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PG 2 PG Course 2013 Non Alcoholic Fatty Liver Disease 서울대학교의과대학분당서울대병원소아청소년과 Non-alcoholic Fatty Liver Disease in Children and Adolescents Hye Ran Yang Department of Pediatrics, Seoul National

1 PG 2 PG Course 2013 Non Alcoholic Fatty Liver Disease 서울대학교의과대학분당서울대병원소아청소년과 Non-alcoholic Fatty Liver Disease in Children and Adolescents Hye Ran Yang Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Seoul National University College of Medicine, Seoul, Korea Recently, the prevalence of nonalcoholic fatty liver disease (NAFLD is increasing in pediatric population along with the increase in the prevalence of obesity in this age group. Because nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis even in children, early detection and accurate diagnosis of NAFLD are important in obese children and adolescents. Although liver biopsy is regarded as the gold standard of diagnosis, its clinical application is somewhat limited in children due to its invasiveness. Clinical features such as central adiposity and acanthosis nigricans and noninvasive diagnostic methods, including imaging studies, biomarkers of inflammation, oxidative stress, hepatic apoptosis, hepatic fibrosis, and noninvasive hepatic fibrosis scores may be useful to predict and diagnose NASH in children. Among treatment options for NASH in children, weight reduction (such as life style modification, diet, and exercise) and some drugs (such as vitamin E) may be effective in treating NASH in obese children. Key words: Fatty liver, Non-alcoholic steatohepatitis, Prevalence, Diagnosis, Treatment, Obesity, Child 소아청소년에서비알코올지방간질환의역학 최근소아비만의유병률이꾸준히증가하면서, 1 비만에합병된대사증후군과비알코올지방간질환의유병률역시꾸준히증가하고있다. 2,3 2008년국내보고에의하면소아청소년에서과체중또는비만의유병률은약 19% 까지보고되고있으며, 1 간조직검사적용의제한점때문에소아청소년에서비알코올지방간염의정확한유병률을파악하기는어려우나, 소아청소년일반인구집단의경우비알코올지방간질환의유병률은간기능검사를적용하였을때미국과국내에서 %, 일본에서초음파검사를적용하였을때약 2.6%, 미국에서시행한부검결과에따르면 9.6% 정도에서보고되고있다. 비만한소아청소년에서의비알코올지방간질환유병률의경우, 간기능검사를적용하였을때 10-80%, 간초음파검사를적용하였을때 15-44% 정도에서비알코올지방간질환이있는것으로보고되고있다. 4 다변량분석에서비알코올성지방간질환의독립적위험인자로비만, 성별 ( 남아 ), 연령 ( 사춘기 ), 인종 ( 히스패닉 ) 등이제시된바있다. 남아에서비알코올지방간질환이호발하는이유로는성호르몬의영향이제기되고있으 34

2 며, 사춘기연령에서의호발은이시기에성호르몬증가에의한인슐린저항성의생리적변화와체구성변화에따른결과로이해되고있다. 소아청소년에서비알코올지방간질환의정의는성인에서의정의와같으며, 소아에서도단순지방간, 비알코올지방간염, 비알코올간경변에이르는질병의스펙트럼을갖는데, 소아청소년기의비알코올지방간질환의자연경과와장기예후는잘알려져있지않다. 단순지방간이양성경과인반면, 비알코올지방간염은진행성으로알려져소아연령에서도간경변이보고되고있는데, 소아에서비알코올지방간염에인한간경변증이보고된가장어린연령은 8세로서, 저자도비만과제2형당뇨가있는만 8세여아에서발생한비알코올간경변을경험한바있으며, 국내에서는뇌하수체기능저하증이있는 16세소아청소년환아에서발병한비알코올간경변증증례가보고된바있다. 5 최근연구에의하면비알코올지방간질환으로진단된소아청소년환자 66명을장기간추적관찰하였을때두명이사망하고두명이간이식을시행받았으나재발하여그중 1명은재이식을받았다고보고되었다. 6 소아청소년에서비알콜지방간질환의진단 1. 임상소견및기본검사은대부분증상이없거나비특이적인증상만보이므로진단을의심하는데그리도움이되지않으나, 최근보고들에의하면복부비만과폐쇄성무호흡증 (obstructive sleep apnea) 이있는경우, 그리고진찰상 acanthosis nigricans가있는소아의경우비알코올지방간질환의가능성이높다고하였다. 7-9 기본혈액검사소견으로는 AST, ALT 등간효소치상승소견과더불어 gamma-glutamyl transpeptidase (γgt) 상승소견을확인할수있다 비만한소아청소년에서비알코올지방간질환에대한선별검사를위한가이드라인이없어서최근전문가합의권고안 (expert consensus) 에서연 2회간기능검사를시행하도록제안하고있는반면, AASLD (American Association for the Study of Liver Diseases)-ACG (American College of Gastroenterology)-AGA (American Gastroenterological Association) 임상가이드라인에서는증거불충분으로소아청소년에서의선별검사를공식적으로권장하지않는다고하였다. 12 국내에서는초등학교 4학년, 6학년, 중학교 1학년, 고등학교 1학년연령에서각각학교건강검진을통해비만여부를판정하고과체중이나비만이있는경우 AST, ALT를선별검사로시행하고있다. 13 소아청소년에서의지방간은성인과는달리다양한유전질환 (Prader-Willi syndrome, Turner syndrome, Bardet-Biedl syndrome, Cohen syndrome 등 ), 대사이상질환 ( 윌슨병, glycogen storage disease, galactosemia, mitochondrial defects of fatty acid oxidation, tyrosinemia type I, homocystinuria, citrullinemia 등 ), 내분비질환 (hypothyroidism, hypopituitarism 등 ) 에의해서도나타날수있으므로처음부터철저한병력청취와진찰및기본검사를통해감별해야한다. 14 특히과체중또는비만상태가없는소아청소년에서지방간질환이의심되거나환자의나이가 3세미만으로매우어린경우대사질환이나다른만성간질환의가능성을반드시배제하기위해검사가필요하다 비침습적진단 소아청소년에서비침습적방법에의한비알코올지방간질환의진단은크게영상검사, 혈액표지자 (biomarker), 간섬유화점수화체계 (hepatic fibrosis scoring system) 등으로분류된다. 35

