Clinical system 2 The epidemiologic concern in alcoholic liver disease Young Kul Jung Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea Alcoholic liver disease remains a significant health burden in Korea and worldwide. The clinical spectrum of this disease spans from simple fatty liver to fibrosis and overt cirrhosis (characterized by ascites, varix, and hepatic encephalopathy). The annual costs associated with the consumption of alcohol in Korea were estimated to be 2.86% of the GDP in 2006; this included medical costs for the treatment of alcohol-related diseases, indirect costs (loss of productivity and decreases in the available workforce resulting from premature death), and other costs. A nationwide knowledge of alcohol consumption and drinking problems can provide a foundation for planning and implementing national intervention programs. However, the consumption of alcohol and alcohol related problems in Korean have not been extensively studied despite the associated social, economic, and public health burdens. So, an exact evaluation of alcoholic epidemiology and risk factors is very important. Through this review, we suggest that high alcohol consumption and alcohol-related problems in Korean are not negligible and require intervention, and also Korean guideline for clinician is necessary. Keywords: Alcoholic liver disease, Epidemiology, Korea 서론 알코올, 즉술은역사적으로도매우오래된음식중의하나로, 우리나라고대기록에동명왕편에서기술될정도로오랜역사를자랑한다. 하지만, 근래에들어음주로인해발생하는질병으로사회경제적비용이늘어나고, 음주로인해이차적으로발생되는폭력, 자살, 성범죄등으로여러가지범국가적인사업들이시행되고있다. 이는우리나라뿐만아니라전세계적으로도흡연등과더불어가장중요한보건문제로인식되는추세이다. 2012년에국민건강보험공단이국회보건복지위원회에제출한자료에서보면지난 2007년부터 2012년 6월말까지음주와관련이큰 8개질환에지출된건강보험진료비가 1조2천877억원이라고보고했다. 여기서음주관련성이큰 8개질환은 ' 알코올사용에의한정신및행동장애 ( 상병코드 F10)', ' 알코올에의한신경계통의변성 (G312)', ' 특별간질증후군 (G405)', ' 알코올성다발신경병증 (G621)', ' 알코올성근병증 (G721)', ' 알코올성심근병증 (I426)', ' 알코올성위염 (K292)', ' 알코올성간질환 (K70)' 이었다 ( 중앙일보 2012년 10월 2일자 ). 그럼에도불구하고우리나라는대인관계에서음주능력을우대할뿐만아니라, 술로생긴문제에매우관대하여사회적인문제로부각이못되고있는것같다. 또한알코올성간질환은진단이어렵다. 일단누구에게나일관된객관적인기준이없고, 일정수준이상의과도한음주를한다는사실과신체이학적검사및혈액학적검사등을바탕으로간접적으로진단함으로불분명한점들이존재한다. 이외도알코올은기호식품이고종류및첨가물또한매우 - 117 -
