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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

1 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 Center, Seoul National University Hospital, Seoul, Korea Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis either by imaging or by histology after the exclusion of other causes of hepatic fat accumulation such as significant alcohol consumption, medication known to produce hepatic steatosis, the other causes of liver disease, or other medical conditions. NAFLD encompasses a broad spectrum of hepatic dysfunction ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The increasing prevalence of obesity and type II diabetes, and the metabolic syndrome is leading to an increased prevalence of NAFLD. NAFLD has been recognized as the most common liver disease with an estimated prevalence of 20-30% in the Western world, and 16-33% in Korea. The increasing prevalence of NAFLD is particularly worrying because patients appear to have a higher mortality from non-liver related as well as liver related death compared to the general population. Because of well-known association with metabolic comorbidities, NAFLD is commonly associated with obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Key words: Nonalcoholic fatty liver disease, Steatohepatitis, Hepatic steatosis, Prevalence, Risk factor 서 론 비알코올지방간질환 (nonalcoholic fatty liver disease; NAFLD) 은유의한알코올섭취가없는데도불구하고알코올간염과유사한조직소견을보이는질환으로비알코올지방간 (Nonalcoholic fatty liver; NAFL) 부터비알코올지방간염 (Nonalcoholic steatohepatitis; NASH), 비알코올지방간연관간경변증이나간세포암과같은만성간질환으로진행되는사실이밝혀지면서만성간질환의중요한부분이되었다. 1 비알코올지방간질환은비만및당뇨인구의증가와함께모든나라에서유병률이급격하게증가하는질환이며우리나라에서는유병률이약 16-33% 정도로추정되는, 임상에서매우흔하게접하게되는질환이다. 2,3 비알코올지방간질환은이전에는대사증후군의하나의간내표현형으로생각되어왔으나최근비알코올지방간이심혈관계질환, 제 2형당뇨, 대사증후군, 고혈압및신장질환발생에있어독립적인위험인자로밝혀지면서그임상적중요성이증가하고있다. 3-5 본고에서는최근까지발표된여러연구결과를토대로비알코올지방간질환의정의와발병률과유병률, 위험인자등에관해간략히소개하고자한다. 3

2 Postgraduate Course 2013 정 의 1. 비알코올지방간질환의정의비알코올지방간질환은유의한알코올섭취, 지방간을초래하는약물의복용, 동반된다른원인에의한간질환등이없으면서영상검사나조직검사에서간내지방침착의소견을보이는질환이다. 비알코올지방간질환은비알코올지방간에서비알코올지방간염, 비알코올지방간연관간경변증을포괄하는진단명이다 (Table 1). 비알코올지방간은조직검사에서 5% 이상의간세포에지방이침착된경우로정의하며주로 macrovesicular steatosis 가특징적인소견이다. 6 Table 1. 비알코올지방간질환과관련된용어의정의 용어비알코올지방간질환 비알코올지방간비알코올지방간염 비알코올지방간연관간경변증 설명비알코올지방간에서비알코올지방간염, 비알코올지방간연관간경변증까지전체질환의양상을포괄하는일종의질환군. 간내지방침착은조직검사에서 5% 이상의간세포에지방이침착된경우로정의됨간내지방침착을보이지만간세포손상 ( 풍선변성 ) 및섬유화의소견은없는경우간내지방침착을보이면서간세포손상 ( 풍선변성 ) 을동반한염증소견이있는경우. 섬유화를동반하기도함조직학적으로비알코올지방간이나지방간염의소견이동반된간경변증, 혹은과거조직학적으로증명된비알코올지방간, 지방간염환자에서발생된간경변증 2. 비알코올지방간질환에서유의한알코올섭취량의정의비알코올지방간질환과알코올지방간질환을구별하는유의한알코올섭취량의상한선은일일 g ( 순알코올량 ) 까지연구마다다양하게정의되어사용되었기때문에명확한기준을제시하기어렵다. 하지만, 최근미국의합의권고안 6 및이탈리아, 미국간학회진료가이드라인에서 7,8 유의한알코올섭취량을최근 2년간남자의경우주당 210 g, 여자의경우주당 140 g을초과하는경우로정의하였다. 현재까지간손상을일으키는알코올의상한용량에대해서는인종간차이가보고된바없고, 향후연구결과의국제적인비교를위해서앞서언급된유의한알코올섭취량의정의를임상진료및연구에사용하는것이바람직할것으로사려된다. 역 학 1. 비알코올지방간질환의발생률과유병률 1) 비알코올지방간질환의발생률 (Incidence) 비알코올지방간질환의발생률에대한연구는아직까지제한적이다 일반적으로단면연구에서의유병률과달리정확한발생률을구하는것이상대적으로어렵기때문에근거가될만한연구가부족한실정이다. 일본에서시행한건강검진을시행한후향적코호트연구에서는 1,000명당연간 86명의발생을보였으나 9 영국에서시행된간클리닉의외래환자를대상으로한연구는 100,000명당연간 29명으로훨씬낮은발생을보고하였다. 11 이스라엘의국민건강영양조사를이용한추적코호트연구는 7년추적검사에 19.0% 의비알코올지방간질환이새로발생했고 36.4% 의지방간환자에서호전된양상을보였다. 13 체중증가와인슐린저항성이비알코올지방 4

