment ou caregve's sous encourage ctv ply that rt rvigrous ete 20 use vigorous- Pens prise avy on al ast 3. dys a wees Sscte-stronathoning: Asp ofthe Brin or or of daly phil acy, chen and “solecents should nue muscle stengheing physi acy ant ast 3 ays wees Bone-stengthening As parc ould reiae bone-svengihening yea 3 3 60min cr more ot daly pryseal acy, chen and adescents cron at ea 3 day wee ritochondrial biogenesis in liver and muscles (32). There is slong evidence that physical exercise promotes a reduction of, fasting insulin levels and decreased insulin resistance in children and adolescents (31). It is helpful in improving lipid profile by increasing HDL concentration and decreasing both LDL and triglycerides concentrations (33). In addition, exercise can result in improvement of endothelial function with reduction, in both systolic and diastolic blood pressure, independently from the type of training (aerobic, resistance, or combined) (G4), It ameliorates body composition and has an abdominal fat reduction effect (34-35). As activity levels increase, pro inflammatory cytokines and markers of oxidative stress decrease (61), producing antiinflammatory effects (37) Structured physical activity interventions favor decreased daily energy intake in obese adolescents (38). The AAP recommends at least 60min of moderate-to-vigorous activity ‘every day for children older than 5 years, including vigorous activity on 3 days per week (8). A more conservative approach for both prevention and treatment of obesity and related rsk factors thas been suggested by the Endocrine Society, They recommend the reduction of inactivity and a minimum of 20 min of moderate to vigorous physical activity daily, with a goal of 60 min, the context of a calorie-controlled diet (20). The most recent American Guidelines on physical activity confirm the AAP and the Endocrine Society recommendations for children and adolescents (Fable 2) (39) In severe obese subjects exercises that ‘cause constant weight or repeated impact on the childs leg, feet, and hips should be avoided (22). Vin OTHER LIFESTYLE MODIFICATIONS AND BEHAVIORAL TREATMENT Other than adopting healthy eating habits and increasing physical activity, the primary goal in prevention and treatment fof obesity and MetS i pediatric population includes lifestyle ‘modifications, such as limiting video exposition time (23, 40) and adopting healthy sleep habits. Disordered sleep length and quality affect appetite and decrease insulin sensitivity (41), The AAP recommends to limit screen time to <2 h/day (8). The National Sleep Foundation recommends 8-11 of sleep for school age children and adolescents (42). ven independently bythe severity of obesity, these additional behavioral modifications reduce the likelihood of developing MetS (20,24), Pediatrician should assess patients and families for readiness to change. This information can guide the type and degree of interventions and may help to avoid excess time investing in non- ‘effective interventions (13). Programs involving the whale family in lifestyle modifications have more positive and durable effects, ‘compared to those ditected at child alone (8,35) PHARMACOLOGICAL AND SURGICAL TREATMENT OF OBESITY ‘Pharmacotherapy of obesity in children is limited. There are poor cendences regarding the safety and efficacy of pharmacological agents aimed to weight reduetion in adolescents, especially in the long term (43). When indicated. pharmacological therapies, should be prescribed by experienced clinicians, who can offer lose monitoring for weight reduction result and potential side effects. In addition, pharmacological option should be considered only after the proved failure of a formal program of lifestyle modification, which should however be continued in parallel, with pharmacotherapy (20). Currently, the US Food and Drug, Administration (FDA) indicates only Orlistat for weight loss in adolescents over 12 years of age (14). By inhibiting intestinal lipase, it reduces the absorption of triglycerides and cholesterol (45). Ithas frequent gastrointestinal adverse effect and can affect the absorption of fat-soluble vitamins (16). Pharmacological ‘treatment efficacy is limited. At 6 and 12 months of follow-up, it determines, respectively, an average weight loss of 3 and 5% (47, 48). Weight loss agents, other than Orlistat, are still under investigation for the use in adolescents (16, 48,50) Bariatric surgery can result in significant short-term weight loss in obese adolescents, but it is reserved for the most severely affected subjects, who have already completed ot almost completed their growth and have completed pubertal, evelopment (22, 51, 52). Surgical option is