3 Postgraduate Course 2013 소아에서비알코올지방간질환의지방간소견또는간섬유화정도를확인하기위한대표적인영상검사로는복부초음파 (abdominal ultrasonography), 복부전산화단층촬영 (abdominal computed tomography), 복부자기공명영상촬영 (magnetic resonance imaging), Fibroscan (hepatic elastography). MR elastography, Magnetic resonance (MR) spectroscopy 등이있다. 15 소아청소년비알코올지방간질환에대한 ESPGHAN 합의안에서는이러한여러영상검사중에서복부초음파가비록지방증및섬유화정량에있어한계를보이기는하지만비교적안전한검사이며, 복부자기공명영상촬영은고가의검사이지만신속한검사가가능하고지방증및섬유화측정이가능한검사로제시한바있다. 하지만, fibroscan은아직근거부족으로권장되지는않는다고하였다. 16 혈액표지자는산화스트레스, 세포사 (apoptosis), 염증및섬유화등에대한표지자로나눌수있으며, 소아에서도이들표지자에대한연구가일부이루어지고있다. 간섬유화점수화체계로는소아에서제시된 PNFI (pediatric NAFLD fibrosis index) 나성인과소아모두에서보고된 ELF (enhanced liver fibrosis test) 또는 AST/platelet ratio index, FIB4 score 등이적용가능하다 소아비알코올지방간질환진단을위한 ESPGHAN 합의안에서는이러한비침습적검사방법들이개발되어소아에서도보고되고있으나향후임상에적용하기위해서는대규모연구를통한검증이필요하겠다고하였다 간조직검사간조직검사가침습적인검사방법이며간전체의병변을반영하지않는다는단점을가지고있고, 위에서제시된바와같이여러다양한비침습적검사방법들이제시되었음에도, 간조직검사는여전히비알코올지방간질환의최종진단에가장중요한검사이다 세소아청소년에서체질량지수 85 백분위수이상이면서 ALT가 6개월이상지속적으로상승소견을보이면 B형및 C형등바이러스간염, 윌슨병등대사질환, 근육질환, 약물유발간염, 자가면역간염등에대한선별검사를시행하여다른원인에의한만성간염을감별한후비알코올지방간질환의확진을위해간조직검사를시행하는것이권장된다. AASLD-ACG-AGA 임상가이드라인에서는소아청소년에서진단이명확하지않거나다양한진단의가능성이있거나간독성있는치료를시작하기전에간조직검사를권하며, 더불어비알코올지방간염의약물치료를시작하려는소아환자에서치료전에확진을위해간조직검사를시행할수도있다고하였다. 12 소아청소년비알코올지방간질환에대한 ESPGHAN 합의안에서는간조직검사가확진검사로요구되지만, 비용문제와검사의침습성으로인해선별검사로는권하지않는다고하였으며, 감별진단을위해서나간경변등으로의진행위험성을평가하기위해또는약물적치료시작전에전문가의견에근거하여적응증을결정하는것이권장된다고하였다. 16 간조직검사는다른비침습검사및대사검사를완료한후마지막으로시행하는최종검사가되어야한다. 소아청소년비알코올지방간질환의간조직검사소견은성인에비해상대적으로심한간세포손상과대수포지방증 (macrovesicular hepatocellular steatosis), 간소엽염증, 심한문맥부위염증 (portal inflammation), 문맥부위섬유화 (portal fibrosis), 풍선변성등의소견이흔히관찰되어성인비알코올지방간질환과구별되는소아비알코올지방간질환의특징적조직소견이라할수있으며, 이러한차이점을보완하기위해최근기존에사용되던점수체계를수정하고문맥부위염증을점수체계에포함하는새로운 Pediatric NAFLD histological score가제시된바있다

