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Definition and Prognosis of Acute-on-Chronic Liver Failure: Western and Eastern Perspectives Tae Yeob Kim 1, Jeong Ho Eom 2, Dong Joon Kim 2 1 Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea 2 Department of Internal Medicine, Hallym University, Chuncheon, Korea Acute-on-chronic liver failure (ACLF) is an increasingly recognized distinct disease entity encompassing an acute deterioration of liver function in patients with chronic liver disease. Although there are no widely accepted diagnostic criteria for ACLF, the Asia Pacific Association for the Study of the Liver (APASL) and the American Association for the Study of Liver Disease and the European Association for the Study of the Liver (AASLD/EASL) consensus definitions are commonly used. It is obvious that the APASL and the AASLD/EASL definitions are based on fundamentally different features. Two different definitions in two different parts of the world hamper the comparability of studies. Recently, the EASL-Chronic Liver Failure Consortium proposed new diagnostic criteria for ACLF based on analyses of patients with organ failure in 2013, and the revised consensus recommendations of the APASL for ACLF was published in 2014. There are areas of uncertainty in defining ACLF, such as heterogeneity of ACLF, ambiguity in qualifying underlying liver disease, argument for infection or sepsis as a precipitating event, etc. Although the exact pathogenesis of ACLF remains to be elucidated, alteration of host response to injury, infection, and unregulated inflammation play important roles. Treatment strategies are limited to organ support but better understanding of the pathophysiology is likely to lead to discovery of novel biomarkers and therapeutic strategies in the future. 서론 (Introduction) Acute-on-chronic liver failure (ACLF) 는만성간질환환자의급성악화를망라하는독립된질환으로인식되고있다. 1 이는비대상간경변이서서히악화되고비가역적인변화를보이는것과달리 ACLF가비대상간경변에비해높은단기사망률을보이며악화요인에의해발생되고가역적인요소를가지고있기때문이다. 중환자실치료가필요한간경변환자의병원내사망률은 50% 이상이며, 간경변환자의중환자실사망률은지난 20년동안크게개선되지않았다. 2 이러한배경으로, ACLF를정의하고그기전을밝히며, 예후를예측하여사망률을개선시키려는노력이필요하다. 최근들어아시아태평양간학회 (Asian Pacific Association for the Study of the Liver, APASL) 와유럽간학회 (European Association for the Study of the www.kast.org 3

2015 대한간학회춘계 Single Topic Symposium Liver, EASL) 를중심으로합의권고와대규모전향연구결과들이연이어발표되고있으나, 아직그개념과정의가혼동되는경우가있으며널리받아들여지는정의도정립되어있지않다. 이에 ACLF의정의와예후척도에대한동서양의차이를살펴보면서향후연구되어야할논점들을개략적으로살펴보고자한다. 3,4 우리나라에서는대한간학회의지원으로 Korean Acute-on-Chronic Liver Faliure (KACLiF) 연구가시작되어, 후향적자료수집을마치고여러연구결과를발표할예정이다. 또한 2015년 4월부터전향적코호트연구및병태생리에대한연구를시작할예정이다. KACLiF 연구자료는참여연구자에게열려있으며, 대한간학회는 KACLiF 연구가열정을가진여러연구자들의적극적인참여를통해우리나라연구자들이간학회의발전에더욱기여하는기회가되길기대하고있다. ACLF 의정의 (Definitions of ACLF) 간부전은크게기존간질환이없이생기는급성간부전 (acute liver failure, ALF), 기저만성간질환에서생기는 ACLF, 또는비대상간경변의간기능저하에따른간부전, 3가지로나눌수있다 (Figure 1). 