recommended only if BME exceeds 40 kg/m? with mild comorbidities or 35 kg/m? with severe comorbidities, Severe comorbidities include type 2 diabetes mellitus (T2DM), moderate to severe sleep apnea, severe hepatic fibrosis resulting ftom non-alcoholic steatohepatitis (NASH), pseudotumor cerebri, or debilitating“Team of Metal Syren Chin orthopedic problems. Mild comorbidities include dyslipidemia, hypertension, mild sleep apnea, moderate orthopedic problems, NASH, and psychological distress related to obesity (20, 22) Bariatric surgery should be considered only alter the failure ‘of a formal lifestyle modification program with documented compliance (20, 22). Prior to proceed with surgery, family ‘competency should be evaluated, as well as should be excluded potential underlying psychiatric illnesses, substance abuse of ‘eating disorders, The benefits of surgery option mustbe evaluated in the context of potential surgical complications (53). The research on the safety, efficacy, and long-term outcomes of Daiatric surgery in adolescents is limited, but data on adults ‘must be considered at currogate evidence (54). Serious and short-term complications (ie, abscess, infections, pulmonary ‘embolism, etc) can occur in 41% ofall patients (53). A recent longitudinal study on a cobort of 161 adolescents reports 1.9% fof mortality in the 5 years after surgery (55). Mild- and long- ‘term complications, which include intestinal obstruction, ulcers and hernia, and metabolic complications (ie, nephrolithiasi, hypoglycemia and vitamin, or mineral deficiencies) may also be considered but are hardly to monitor because of the high rate of dropout to the follow-up (53). Bariatric surgery in adolescents can result in improvement or resolution of comorbid conditions, such as T2DM, sleep apnes and hypertension, and ‘ean lead to good effect on weight loss (55, 56). However, further research is required because of the impact of the development ‘of complications and the relatively poor number of trials which «determine the long-term efficacy and safety in adolescents (53,54, 5), Literature consistently reports that both surgeon and surgical, ‘center experience are predictors of safety and a team of specialists ‘capable of long-term medical and psychological follow-up care forthe patient is essential (20,54). TREATMENT OF MetS RISK FACTORS OR COMPONENTS OTHER THAN OBESITY ‘Treatment of childhood MetS disease-specific management of its various components. Cardiovascular ‘morbidity represents the eflect of a continuum in the spectrum of the single CVR factors and a youth with multiple borderline risk factors might have equivalent risk of a person with extreme abnormality of a single major risk factor (8). The presence fof any combination of multiple risk factors should prompt intensification of therapy (8). include HYPERTENSION “The overall aims of hypertension (ITN) treatment in pediatric population should include obtaining a blood pressure (BP) level Uhat reduce the risk of target organ damage and reducing the risk of maintaining hypertension and related increasing CVR in adulthood (58). The new Guidelines for High Blood Pressure in children and adolescents, published in 2017, indicate as the goal of non-pharmacological and pharmacological therapy a BP <90th percentile or 130/80 mmHg in adolescents 13 years old (58). Lifestyle intervention are the first-line approach recommended for HTN (58). There is good evidence in adults as in childhood that nutritional interventions, including reduced dietary sodium and increased olive oil polyphenols intake, result in lowering BP levels and cardiovascular mortality, (69-51), In addition, higher intake of fruits and vegetables are also associated with lower BP and with lower risk of high BP in, ‘young adulthood (62, 63). Several studies conducted in children, land adolescents support the evidence of the benefit of physical activity on BP (64) also independently from the type of exercise (acrobic training, resistance taining or combined training) Gi), AAP recommends sessions of 30-60min of moderate to vigorous physical activity a least 3-5 days per week (58). ‘When HTN persists despite lifestyle modifications or in ‘eae of symptomatic HTN or stage II hypertension without ‘modifiable factors, pharmacologic treatment should be initiated (68). Therapy should be started with a single medication at the low end of dosing range and can be titrated every 2-4 weeks, The patient should be seen every 4-6 weeks until BP has normalized (eg.. <80th percentile) than the frequency of vis ‘ean be extended to every 3-4 months (58). Treatment should be initiated with an ACE inhibitor, angiotensin receptor blocker (ARB), long acting calcium