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1 Korean J Gastroenterol Vol. 65 No. 1, pissn eissn REVIEW ARTICLE 중증알코올간염의진단및치료전략 김원 서울특별시보라매병원소화기내과 Diagnostic and Therapeutic Strategies for Severe Alcoholic Hepatitis Won Kim Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea Alcoholic hepatitis (AH) is defined as an acute hepatic manifestation resulting from heavy alcohol intake. Histologically, alcoholic steatohepatitis (ASH) is characterized by hepatocellular steatosis, inflammation, and fibrosis. Alcohol abstinence is the sine qua non of therapy for AH and, in the milder forms, is prerequisite to clinical recovery. Severe ASH may lead to multi-organ failure such as acute kidney injury and infection, which has a major impact on survival and thus should be closely monitored. Patients with severe ASH have a drastic short-term mortality of up to 40-50%. Specific therapies should be considered for patients with severe ASH at risk of early death. Corticosteroids are the standard of care for patients with severe ASH. When corticosteroids are contraindicated, pentoxifylline may be an alternative option. Steroid responsiveness should be evaluated on the basis of Lille score. Tactically, we should explore novel therapeutic targets to suppress inflammation based on cytokine profiles, promote hepatic regeneration, limit innate immune responses, and restore altered gut mucosal integrity in severe ASH. (Korean J Gastroenterol 2015;65:4-11) Key Words: Alcoholic steatohepatitis; Infection; Renal insufficiency; Corticosteroids; Pentoxifylline 서론 알코올간질환은세계적으로만성간질환의주요원인중하나로서단순지방간, 지방간염, 간경변등다양한간질환을포괄한다. 1 특히중증알코올지방간염환자의 3개월단기사망률은 40-50% 에이를정도로매우높다. 2,3 몇가지약물치료법은중증알코올간염환자의생존율개선에유용하지만, 전반적예후는이러한치료에도불구하고여전히불량한것으로알려져있다. 최근미국에서다양한입원상병중가장의료비용이많이요구되는질환은높은합병증발생률과사망률을보이는중증알코올간염인것으로보고되었다. 4 따라서고위험환자의조기발견과즉각적치료는중증알코올간염과관련된의료비 용을최소화하는데도움이될뿐만아니라정확한예후예측은알코올간염환자들의개별화된치료법선택에있어매우필수적인단계라할수있다. 최근까지중증알코올간염과관련한몇가지예후점수체계들이서구에서개발되어유효성이검증되었다 알코올남용자에서보이는황달과간기능이상등의임상증후군을흔히 급성알코올간염 이라고부르지만, 알코올간염은대개장기간의광범위한간섬유화및간경변과관련되기때문에현재는 급성 이라는용어를사용하지않는다. 알코올지방간염은 지방침착, 간세포팽창성변성, 중성백혈구침윤및동주위섬유화등의혼재 로정의되는병리학적진단명이다. 11 알코올지방간염은알코올간염에서만나타나는것은아니고단순지방간, 간염, 섬유화, 간경변등알코올간질환의 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 김원, , 서울시동작구보라매로5길 20, 서울특별시보라매병원소화기내과 Correspondence to: Won Kim, Department of Internal Medicine, SMG-SNU Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul , Korea. Tel: , Fax: , drwon1@snu.ac.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 65 No. 1, January

