Review Korean J Obes 2016 June;25(2): pissn X eissn 비만소아청소년에서대사증후군발생의임상적예측인자 이지은 * 인

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1 Review Korean J Obes 2016 June;25(2): pissn X eissn 비만소아청소년에서대사증후군발생의임상적예측인자 이지은 * 인하대학교의학전문대학원소아과학교실 Clinical Predictive Factors for Metabolic Syndrome in Obese Children and Adolescents Ji-Eun Lee* Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon, Korea The prevalence of obesity and metabolic syndrome in children and adolescents continues to increase worldwide. Childhood obesity is associated with adulthood obesity and increases the risk of developing adult metabolic syndrome. Metabolic syndrome is a well-documented risk factor for the co-occurrence of cardiovascular disease and type 2 diabetes mellitus. Thus, early detection and early intervention to prevent metabolic complications are critical in obese children and adolescents. This review article describes clinical predictive risk factors for metabolic syndrome in obese children and adolescents and provides a comprehensive understanding of each risk factor in pediatric metabolic syndrome. Key words: Obesity, Childhood, Metabolic syndrome, Risk factor 서론 전세계적으로소아청소년의비만증가속도는성인의비만증가속도를넘었다. 1 세계보건기구 (WHO) 에서는비만을 21세기의신종전염병으로지목하고, 적극적으로대처할것을권고하고있다. 우리나라도소아청소년의비만의빈도는 10-19% 로점차증가하고있다. 2 국민건강영양조사에따르면한국소아청소년비만유병률은 1997년 5.8%, 2005년 9.7%, 2007년 10.9%, 2010 년 10.8% 로 10년사이약 2배정도증가하고있고특히연령에따라비만도가증가하여고등학생의 5명중 1명이비만으로보고되는실정이다. 소아청소년기의비만은성인비만으로이어지고대사증후군의위험도를높인다. 대사증후군은복부비만, 고혈압, 이상지질혈증, 당불내성등의요소들이복합적으로나타나는질환으로개인에게여러위험인자들이다발성으로발생하여동맥경화성심혈관계질환과제 2형당뇨병의발병위험을높이게된다. 3,4 특히사춘기의비만은성인 에서질병의이환및조기사망위험을증가시키며 5 이시기에시작된대사이상은성인기까지지속되는경향을나타낸다. 6,7 따라서비만소아청소년에서대사증후군발생위험요소를조기선별하고치료하는것은성인기대사증후군을예방하고미래의심혈관질환을감소시키는데무엇보다중요하다. 본종설에서는비만소아청소년에서대사증후군의진단기준에해당하는위험인자와대사증후군발병위험예측정도를살펴보고대사증후군의위험인자각각에대한독자들의폭넓은이해를돕고자한다. 본론 소아청소년에서의대사증후군진단기준소아청소년의대사증후군진단기준은성인의기준을변형, 사용되고있으며일치된진단기준이없으므로다양한진단기준이혼용되고있다. 흔히쓰이는것은 2007년 International diabetes federa- Corresponding author Ji-Eun Lee Department of Pediatrics, Inha University Hospital, Inha University School of medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea Tel Fax anicca@inha.ac.kr Copyright 2016 Korean Society for the Study of Obesity This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 50