5 Figure 1. A conceptual schema of acute liver failure, acute-on-chronic liver failure, and decompensated liver cirrhosis. The gray line describes the course of a patient with acute liver failure. Acute-on-chronic liver failure (ACLF) is depicted by the black line. The dotted line indicates the expected course of chronic liver disease without precipitating insults. The patient with ACLF who may often have good liver function reserve can deteriorate acutely, usually in association with a precipitating event which results in organ failure and high risk of death. This patient has a potential for reversibility and recovery to the state the patient was in, although not complete. The ACLF encompasses severely acute on moderate chronic liver disease entity (A) and moderately acute on severe chronic liver disease entity (B) of ACLF. The clinical concept of ACLF is different from that of life-threatening decompensation of liver cirrhosis. During the course of a patient with decompensated cirrhosis, life threatening exacerbation will at some point develop organ dysfunction where the chance of reversibility is very limited (C). 4 대한간학회 The Korean Association for study of the Liver

김동준 Definition and Prognosis of Acute-on-Chronic Liver Failure: Western and Eastern Perspectives ALF는기저간질환이없는환자에서간기능의급성악화로인해의식변화와응고장애가생기는드문질환이다. ALF의일반적인정의는이전에간경변증이없는환자에서 26주이내에응고장애 (International Normalized Ratio [INR] 1.5) 와함께의식변화 (hepatic encephalopathy, HE) 가나타나는경우를말하는데, 이 ALF는 ACLF와는다른양상으로나타난다. 6 개념적으로, 다발장기부전은점진적으로진행되는말기간경변의비대상에의해혹은안정적인만성간질환을가진환자에서유발요인에의해짧은기간내에생길수있다. 두가지모두다양한다발장기부전을보일수있지만, 간부전과간외장기부전의기전및그에따른임상적결과는크게다르고후자를 ACLF 라고한다. 7 ACLF는 2002년 London group에의해 2-4주에걸쳐유발요인에의해갑자기간기능이악화되어황달, 간성뇌증, 간신증후군과같은심각한합병증을동반하면서, 높은 Sequential Organ Failure Assessment (SOFA)/Acute Physiology and Chronic Health Evaluation (APACHE) II 점수를보이는상태로정의가제안되었다. 8 현재까지 ACLF에대해 13개가넘는다양한정의가있다. 비록 ACLF에대해널리통용되는진단기준은없지만, 대표적으로사용되는정의들이있다. 2009년 APASL의 ACLF에대한합의권고가발표되었고, 2014년 APASL ACLF Research Consortium (AARC) 에의해개정되었다. 5,9 AARC의 ACLF 정의는이전에만성간질환 / 간경변진단을받았거나또는받지못하였던환자에서, 높은 28일사망률을가지며, 4주이내에생긴복수나간성뇌증과같은합병증을동반한황달 ( 빌리루빈 5 mg/dl [ 85 micromol/l]) 과응고장애 (INR 1.5 or prothrombin activity <40%) 를보이는급성간손상이다 (The ACLF is an acute hepatic insult manifesting as jaundice (serum bilirubin 5 mg/dl [ 85 micromol/l]) and coagulopathy (INR 1.5 or prothrombin activity <40%) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, and is associated with a high 28-day mortality). 한편, ACLF는 2011년미국간학회 (American Association for the Study of Liver Disease, AASLD) 와 EASL의연구컨소시엄에의해달리정의되었다. 이 AASLD/EASL의정의는보통유발요인을가지며다발장기부전으로 3개월사망률의증가가동반된기존만성간질환의급성악화이다 (Acute deterioration of preexisting, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multisystem organ failure). 10 이들 APASL, AASLD/EASL 정의는모두근거중심의정의는아니며합의에의한정의이다. 유럽에서는 EASL-Chronic Liver Failure (EASL-CLIF) 컨소시엄을구성하여간경변환자의높은단기사망률을확인할수있는근거중심의정의를개발하기위해 EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) 연구를시행하였다. EASL-CLIF 컨소시엄은 1,343명의급성비대상 (acute decompensation, AD; 복수, 간성뇌증, 위장관출혈, 세균감염의발생으로정의 ) 과장기부전 (chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score로정의 ) 이있으면서높은 28일사망률 (>15%) 을 www.kast.org 5

