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1 Parallel symposium A. 급성간부전 (Acute liver failure: ALF) 울산대학교의과대학서울아산병원소화기내과 From fulminant to acute changes in definition and epidemiology of acute liver failure in Korea-implications for prognosis and management Young-Suk Lim, M.D., Ph.D. Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Abstract The most widely accepted definition of ALF includes evidence of coagulation abnormality, usually an INR 1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an illness of < 26 weeks duration. Terms used signifying length of illness such as hyperacute, acute and subacute are not particularly helpful since they do not have prognostic significance distinct from the cause of the illness. The outcomes of patients with ALF vary greatly according to etiology, and the etiology of ALF varies markedly by geographical region. In Korea, about 90% of ALF are associated with etiologies that usually result in poor outcomes, including HBV infection and herbal remedies. The main causes of death in patients with ALF are increased intracranial pressure, systemic infection, and multi-organ failure. Recent advances in the intensive care of patients with ALF have contributed to a marked improvement in their overall survival. The necessity of emergency adult to adult living-donor liver transplantation (LDLT) is more emphasized in this country not only because of the limited supply of organs from deceased donors but also because of the common etiologies associated with extremely poor transplant-free survival rate. 서 론 급성간부전 (Acute Liver Failure, ALF) 은간성뇌증과혈액응고장애 (coagulopathy) 로특징되는급성간손 - S87 -

2 2010 년대한간학회추계학술대회 상의비교적드문합병증이다. 1 급성간부전의예후는최근적극적인내과적치료와간이식술의발전에힘입어많이호전되었지만, 응급간이식을받지못하는경우환자사망률이 50-80% 에이를정도로불량하다. 따라서, 환자들의예후를정확하게판정하고올바른치료방침을결정하기위해서는먼저이독특한급성질환에대한정확한이해가필요하다. 급성간부전의정의 급성간부전의일반적인정의는이전에간경변증이없던환자에서급성간손상으로인해발생하는급격한간부전으로간의합성능의장애와함께간성뇌증이나타나는경우를말한다. 1 심한황달과혈액응고장애는있지만간성뇌증을동반하지않는급성간손상은급성간부전으로진단할수없고, 중증급성간염 (severe acute hepatitis) 으로분류되며, 일반적으로예후가좋다. 급성간부전은 1970년 Trey and Davidson에의해전격성간부전 (fulminant hepatic failure) 으로처음정의된이후, Bernuau와 O Grady 등에의해다양한기준으로분류되어왔다 ( 표 1). 즉, 황달혹은증상발현으로부터간성뇌증발생까지소요되는시간에따라초급성간부전 (hyperacute liver failure, 1주이내 ), 급성간부전 (1~4주사이 ), 아급성간부전 (subacute liver failure, 4~24주사이 ) 등으로나누는분류법들이이용되었는데, 2,3 그이유는, 증상이나황달발생으로부터간성뇌증발현까지의기간에따라서예후가다르다는점이알려졌기때문이다. 그러나최근에간성뇌증발생시기와예후가모두급성간부전의원인과깊은관련이있으며, 원인의영향으로보정할때간성뇌증의발생시기는예후예측지표로서의의미가없어짐이알려졌다. 즉, 황달발생으로부터 7일이내에간성뇌증이발생하는초급성간부전의경우는예후가비교적양호하지만, 이것은초급성간부전의원인중대부분이좋은예후를나타내는아세트아미노펜 (acetaminophen) 이나급성 A형간염이라는점에기인한다. 3-5 반면, 초급성간부전이라도 B형간염바이러스나특이약물반응이원인인경우에는예후가불량하다. Table 1. Definitions of acute hepatic failure Authors Term Time to Encephalopathy Onset Trey and Davidson 1970 Fulminant hepatic failure <8 week Symptoms Bernuau et al Fulminant hepatitis <2 week Jaundice Subfulminant hepatitis 2-12 week Jaundice O Grady et al Hyperacute liver failure <1 week Jaundice Acute liver failure 1-4 week Jaundice Subacute liver failure 4-24 week Jaundice AASLD Acute liver failure <26 week Symptoms - S88 -