2 Kim W. Diagnostic and Therapeutic Strategies for Severe Alcoholic Hepatitis 5 어느단계에서나중첩되어나타날수있다. 12,13 그러나알코올지방간염환자중어떤경우에임상적으로뚜렷한알코올간염으로진행하는지에대해서는알려진것이거의없다. 뿐만아니라일반인에서알코올지방간염혹은알코올간염의실제발생률이나유병률에대해서도알려진것이거의없는데, 이는알코올간염에대한임상진단기준이모호하고조직검사에의해확인된알코올지방간염을보고한연구결과가지금까지거의없기때문이다. 최근발표된알코올간질환의치료와관련된임상지침을미국간학회와유럽간학회에서보고하였다. 14,15 따라서본고에서는알코올유발간부전의개념과유형, 알코올간염의새로운예후예측체계, 그리고중증알코올지방간염환자들을위한잠재적표적치료법들에대해임상적견지에서고찰하고자한다. 진단 1. 알코올유발간부전의유형전통적으로서로다른예후를보이고다른치료적접근을요하는두가지유형의간부전이있다. 첫번째는기존간질환이없는환자들에서갑자기발생하는급성간부전이다. 두번째는기저간질환의진행결과로서, 말기간경변환자에서나타나는만성대상부전형태의만성간부전이다. 알부민투석의도입과함께, 새로운유형의만성간부전인만성간부전의급성악화 (acute-on-chronic liver failure, ACLF) 개념이최근임상에도입되어주목받고있다 ACLF는기저대상성간경변이수주내급성으로급격하게간기능이악화되면서초기단계에심한황달, 신손상, 간성혼수, 다발성장기부전등이동반되는것을특징으로한다. 19 알코올간경변으로입원한환자중만성대상부전의경우 20% 의 3개월사망률을보이는것에반해 ACLF는 60% 의 3개월사망률을보여 ACLF 가만성간부전에비해중증도가더높음을알수있다. 20 최근연구결과에따르면, 장내미생물과지질다당류와같은세균 성분에대한과도한염증유발반응이장과간혹은문맥및전신혈류의연결고리로서 ACLF의병태생리에중요한역할을수행하는것으로알려져있다. 21 마찬가지로알코올역시두가지유형의간손상 (ACLF와만성대상부전 ) 을초래할수있다. 알코올유발간부전중가장심각한경우는알코올간경변에중첩된중증알코올지방간염환자들이고 (ACLF), 그외에도비대상성알코올간경변등이간부전의원인일수있다. 정맥류출혈, 세균감염, B형간염바이러스의재활성화등과같은악화인자가 ACLF 발생에중요한데, 그이유는이러한악화인자들의교정이 ACLF의완전한호전을가져올수있기때문이다. 이러한견지에서조기에경경정맥간내문맥전신단락술을시행하게되면, 고위험정맥류환자에서 ACLF 발생을효과적으로예방할수있다. 22 또한강력한항바이러스제치료로조기에 B형간염바이러스증식을억제하는것이, B형간염환자에서자발적활성화에이은다발성장기부전으로의진행을막는데도움이된다. 23 만성대상부전은알코올유발간부전의가장흔한형태로, 간문맥고혈압의합병증이빈번하게나타나고조기에중등도의황달이나타난다. 알코올간경변환자에서간문맥고혈압의합병증으로서복수가출현하는경우 1년사망률은 29% 이고간성혼수가발생하는경우 64% 로추정된다. 24 ACLF는알코올유발간부전의또다른형태로서 3차의료기관을통한응급입원환자중 40% 이상의원인이다. 20 ACLF 의가장흔한유발인자는중증알코올지방간염으로전체 ACLF 환자중대략 25% 의유발원인으로알려져있다 알코올간염의예후점수체계알코올유발 ACLF를호전시키는가장좋은방법은저절로회복될가능성이거의없는중증알코올지방간염을가능한한조기에발견하고치료하는것이다. 