2015 대한간학회춘계 Single Topic Symposium Table 1. Definitions of acute-on-chronic liver failure Proposed by APASL (2009) AASLD-EASL (2011) EASL-CLIF Consortium (2013) Definitions and Descriptions Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease. [Note: Jaundice (serum bilirubin 5 mg/dl [85 μmol/l]) and coagulopathy (INR >1.5 or prothrombin activity <40%) are mandatory in defining ACLF] Acute deterioration of preexisting, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multisystem organ failure. Definitions of Organ Failures (using a modified SOFA score, called the CLIF-SOFA score): Liver failure was defined by a serum bilirubin level of 12.0 mg/dl; Kidney failure was defined by a serum creatinine level of 2.0 mg/dl or the use of renal replacement therapy; Cerebral failure was defined by grade III or IV hepatic encephalopathy, according to the West Haven classification; Coagulation failure was defined by an international normalized ratio >2.5 and/or a platelet count of 20x10 9 /L; Circulatory failure was defined by the use of dopamine, dobutamine, or terlipressin; Respiratory failure was defined by a PaO 2/FiO 2 200 or an SpO 2/FiO 2 200. Diagnostic Criteria and Grade of ACLF: No ACLF This group comprises 3 subgroups: (1) patients with no organ failure, (2) patients with a single non-kidney organ failure (ie, single failure of the liver, coagulation, circulation, or respiration) who had a serum creatinine level <1.5 mg/dl and no hepatic encephalopathy, and (3) patients with single cerebral failure who had a serum creatinine level <1.5 mg/dl. [Note: The 28-day and 90-day mortality rates were 4.7% and 14%, respectively.] ACLF grade 1 This group includes 3 subgroups: (1) patients with single kidney failure, (2) patients with single failure of the liver, coagulation, circulation, or respiration who had a serum creatinine level ranging from 1.5 to 1.9 mg/dl and/or mild to moderate hepatic encephalopathy, and (3) patients with single cerebral failure who had a serum creatinine level ranging from 1.5 and 1.9 mg/dl. [Note: The 28-day and 90-day mortality rates were 22.1% and 40.7%, respectively.] ACLF grade 2 This group includes patients with 2 organ failures. [Note: The 28-day and 90-day mortality rates were 32.0% and 52.3%, respectively.] ACLF grade 3 This group includes patients with 3 organ failures or more. [Note: The 28-day and 90-day mortality rates were 76.7% and 79.1%, respectively.] APASL (2014) The ACLF is an