4 소아청소년에서비알코올지방간질환의치료 과체중또는비만이소아청소년에서비알코올지방간질환의대부분원인을차지하는만큼식이요법, 운동을포함하는생활습관의교정이소아청소년에서비알코올지방간질환치료의기본이다. 23 기존의소규모연구들에서비알코올지방간질환이있는소아청소년의체중감소는간효소치호전과지방간소견을호전효과가있다고보고된바있으며, 최근전향적연구에서식이요법과운동요법등생활습관의교정은비만한소아청소년에서 ALT와초음파검사소견의호전효과를보였다. 23 소아청소년기의비알코올지방간질환에대한약물치료는, 최근미국에서보고된 TONIC study 연구결과에따라간조직검사로진단된 8-17세소아청소년비알코올지방간염환자 173명에게대상으로무작위배정이중맹검방법으로 metformin 1,000 mg과비타민 E 800 IU를투여하였을때비록 96주경과시점에서대조군과 metformin 투여군과비타민 E 투여군간에간효소치에있어차이는없었으나적어도비타민 E 투여군에서간효소수치와더불어간조직소견의호전을 58% 에서보였던결과에근거하여, 24 비타민 E의조직학적개선효과가기대되나장기적사용에대한근거가부족하므로향후임상적용을위해보다많은연구가필요하겠다고하였다. 12 마지막으로, 최근발표된비알코올지방간질환소아에서 DHA (docosahexaenoic acid) 투여효과효과에대한무작위대조군연구에서중성지질, 인슐린저항성지표인 HOMA-IR 뿐만이아니라간효소치와초음파지방간소견을개선시켰다는보고와더불어소아청소년에서 Lactobacillus GG를 8주간투여한결과간효소치의호전을보였다는보고에근거하여향후발병기전에근거한추가적인치료들이소아청소년연령에서의비알코올지방간질환치료에적용될수있을것으로기대된다 참고문헌 1. Oh K, Jang MJ, Lee NY, Moon JS, Lee CG, Yoo MH, Kim YT: Prevalence and trends in obesity among Korean children and adolescents in 1997 and Korean J Pediatr 2008;51: Bellentani S, Scaglioni F, Marino M, Bedogni G: Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010;28: Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE: Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;28: Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW: The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11: Park JY, Ko JS, Seo JK, Lee R, Shin CH, Kang GH, et al. Nonalcoholic Fatty Liver Disease Progressing to Cirrhosis in an Obese Boy with Hypopituitarism. Korean J Pediatr Gastroenterol Nutr 2008;11: Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009;58: Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 2009;50: Papandreou D, Rousso I, Mavromichalis M. Update on non-alcoholic fatty liver disease in children. Clin Nutr 2007;26: Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathogical correlations of pediatric nonalcoholic fatty liver disease. J Pediatr 2003;143: Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 2008;135: Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50: Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The Diagnosis and Management of Non-alcoholic Fatty Liver 37

5 Postgraduate Course 2013 Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association (vol 107, pg 811, 2012). American Journal of Gastroenterology 2012;107: Moon JS, LEE KO, Hwang SS, Ko JS, Lee HK, Shin HJ, et al. Analytic Report on the Revised Korean National Sample Data from the National School Health Examination in 2009 and In: Korean Educational Development Institute MoH, Science and Technology, ed. Seoul; Roberts EA. Pediatric nonalcoholic fatty liver disease (NAFLD): a "growing" problem? Journal of hepatology 2007;46: Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008;134: Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 2012;54: Alkhouri N, Carter-Kent C, Lopez R, Rosenberg WM, Pinzani M, Bedogni G, et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin Gastroenterol Hepatol 2011;9: Alkhouri N, De Vito R, Alisi A, Yerian L, Lopez R, Feldstein AE, et al. Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. Journal of hepatology 2012;57: Yang HR, Kim HR, Ko JS, Seo JS. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol 2012; 18: Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005;42: Takahashi Y, Inui A, Fujisawa T, Takikawa H, Fukusato T. Histopathological characteristics of non-alcoholic fatty liver disease in children: Comparison with adult cases. Hepatology research : the official journal of the Japan Society of Hepatology 2011;41: Ko JS, Yoon JM, Yang HR, Myung JK, Kim H, Kang GH, et al. Clinical and histological features of nonalcoholic fatty liver disease in children. Dig Dis Sci 2009;54: Nobili V, Marcellini M, Devito R, Ciampalini P, Piemonte F, Comparcola D, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 2006;44: Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA ;305: Nobili V, Alisi A, Della Corte C, Risl P, Galli C, Agostoni C, et al. Docosahexaenoic acid for the treatment of fatty liver: Randomised controlled trial in children. Nutr Metab Cardiovasc Dis 2012 Dec 7. [Epub ahead of print] 26. Vajro P, Mandato C, Veropalumbo C, De Micco I. Probiotics: a possible role in treatment of adult and pediatric nonalcoholic fatty liver disease. Ann Hepatol 2013;12:

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<303120C2F7B7CA2E687770> PG 1 PG Course 2013 Non Alcoholic Fatty Liver Disease 비알코올지방간질환의역학 서울대학교병원강남센터소화기내과 김동희 Epidemiology of Nonalcoholic Fatty Liver Disease Donghee Kim Department of Internal Medicine, Gangnam Healthcare