이러한관점에서다양한예후점수들이일차적으로조기사망의고위험군에속하는중증알코올지방간염환자들을선별하기위해개발되었다 알코올간질환특이적예후모델에는 Maddrey s dis- Table 1. Components of Clinical Scoring Systems to Assess Prognosis in Alcoholic Hepatitis Bilirubin PT/ INR Cr/ BUN WBC Age Albumin Potassium Change in bilirubin from day 0 to day 7 MDF MELD GAHS ABIC Lille MAGIC Cr, creatinine; WBC, white blood cell; MDF, Maddrey s discriminant function; MELD, model for end-stage liver disease; GAHS, Glasgow alcoholic hepatitis score; ABIC, age-bilirubin-inr-creatinine score; MAGIC, model for alcoholic hepatitis to grade severity in an Asian patient cohort. Vol. 65 No. 1, January 2015

3 6 김원. 중증알코올간염의진단및치료전략 criminant function (MDF), Glasgow alcoholic hepatitis score (GAHS), age-bilirubin-inr-creatinine score (ABIC), Lille model, model for alcoholic hepatitis to grade the severity in an Asian patient cohort (MAGIC) 등이있고, 알코올간질환비특이적모델에는 model for end-stage liver disease (MELD) 가있다 (Table 1) MDF는 32점을기준으로, 알코올지방간염환자들의생존여부를예측하는데가장흔히사용되는예후모델이다. 10,25 MDF 32점이상의중증알코올지방간염은대개다른원인의 ACLF에서도종종관찰되는전신염증성반응증후군과다발성장기부전으로진행할수있다. MAGIC은알코올간염으로입원한한국인에서간질환관련사망을예측하기위해최근에개발된새로운모형이다. 8 이모델의독특한특징은알코올간염을갖는동양인에서최초로개발된예후모형이고, 치료받지않은알코올간염환자들의자연경과예측에초점을두었고, 알코올간염에서고칼륨혈증의예후예측역할을최초로밝혀냈으며, 무엇보다중요한것은자발적빌리루빈의호전여부가모형에포함됨으로써생존율향상과관련하여조기간기능호전의중요성을강조하였다는점이다. 그러나추후다른인종의중증알코올지방간염환자군에서도유효성평가가이루어져야한다. 스테로이드는위장관출혈, 간신증후군, 조절이안되는감염, B형간염, 췌장염등의금기증이없는중증알코올지방간염환자들에서생존가능성을증가시킨다. 14,15 최근 5개의무작위대조군연구의개별환자데이터를이용한메타분석에서 28일생존율이위약군보다스테로이드치료군에서유의하게높았다 (80% vs. 66%). 26 초기단계에서 MDF, GAHS, MELD 등은중증알코올지방간염을진단하고언제스테로이드치료를시작할지결정하는데도움이된다. 반면에치료전후빌리루빈의조기변화, 체외스테로이드내성검사, 치료후 1주째 Lille 점수등은스테로이드반응성과중단여부를결정하는데도움이된다. 9,27-29 최근개발된알코올간염조직학적점수가조직검사에서입증된알코올지방간염환자들의생존가능성을비교적정확하게예측한다고보고되었다. 30 또한이점수체계는간섬유화의범위, 중성백혈구침윤정도, 빌리루빈정체유형, 거대미토콘드리아유무를등급화함으로써계산된다. 30 특히빌리루빈정체유형은입원기간중세균감염발생과밀접하게관련되는것으로알려져있다. 30,31 치료 1. 일반적치료방법금주실패는알코올간염환자에서사망률을높이기때문 에금주는알코올간염치료의근간이다. 32 그러나항갈망제 (disulfiram, naltrexone, acamprostate) 의잠재적간독성때문에단주치료가중증알코올간염환자에서항상추천되는것은아니다. 중증알코올간염으로입원한환자들에서비록시급하게투여되지는않더라도간기능회복후에알코올사용장애재발을줄이기위해서단주치료는꼭필요하다. 바클로펜은간독성유발없이알코올간경변환자들에서알코올갈망을억제하고금주를유지하는데효과적이다. 따라서향후중증알코올간염환자에서바클로펜이음주에대한항갈망효능을보이는지확인하기위한추가연구가필요하다. 33 알코올간염환자는불규칙한식이습관, 알코올관련설사, 소장흡수능감소, 식욕부진, 과도한이화상태등에의한심각한영양불량으로고생하는데이는직접적으로사망률증가와관련된다. 34 따라서대부분의경우적절한칼로리와단백공급뿐만아니라비타민 B, 미네랄보충등을포함한영양공급이필요하다. 경구식이가불가능할때에는지용성비타민과경장영양공급이필요할수도있다. 그러나중증알코올간염환자에서경장영양공급과스테로이드를비교하는이전연구에서 1개월생존율의유의한차이는나타나지않았다. 35 그럼에도불구하고조기사망은경장영양공급군에서흔하고후기사망은스테로이드치료군에서흔하였기때문에향후병용치료군이생존율에미치는영향에대한추가적연구가시행되어야한다. 