acute hepatic insult manifesting as jaundice (serum bilirubin 5 mg/dl ( 85 micromol/l) and coagulopathy (INR 1.5 or prothrombin activity <40 %) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, and is associated with a high 28-day mortality. ACLF, acute-on-chronic liver failure; APASL, Asia Pacific Association for the Study of the Liver; AASLD-EASL, American Association for the Study of Liver Disease/ European Association for the Study of the Liver; EASL-CLIF, the EASL-Chronic Liver Failure (EASL-CLIF) Consortium; AARC, APASL ACLF Research Consortium; CLIF-SOFA, Chronic Liver Failure- Sequential Organ Failure Assessment; INR, International Normalized Ratio. 보이는간경변환자를분석하여 ACLF 의진단기준을제시하였다. 11 이이정표가되는 CANONIC 연구에 의해 ACLF 가매우흔하고 ( 유병률 30.9%), 장기부전이동반되며, 높은사망률 (AD 에비해 15 배높은단기 사망률 ) 을보이고, 나이, 유발요인, 전신염증반응등이단순한 AD 와구분되는, 별도의질환임을알게되었 다 (Table 1). 2014 년 CANONIC 연구를바탕으로또하나의근거를제시하는연구결과가발표되었다. 12 이연구에서 6 대한간학회 The Korean Association for study of the Liver

김동준 Definition and Prognosis of Acute-on-Chronic Liver Failure: Western and Eastern Perspectives Table 2. Differences in current definitions of acute-on-chronic liver failure Qualification for chronic liver disease Acute decompensation Acute insult (AARC) or precipitating event (EASL-CLIF) - Time frame (duration between insult and ACLF) - Hepatic vs. non-hepatic - Variceal bleeding - Infection or sepsis Organ failure - Kidney faliure Predefined significant mortality rate AARC (APASL, 2014) EASL-CLIF consortium (2013) Both cirrhotic and non-cirrhotic chronic liver diseases Not use the term acute decompensation ( Acute decompensation of cirrhosis is a different entity than ACLF. ) Must be new and acute ( Patients with known previous decompensation with jaundice, HE, and ascites should be excluded. ) 4 weeks Should be hepatic (the core premise of ACLF) Non-hepatotrophic insults like surgery, trauma, and viral infections if producing hepatic insult could lead to ACLF. Variceal bleed per se may not qualify unless it produces jaundice and coagulopathy (need more data) Whether sepsis is a consequence of or a cause of liver failure is not clear from the current data on ACLF. Do not incorporate organ failure in the definition Quite different (higher prevalence, rapid progression to tubular damage, and mortality), but not incorporate into diagnosis Only cirrhosis In CANONIC study, include patients with cirrhosis and acute decompensation defined by major complications of liver disease, ie, ascites, encephalopathy, GI hemorrhage, bacterial infection (no jaundice) Including those with prior decompensation Not defined Hepatic and non-hepatic Non-hepatic events also qualifies as precipitants Variceal bleeding also qualifies as precipitants Bacterial infection or sepsis are major events ACLF diagnosis and grading by organ failure