channel blocker or thiszide diuretic ‘Studies completed in children do not find significant differences inthe effectiveness between these different agents and show few adverse elects (65, 66). When hypertension is in combination, ‘with T2DM, ACE inhibitor or ARB are recommended as fist- line therapy (8, 58, 67). Combination therapy may be required if HTN does not normalize on single agent therapy (58) In children requiring pharmacologic treatment, lifestyle changes should be ‘continued, also in order to improve antihypertensive medications efficacy (58). DYSLIPIDEMIA "The association of obesity and hyperlipidemia is predictive of fatal and non-fatal cardiovascular events in adult life (68). The role of dietary fat intake in increasing cardiovascular risk is still debated (69, 70). A review of De Souza et al. reports no association between saturated fat intake and cardiovascular disease (68). In addition available evidence from randomized ‘controlled trials shows that saturated fatty acids replacement with polyunsaturated fatty acids reduces serum cholesterol levels but, rot results ina lower risk of death fcom coronary heart disease (70). However, recent evidences support the importance of the ‘ype of fats consumed rather than total fat intake in influencing ‘cardiovascular health and recommend to avoid industrially produced trans-fate (72) The type of dyslipidemia associated with Mets is usually tceated with lifestyle interventions only, but medications should bbe initiated when appropriate, The authors of the Expert Panel Guidelines for Cardiovascular Health and Risk Reduction published in 2011 provide the evidence based guidance for dietary management of dyslipidemia in children and adolescents (CHILD 1 and CHILD 2 approach) (6). A reduction of total fat, between 25 and 30% of daly calories and of saturated fat <10%“Team of Metal Syren Chin ‘lores and a cholestrol intake <300 mg/day has been shown to safely and effectively reduce total cholesterol and LDL. cholesterol (8). When indicated, more stringent dit restrictions have been shown tobe sale and modestly elective (8) In children with obesity and elevated triglyceride level, seduction of simple carbohydrates intake i alo effective The use of plant sterols or stanol esters is usually reserved for children with primary elevation of LD. cholerteral (8) For children who will unlikely achieve lipid targets with ‘behavioral modifications alone, pharmacologic Weatmeat should by evaluated and it should always be proposed considering the context of complete CVR profile ofthe patient (8). To define the cutoff points at sehich the pharmacologic therapy should bbe considered the American Academy of Peditrice refers to 1992 National Cholesterol Education Program Guidelines (72) Blevated triglycerides and low HDL cholesterol with relatively normal LDL cholesterol represent the specific features of Aysipidemia in MetS (5,13). Pharmacological treatment i rarely necessary for children with elevated triglyceride levels that have 4 good responce to weight loss and lifestyle changes. Increased fish intake or fsh-oil supplementation may be considered (6) Initiation of medication therapy should be proposed on the bass ‘of a specific step intervention well described in the AAP Expert Panel Guidelines (6). tn particular, the use of statin is indieated when @ moderate hypertigyceridemia (200-499 mg/dl—2.26~ 5.64 mmoll]}) is asocated with non-HDL cholesterol level above 145 mgldl-3.76 mmol (8, 73). At present, EDA docs not approve in children the use of other triglycerides level-lowering redications, such as fibrate and nicotinic acid (3). GLUCOSE IMPAIRMENTS AND TYPE 2 DIABETES MELLITUS ‘Treatment modification on! adolescents with IR but not abnormal glucose concentrations is uncommon, Although some beneficial elects of metformin ‘on BMI reduction have been demonstrated, there is no clear evidence for long-term benefits (74~76), In obese adolescents impaired fasting glucose or impaired glucose tolerance are ‘often transient and about 60% of them revert to normal glucose tolerance within 2 years as the IR of puberty is reduced (77). Less than 296 of European adolescents with glucose abnormalities develop type 2 diabetes mellitus (I2DM) in the next § years (78, 79). Therefore, there is currently no evidence base for the use of metformin or other medications for the pharmacological treatment of IR (67, 80). Lifestyle intervention, including dietary and exercise changes, is also the core of treatment of T2DM. Healthy behavioral changes are essential for success also when pharmacological ‘treatment is indicated and should be periodically checked. Initial ‘treatment of youth with T2DM should include metformin