중증알코올간염환자에서신손상은입원중흔한증상이고감염과생존의중요한예측인자이기도하다. 급성신기능저하의가장흔한원인은간신증후군이다. 간신증후군을예방하기위해서는비스테로이드항염증약제, 아미노글라이코사이드, 이뇨제, 조영제등과같은신독성약제들의사용을피해야하고알부민이나신선냉동혈장과같은혈액확장제의투여가필요할수있다. 알코올지방간염에서나타나는비감염성염증과관련하여전신염증성반응증후군의진단기준에부합할경우세균감염의동반여부를감별진단하기어려울수있다. 세균감염은입원시중증알코올지방간염환자의 25% 에서관찰되고또다른 25% 에서는입원중스테로이드치료중새롭게발생한다. 36 감염과신부전은알코올지방간염환자에서생존율에지대한영향을미치므로입원중어떤시기에도선별검사와예방및치료에최선을다해야한다. 경험적항생제예방치료는입원시실제광범위하게사용되고있지만항상추천되는것은아니다. 최근보고에따르면, 감염을완전히조절한후알코올지방간염환자는스테로이드치료가더이상금기대상이되지않는다. 36 그러나스테로이드치료중발생한감염은스테로이드자체의면역억제에의한것이라기보다는심각한간손상을시사하는스테로이드불응성의결과로보는것이 The Korean Journal of Gastroenterology

4 Kim W. Diagnostic and Therapeutic Strategies for Severe Alcoholic Hepatitis 7 타당하다. 36 따라서경험적항생제치료는스테로이드반응군에서생존율을개선함으로써스테로이드무반응군보다더유용하게사용될수있겠다. 2. 특이적치료방법 1) 스테로이드일반적치료방법과별개로조기사망위험이높은 MDF 32점이상의중증알코올간염환자에서는특이적치료법이필요하다. 26 다양한연구디자인의이질성과조직학적확인이누락된모호한진단기준으로인한선택편견때문에지난수십년간스테로이드치료가중증알코올간염환자의생존에미치는영향은계속논란이되어왔다. 더욱이알코올간염에대한스테로이드의치료기전은여전히불확실하다. 최근알코올간손상실험모델에서스테로이드의간손상과재생에대한흥미로운연구결과가보고되었다. 37 일반적으로스테로이드는염증성혹은면역매개간손상을억제하지만현저한항동화작용때문에간재생을억제하고간세포증식과재생을조절하는유전자 (pstat3) 발현을억제함으로써염증치유속도를늦춘다. 37 최근의메타분석에서스테로이드치료군은위약군에비해유의하게 28일생존율이향상되었기때문에스테로이드는현재조직학적으로확진된, 중증알코올지방간염의일차적표준치료로인정받고있다. 26 스테로이드는종종알코올지방간염이배제된상태에서는오히려해로울수도있는데, 즉임상적으로진단된알코올간염의 10-30% 에서는지방간염이아닌세균감염과관련한대상부전에의해간기능이악화되기때문이다. 또한경미한알코올간염에대해서는일반적으로스테로이드치료가추천되지않는다. 스테로이드에의한생존향상이득은오직조직학적으로입증된, 중증알코올지방간염에만국한되며, 중증알코올지방간염환자의대략 60% 에서스테로이드에대한반응을보인다. 조기에스테로이드무반응군 (40%) 을확인하는것은, 스테로이드중단규칙을정의하고불필요한스테로이드노출을최소화하기위해반드시필요하다. 9 스테로이드치료 1주째 0.56 이상의 Lille 점수를보이는경우스테로이드무반응군으로정의된다. 지속적스테로이드치료에도불구하고무반응군에서는 28일생존율이 50% 를넘지못한다. 26 2) 펜톡시필린펜톡시필린은항산화효과를보이고종양괴사인자 (tumor necrosis factor-alpha, TNF- ) 합성을경미하게억제한다. 펜톡시필린치료를받는중증알코올지방간염환자에서 6개월생존율은위약군보다유의하게높았다. 38 이러한생존율증가는간신증후군발생률의감소에서비롯된것이지만, 이러한이로운효과는최근에시행된두개의메타분석에서상반된 결과가발표되었다. 비록최종결론이난것은아니지만, 메타분석결과펜톡시필린은심각한간신증후군의위험을줄였지만위약군에비해생존율을유의하게향상시키지는못했기때문이다. 39,40 최근시행된국내다기관임상연구는펜톡시필린과스테로이드의알코올간염환자에서생존율의차이를직접전향적으로비교하였다. 41 6개월생존율의견지에서펜톡시필린의효능은스테로이드와통계적으로동등하지못했고, 이는스테로이드가중증알코올간염환자에서펜톡시필린보다우선적으로선호되는치료라는점을시사한다. 그러나스테로이드금기를보이는중증알코올간염환자에서는여전히펜톡시필린이대체약제로고려될수있다. 14,15 중증알코올지방간염환자 270명을포함한전향적연구에서펜톡시필린과스테로이드병합치료는스테로이드단독에비해유의한생존율향상을가져오지못했다. 42 그러나이연구의제한점은펜톡시필린단독군을포함하지못했다는점이다. 43 이를극복하기위해최근펜톡시필린, 스테로이드, 병합치료를중증알코올간염환자에서비교하는대규모무작위연구가영국에서진행되고있다. 