Kidney failure and serum creatinine level is important in ACLF diagnosis and grading >33% at 4 weeks >15% at 28-day (increased mortality at 3 months, AASLD/EASL 2011) ACLF, acute-on-chronic liver failure; APASL, Asia Pacific Association for the Study of the Liver; AARC, APASL ACLF Research Consortium; EASL-CLIF, the EASL-Chronic Liver Failure (EASL-CLIF) Consortium; AASLD-EASL, American Association for the Study of Liver Disease/ European Association for the Study of the Liver; AD, acute decompensation; GI, gastrointestinal; HE, hepatic encephalopathy 복잡한 CLIF-SOFA score를단순화하여 ACLF의진단과층화를보다쉽게하게위하여 CLIF Consortium Organ Failure score (CLIF-C OFs) 와함께 ACLF에특이적인예후지표인 CLIF-C ACLF score (CLIF-C ACLFs) 가발표되었다. CLIF-C OFs와 CLIF-C ACLFs 는향후 ACLF에관한연구에서널리적용될것이예상된다. 이상에서약술한 APASL (AARC) 와 AASLD/EASL (EASL-CLIF 컨소시엄 ) 의 ACLF 정의는근본적으로다 www.kast.org 7

2015 대한간학회춘계 Single Topic Symposium 른특징을가지고있다 (Table 2). AARC의정의는만성간질환에서발생한복수나간성뇌증에초점을맞추고있는반면, EASL-CLIF 컨소시엄의정의는만성간질환환자의다발장기부전발생을강조하고있다. AARC 정의에서는황달과응고장애가모두있는간부전이 ACLF 진단의필수요건이다. 그러나, EASL-CLIF 정의는빌리루빈수치가 12 mg/dl 이상이더라도 creatinine이 1.5 mg/dl 미만이면서간성뇌증이없는경우 ACLF로진단하지않는다. 서양에서는감염이밝혀진악화요인가운데가장흔하고나쁜예후를갖는다고알려져있다. 그러나 2014년 AARC 권고에서는 ACLF 환자에서염증과선천적그리고후천적면역반응의불균형이중요한역할을한다. 간경변에서조기패혈증과 SIRS(Systemic Inflammatory Response Syndrome, 전신성염증반응증후군 ) 를구별하는것은어렵다. ACLF 환자에서패혈증이발생하면다발장기부전을초래하여높은사망률을보인다. 그러나, 패혈증이간경변의결과인지아니면원인인지는현재의 ACLF에대한자료로는알수없다. 고기술되었다. 한편, CANONIC 연구에서세균감염은 ACLF가심할수록더자주나타났고높은 CLIF-SOFA score와백혈구수의증가는독립적으로사망률과유의하게연관되어있었다. 11,13 더욱이세균감염의유병률은보다높은민감도의검사방법이사용되면더높았다. 또 North American Consortium for the Study of End-Stage Liver Disease (NACSELD) study에서도간경변환자에서감염이있으면간질환의중증도와는독립적으로사망의위험률이현저히높았다. 14 EASL-CLIF 컨소시엄에서는위장관출혈을만성간질환에서발생하는급성악화의흔한유발요인으로간주한다. 1 그러나정맥류출혈에대한 AARC의권고는 정맥류출혈그자체는 ACLF의유발요인이아닐수도있으며추후더많은자료가필요하다 고기술하였다 (Variceal bleed per se may not qualify as an acute insult for ACLF, and we need more data to ascertain this [5,D].). 흥미롭게도 CANONIC 연구에서위장관출혈이 ACLF 등급을더악화시키지는않는것으로나타났다. ACLF의정의에대한 AARC와 EASL-CLIF 컨소시엄에서의차이를표로요약하였다 (Table 2). 이러한동서양의각기다른정의는연구의상호비교를어렵게하고 ACLF와간경변의급성악화를혼동하는오해를일으키기도한다. 3 빠른시일내에 ACLF의정의에대한전세계적인합의가필요하다. 아마도 ACLF의정의에대한동서양의차이가간질환급성악화의유발요인의차이에기인할수도있다. 아시아에서 ACLF의유발요인은 B형간염의급성악화와만성간질환 ( 간경변에상관없이 ) 과동반된급성A형또는 E형간염이다. 이와는대조적으로서양에서는이미간경변이있거나입원시간경변이진단된환자에서바이러스간염이아닌알코올이원인인경우가많고, 특히세균감염이많다. 황달, 복수, 간성뇌증, 정맥류출혈은비대상을나타내는합병증인데, 비대상간경변의합병증은 ACLF로간주되지않는다. 그러나때로이의구분이어렵고, 둘사이의회색지대에서분명한경계를나누는것이어렵기도하다 (Figure 1C). Olson 등은간경변의자연경과로인한생명을위협할정도의비대상상태와 ACLF를구분하였다. 10 간경변의비대상이급성손상이오기전에왔다면이는 ACLF가아니라는것이다. 8 대한간학회 The Korean Association for study of the Liver

