대한내과학회지 : 제 75 권제 5 호 2008 알벤다졸 (400 mg) 1 회복용에의해유발된급성독성간염 1 예 한림대학교의과대학내과학교실 1, 병리학교실 2 김민관 1 박혜원 1 김원진 1 박철민 1 홍지연 1 조성진 2 장명국 1 case of acute drug-induced hepatotoxicity after albendazole treatment Min Kwan Kim, M.D. 1, Hye Won Park, M.D. 1, Won Jin Kim, M.D. 1, Chul Min Park, M.D. 1, Ji Yeon Hong, M.D. 1, Seung Jin Cho, M.D. 2 and Myoung Kuk Jang, M.D. 1 Departments of Internal Medicine 1 and Pathology 2, Kangdong Sacred Heart Hospital, College of Medicine Hallym University, Seoul, Korea Drug-induced hepatotoxicity is injury to the liver as a result of drug exposure. Due to their unpredictable nature, drug-induced liver injuries pose a serious problem for clinicians, health agencies, and pharmaceutical firms. lbendazole is a benzimidazole with wide spectrum coverage as an antiparasitic drug. Very few cases of high-dose albendazoleinduced hepatotoxicity have been reported so far, and no case in response to a single dose. 25-year-old man presented to our hospital with dark urine. Twenty days prior to presentation, he took a tablet of albendazole (400 mg) as a prophylactic treatment for lumbricosis. Upon laboratory analysis, aspartate aminotransferase (ST) was 748 IU/L, alanine transaminase (LT) was 939 IU/L, and total/direct bilirubin was 9.3/7.3 mg/dl. The patient was negative for viral markers (HV, HV, and HCV) and autoantibodies. bdominal ultrasonography revealed no evidence of chronic liver damage. The pathology was compatible with drug-induced hepatotoxicity. The patient improved with conservative management only. (Korean J Med 75:564-568, 2008) Key Words: lbendazole; Hepatotoxicity 서론약제에의한독성간염은 10만명당 1명에서 10명의빈도로보고되고있지만발견및진단의어려움, 노출된환자의추적관찰의어려움등으로그빈도는더높을것으로추정된다 1). 약제에의한독성간염은약제의직접독성작용혹은약제의개별적인특이작용등다양한기전에의해발생하며, 임상양상및간생검이진단에도움이된다 2). 한편, 알벤다졸은간에서 100% 1차대사되는기생충치료제로세계적으로널리사용되고있으며, 매우안전한약제로알려져 있다. 그러나약동학적으로, 알코올과유사하게싸이토크롬 P450 산화효소에전적으로의존해약물대사가이루어지게되므로, 장기간사용할경우에는간기능에대한추적검사가필요한약제이다 3, 4). 전세계적으로알벤다졸에의한독성간염은극히드물게보고되고있으며, 모두포낭충증또는낭미충증에대해알벤다졸을 400 mg 하루 2회, 3주이상의기간동안장기간복용한경우이다 5, 6). 이에저자들은간경변증등만성간질환의증거가없으나, 장기간의알코올섭취로싸이토카인 P450 산화효소의기능이저하되었을것으로예상되는환자에서알벤다졸 400 mg 1회복용으로급성 Received: 2007. 7. 2 ccepted: 2007. 8. 16 Correspondence to: Myoung Kuk Jang, M.D., Department of Internal Medicine, Kangdong Sacred Heart Hospital of Hallym University Medical Center, 445, Gildong, Kangdong-gu, Seoul 134-701, Korea E-mail: mkjang2@medimail.co.kr - 564 -