2012 년대한간학회추계학술대회 다양하여정확한음주량과음주기간등을알기가힘들다. 1 각개인별로차이도존재하는데이는유전적차이, 인종, 성별, 식생활습관, 영양상태등여러복잡다단한요인도작용한다. 그럼에도불구하고알코올성간질환에이환되는가장대표적인위험요인은역시알코올섭취량이다. 2 알코올의섭취량과꼭일관된상관관계를보이는것은아니지만, 대략남자의경우 40-80 g/day 음주시지방간의위험이, 160 g/day 이상 10-20년음주시약 15% 정도의간경변발생위험이있고, 여자인경우 20 g/day 라도간질환의위험이높다고알려져있다. 4,5 하지만, 매일 120 g/day 이상으로마시는심한음주자에서도간질환의발생률은 13.5% 로높지만은않다. 6 이러함에도불구하고서구에서는알코올성간질환의빈도가높아서이에관한많은연구가진행되어왔고, 미국간학회에서는가이드라인을만들어서발표하였다. 1 그러나우리나라에서는아직도알코올성간질환에대한자료들이매우충분하지는않으며병태생리, 진단및환자치료관리에대한기본적인지침은아직마련되어있지않다. 따라서, 저자는최근에국내외에발표된알코올성간질환에대한역학자료들을살펴보고, 국내의연구현황과환자분포등을이해하고자하였다. 본론 1. 음주의행태와변화우리나라국민중고위험음주자가계속증가하고있다 (Figure 1). 2010년기준으로 6명중 1명이고위험음주자이며, 이는 2005년에비해 18% 정도늘어난것이다. 국민건강영양조사 (2010) 결과를통해보면, 우리나라성인의음주현황에서 19세이상성인 6257명중고위험음주자가 17.6% 였다. 7 이는세계보건기구 (WHO) 기준으로 1회평균 60g( 여성은 40g) 이상의순수알코올을섭취하고, 주 2회이상술을마시는사람이해당하며, 소주를기준으로할때 1회평균남성은 7잔이상, 여성은 5잔이상 100% 100% 80% others 80% others 60% 40% NAFLD HCV HBV 60% 40% NAFLD HCV HBV 20% alcohol 20% alcohol 0% A 99-'00 05-'10 0% B 91-'99 05-'10 Figure 1. The bar graph of comparison according to the overall causes in chronic liver disease (A) and liver cirrhosis (B). The alcoholic cause of chronic liver disease did not change significantly, while that of nonalcoholic fatty liver disease progressively increase from the late 1990s to 2000s. - 118 -
정영걸 The epidemiologic concern in alcoholic liver disease 을마시는정도다. 2010년여성고위험음주자는 7.6% 였지만남성고위험음주자는 25.5% 였으며, 과거 2005년결과보다증가추세이며, 특히여성의음주가빠르게증가하고있음을알수있다 (Figure 2). 이는사회적으로여성의지위가올라가고사회적활동이많아지면서생기는이차적인요인으로생각되며, 여성이알코올에좀더민감하다고생각해볼때주의가요망된다. 그밖에도연령별로는남자는 30-50대, 여자는 20-40대에서높았으며, 소득수준이낮을수로고위험음주율이높았다. 100 80 72.9 73.5 74.6 75.7 77.8 100 80 60 40 20 0 36.9 41.5 44.9 05 06 07 08 43.3 09 43.3 10 60 40 20 0 23.2 4.6 05 06 24.5 28.4 5 8.4 07 08 7.5 09 24.6 7.4 10 24.9 A Women Men B Women Men Figure 2. (A) Monthly alcohol consumption trends according to gender. In only adult, bar showed a percentage of at least once a month per a year. (B) Monthly alcohol consumption trends according to gender in high risk patients drinking at least twice a week and once a month. 2. 알코올성간질환분포의변화전반적인알코올성간질환의분포를대규모로조사한대표적인연구는없다. 하지만, 몇가지큰연구들을살펴보면, 1999년부터 2000년까지일년동안국내 18개병원의만성간질환환자 16,436명을대상으로원인분석한결과에서는 B형바이러스간질환 68.8%, 알코올성간질환은 14.5%, C형바이러스는 9.4% 를차지하여, 알코올성간질환이 2번째로높음을알수있다. 8 간경변증입원환자를대상으로한연구에서도알코올성간경변증의빈도는 26-42.9% 를차지하여, 역시 B형간염에의한간경변증다음을차지하였다. 9,10 최근에 3차단일기관에서 2005년부터 2010년까지 6,307명환자분포를본연구에서는만성간질환자중 B형바이러스간질환 51.2%, 비알코올성간질환자 33.3%, 알코올성간질환자가 13.0% 로세번쨰를차지하였으나, 간경변증환자에서는 18.1% 를차지하여간염에의한간경화환자에이어 2번째빈도를보여주었다. 11 또한약 10여년전과비교하여도만성간질환에서는비알코올성간질환의빈도가더높아지긴했지만, 전체적인비율에서는과거와큰차이를보이진않고있었다. 3. 음주행태, 성별, 나이, 유전적요인등과알코올독성및간질환과의관계간혹 2-3일폭주하곤간을위해서며칠금주하는사람들이있는데, 폭주를하거나늦은밤에식사와상관없이술을먹는것도알코올성간질환의빈도를 2배이상올리는위험인자이다. 12,13 성별에서도차이가나는데, 여자는남자에비해같은양의알코올을섭취했을때혈중알코올농도가더높다. 그이유는체격이작고, 지방이상대적으로많아알코올이분포되는수분함유공간이적기때문이라 - 119 -