3 Table 2. Classification, prognosis, and causes of the three subtypes of acute liver failure (O Grady et al.) Time from jaundice to encephalopathy Transplant-free survival rate (%) Typical cause Hyperacute Acute Subacute <8 d 8-28 d 4-24 wk Acetaminophen, hepatitis A and E Hepatitis B non-acetaminophen drug, unknown Figure 1. Presumed causes and outcomes in 308 patients with acute liver failure in the US. (George Ostapowicz, et al. Ann Intern Med. 2002;137: ). 따라서, 급성간부전환자들을간성뇌증의발생기간으로분류하고예후를예측하는것보다는그원인을철저하게조사하는것이매우중요하다는점에서, 2005년미국간학회에서는증상발현으로부터 26 주이내에간성뇌증이발생한모든환자들을급성간부전의단일분류로포함시키는정의를제안하였다 ( 표 2). 원인과예후 급성간부전의임상상은원인에관계없이비슷하지만, 예후를예측하고적절한치료를적용하기위해서원인파악이매우중요하다. 급성간부전의원인은환자의예후를결정하는가장중요한요인이다. 미국의 3차의료기관들에서진단된급성간부전환자들의원인과예후의연관성에대한전향적조사에의하면, 아세트아미노펜, A형간염, 임신, 쇼크가원인이었던환자들의경우비이식생존률 (transplantation-free survival rate) 이 60% 이상이었다 ( 그림 1). 6 반면에, 비아세트아미노펜약제, B형간염, 자가면역성간염, 윌슨병, 버드- 키아리 (Budd-Chiary) - S89 -

4 2010 년대한간학회추계학술대회 % Acute hepatitis B Severe acute exacerbation of chronic hepatitis B Patients, n % 7% 7% 6% 5% 3% 6% 10% 0 Cause Figure 2. Causes of acute liver failure in 110 patients in Korea. HAV, hepatitis A virus; HBV, hepatitis B virus. 증후군, 악성종양, 기타, 원인불명등의경우의비이식생존률은 30% 이하였다. 따라서, 급성간부전의원인은진단과동시에반드시밝혀야하지만, 매우다양한원인들이급성간부전을유발할수있으므로, 철저하게조사하지않으면찾지못하는경우가많다. 일례로, 본저자의기관에서후향적으로조사했을때는무려약 30% 에서원인을알수없었으나, 7 전향적코호트연구에서는원인을찾지못하는경우가 10% 에불과했다. 8 급성간부전의원인은지역과시대에따라서큰차이를보임이잘알려져있다. 9,10 영국, 미국, 호주등에서는아세트아미노펜과다복용이가장흔한원인이지만, 우리나라를비롯한많은아시아국가들에서는 B형간염바이러스가가장흔한원인이다. 우리나라의경우, 2004년부터 2007년사이에 110명의환자들을전향적으로조사한자료에의하면 B형간염바이러스가약 37% 로서가장많은원인을차지하였고, 한약재를포함한각종생약제가 19% 로두번째흔한원인이었다 ( 그림 2). 8 전체적으로약 90% 의환자들의원인은불량한예후를나타낸다고알려진것들이어서, 우리나라급성간부전환자들의예후가서구에비해불량한한이유로설명된다. 특기할사실은, 최근 10여년사이에우리나라에서급성B형간염의발병률이급격하게줄어들고, 급성 A형간염의발병률은매우빠르게증가하고있다는것이다. 이런현상에따라, 최근수년간전체급성간부전중급성A형간염이원인으로차지하는비중이급격히증가하고있다. 이런급격한역학의변화는전세계적으로도매우독특한현상으로서, 급성간부전환자들의자연생존률에어떤영향을미칠지주목된다. 급성간부전의원인에있어서특기할두번째사실은, 서구에비해서아세트아미노펜 (acetaminophen) 의비중이매우낮고, 비아세트아미노펜 (non-acetaminophen) 의원인적비중이상당히높다는점이다. 특히, 생약제제를비롯한식물제제에의한간손상은 B형간염바이러스에이어두번째로매우높은데, 독버섯이원인인경우를합한다면그원인적비중은더욱높아진다. 11 문제는이런생약제제에의한급성간부전환자들의예후는 B형간염의경우에못지않게불량하다는점이다. - S90 -