김동준 Definition and Prognosis of Acute-on-Chronic Liver Failure: Western and Eastern Perspectives 이에대해서 Garg 등도동의하였다. 15 그럼에도불구하고비대상간경변과 ACLF를구분할수있는진단도구는아직없는실정이다. 두질환의중요한구분점중하나는 ACLF가유발요인을제거함으로써가역적일수있다는것이다. 16 한편, World Gastroenterology Organization Working Party에서는 ACLF를간경변의유무에따라, 또이전에비대상이있었는지여부에따라 3가지카테고리로나눌것을제안하였다. 17 Type A (Noncirrhotic) ACLF는간경변이아닌만성간질환환자에서급성악화가있는경우인데, 급성또는아급성간부전과임상증상으로는종종구별하기어렵다. 이러한환자들은 B형간염재활성화, 만성B형간염에동반된 A형또는 E형간염, 자가면역간염, ( 비 ) 알코올지방간염, 만성간질환이있거나가능성이있는경우와동반된약인간손상이있는경우이다. 이 type A ACLF는동양에서더흔하다. Type B (Cirrhotic) ACLF는대상간경변환자가급성바이러스간염, 약인간손상, 알코올간염, 감염또는수술로인해간손상을받은후에급격히악화되는경우이다. 그러나유발요인이항상밝혀지는것은아니다. Type C ACLF (Cirrhotic ACLF with previous hepatic decompensation) 는과거에황달, 정맥류출혈, 복수, 간성뇌증과같은문맥고혈압의합병증이있는경우에발생한다. CANONIC 연구에서과거에비대상이있던환자 (C형 ACLF) 가과거에비대상이없던환자 (B형 ACLF) 에비해단기사망률이유의하게낮았다. 예후평가 ( 등급또는점수체계 ) Prognostic evaluation (Grading or scoring systems) ACLF는급성손상과만성손상이동시에나타나는질환이다. ACLF는급성손상의중증도와기저만성간질환의정도에따라달리나타나지만, 각기다른손상정도의조합으로같은정도의 ACLF가나타날수도있다. 도식적으로두가지상황을생각해보면, 중등증의만성간부전과중증의급성간부전에의해 ACLF가생긴경우 (Fig. 1A) 와중증의만성간질환과중등증의급성간손상으로 ACLF가생긴경우 (Fig. 1B) 이다. 두상황에서의 ACLF 중증도는결과적으로같다. 이와같이 ACLF에서는동시에급성과만성, 두종류의손상이있으므로예후를예측하는것이어려울수있다. 환자의예후가급성손상의중증도, 기저만성간질환의중증도, 혹은두가지모두중어느영향을받는지불명확하기때문이다. 18 그럼에도불구하고 ACLF에서의예후예측은매우중요하다. 인도에서시행한전향연구에서 30일과 90일사망률은각각 50% 와 63% 로서양의연구결과들과유사하다. 14 중환자실로입원한간경변환자의예후에대한사용가능한자료를모아서분석한결과는두가지중요한결론에도달한다. 첫째, 간경변환자에서장기부전의발생은중환자실입원기준이되고이는나쁜예후를나타내며, 둘째, Child-Turcotte-Pugh (CTP) score로측정한간질환의중증도가아니라장기부전의정도가예후를결정한다는것이다. 4,13 예후평가방법은크게 3가지로나눌수있다. 첫째, 특히간질환자체의중증도를평가하는 CTP score, www.kast.org 9

2015 대한간학회춘계 Single Topic Symposium Table 3. CLIF-SOFA Score Organ/system 0 1 2 3 4 Liver (bilirubin, mg/dl) <1.2 1.2 to <2.0 2.0 to <6.0 6.0 to <12.0 12.0 Kidney (creatinine, mg/dl) <1.2 1.2 to <2.0 2.0 to <3.5 3.5 to <5.0 5.0 or use of renal replacement therapy Cerebral (HE grade) No HE I II III IV Coagulation (INR) <1.1 1.1 to <1.25 1.25 to <1.5 1.5 to <2.5 2.5 or platelet count 20 x 10 9 /L Circulation (mean arterial 70 <70 Dopamine 5 or Dopamine >5 or Dopamine >15 or pressure, mm Hg) dobutamine or E 0.1 or E >0.1 or terlipressin NE 0.1 NE >0.1 Lungs PaO 2/FIO 2 or >400 >300 to 400 >200 to 300 >100 to 200 100 SpO 2/FIO 2 >512 >357 to 512 >214 to 357 >89 to 214 89 NOTE. Like the SOFA score, the CLIF-SOFA score includes subscores ranging from 0 to 4 for each of 6 components (liver, kidneys, brain, coagulation, circulation, and lungs), with higher scores indicating more severe organ impairment. Aggregated scores range from 0 to 24 and provide information on overall severity. The text in bold indicates the diagnostic criteria for organ failures. HE, hepatic encephalopathy; E, epinephrine; NE, norepinephrine; PaO 2, partial pressure of arterial oxygen; FiO 2, fraction of inspired oxygen; SpO 2, pulse oximetric saturation. Model for End-stage Liver Disease (MELD) score 등이있고, 둘째, 질환의중증도를평가하는 APACHE II와 III, Simplified Acute Physiology Score (SAPS) II, Mortality Prediction Model II 등이있으며, 셋째, 장기부전을평가하는 Logistic Organ Dysfunction System, Multiple Organ Dysfunction Score, Organ System Failure (OSF), SOFA 등이있다. 