andlor insulin alone or in combination, considering the symptoms, the severity of hyperglycemia and the presence or absence of ketosis/ketoacidosis (67). The goal of pharmacologic treatment in an HAL <7.0% (67) fof insulin resistance (IR) involves lifestyle ‘The use of metformin to treat children and is toobt When IbAlc is <8.5% (which corresponds to an estimated average glucose of 200 mg/dl) and the patient is asymptomatic and metabolically stable, (eatment should be started with ‘metformin with a target of HbAle <7% within 4 months (67, 74). Metformin acts reducing hepatic gluconeogenesis and simulating peripheral glucose uptake (80), Gastrointestinal symptoms ((ransient abdominal pain, diarchea or nausea) are the most common side effects reported for metformin use (81). ‘They generally resolve or ameliorate with time or with dose Litration and they may be attenuated using extended release formulations (67). The risk of lactic acidosis is extremely low. Addition and titration of basal insulin and, if necessary, of, prandial insulin, ie recommended when patients fails to reach HIbAe target within 4 months of metformin monotherapy oF if contraindications or intolerable side effects of metformin develop (67, 74 When ketosis and/or ketoacidosis are present, intravenous ‘or subcutaneous insulin treatment is recommended (67, 74). Once corrected the acute metabolic abnormality a therapy with {ntermediate-acting or basal insuhin once daly is usually effective Metformin can also be started along with insulin therapy, also in order to achieve, within 4-6 weeks, effective metformin, ‘monotherapy (67). Blood glucose sel monitoring should be performed regularly during therapy, individualizing the frequency and considering the avallable resources, Continuous ghicose monitoring bene! are sill not clearly examined in youth onset T2DM NAFLD Non-aleoholic fatty liver disease (NAFLD) represents the hepatic ‘manifestation of MetS. The goal of treatment of pediatric NAFD is to stop liver injury and reverse the progress form steatosis to steatohepatitis, cithosis and its complications (82). The mainstay. fof treatment for NAFLD remains lifestyle modifications and ‘weightloss. Probiotics and «-3 fatty acids may ameliorate disease progression (62). Two different double-blind randomized tials, demonstrate the favorable eflects of probiotice (Lactobacillus GG and VLS#3) in obese children with steatosis (83, 84) However, long-term follow-up studies are necessary to confirm these rerults. In NAFLD experimental models the use of ©: 5 fatty acids showed benefit in reducing liver steatosis and ameliorating insulin sensitivity and markers of indammation (65), but clinical trials in humans are still contradictory (66). Although Vitamin E does not appear to be effective in improving liver histology and reducing aminotransferase levels (87), it is able to improve hepatocellular ballooning {in about 40% of patients with NASII or borderline NASI (88), so it may be considered as a NASH-specific therapy in children (82). CONCLUSIONS ‘Although there ie still a lack of consensus on how to define MetS and its components in. pediatric population, ication and weatment of obese children and carly i“Team of Metal Syren Chin adolescents with multiple metabolic derangements allows to concentrate resources, particularly for children at higher risk, and to target focused intervention aimed to reduce the risk of cardiometabolic disease, Although sometimes the diagnosis is delayed because MetS, as obesity, is underperceived by families, general pediatriciane and other pediatric sub specialists, carly identification, and management are crucial and may help to attenuate the disease process. An expert ‘multidisciplinary team, which includes pediatrician, mental health practitioner, dietician, nurses, and other referral specialists for the single complications is pivotal, both at the level of prevention and therapy, also in order to offer individualized Uueatment (8, 22, 67, 88). The economic sustainability of the multidisciplinary team is a challenge for the health system. ‘A policy that involves more investments on this topic would be erucial (80,81). REFERENCES 1 Steinberger, Dales SR, Eckel RH, Hayman L, Lusig RH MeCiinde Bet al Amencan heart auocaton atherosclerosis, hypertension, 20d techy in the young commits of the counel| on cardorclar Cisewe i the young, coune on eazdiowaclar nuringy and couse os bution, physical actin, and rovabolien. Proger and callnget in Imeabole syndome in chldeen and adolescents scene steest from the American heart astocation atbrordeos, hypertension, and shesty ia the young_commitee of the coundl on ardorscla Giorat in the young fovnel on exrdiorsclar