3 김동희 비알코올지방간질환의역학 간질환의발병의위험인자였다. 13 국내에서건강검진수진자를대상으로시행한 5년간의후향적코호트연구에서는 1,000명당연간약 26명의발생을보였다. 12 이러한연구마다발생률의상당한차이는앞으로정확한비알코올지방간질환의발생률에대한전향적인코호트연구가필요할것을시사한다. 2) 비알코올지방간질환의유병률 (Prevalence) (1) 조직학적진단기준비알코올지방간질환의유병률은연구대상및비알코올지방간질환의진단기준및정의에따라다양하게나타난다. 비알코올지방간질환특히지방간염의진단의 gold standard인간조직검사는침습적이어서 general population을대상으로한연구에서는사용될수없기때문에연구의선택편향 (selection bias) 으로인한한계가있다. 미국의생체간공여자를대상으로한연구에서조직학적으로 > 30% 이상의지방침착있는공여자 20% 로나타났다. 14 반면국내생체간공여자 589명을대상으로시행한연구에서조직학적으로확인된비알코올지방간질환의유병률은 51% 로나타났다. 15 미국의중년인구를대상으로시행한대규모연구에서조직학적으로확인된비알코올지방간과지방간염의유병률은각각 46% 및 12.2% 였다. 16 (2) 영상의학적진단기준미국의 Dallas Heart Study의코호트 2,287명의 magnetic resonance spectroscopy로측정한간내중성지방이 > 5.5% 이상을지방간으로정의하였을때유병률은 31% 였다. 17 특히비알코올지방간질환의유병률은 Hispanic 45%, White 33%, Black 24% 으로인종간차이가두드려졌다. 17 미국내대규모코호트연구인프래밍함연구 (Framingham Heart Study) 에서는전산화단층촬영 (computed tomography, CT) 을진단기준으로사용하였는데이에따른비알코올지방간질환의유병률은 17% 로나타났다. 미국 3차국민건강영양조사 ( 18 National Health and Nutrition Examination Survey III) 를이용하여일반인구집단을대상으로시행한연구에서는초음파검사를진단기준으로사용하였고이때의비알코올지방간질환의유병률은 34%, 진행성섬유화는 3.2% 였다. 19 요약하면, 비알코올지방간및비알코올지방간염의유병률은각각 6-35% ( 중앙값 20%) 와 3-5% 정도로추정된다. 국내에서는일반인구집단을대상으로한연구가제한적인실정이지만건강검진수진자를대상으로초음파검사를이용하여진단한비알코올지방간질환의유병률은 16-33% 로나타났다. 2,3,20 2. 비알코올지방간질환의위험인자 (Table 2) 비알코올지방간질환은나이에따라증가하는양상을보이는데특히남녀별로차이가있는것으로생각된다. 3 나이증가에따른인슐린민감도의감소와호르몬변화가원인일것으로생각된다 (Figure 1). 3 비알코올지방간질환은비만, 제2형당뇨병, 이상지질혈증, 대사증후군등과밀접한연관성을보인다. 비알코올지방간질환환자의 90% 에서대사증후군의요소중한가지이상을가지며 1/3에서대사증후군을동반한다. 21 과체중및비만은비알코올지방간질환의위험인자이지만특히중심성비만이강력한위험인자이다. 비만수술을받은비만환자를대상으로시행한연구에서비알코올지방간질환및지방간염의유병률은 91%, 37% 로나타났다. 제2형당뇨병환자에서도비알코올 22 지방간질환은높은유병률을보여최근한연구에서 69% 의유병률을보고한바있다. 뿐만아니라, 국내에서시행된코호트연구에서비알코올지방간질환은남성에서제2형당뇨병발생의독립적인위험인자임이확인되었다. 23,24 갑상선기능저하증과의연관성을조사한연구에서는, 갑상선기능이정상인경우비알코올지방간질환의유병률이 19.5% 인데반해갑상선기능저하증이있는경우에는 30.2% 로갑상선기능저하증환자에서비알코올지방간질환의유병률이의미있게높게나타났다. 25 한편, 다낭성난소증후군과비알코올지방간질환과의연관성 5

Postgraduate Course 2013 Table 2. 비알코올지방간질환의위험인자 입증된인자비만제2형당뇨병이상지질혈증대사증후군 * 가능성이있는인자다낭성난소증후군갑상선기능저하증수면무호흡증뇌하수체기능저하증생식선기능저하증췌-십이지장절제술 * 아래의기준중세가지이상이해당되면대사증후군으로정의한다.