위에서언급한대로 ACLF를동반한비대상간경변환자에있어서예후를결정하는주된요인이간질환의중증도가아니므로간질환특이적인 CTP, MELD score는 ACLF 환자의예후를예측하는데있어정확도가떨어지며, 장기부전을평가하는 SOFA score 등이보다도움이된다. 10,16 그러나 SOFA score의중요한문제점은장기부전을반영하지만예측하지는못한다는것이다. 예측할수없다면, 조기중재술을사용하는데한계가있게된다. 간경변환자에서 ACLF 발생을조기에발견할수있는완벽한시스템은아직없다. CLIF SOFA score는예후예측이아니라 ACLF의진단을위해만들어진것이다. 이를기반으로 ACLF의진단기준과등급 (grade) 을나눌수있고, 높은등급으로갈수록뚜렷이사망률이높아지지만, 이 CLIF-SOFA score의기준이전문가의견에근거하여만들어졌으며, 복잡하여사용이쉽지않은단점이있다 (Table 3). 3,11 EASL-CLIF 컨소시엄에서 CLIF-SOFA score를단순화한 EASL-CLIF Consortium Organ Failure Score (CLIF-C OFs) 를개발하였다 (Table 4). 12 이와함께 CLIF-C OFs에는포함되어있지않으나사망률에영향을주는요인인백혈구수와나이를포함한예후지표인 EASL-CLIF Consortium ACLF Score (CLIF-C ACLFs) 를개발하였는데, CLIF-C ACLFs 는 internet (http://www.clifconsortium.com/) 을통해계산할 10 대한간학회 The Korean Association for study of the Liver

김동준 Definition and Prognosis of Acute-on-Chronic Liver Failure: Western and Eastern Perspectives Table 4. CLIF Consortium Organ Failure Score (CLIF-C OFs) Organ/system Subscore = 1 Subscore = 2 Subscore = 3 Liver Bilirubin <6 mg/dl Bilirubin 6 mg/dl Bilirubin 12 mg/dl and <12 mg/dl Kidney Creatinine <2 mg/dl Creatinine 2 mg/dl and <3.5 mg/dl Creatinine 3.5 mg/dl or renal replacement Brain (West-Haven grade for HE*) Grade 0 Grade 1-2 Grade 3-4 Coagulation INR <2.0 INR 2.0 and <2.5 INR 2.5 Circulatory MAP 70 mmhg MAP <70 mmhg Use of vasopressors Respiratory PaO 2/FIO 2 or SpO 2/FIO 2 >300 or >357 300 and >200 or >214 and 357 200 or 214 NOTE: The shaded area describes criteria for diagnosing organ failures. * HE, hepatic encephalopathy; FiO 2, fraction of inspired oxygen; PaO 2, partial pressure of arterial oxygen; SpO 2, pulse oximetric saturation. Patients submitted to Mechanical Ventilation (MV) due to HE and not due to a respiratory failure were considered as presenting a cerebral failure (cerebral subscore = 3). Other patients enroled in the study with MV were considered as presenting a respiratory failure (respiratory subscore = 3). 수있으며아래의식으로표시된다. CLIF-C ACLFs = 10 x [0.33xCLIF-OFs + 0.04xAge + 0.63xln(WBC count) 2] 어느주어진시점 (t) 에서의사망확률은다음과같다. P = 1 e [-CI(t)xexp(β(t)xCLIF-C ACLFs)] (NOTE: CI(t) and β(t) are the cumulated baseline hazard and the score coefficient estimated by the model fitted for time t.) CLIF-C ACLFs 값은 0부터 100까지이며, 40 이하일때사망에대해 90% negative predictive value와 97% sensitivity를갖는반면, 60 이상이면 82% positive predictive value와 94% specificity를가진다. 특히이 CLIF-C ACLFs 는진단시점뿐아니라진단이후에도연속적으로사용할수있어앞으로 ACLF 환자에서 MELD score처럼널리사용될수있을것이다. 이 CLIF-C ACLFs 는 2014년 10월에발표되어아시아환자에서도같은결과를얻게될지귀추가주목된다. AARC는 MELD와 lactate에기반한 ACLF의 AARC dynamic model이 MELD나 CLIF-SOFA score에비해특이도와민감도가높지만후향적인검증이필요하다 ( 권고등급 2b, C) 고권고하였다. 이와별도로빌리루빈, INR, 복수, 간성뇌증의 4가지항목을이용한점수체계또는빌리루빈, INR, 간성뇌증 3가지항목을이 www.kast.org 11