nursing, and counell on utaton, plyacal acts and metal Creation. (2038) 19-28- {do 10 LGL/CIRCULATIONAMA 108191394 2 Limmet F Ader KG, Keuiman F Taina N, Sink M. Atlin s {al TDF Gonsensos Group. The metabolic sydtome in cen abd Solexente an IDF convensss repr. Pediatr attr (2097) 429%= $06, dos 10.1011) 1399 148 20070271 5. ord 5,11 C Delining the metabolic ydrome incon and adolescents wll the rea definition. please wand up? J Pedr. (2008) 1S2160~ 4 do 101018 peds 20070705 4 Wels R, Bremer AA, Lisig RH, What & matabalic syndrome, and why are children geting Awe NY Acad Se (2019) 126123 1 dot 1011DUnyae 12030 5. Magge SN. Gopdian E. Armutrong SC, Commitee on Nutriton Section on Endecinolgy, ection on Obey. The metabolic syndrome in chien tnd adolescents shiting the foes to cardlametabai ek ctor datesng Peds (2017) 142017160, do 10 154pede 2917-1608 6 Berenson GS, Sriniazan SR, Bho W. Newnan WP I, Tray RE Waltigney WA. Association between wap adieu ik ctor nd stheosclos i cles nd Young ada The Bogalusa Hear study. 57 Engl Me (19) 998 1650-36 do 1010/NETM19980601382902 7 Baslow SE. Expert Commitee Bxper commie recommendations reguding the prevention, aecment, and tment af child and. adaecet lverght and obesity summary report Petrie (2007) 12016 Sh do 10 1s4zipedaa00r 25096 4. Expert Pad on Integrated Guideline for Cardovuclar Heath and Rok Reduction in Children and Adslecnt, National Heat, Ling, and Blood Tositte Exper pane! on tegrated gies for exrlovasclar health abd relereducion in hile ad adsercene smmaryepar Pediatr 2011) 128213456 dat 101scipede 200821076 9. Morven IA, Inledman LA. Wang P, Gluck Cl Metabolic eyadtome 2 ‘ildhood predicts aul etal yndcome and ype 2 diabetes nlitur 25 {e 30 years le. J Peat (208) 12:201-6 dt 10 1016) pds 2007010 10, Steinberger, Daniele SR. Angrican Heart Aueciaion,Aiheroceod, Typerension, and Obenty in the Young Commie (Counc on Cindiomscuar Duewe inthe Young), Ameican Hear Avociston AUTHOR CONTRIBUTIONS EF and CM gave a substantial contribution to the conception of the work, the acquisition, analysis, or interpretation of data for the work, provide approval or publication of the content, and, agree to be accountable for al aspects of the work in ensuring ‘that questions related to the accuracy or integrity of any part ‘of the work aze appropriately investigated and resolved. EF ‘wrote the manuscript and CM revised it critically for important intellectual content. FUNDING "This work was supported by the FURMAFE, Department ‘of Surgical Sciences, Dentistry, Paediatrics, and Gynaccology, University of Verona Diabetes Camaaitee (Cound) on Nution, Physical Acwiy. and Metaboli). Obeity, insulin rabtice dabete, and cardovasclar fic in diem an American Heart Avocton sce #aement fom the Atherosclerosis, Hypertension, and Obesity i the Young Commitee (Gounel en Cartioruclar Diste in the Yeung) and the Diabetes Commitee (Counc on Netrton, Phycal Acity, and Metaboli) CGredaon. (2003) "10748083. doe” 1011610 ci 09060323, osn 1, Ogden CL, Call MD, Lawanan HG, Frat CD, Kroson-Moran Kit BK, et a Trend in obesty prevalence amang chiléen and adlescets 0 the United Sate, 188 1994 Through 2015 2014 JAMA. (2016) 35:292— 9-dos 101001/ama2016.361 12 legal Ki, Caroll MD, Ke BK Ogden CL, Prevalence of obesity and ends Inthe dsubaton of body mass ndex among US ads, 1999-2010 JAMA, (2012) 9074917, do 101091201239 13, Witeapp €, Conroy R Metabolic syndrome in childrenand adlecent Pedy es (2016) 32193-20210 1542p 20140095 1M Whidock EP O'Conner EA, Willams SB, Bel TE, Late KW. Mectvenee of primary care snervenions for weght management sa ilren end leceate an updated, targeted systematic renew fo the USPSTE: nts 2010) 12583641, do 10 1532)peds 209-1955 15. Hot, Gare $2, Ssur 1, urtows 7 Stewart Neve Metal HBecveees of aye nterentions incl abs: spermatic eviw va metals. Pedr (2012) 130 e647-71, dak 101542)peds2012 1176 16 Rajo T Mohammed K, Alsawis M, Ahmed AT, Farah W, As! N, et A Treviment of pias obesity an umbela systematic review. J li Enacrinl Meta, 2017) 10274375 do 101210} 2016-2574 17 Meyer AA, Kune\ Genco U Seb Werner, Kena! W. Improvement of enly vovelar changes and crdovselar ik factor Sp ober cles tera smonth excrave program.) Am Coll Cadel. (200) 481865- 2. dk: 101016) 06209607035 18. Kamath Co, Vickers KS, Bhch A. MeGover I Johnson Singhal et A Clinical review: Behavioral intervention to prevent childhood oes ‘yaemate review and metanayer of rendomised ae. [Cin Eads ‘Meta (2008 9406-15 dot 101210} ¢2006 201, emer AA, MicturSoyder M. Lang RE Toward hypothos of metabolic syadiome Pedutres. (2012) 2. do 10158n)peds 011-2912 20. Seyne DM, Atlan SA, Connor EL, arog IS. Marad MIE, Sverteint fa Pedic abeckyasesmen, eaten, and