44 스테로이드무반응의중증알코올지방간염환자에서펜톡시필린조기교체는생존율향상에기여하지못했다. 45 종합적으로펜톡시필린은중증알코올지방간염환자에서스테로이드와병용하더라도추가적생존이득이없었고, 스테로이드무반응군에서펜톡시필린으로의단독교체역시이로운효과가없었다. 3) 아세틸시스테인최근항산화제인아세틸시스테인과스테로이드병합치료는비록장기적효과는보이지못했지만, 간신증후군과감염을예방함으로써 1개월생존율에서스테로이드단독치료보다우월한생존율을보였다. 46 그러나아세틸시스테인병합치료군에서생존율증가쪽으로의경향성을고려한다면, 최적의용량과치료기간결정을위한추가적연구가필요하다. 4) 항종양괴사인자약제알코올간질환실험모델에서 TNF- 의중추적역할에대한강력한근거들이존재하기때문에중증알코올지방간염환자들에서 infliximab과스테로이드병합치료에대한무작위임상시험이시행되었다. 47 TNF- 를차단하는치료는위약군에비해유의하게높은감염률과사망률을보였다. 47,48 아마장기간의과도한 TNF- 차단은현저한면역억제를초래하고, 간재생에부정적영향을미치기때문일것으로추정된다 ) 간이식대부분의알코올간염환자들은금주후적어도 6개월동안간기능이완전히회복되고, 6개월금주규칙을통상이식전에따르기때문에초기단계에서는일반적으로간이식을즉각적으로고려하지않는다. 52 6개월금주규칙이사회적으로통용되고낮은유해음주재발률과깊은관련을보이지만사 Vol. 65 No. 1, January 2015

5 8 김원. 중증알코올간염의진단및치료전략 회및가정내지지나정신과적중독질환의부재와같은금주유지성공을예측할수있는다른요인들이 6개월금주규칙을대신할수도있다. 52 Lille 모델은 6개월생존율이 25% 에불과한스테로이드무반응군의조기확인에도움이된다. 최근조기간이식개념이스테로이드에반응이없는, 처음발생된중증알코올지방간염환자들을위해제안되었다. 53 스테로이드무반응대조군에비해조기간이식군에서뚜렷한생존율의증가를관찰할수있었다. 53 따라서조기간이식은처음발생한, 중증알코올지방간염이면서양호한중독성향을보이고스테로이드에반응이없는, 일부선택된환자군에서만고려될수있다. 3. 새로운치료방법중증알코올간염에대한기존의특이적치료에도불구하고전반적예후는여전히매우불량하다. 이용가능한치료적방법은제한되어있으므로새롭고혁신적인중증알코올간염에대한치료법의시급한도입이간절한상황이다. 지난수십년간알코올간염의임상경과를이해하는데커다란발전이있었지만, 새로운치료적목표를탐색하는데성공하지는못했다. 알코올간염에서대부분의임상시험이실패한이유는, 우선핵심질환유발원인에대한지식이부족하고, 목표지향임상연구를시작하기전에체계적대규모연구가필요하지만현재까지거의없었으며, 대부분의동물모델은인체에서의중증간질환보다는경미한알코올간질환만을재현하기때문이다. 상기의문제들의해결을위해공통의임상프로토콜을사 용하고, 생물표지자연구를포함하며, 다양한범주의알코올간염을포함하는다기관협동연구가먼저수행되어야한다. 최근이러한목적달성을위해미국 National Institute on Alcohol Abuse and Alcoholism (NIAAA) 는알코올간염을위한중개및임상연구를진행중인 4개의알코올간염컨소시엄에대한연구지원을결정하였다. 54 상기임상연구들에서유전학적혹은생물학적검체를수집및보관하고분자생물학, 유전학, 후생유전학및시스템생물학등의중개연구를위한사전동의를환자들에게취득할예정이다. 현재이미여러중재연구가알코올간염에대한신약의기전관련개념증명을위해다기관컨소시엄형태를통해진행중이다 (Table 2) 최근알코올간염의새로운생물표지자와표적치료개발을위해과학적통합접근법을통해몇가지알코올간염의병인에대한핵심요소들에초점을맞추고있다. 우선첫번째로염증반응과선천면역계활성화는경증알코올간염에비해중증알코올간염에서관찰되는현저한특징들이다. 60,65,68,69 즉, 알코올간염증후군의기저병인은심한간내염증과사이토카인이상조절로알려져있다. 65,70 두번째는알코올간염에서장관방어능 (gut integrity) 이감소하기때문에병원체-연관분자패턴 (pathogen-associated molecular pattern, PAMP) 이간문맥과전신혈류순환계로쉽게유입되고선천면역의활성화를유발한다. 71,72 염증을유발하는장관유래내독소와기타세균산물들은모두장관투과성의증가와장벽기능변화의결과물들이다. 