2 Table 1. Definitions of metabolic syndrome in children and adolescents Variables International diabetes federation 10 to 16 years Modified NCEP-ATP III Obesity (waist circumference) 90th percentile or adult cut-off if lower 90th percentile (age, gender, ethnicity specific) Triglyceride (mg/dl) HDL-Cholesterol (mg/dl) < 40 < 40 BP (mmhg) Systolic BP 130 or Diastolic BP 85 90th percentile (age, gender, ethnicity specific) Fasting Plasma glucose (mg/dl) FPG 100 or known T2DM 110 Diagnosis Central obesity plus 2 or more of 4 factors 3 or more of 5 factors tion (IDF) 의기준 8 과 2005년 ATPIII의기준이다 (Table 1). 9 소아는성인과달리대사증후군의기준을정하기가어려운데, 이는대사증후군의각기요소의해당정상치가인종, 연령, 성별에따라차이가있고사춘기시기에는인슐린저항성이정상적으로발생하기때문이다. 또한소아에서성인까지장기적인전향적대사증후군연구가드물어서진단기준의적정여부를평가하기어려운문제가있다. 1. 비만비만은체지방이증가한상태로체지방평가가중요하다. 체지방직접측정은 dual energy X-ray absorptiometry (DEXA) 가정확하지만임상에서실용적이지않다. 진료현장에서선별검사는신장, 체중을이용한체질량지수가권고되며그외허리둘레, 허리둘레 -신장비율이유용한평가도구로이용된다. 신체계측지수는성인 2형당뇨병과심혈관질환발생예측의위험인자이지만단일인자로의관련성은약하다는단점이있다. 1) 체질량지수소아청소년의비만지표는체질량지수 (body mass index, BMI) 백분위수를이용하여나타내고성, 연령별 BMI 95 백분위수이상이면비만으로정의한다. 2016년최근발표된이스라엘의대규모전향적코호트연구 10 에의하면평균연령 17세인청소년 230만명을 40년간추적관찰한결과 BMI 95 백분위수이상의비만청소년은 BMI 5-24 백분위수인청소년에비해성인기심혈관사망률이 3.5배증가하였다. 소아대사증후군 31명을관찰한다른전향적연구에서 25년후 21 명이성인대사증후군으로이행하였는데, 이들의경우성인기이행시동반된 BMI 백분위수증가가공통위험인자였다. 11 두종단연구모두장기간의높은 BMI 수치와대사증후군발생과의연관성을시사한다. 한편, 소아기에비만했으나성인기에정상체중을보인그룹의대사증후군발병위험률은비만한소아기가없는정상체중성인그룹과유사하다고알려졌다. 12 따라서대사증후군의발생위험을감별하기위해성장기과정의소아청소년에게신장과체중, 체질량지수를연속적으로평가해야하는것은중요하다. 2) 허리둘레내장지방축적량은소아청소년기대사증후군과후기심혈관질환의강력한예측인자로이는인슐린저항성증가와연관이있다. 허리둘레는특히소아에서내장지방축적량의가장좋은간접적예측인자로알려져있다. 13,14 1,000여명의 9-10세여자아이대상으로 10년간관찰한전향적연구에서 2년간허리둘레가 1 cm씩매회증가되면대사증후군의발생위험은 7.4% 증가하여, 복부비만과대사증후군과의연관성을확인하였다. 15 소아청소년의허리둘레는나라별로연령, 성별백분위수가조사되어있고 90 백분위수부터복부비만으로정의한다. 한국소아청소년의허리둘레백분위수는 2005년대한소아과학회표준성장도표를이용할수있다. 16 비만한소아청소년에서는신장, 체중뿐만아니라허리둘레측정이필수적이다. 3) 허리둘레 신장비율허리둘레 -신장비율 (waist-to-height ratio, WHtR) > 0.6이면비만소아에서대사증후군과심혈관계위험발생의유의미한예측인자이다. 17,18 이는내장지방축적량과상관이있으며연령별체지방분포정도를추적관찰하기쉽고성별일치도가높은장점이있다. 19 소아청소년의허리둘레표준데이터가없거나정확치않은경우 WHtR을이용하면유용하다. 성인에서는 WHtR이 BMI나허리둘레보다심장대사위험을나타내는인자로더좋은선별검사라고하였다. 20 하지만아직소아에서는연령별 WHtR 표준치가없고, 일상적사용에대한합의된지침이없다. 또한최근대사증후군의심장대사위험질환의예측인자로서내장지방축적량의예측인자인허리둘레나 WHtR가 BMI 나 BMI-Z 수치보다열등하다는반대되는연구결과도나오고있다 이상지질혈증한국소아청소년의이상지질혈증기준은중성지방 150 mg/dl, high density lipoprotein-cholesterol (HDL-콜레스테롤) <40 mg/dl, total Cholesterol >200 mg/dl, low density lipoprotein-cholesterol (LDL- 콜레스테롤 ) >130 mg/dl로정의할수있다