prevention: an endocne ‘octyl pracivepuelie J Cle Endocrinol Meta. (2017) 102703- 57 de 101210}¢2017-60561 21 Gow Mt, Ho M. Burrows Th, Baur LA, Stewart b Hutcheson MI et Inopact of etary macronutrient ditbation on BNE and cardometabaie futomes in avere:ght and obese children and aalescenis 9 systematic reve: Nutr Rey (201) 7245370 da: 111 nare LLL + unihing“Fearne of Metal Sytem Chiron Py 2% a » o ‘Valeo G, Mallets , Sages G, Amram MA, Salame A, Bllne S cal Diagnose, ueatmentsbd prevention of pediabie obey: consensus postion satement af the Taian Society fr Pedic Endocrinology eo Disbetoogy and the Tedlan Society of Pedic. al J Pediat (2018) “4646 dot 10 186/19050.008.0525-6 French SA, Sherwood NE, Ae MM Haapala Ebbeing CB, Lodi DS. Physcal changer ia the home exvzonment to reauce tlevios| sewing aad sugarawecened beverage consumpucn among S- to 12 yeeolé dudtes « randamied plot study. Pedy Ober (2016) te So 1011131)p0 12047 James , Thomas P Cavan D, Kerr D, Preventing childhood sbesity by ‘educing coneumpton of ethonaed drink cuter rndomiedcontalled teal BA. (2009) 3281397 dat 101136/bm 28077 SHAH ene, Widhaln K, TAlemand D, Wiegand S, Webiach M Holl We A Two-year fallow-up in 21.784 overweight cen and adolescents wth ‘este intervention. Obesity (208) 1711969, do 1 1038097200817 NMageir © Cartelans M- Physical actiy an efecive way fonzal weight io chien? Nutr) Metab” Carionte Dic” (2087) 1739408 do 1010165 sumo 200608006 Maes 6, ZaffnlloM, Pegi M, Banzato C, Bogon G Vivant Fea [Nuttent oxidation daring modrsey intense exerci in obese prepubertal ‘boys. F hin Badorn Mea 2005) 0281-6 do 10 210, 2008-0715 Sle SP, Browning RC, SebsteY, Mae. Ue AP. Choos obesity sd wrlingqudenes and challeger It Pity Ober (2011) 6332" ‘dor oalowarerise 201130202 Lee IM, Soma # LobeloF, Pusha Base SN, Ketareyk PE eal Bec ‘of physialnacnty on major noncommunicable dieses worden ‘sie of burden af esse and Le expectancy Lance (2012) 300219 25. do 100160140 73a(3}s1091 9 Stabelni Neto A. de Campor W, Dos Stator GC, Mazardo Junior ©. Metbelic qdrome ik ert and ine expended in moderate te vigorous physica) acy in adleceats BMC Pediatr (2018) 1:42 ot 1011864712031-1642 Schmit Ki, nabs DR Je Hong CR Steinberger Moran A. Simao AR. ‘Aovoction of phe actty within sents cdren tJ Ober elt Metab Dred (2002) 16131016 do: 1010385 0802137 Moghet P Bacchi E,Branga C. Doak 5, Neg © Metbobc eet of ‘exes Front Hor Res: (2016) 478-87 da 101159/00348156 cane, Sansera JM, Gui Heros A Doriguez AM, Improvement ofthe pi pole wth eerie in ober chen: a syematie review Prey ‘Med (2013) 54291 90],dat 10 016)jypmed.201202008 pour Lambert N), Aggoun Y, Marchind IM, Mars XE, Hermans A, BeghctsM Physical att reduce systemic blod pres and improve ‘ety makes of aberonclerei in prepubertal ebese den, J Ar Coll Cant 2009) 542396406 do 101086 jae 200808 90 MeGarernf,Johneon IN, Paso R,Hetinger A, Singha V Kamath Ce al Clinial review treatment of pedatie bert: x pemaicreew tod ‘aca soap of randomized Wale J Clin Brdberina Metab 008) 93600= Sides todzi0} 2006-2409 ‘Stoner 1, Rowlands D, Monon A, CiedeurD, Hanlin M, Gaiey K, st AL Efieay of exerci intervention for weight los in overweight and shee test tina nd eis Sr Me (10) 47~ Rubin DA, Hadacy AG Infmanalry cytokines and melaboe rk for Arne growth and matraion dance af physical ay. Med Spor (2010) 3543-55 do L01189/00321971 Sedat C. King NA, Petia B Blandl [E,Thivel DA sptematic evi snd et aah of energy ané acronis nak response to pi Actnty intervention incon and adaevcente with bey. Petr Obes (@o17 279-94 do 1014p aziz Psey KL. Toino RP, Bulard RO, Culion SA, Futon J, Gala DA, et Al The physi actsity guidelines for Americans JADA. Goi) 3202020- 4: do 10.1001ma 2008 4854 Epstein 1, Roemich JN, Robinson [, Paluch RA, Winewier DD, Foch Ficetal A andomsied trio the elects of seducing eleision viewing end complies woe on body mass index im Young dleen Arch Pediatr loc ‘Med (2908 162239645 dak 101003/acbpeditecs 00745 a ” st 6 Wong Si Reda SA, Swit JA Yang M. Glaehook CP Epc sew” ad tntanee of ak fcr for cho overweight idntSabe hing nny. Arch Ds CRM. O3) 97101936 do 10 Issacheucil- 2012-0020 atonal Sep Foundation, Nation exp Fundtin Recommends New ‘Slap Durtio 2010, Adaline st hip Ieepoonton pe thnnennecdaepaundnoerenennenicne ep tat Coed ater 42019, Caen See CM, Bia, Geenld JR, Bar LA, Chats Ecc of weight on dragon bey and croc kfc in cbse ‘olcente sete sais anomie conte tile Obes Re 200) soc. dat 10111067 Pex aoononeto “toot SZ, Yano A. Longin drag ee fo obesity tea td inc reve, JAMA. QOH) 31 746 oy 1100uma201.261361 Roland Ch Hues TB, Haris KB Phamaclogal-manogeat of bey in pede patent Ann Phaser (215) Sande do 1 7106028055759 McDutie RCs KA. Uwe Cl