72 세번째로알코올간염에서세포생존과사멸신호는간기능저하와손상된세포-관련분자패턴 (damage-associated molecular pattern, DAMP) 방출에 Table 2. Summary of Potential Molecular Targets and Novel Targeted Therapies for Alcoholic Hepatitis Key element of the pathogenesis Treatment Effect Clinical trial FXR dysregulation OCA 55 FXR agonist Moderately severe AH (placebo vs. OCA) Altered gut integrity Zinc 56 Restoration of gut integrity Severe AH LGG 57 Probiotic effect Mild to moderate AH (placebo vs. LGG) Rifaximin 58 Intestinal decontamination Severe AH (steroid vs. steroid+rifaximin) Innate immune activation Imm 12-E 59 Anti-LPS antibody Severe AH (steroid vs. steroid+low/high dose Imm 12-E) Anakinra IL-1RA Severe AH (steroid vs. anakinra+pentoxifylline+zinc) Rilonacept 60,61 IL-1 inhibitor Severe AH with response to steroid at day 7 (steroid vs. steroid+rilonacept) Mycophenolate mofetil IMPDH inhibitor Severe AH without response to steroid at day 7 (standard of care vs. steroid+mycophenolate) Sterile necrosis and apoptosis Emricasan Pancaspase inhibitor Severe AH with steroid contraindications (placebo vs. emricasan) Impaired regeneration G-CSF 63,64 IL HPC mobilization Hepatoprotective effect Severe AH without response to steroid at day 7 (placebo vs. G-CSF) Only preclinical studies FXR, farnesoid X receptor; OCA, obeticholic acid; AH, alcoholic hepatitis; LGG, lactobacillus GG; LPS, lipopolysaccharide; IL, interleukin; IL-1RA, IL-1 receptor antagonist; IMPDH, inosine-5'-monophosphate dehydrogenase; G-CSF, granulocyte-colony stimulating factor; HPC, hepatic progenitor cell. The Korean Journal of Gastroenterology

6 Kim W. Diagnostic and Therapeutic Strategies for Severe Alcoholic Hepatitis 9 기여하는데, 이는간세포자멸사, 무균성괴사, 간손상을더욱부채질하게된다. 71 마지막으로간부전이나타난심한알코올지방간염환자에서간세포재생능은심오하게손상된다. 이러한견지에서불량한간세포재생기전을규명하고, 간전구세포의기능성성숙간세포로의분화를촉진시킬수있는것이치료적으로중요하다. 63,64,73,74 결 론 알코올간염을다른간질환과감별하기위해새롭게정립된질병정의의필요성이날로증대되고있다. 질병정의는분류학적명료성을극대화하고기초병인대임상양상에따른분류간차이를최소화하며치료결정과정에도움이되도록질병위험도와임상경과를내포하고있어야한다. 알코올간염의명명법을표준화하기위해무증상의초기알코올지방간염과황달혹은대상부전이나타나는전통적중증알코올간염의임상적, 분석적, 분자생물학적특징을서로비교할필요가있다. 금주는알코올간염치료의근간이면서특히경미한경우에는임상적회복을위한필수전제조건이다. 중증알코올지방간염은다기관부전으로진행할수있는데, 특히신손상이나감염은선별, 예방, 치료가필요한가장중요한합병증들이다. MDF나 MELD와같은임상예후점수는치료를시작할지여부를결정하는데유용한지표들이고치료후 1주째 Lille 점수는스테로이드반응성을평가하여치료중단여부를결정하는데활용될수있다. 펜톡시필린은스테로이드금기증이있는중증알코올지방간염환자에서 1차치료로서대신사용될수있다. 그러나펜톡시필린은스테로이드를투여받는중증알코올지방간염환자들에서병용시추가적이득은없다. 