3 인슐린저항성과고인슐린혈증은간내지질대사효소유전자의전사를증가시켜서중성지방형성을증가시킨다. Small dense LDL-콜레스테롤은동맥경화증을유발하며비만소아의대사증후군에서심혈관질환의위험을가중시킨다. 23 혈액내중성지방수치증가와 HDL 콜레스테롤수치감소는비만소아에서 small dense LDL-콜레스테롤의표지자로알려져있다. 1) 중성지방수치 9-10세여자아이 1,000명대상 10년추적연구에서혈액내중성지방 1 mg/dl가증가하면대사증후군위험은 1.3% 증가하였고, 미래대사증후군발생예측인자는처음측정된허리둘레와혈액내중성지방수치였다. 15 Princeton LRC 추적연구에의하면소아기고중성지방혈증시작군이성인고중성지방혈증시작군에비해성인기심혈관질환발생이 5배증가하였다. 24 2) 중성지방 /HDL 콜레스테롤비율혈중중성지방수치단독인자보다는 HDL-콜레스테롤로보정한, 중성지방 /HDL-콜레스테롤비율 (triglyceride-hdl cholesterol ratio, TG/HDL-C ratio) 에대해연구가늘어나고있다. 과체중또는비만소아청소년의 TG/HDL-C ratio는 small dense-ldl 콜레스테롤의우수한표지자이며, BMI나혈압과는무관하게소아청소년및젊은성인에서의동맥경화정도의예측인자이다. 25 TG/HDL-C ratio 3은 3 미만에비해높은 small dense LDL-콜레스테롤농도와연관이있다. 23 최근단면조사연구에서과체중또는비만소아에서 TG/HDL-C ratio 는내당능장애진단용선별검사도구로유용하다고했다. 26 새로진단된 2형당뇨병소아청소년에서 TG/HDL-C ratio가경동맥내막두께 (carotid intima-medial thickness, CIMT) 증가를예측할수있다는연구결과도있어 27 내당능장애와심혈관계예측인자로유용하다. 3. 고혈압국내에서는수축기또는이완기혈압이성별, 연령별, 신장별기준의 95 백분위수이상이면고혈압으로진단하고, 백분위수와무관하게수축기혈압 130 mmhg 이상또는이완기혈압 80 mmhg 이상이거나, 백분위수혈압을고혈압위험군으로정의하도록하였다. 소아청소년의고인슐린혈증은혈압에직접적인영향을미친다. 인슐린저항성은고혈압의독립적위험인자이다. 28 혈중인슐린수치는 6년후혈압의예측인자이기도하며이는교감신경계과다활동과신장의나트륨축적, 인슐린자극에의한평활근발달등의다양한기전에의하여발생한다. 29 소아기부터고혈압또는높은중성지방수치를보인그룹에서성인기에동일한위험인자가시작된군에비해 2형당 뇨병발생위험이 3배증가한다. 24 고혈압발생의높은위험률은비만도의증가과연관이있으며중등도와고도비만소아청소년에서고혈압은 3배증가된다 당불내성과 2형당뇨병인슐린저항성이계속되면일정기간혈당은정상으로유지되지만고인슐린혈증이발생한다. 당불내성은공복혈당 mg/dl인공복혈당장애와경구당부하검사 2시간혈당 mg/dl 인내당능장애로나뉘며, 청소년기의내당능장애와공복혈당장애는모두심혈관질환의위험인자로서성인기심혈관질환의발생위험률을증가시킨다. 31 과체중청소년대사증후군에서당불내성은경동맥내막두께 (CIMT) 증가와상관이있다. 32 1년이상내당능장애를지닌비만청소년의 2년후경과를보면 46% 가정상혈당상태로돌아왔고, 30% 는내당능장애유지, 24% 는 2 형당뇨병으로진행하였는데비만이심할수록진행하였다. 33 또한고인슐린혈증이동반된대사증후군이있는 10세흑인 / 백인여자아이대상의전향적연구에서 15년관찰한결과 BMI가증가되면서평균 26세에공복혈당장애와 2형당뇨병이발생하였고 10세진단된공복혈당장애가당뇨병발생의예측인자였다. 34 성인과유사하게비만청소년에서도경구당부하검사 1시간혈당 155 mg/dl는당뇨병발병위험의예측인자로서, 이는인슐린감수성에비해베타세포기능저하가있고미래당뇨병발생위험이높다는것을의미한다. 35 성인의내당능장애선별검사기준은 HbA1c 5.8% 인반면, 비만소아청소년에서내당능장애 HbA1c 기준은더낮은값을제시하기도한다. 비만소아청소년 1,000여명대상다인종코호트연구에서내당능장애컷오프기준은 HbA1c 5.5%, 2형당뇨병은 HbA1c 5.8% 를제안한바있고 36 다른연구에서도선별검사로동일한기준을제시하였으나 37 성인처럼전세계적으로정해진지침은아직없다. 이처럼비만소아청소년에서미래의당뇨병발생의예측은중요하며, 무증상이더라도내당능장애또는공복혈당장애를보이는비만청소년은조기중재가필요하다. 5. 대사증후군위험인자와 2형당뇨병의연관성소아청소년에서 4개이상의대사증후군기준이전부있는경우는청년기에 2형당뇨병발생가능성이있음을강하게의미한다. 38,39 비만소아청소년에서내당능장애의위험인자예측의선별검사로대사증후군의진단기준에해당하는지질수치인 TG/HDL-C ratio가유용하게이용되며, 성인처럼공복중성지방수치와공복혈당수치로평가하는연구들도보고되고있다. 40,

4 결론 소아비만이증가할수록소아청소년의대사증후군이증가한다. 2001년국민건강영양조사분석에서정상체중군, 과체중군, 비만군의대사증후군유병률은각각 2.5%, 11.2%, 36.6% 로급격히증가하였다. 이는소아청소년의비만정도가심할수록대사증후군의빈도가증가함을보여주며, 과체중소아청소년의대사증후군발생위험은정상체중소아청소년에비해 5배, 비만군은약 23배증가하였다. 42 비만과연관된대사증후군발생의가장좋은예방법은유아기부터적절한체질량지수를유지하는것이다. 43 하지만소아기비만이있더라도성인이되기전정상체중으로회복되면심혈관계질환의발생률이소아기비만이없는성인과유사하다. 44 그러므로이미비만한소아청소년에서는비만을조절하면서대사증후군발병위험이높은군을감별및관리하는것이비만합병증을조기에예방할수있는방법이기도하다. 체질량지수, 허리둘레, 허리둘레 -신장비등의신체계측지수는성인 2형당뇨병과심혈관질환발생예측의위험인자이지만예측정도가약하여 32 공복혈중지질검사와공복혈당검사, 혈압측정등이추가로필요하다. 