5 급성간부전의주요임상양상과사인 급성간부전의가장특징적인임상상은간성뇌증과혈액응고장애다. 혈청아미노전이효소 (aminotransferase) 는대부분매우높이증가하지만, 그최대증가치및감소속도는환자의예후와무관하다. 3 회복되는환자들은프로트롬빈시간 (prothrombin time) 이호전되며, 반대로간부전이진행하는환자들은혈청아미노전이효소가감소함에도불구하고프로트롬빈시간이연장된다. 1 급성간부전은간손상외에도거의모든장기의기능에영향을미치며, 뇌부종, 패혈증, 신부전, 심폐부전등다장기부전 (multi-organ failure) 형태의합병증으로나타나서급성간부전의높은사망률의원인이된다. 12 급성간부전환자사망의 4대사망원인은뇌부종, 전신감염증, 다장기부전, 출혈의순이다. 12 환자사망의원인이되는각종합병증들은진단시점으로부터의시기에따라다르게출현한다. 즉, 진단으로부터 1주이내에는거의전적으로뇌부종이사망의원인이되는데, 1~2주사이에는뇌부종과전신감염증이비슷한비중을차지하고, 이후부터는전신감염증과다장기부전이가장중요한사망원인이다 ( 그림 3). 8 최근내과적치료의발전으로인해출혈로인한사망은현저히감소했다. 급성간부전의예후예측지표들 급성간부전은잠재적으로치명적인질환이므로생존률을개선시킬수있는유일한치료인응급간이식의적용을신중히고려해야한다. 과거로부터 King s college criteria를비롯하여다양한예후지표들이응급간이식의필요성을평가하기위해이용되어왔다. 그러나, 이런지표들은모두간이식의필요성을정확하게예측하는데만족스럽지못한결과를보여서환자의치료결정에이용하는것은추천되지않는다. 1 급성간부전의원인이외에가장중요한것으로평가되는예후예측인자는간성뇌증의단계이다. 우리나라급성간부전환자들의경우경과중간성뇌증 1~2단계이상으로진행하지않는경우자연생존률이 100% 였으나, 반대로 3~4단계이상으로진행한경우는 10% 미만의자연생존률을나타냈다. 8 (n) Increase of intracranial pressure Infection Multiorgan failure Others 0 Total <1 wk 1-2 wk >3 wk Time interval from diagnosis to death Figure 3. Cases of death in patients with acute liver failure. - S91 -

6 2010 년대한간학회추계학술대회 급성간부전의치료 - 간이식술 간이식술은급성간부전환자들의생존률을개선시킬수있는확실한치료법이다. 간성뇌증이 3-4단계에이른경우자연생존률이 10% 정도에불과하다. 이런진행된급성간부전환자들에서응급뇌사자간이식혹은성인간생체간이식술 (adult to adult living-donor liver transplantation) 은급성간부전환자들에서단기및장기생존률을분명히증가시킴이증명되어있다. 8 우리나라의경우, 뇌사자공여간의이용은매우드물다는점이외에도, 급성간부전원인의약 90% 가불량한예후와관련이있고, 환자의병세는일반적으로매우급격하게진행하여간이식을받을수있는적합한시간이제한적이라는점에서서구에비해응급생체부분간이식의필요성이훨씬높다. 따라서, 환자가아직이식의기준에해당하지않는것으로평가된다하더라도가능한공여자를조기에확인하여준비를해두고이식팀을환자의평가에참여시키는것이좋다. 그러나다장기부전과대사성산증이진행된상태일수록이식후예후가나쁘다. 8,13 따라서, 급성간부전으로진단하는즉시응급간이식을위한준비를신속히실시하고, 간성뇌증이 3~4 단계이상으로진행하는경우에는응급간이식을즉각시행하는것이가장적절한치료전략이될것이다. 결 론 급성간부전은드물지만치명적인질환이다. 원인이예후판정의가장중요한요인인데, 우리나라환자들의경우약 90% 정도의원인이불량한예후와관련있다. 사망의가장중요한원인은뇌부종, 전신감염증, 다장기부전으로서철저한예방과적절한치료가필요하다. 진행된환자들의경우생존률향상이입증된유일한치료는간이식술뿐이므로진단시점부터내-외과간의신속하고긴밀한협진이필요하다. 참고문헌 1. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41: 전격성간염의진단및치료. In: 이창홍, ed. 대한소화기학회총서 2. 2nd ed: 대한소화기학회, Lim YS. Diagnosis and treatment of fulminant hepatic failure. In: Lee CH, ed. Hepatitis. Volume 2. 2nd ed: Korean Society of Gastroenterology, Lee WM, Squires RH, Jr., Nyberg SL, et al. Acute liver failure: Summary of a workshop. Hepatology 2008;47: O'Grady JG, Williams R. Classification of acute liver failure. Lancet 1993;342: Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137: Heo NY, Lim YS, Kang JM, et al. [Clinical features of fulminant hepatic failure in a tertiary hospital with a liver transplant center in Korea]. Korean J Hepatol 2006;12: Park SJ, Lim YS, Hwang S, et al. Emergency adult-to-adult living-donor liver transplantation for acute liver failure in a hepatitis B virus endemic area. Hepatology Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008;28: S92 -

7 10. Polson J, Lee WM. Etiologies of acute liver failure: location, location, location! Liver Transpl 2007;13: Ahn BM. [Herbal preparation-induced liver injury]. Korean J Gastroenterol 2004;44: Stravitz RT, Kramer DJ. Management of acute liver failure. Nat Rev Gastroenterol Hepatol 2009;6: Polson J. Assessment of prognosis in acute liver failure. Semin Liver Dis 2008;28: S93 -

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