Seng NG, Fan EM, HsSbard tal Three month leben in adler i bey ened ‘emo condos. Oe Re (202) 1642-50 1040Dooby 300287 Mintle IR Can KA. Unto Gh Sebing NG, Falon BM, Fase ‘T, etalEecy of onitarar am anc fo behavior eset 3 tvecwight Aan Ainecan and Conan adolescents win obesity Sstedso mori condiens Y Pdr Ruder! tah. O60) 17307- 1b. dot1olsisfeneaco4 7307 hors R Murad MEE, Chandar AK Dub PS, Wang 2 Prokop Ub A Asin of pharmaolge uetens fr abesty wth welt os tg aéverte event a syremate tev an taal JAMA. O16) Kelly AS, Rodi KD, Nahon BM Fox CK. Metre AM, Coombes BL et al The edect of glucagendie peplde replat agent they an body us index in alleen wh severe bea 4 fandamined, platdo-contoeé, cine tal. JAMA’ Pei COD) 16735580, oh 2 oo pamapeier 2018 1045 Mead E Alanon G, Beer 5 Metzendor’ ML Baur, Finer No et al Drop. interwntions for the twetnent of oberily in ddildsen and) adslecntsCachane Dabur Spot Rev O16) TE:CDoi2A6 dot 10 OMIAesI¥SA COOLERS Inge TH, Courcolat AR, Jenkins TM, Michluky ME, Helmrath MA, Brand Ml, et al Ten LABS Consortium. Weight lve and health ae 3 years ser basic rrpery i. alecents N Engl J Med (2016) 374115 23. do 1010S6/NEIMosIS00699| AeA, White B Viner RM, Siamons RK Basic surgery fr obese lien and adoecea's assem review abd meteamlyi Os Res (aot) 14634-4410 1101/60 12097 Bray GA, Teel WR Ahn 8, Jensen MD, Diets WIL, Long ME ot The scene of chesty management: an edcroesocety scene Hferant ‘Ender. (2018) 3979-182 dak 10121022017 0053 Spear BA. Barlow SE, Bivin Ludwig DS, Sudens BE, Sebetana KE, et A Reconiendstions for eam of cid abd adolescent overweight a8 hey Pediatrics (2007) 1205254-48 do 10154/peds 2007 929% foge Gourclts AR, Jehine TM, Michaky MR Brandt Mt Xanthaloe SA, etal Hve-yearauteomes of gute Bypass in dolscenls 2 compared wah adli Nf! J Med. (2019) 340213645. dak 101056! Netoui83909 loge TH. Jenkins TM, Xanthos $A, Dion TB, Daniels SR, Zeer MEL tal Tong teen ostomer of Bare surgery in adlecets wth severe shire lrg uns et io Bint 56-79. dot 110162219 85870630315 1 eden FE Angiman K Endo A, Davenbiock H, Stsao A, Cutie Ret al Weight low afer basntic surgery in obese adores: a systematic review and mec-anlis. Sug Obes Relat Ds (2018) 14413 2. ei 10046} s0aré2017. 10.08 yan Th Kaeloer DG, Baker Snath CM, Blowey D, Carell AE, Daniels SK, et al Cliueal practice guideline lor saening snd management of bigh blood preste in children and adlecens. Petre (2017) 1420171908, do 10.1542)pds2017-3035 Frontre in Endoebloy | wontons. org“Fearne of Metal Sytem Chiron e a 6 a ” ‘Adler Aj, Tylor F Marta N, Got, spor RS, Brahim S. Reduced icay fr the preveton of eardivasaar dee. Cochrane Database ‘Spt ey. (2018) 18: GDOOII7 do 0100214651858 CHOOT pbs ‘Yang Q Zhang Z, Kukna EV; Fang} Ayala C, Hon ¥ «al Sodium take snd blod presre among US ehdren and adlecets, Peirce, 2012) oi- 19" dei 10 5¢%pede 20113070, Moreno Luna R, Mator Hernander , Mirunde Ml, Cort AT jimener Fasenee,Vllejo-ee Al ta. Olive ol polpheaol decease bod pene And improve endoteal function in young women with ald bypertension, ‘Am Aypertnn, 02) 25:1398-904, do 1010382012198 Damasceno MN, de Araso Mi de Fras RW, de Almeida PC Zanes ME, ‘The rocitin between Sood preteen adalecets ad the consumption frat, vegetables and ft jean exploratory tay. Clin Nurs (2012) 20155240 10,111} 1365-2708 201003608. Moore Li, Bele ML. Singer MR, Qutethi MM, Buena JR Daniels SR Dietary aproaces co stop hypertension (DASH) eating pacers and risk of elerated blood presrere in adolescent ie. Br] Nut (2012) 0417 “dot 10 101/sonor as1100715x TeeranceB McGuire KA Lewanerk R, McGavock J. Overweight physic sctnty and high bloodpressure in chlven «review af heer. Ve “Hea Rok Manag. (2007) 3138-49. Herder SD, WebetE, Winkemsn A, Herder Mork H.Biccy and ety fof angiotensin I recepor spe 1 antagonism ehidren and alecente Pedal Nephrol (2010) 2540-11 das 10100710867 O09 1346-x Seine Lutvia M, Zac Zarowsha A Tus, Gro Atal Bieaey and elt of valartn connate to eon in hypertensive hire: #12 reek, randomized. doabe lind. paral-goup sey. } Hypertens O13) 29248490 go: L097MELGbOIBeS28825¢ esl R Ardaian $ Fa, Pibas Hansel O, Renehe Tandon Net al PAD incl practise comsenrus gUidelines 2016 type 2 lable sets in youth Pediatr Diakte (2018) 1928-46, doe 10.011 pears Mowion JA Glueck Ch. Woo 16. Wang P. Risk fico for erlovsclar| ives and ype dubetecetaned rom hood wo adsthood presse butomer:thePrincton LRC ‘lla up uly nt] Pediatr Endornal 2012) po124 dt 1oduasi647 9856-20126 De Sous Rj Mele A Maclans A, Couns AL Ha Y, Kubibe Tot a Intake of saturated and tans unaurted fy acd and rule of al ease mort, exdovsclr diese, and ype 2 dete ‘yeematc rer and met aa of obrerrasonl wader BD. 2015), 51078 dot 10 