성인에서처럼소아청소년에서도여러개의대사증후군위험인자와 2형당뇨병, 심혈관질환발생위험을예측하는연구가활발히이루어지고있다. 비만청소년에서는대사증후군의진단기준에해당하는위험인자를평가하여위험군을선별해야하며조기진단및중재를통하여미래의 2형당뇨병과심혈관질환을예방해야한다. 요약 전세계적으로소아청소년기의비만과대사증후군은증가하고있다. 소아비만은성인비만으로쉽게이행되며, 성인대사증후군의발생위험을증가시킨다. 대사증후군은심혈관계질환과제2형당뇨병의이환율과사망률을증가시키므로비만소아청소년대상으로대사적합병증을조기발견하여예방하는것이매우중요하다. 본종설에서는비만소아청소년에서대사증후군의진단기준에해당하는위험인자와대사증후군발병위험예측가능성을살펴보고대사증후군의위험인자각각에대한폭넓은이해를돕고자한다. 중심단어 : 비만, 소아, 대사증후군, 예측인자 Conflicts of Interest No conflict of interest to be declared. References 1. Popkin BM, Conde W, Hou N, Monteiro C. Is there a lag globally in overweight trends for children compared with adults? Obesity (Silver Spring) 2006;14: Oh K, Jang MJ, Lee NY, Moon JS, Lee CG, Yoo MH, et al. Prevalence and trends in obesity among Korean children and adolescents in 1997 and Korean J Pediatr 2008;51: Liese AD, Mayer-Davis EJ, Tyroler HA, Davis CE, Keil U, Duncan BB, et al. Development of the multiple metabolic syndrome in the ARIC cohort: joint contribution of insulin, BMI, and WHR. Atherosclerosis risk in communities. Ann Epidemiol 1997;7: Wilson PW, D Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112: Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, et al. Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 2001;358: Styne DM. Childhood and adolescent obesity. Prevalence and significance. Pediatr Clin North Am 2001;48: Srinivasan SR, Bao W, Wattigney WA, Berenson GS. Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism 1996;45: Zimmet P, Alberti G, Kaufman F, Tajima N, Silink M, Arslanian S, et al. The metabolic syndrome in children and adolescents. Lancet 2007;369: Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third national Health and Nutrition Examination Survey, Arch Pediatr Adolesc Med 2003;157: Twig G, Yaniv G, Levine H, Leiba A, Goldberger N, Derazne E, et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N Engl J Med 2016 [Epub ahead of print]. 11. Morrison JA, Friedman LA, Gray-McGuire C. Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics 2007;120: Juonala M, Magnussen CG, Berenson GS, Venn A, Burns TL, Sabin MA, et al. Childhood adiposity, adult adiposity, and cardio

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DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%) aged over 30 years or older had diabetes in 2010. Based on fasting g

DIABETES FACT SHEET IN KOREA 2012 Korean Diabetes Association (KDA) / Korea Centers for Disease Control and Prevention (CDC) DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%)