4 Postgraduate Course 2013 Table 2. 비알코올지방간질환의위험인자 입증된인자비만제2형당뇨병이상지질혈증대사증후군 * 가능성이있는인자다낭성난소증후군갑상선기능저하증수면무호흡증뇌하수체기능저하증생식선기능저하증췌-십이지장절제술 * 아래의기준중세가지이상이해당되면대사증후군으로정의한다. 1) 허리둘레 : 남자의경우 90 cm 초과, 여자의경우 80 cm 초과 2) 중성지방 : 150 mg/dl 이상 3) 고밀도지단백콜레스테롤 : 남자의경우 40 mg/dl 미만, 여자의경우 50 mg/dl 미만 4) 공복혈당 : 100 mg/dl 이상 5) 수축기혈압이 130 mmhg 또는이완기혈압이 85 mmhg 이상인경우 도제시되고있는데, 26 비알코올지방간질환의유병률은대조군에서는 19% 인데반해다낭성난소증후군환자에서는 41% 였다. 27 그밖에비알코올지방간질환의위험인자또는동반질환으로수면무호흡증, 뇌하수체기능저하증, 생식선기능저하증등이제시되고있다. 21,22 결 론 비알코올지방간질환은유병률이 20-30% 이를정도로가장급격히증가하는만성간질환으로비 Figure 1. 나이, 성별에따른비알코올지방간질환과대사증후군알코올지방간, 비알코올지방간염, 비알코올지방의유병률, Framingham risk score. NAFLD, nonalcoholic fatty 간연관간경변증에이르는다양한범주를갖는질 liver disease; MS, metabolic syndrome; FRS, Framingham risk score (The relation between non-alcoholic fatty liver disease and 환의총칭이다. 단순한간질환이아닌여러대사적 the risk of coronary heart disease in Koreans. Am J Gastroenterol 질환과유의한연관성을갖고있음이알려져있다. 2009;104: ). 비알코올지방간질환을비교적양성경과를지닌간질환의하나로간과할것이아니라심혈관계질환이나대사증후군과같은질환의발생을예측하고예후를감시할수있는하나의질환으로새롭게조명되어야할것이다. 참고문헌 1. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006;40 Suppl 1:S Bae JC, Cho YK, Lee WY, Seo HI, Rhee EJ, Park SE, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am J Gastroenterol 2010;105: Choi SY, Kim D, Kim HJ, Kang JH, Chung SJ, Park MJ, et al. The relation between non-alcoholic fatty liver disease and the risk of 6

5 김동희 비알코올지방간질환의역학 coronary heart disease in Koreans. Am J Gastroenterol 2009;104: Kim D, Choi SY, Park EH, Lee W, Kang JH, Kim W, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology 2012;56: Musso G, Cassader M, Gambino R. Diagnostic accuracy of adipose insulin resistance index and visceral adiposity index for progressive liver histology and cardiovascular risk in nonalcoholic fatty liver disease. Hepatology 2012;56: Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011;54: Loria P, Adinolfi LE, Bellentani S, Bugianesi E, Grieco A, Fargion S, et al. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig Liver Dis 2010;42: Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55: Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143: Suzuki A, Angulo P, Lymp J, St Sauver J, Muto A, Okada T, et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 2005;41: Whalley S, Puvanachandra P, Desai A, Kennedy H. Hepatology outpatient service provision in secondary care: a study of liver disease incidence and resource costs. Clin Med 2007;7: Lee JW, Cho YK, Ryan M, Kim H, Lee SW, Chang E, et al. Serum uric Acid as a predictor for the development of nonalcoholic Fatty liver disease in apparently healthy subjects: a 5-year retrospective cohort study. Gut Liver 2010;4: Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012;56: Marcos A, Fisher RA, Ham JM, Olzinski AT, Shiffman ML, Sanyal AJ, et al. Selection and outcome of living donors for adult to adult right lobe transplantation. Transplantation 2000;69: Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47: Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140: Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40: Speliotes EK, Massaro JM, Hoffmann U, Vasan RS, Meigs JB, Sahani DV, et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 2010;51: Kim D, Kim WR, Kim HJ, Therneau TM. Association between non-invasive fibrosis markers and mortality among adults with non-alcoholic fatty liver disease in the united states. Hepatology Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 2006;21: Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37: Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 2006;45: Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int 2009;29: Park SK, Seo MH, Shin HC, Ryoo JH. The clinical availability of non-alcoholic fatty liver disease as an early predictor of type 2 diabetes mellitus in korean men: 5-years' prospective cohort study. Hepatology

6 Postgraduate Course Chung GE, Kim D, Kim W, Yim JY, Park MJ, Kim YJ, et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol 2012;57: Baranova A, Tran TP, Birerdinc A, Younossi ZM. Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011;33: Cerda C, Perez-Ayuso RM, Riquelme A, Soza A, Villaseca P, Sir-Petermann T, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol 2007;47:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R