113fbmsba97e Rameden CR Zamora D,Majehrrak Hong S,Farot KR, Brot SK, Fast Bb et a Re-evahation of the tain tbat hypotes: aall of ecoyeed dita om Minnesota Goronty Experiment (1968-73) BM 2016) 3591126, do 10 1136246 Foroahi NG, Krause BM Tauber G, Willtt W Dietary &t and cardiomctabalic hel: evidence, controversies, and eonseava for aidan ‘BMF. Go18) 36142129 dav L0L36/bm a9 [NGEP Expert Panel of Blod Chaetrl Lees in Chien and Adelescnt "Nuuonal Cholesterol Eduction Program (NCEP): highlight of the repo. ‘ofthe expet pane! on blood chalet! levi chien and adlecent Pediatrie (1992) 8943550 Vasivapath 8, Sond BAubsal AP. Approsch to Hypertgcendemsa| Jp the peace population. Pedr Rey. (2017) 3842 34. do 101542/pe2016-0138 ‘American DabeesAnocition — Chien Jeandards of mecca) cae in dabtes2004 126-36 doi 102897 dele 012 snd adolescent isiter Care (2018) MeDonagh MS. Seph 5, Ompinar A. Foley C. systematic zeiow the beset: and ride of motfrmin in tedling betty in fhldeen aged 18" yes and younger JAMA” Pedi O10) 16817446: 101001) amapediatis 20134200, Park MI, Kira, Ward KI, White B, Viner RM, Metormin fr abesty in thlden and adolescent steric revee Diabetes Care (208) 321703— So: 10a337/dt9 ase 77. Renee T, Wolters B Kaap CLs N, Halt RW. Soong elec f pubertal statue en rcabolic eathin ober children: lonpitatoal study. 7 lin Endocrine Metab. (2015) 100301 doe 10 1210)¢ 20142674 17%, Kher M dsousa 6, Pape 8, Walch M Rene T. Impaled Jocoe telernce in obese white cdren and adolescents thee to five yea flow ep sp untested patente Esp Clin Endocrine! Diaber (2011) 119172— fda 101055) 0030 1263150 179, Rider M. Las N, Pape $, Webiuch M, Reichs T. One-year fw up of uaueted obese white dulden and adolescents with impure Qucose tolerance: high conversion rate to poral glucose tlerancel. Dich Med (2010)27 516-21 dob 101131) 1464 5912010029918 0, Gianarelh RAragona M, Coppell A, Del Prato 5. Reducing inulin Ferdtance with snelirmin: the evidence tdsy, Dishes Metab. (2003) 29628-35 do: 101011262 3635(03)72785-2 {5 MeCeeight Lb Bae Cl Person BR MetToma andthe gastointestin wet Diabet (2016) 8426-35, dt 10100700125-015 384493 “2, Nobis Allhour N Alt A, Della Corte C,FiparckF Raps MG, Nenalcoole ty iver due: + challenge or pecans JAMA Pdi (G015) 16170-€ de 101001 mspedines 20142702 o5, Varo B Mandato C. Lent MR, Frnzese A, Ville DE Lente Se al. Bees of Laoboclue rhannoar stan GG in pede bei eated er disease Pediatr Gastroenterol Naty (2011) 92740" 5.dos101097/MPGobaises182169beS SL Alt A. Belopas G, Sanit G. Giorpe V, Porro K Pats Get a Randoibed clea tek the beneficial elects of VSLAD in obese chen with nonalcoholic steatahepeti Ament Pharmac! Ther, (2018) 3:1276— 45. dov 10 taperz7se |5, Nasteton GS, Ples IN, Hayes PC Review ace: omega fat acids— 2 promising novel therapy for non-alcoholic fatty liver tee. Aliment ‘Phmacl Ther (2010) 3179-92 do 10110151365 2036201008330 46, Tanemk W, Lebenea D, Wiebicka Racoska A. Masur A, Nell ‘Maras J Matus Beal Omepe-3 Fat ads therpy sn chen eh nooaleoboke Faty ler dease «randomized cootoied tal 7 Pedi (2015) 14513566). dt 101016) pede 201501056 (7, Nob ¥ Anco M, Dent R Campa F, Peon Marcel M. Ee of in censor el linen vesitanesnchlon wet, onalesholie ay Iver dsewe. Alert Pharmacel The. 2096) 261555- doe 101111).1348 205200603161. 4%, Lavin J, Schwtmer JB, Van Nata MI, Mollet J Murray KB Rosenthal Poet al Nonaeohaieseatobepatise cnc rear network Het of ‘tania Bor metdormin for treatment af monastic ty Bre eve Children snd adolescents the TONIC rendomised conte te JAMA {aoin) 3051659-68 do 1010012012520 4 Buchot SC, Bone Y, Cedehelm T Chourdks M, Cue ¢. Deanne NM, etal Towards + miduciginary approach nderand and manage obesty and rated cueses Cli Nur (2017) 56917-3810 LOL ens20151. 007 90, Lobelia, Judson Leach R, Moodie Ml, Hall KD, Gorter St, Swinbars BA etal. Cid and adleceat obesity put of bigger pstre. Lance 201) 345251020 do 10 10LS0L40-€73610617463 91, Zanes, Leach R. Trimmer C, Lobtein T Mars S,fames WR, fecrenes and co-eectivence of interventions that cnse weight last and redore thers of erinvsclar diese, Diabetes Obes Metab (2017) Tien doe 01111¢om 1272, ‘Cont of Interest The authors declare hal the reenrch was condaced in the teen of ex emer Bnancal reams thet cred be centred a potent cone of eet Copyright © 2019 ornat and Maes Tir an open aces ate diriuted nde the tere of he Creative Commons Atbutin Licenre (CC BY}. The wt ‘earibton or reproduction in other fons permite, provided he og thors) and he copyright owner) are ceded otha ke srg pubiction tn is journal i te on wecandance th aeeped academic practice. No we, ‘atribcon or rprodactionspermited which oe nt comply with the tem, Frontre in Endoebloy | wontons. org