2015 대한간학회춘계 Single Topic Symposium 용한간략한점수체계가발표될예정이다. CLIF-C ACLFs 또는 AARC dynamic model과같이주기적으로계산할수있는 동적 점수는중환자실치료의결정이나간이식등의치료가언제필요할지를결정하는데있어특히유용할것이므로향후연구의중요한주제가될것이다. 18 결론 Conclusions ACLF는만성간질환환자에서장기부전과높은사망률을보이고임상양상과병태생리및예후가뚜렷이다른별도의질환이다. ACLF에대한동서양의생각을통일시키는노력은새로운생물학적지표를개발하여사망과비가역적인상태를조기에예측하고적시에필요한치료를제공하기위해시급히필요한일이다. 아울러간경변을기저질환으로하면서도간경변의비대상과정과는다른병태생리를갖는 ACLF에대한연구는간질환전반에대한이해를높여줄것이다. References 1. Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on chronic liver failure. J Hepatol 2012;57: 1336-1348. 2. Olson JC, Wendon JA, Kramer DJ, Arroyo V, Jalan R, Garcia-Tsao G, et al. Intensive care of the patient with cirrhosis. Hepatology 2011;54:1864-1872. 3. Bajaj JS. Defining Acute-on-Chronic Liver Failure: Will East and West Ever Meet? Gastroenterology 2013;144:1337 1339. 4. Kim TY, Kim DJ. Acute-on-Chronic Liver Failure. Clin Mol Hepatol 2013;19:349-359. 5. Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2009;3:269-282. 6. Lee WM, Stravitz RT, Larson AM. AASLD Position Paper: Introduction to the Revised American Association for the Study of Liver Diseases Position Paper on Acute Liver Failure 2011. AASLD web site, <www.aasld.org/practiceguidelines/documents/ AcuteLiverFailureUpdate2011.pdf>. accessed 2015. 7. Jalan R, Stadlbauer V, Sen S, Cheshire L, Chang YM, Mookerjee RP. Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study. Crit Care 2012;16:R227. 8. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002;20:252-261. 9. Sarin SK, Kedarisetty CK, Abbas Z, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int 2014;8:453 471. 10. Olson JC, Kamath PS. Acute-on-chronic liver failure: concept, natural history, and prognosis. Curr Opin Crit Care 2011;17:165-169. 11. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426-1437, 1437 e1421-1429. 12 대한간학회 The Korean Association for study of the Liver

김동준 Definition and Prognosis of Acute-on-Chronic Liver Failure: Western and Eastern Perspectives 12. Jalan R, Saliba E, Pavesi M, Amoros A, Moreau R, Gines P, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014;61:1038 1047. 13. Moreno RP, Metnitz B, Adler L, Hoechtl A, Bauer P, Metnitz PG. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008;34:496-504. 14. Bajaj JS, O Leary JG, Reddy KR, Wong F, Olson JC, Subramanian RM, et al. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012;56:2328-2335. 15. Garg H, Kumar A, Garg V, Sharma P, Sharma BC, Sarin SK. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure. Dig Liver Dis 2012;44:166-171. 16. Graziadei IW. The clinical challenges of acute on chronic liver failure. Liver Int 2011;31(Suppl 3):24-26. 17. Jalan R, Yurdaydin C, Bajaj JS, Acharya SK, Arroyo V, Lin HC, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014; 147(1):4-10. 18. Wlodzimirow KA, Eslami S, Abu-Hanna A, Nieuwoudt M, Chamuleau RA. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int 2013;33:40-52. www.kast.org 13