스테로이드무반응군에서조기에펜톡시필린으로변경하는것역시생존율의유의한증가가관찰되지않아추천되지않는다. 결론으로향후알코올간염에대한연구는균일한환자들을대상으로하면서, 특히중등도의알코올간염이나스테로이드치료부분반응군혹은무반응군에집중해야한다. 전략적으로중증알코올지방간염에서손상된장관점막방어능을회복하고, 사이토카인특성에따른염증반응을억제하며, 간재생능을촉진하면서, 선천면역반응을제한하는것이새로운치료제개발과관련되어중요하다. REFERENCES 1. Kim WR, Brown RS Jr, Terrault NA, El-Serag H. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002;36: Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360: Mathurin P, Duchatelle V, Ramond MJ, et al. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology 1996;110: Liangpunsakul S. Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States. J Clin Gastroenterol 2011;45: Dominguez M, Rincón D, Abraldes JG, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol 2008;103: Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology 2005;41: Forrest EH, Evans CD, Stewart S, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut 2005; 54: Lee M, Kim W, Choi Y, et al. Spontaneous evolution in bilirubin levels predicts liver-related mortality in patients with alcoholic hepatitis. PLoS One 2014;9:e Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007;45: Maddrey WC, Boitnott JK, Bedine MS, Weber FL Jr, Mezey E, White RI Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75: MacSween RN, Burt AD. Histologic spectrum of alcoholic liver disease. Semin Liver Dis 1986;6: Dhanda AD, Collins PL, McCune CA. Is liver biopsy necessary in the management of alcoholic hepatitis? World J Gastroenterol 2013;19: Sougioultzis S, Dalakas E, Hayes PC, Plevris JN. Alcoholic hepatitis: from pathogenesis to treatment. Curr Med Res Opin 2005;21: European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012;57: 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: Bañares R, Nevens F, Larsen FS, et al; RELIEF study group. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013;57: Hassanein TI, Tofteng F, Brown RS Jr, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007;46: Kribben A, Gerken G, Haag S, et al; HELIOS Study Group. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 2012;142: e Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver fail- Vol. 65 No. 1, January 2015

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