2012 년대한간학회추계학술대회 고알려져있다. 14 또한 50세미만의연령에서여자는남자보다위에서알코올을분해할수있는 gastric alcohol dehydrogenase가적기때문에같은양을마셔도더많은양의알코올이혈중내로유입되게된다. 15 또한여자는간내알코올대사과정과 Kupffer 세포로부터사이토카인생성등에서남자와차이를보여간손상이더잘발생하는것으로생각되고있다. 16,17 따라서, 간경변증의발생이의미있게증가하기위해서는남자는하루 40~60g 알코올섭취가지속적으로필요한반면여자는 20g의알코올섭취가필요한것으로보고되었다. 18 물론인종간의차이에대한보고도있다. 알코올섭취의양에상관없이백인보다흑인이나히스패닉에서알코올성간경변증의유발이높음이보고되었다. 19,20 나이도알코올독성의중요한요소의하나로서대개노령자는젊은이에비해적은알코올을섭취하지만체액량의감소로인해같은양을섭취했을때혈중알코올농도가높다. 또한고령자에서의알코올성간경변환자는젊은이에비해사망률이현저히높다고알려져있다. 21 유전적요인은알코올의존의위험성을 40~60% 를설명하는주요요인인데특히알코올대사효소유전자다형성으로인한활성차이가음주행동과밀접하게연관되어있다. 22 알데히드탈수소효소 (aldehyde dehydrogenase, ALDH) 의 ALDH2*487Lys 변이형은정상형 ALDH2에비해활성이거의없어음주후높은체내아세트알데히드농도를초래하여알코올의존이나음주행동에대한예방효과를보인다. 23,24 ALDH2 유전형과함께음주행동에영향을미치는다른유전요인으로잘알려진것이알코올탈수소효소 (alcoholdehydrogenase, ADH) 의활성이다. 25 ADH 유형중에서특히에탄올산화의대부분을차지하는베타하단위 (β subunit) 를발현하는 ADH1B의단일염기다형성의효과가잘알려져있다. ADH1B*2 대립유전자는베타2 하단위를발현하며 ADH1B*1이발현하는베타1 하단위보다 70~80배높은전환율을보인다. 26 결국한국인을포함한아시아인에흔한 ADH1B*2 대립유전자는활성 ADH를발현시켜알코올의존에예방효과를보이는것으로알려져있다. 27 하지만효과가충분히확인된 ALDH2의유전형에비해 ADH1B 유전형이미치는효과에대한연구결과는대상의인종이나연령에따라다양한양상을보인다. 28,29 최근에활성화된 GWAS 연구를통해서한국인에서 ADH1B와 ADH1C 주변단일염기서열변이 (SNP) 를조사한결과, ADH1B*47Arg 가특히알코올대사및의존에깊이관여함을보고하였다. 30 결론 우리나라에서음주의현황에대한역학적연구를보면, 최근평균음주량은조금씩늘고있음을보여준다. 특히일부여성에서음주인구가증가함을알수있다. 특히고위험군음주에서여성의빈도가빠르게늘고있음을주의깊게살펴볼필요가있다. 그리고전체알코올성간질환환자에서도과거에비해빈도수가한계단뒤로밀려나는것처럼보이지만, 실제로바이러스성간염의빈도가줄어서생기는변화일뿐, 여전히전체에서차지하는비중은크게달라지지않았음을보여준다. 그밖에알코올대사효소의유전적분포에서는대사효소의유전적다양성이일본이나중국과비슷한모양을보여주고있다. 하지만, 여전히우리나라에서는알코올성간질환에대한여러자료는충분하지않으며, 병태생리, - 120 -
정영걸 The epidemiologic concern in alcoholic liver disease 진단, 치료및관리에대한기복적인지침이없는상황이다. 그럼에도불구하고, 대한간학회에서는 2012년알코올성간질환진료가이드라인제정위원회 ( 위원장 : 김동준 ( 한림의대 )) 를발족하였으며, 지난 2012년 7월에첫회의를열고, 가이드라인제정작업을시작하였음은매우고무적인일이라할수있겠다. 앞으로우리나라실정에합당한치료지침을기대해본다. 참고문헌 1. O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic Liver Disease. Hepatology. 2010;51:307-28. 2. Galambos JT. Natural history of alcoholic hepatitis. 3. Histological changes. Gastroenterology 1972;63:1026-1035. 3. Savolainen VT, Liesto K, Mannikko A, Penttila A, Karhunen PJ. Alcohol consumption and alcoholic liver disease: evidence of a threshold level of effects of ethanol. Alcohol Clin Exp Res 1993;17:1112-1117. 4. Brick J. Standardization of alcohol calculations in research. Alcohol Clin Exp Res 2006;30:1276-1287. 5. Teli MR, Day CP, Burt AD, Bennett MK, James OF. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet 1995;346:987-990. 6. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut 1997;41:845-850 7. Korea Institute for Health and Social Affairs. Korea National Health and Nutrition Examination Survey 2010. Seoul: Ministry of Health and Welfare of Korea, 2010. 8. Kwon SO. Clinical significance and current status of alcoholic liver disease in Korea. In: Lee CH, ed. Hepatitis. 2nd ed. Seoul: Kunja, 2005:219-231 9. Kim YS, Um SH, Ryu HS, Lee JB, Lee JW, Park DK, et al. The Prognosis of Liver Cirrhosis in Recent Years in Korea. J Korean Med Sci 2003;18:833-41 10. Seo KS, Lee BS, Sung JK, Lee SO, Kim SH, Kim KT, et al. The Cause and Complication of Liver Cirrhosis during the Reccent 5 Years. Clin Mol Hepatol 1997;3:202-209. 11. Lee SS, Byoun YS, Jeon SH, Kim YM, Gil H, Min BY, et al. Type and cause of liver disease in Korea: single experience, 2005-2010. Clin Mol Hepatol 2012;18:309-315. 12. Lu XL, Luo JY, Tao M, Gen Y, Zhao P, Zhao HL, et al. Risk factors for alcoholic liver disease in China. World J Gastroenterol 2004;10:2423-2426. 13. Barrio E, Tome S, Rodriguez I, Gude F, Sanchez-Leira J, Perez-Becerra E, et al. Liver disease in heavy drinkers with and without alcohol withdrawal syndrome. Alcohol Clin Exp Res 2004;28:131-136. 14. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, et al. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res 2001;25:502-507. 15. Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med 1990; 322:95-99. 16. Sato N, Lindros KO, Baraona E, Ikejima K, Mezey E, Ramchandani VA, et al. Sex difference in alcohol related organ injury. Alcohol Clin Exp Res 2001; 25: 40S - 5S 17. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Lieber CS, et al. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res 2001; 25: 502-7 18. Parrish KM, Dufour MC, Stinson FS, Harford TC. Average daily alcohol consumption during adult life among decedents with and without cirrhosis: the 1986 National Mortality Followback Survey. J Stud Alcohol 1993; 54: 450-6 19. Stinson FS, Grant BF, Dufour MC. The critical dimension of ethnicity in liver cirrhosis mortality statistics. Alcohol Clin Exp Res 2001;25:1181-1187. 20. Wickramasinghe SN, Corridan B, Izaguirre J, Hasan R, Marjot DH. Ethnic differences in the biological - 121 -
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