Min Kwan Kim, et al: case of acute drug-induced hepatotoxicity after albendazole treatment Figure 1. bdominal ultrasonography revealed normal echo texture of the liver, except for mild gall bladder (G) wall thickening secondary to hepatitis. C Figure 2. Microscopy revealed the following signs suggestive of acute cholestatic hepatitis: () severe portal inflammation; () severe lobular inflammation; (C) infiltration of numerous lymphocytes and neutrophils. - 565 -
- 대한내과학회지 : 제 75 권제 5 호통권제 579 호 2008 - HD#1 HD#3 HD#6 HD#9 HD#22 Hospital day HD#1 HD#3 HD#6 HD#9 HD#22 Hospital day Figure 3. Liver-related laboratory parameters normalized with conservative management only. 간독성이유발된 1예를경험하고, 이를보고한다. 증례환자 : 김 석, 25세남자주소 : 황달현병력 : 25세남자로 4년전부터일주일에 3~4 회, 매번소주 1~2 병씩내원 2개월전까지마셔왔다. 3년전회충약 ( 내원당시복용한약과동일한약으로알벤다졸로추정됨, 1알, 1회 ) 에의한급성간염으로타병원에입원한병력이있었다. 본원에방문하기 20일전약국에서기생충을예방할목적으로처방전없이회충약을 1회 ( 알벤다졸 400 mg) 복용하였다. 약제복용후다음날부터소변색깔이점차진해지고, 피곤함이발생해응급실을통해입원하였다. 사회력 : 4년전부터일주일에 3~4 회, 매번소주 1~2 병씩내원 2개월전까지마셔왔다과거력 : 3년전타병원에서현재와동일한약제로추정되는회충약 1알 1회복용후급성독성간염으로입원 ( 퇴원시간수치는정상화됨.) 진찰소견 : 신체검사에서전신및공막의황달소견이외에특이소견은관찰되지않았다. 검사실소견 : 내원후시행한일반화학검사에서혈청 ST/LT은 748/939 IU/L ( 참고치 : 8-3/4-44) 로증가되어있었으나, ST/LT 비율은 2 미만이었으며, LP 와 r-gt 는각각241 IU/L ( 참고치 89-273) 과 68 IU/L ( 참고치 11-75) 로정상이었다. 혈청총빌리루빈 / 직접빌리루빈은 9.3/7.3 mg/dl ( 참고치 : 0.2-1.2/0.1-0.4 ) 로크게증가되어있었으며, PT와 INR은각각 12.8초 ( 참고치 10.1-12.9) 와 1.13 ( 참고치 0.9-1.14) 으로정상이었다. 형, 형, C형간염바이러스항 원, 항체검사및자가면역항체검사는모두음성이었다. 약물에의한간독성의판단근거가되는 RUCM (Roussel Uclaf Causality ssessment Method) Score 는 14점만점중 12점으로 Highly Probable 소견을나타냈다. 방사선검사 : 복부초음파검사에서간실질은정상이었다. 담낭벽이경미하게비후되어있었으나, 담도폐쇄나비장종대등의특이소견은없었다 ( 그림 1). 치료및임상경과 : 약제에의한독성간염의확인을위해간생검을시행하였다. 간조직의병리학적검사에서섬유화등알코올에의한만성간손상의증거는없었으며, 간엽및간문맥의심한염증, 간문맥의확장및중성구와림프구의침윤등약제유발급성간손상에합당한소견을보였다 ( 그림 2). 이후간보존제및수액등보존적인치료로생화학검사수치가정상화되고, 임상적관해를보여서퇴원하였다 ( 그림 3). 이후외래추적검사에서환자의간수치는정상을유지하였다. 고찰일반적으로간독성은내인성간독성 (intrinsic hepatotoxicity) 의기전과특이반응 (idiosyncrasy) 의기전에의하여유발된다. 내인성간독성은용량의존성이있으며, 고용량에노출된개체들에서높은빈도로발생된다는점이특징적이다. 그러나특이반응에의한간독성은노출된개체들일부에서발생하며용량의존성이없거나적은것이특징이다. 특이반응을세분하면면역- 알러지반응 (immunoallergic response) 의소견즉, 발열, 림프절종대, 피부발진, 관절통, 호산구증등의전신소견을보이는면역적특이반응 (immunologic idiosyncrasy) 의기전과그러한소견을보이지않는대사성특이 - 566 -
- 김민관외 6 인 : 알벤다졸 1 회복용에의한독성간염 - 반응 (metabolic idiosyncrasy) 의기전으로나누어진다 7). 특히약제에의한독성간염은파괴된세포의단백질과약물의면역학적상호작용, 약물대사의세포학적연결과정의차단, 세포의파괴로인한담즙배설의장애, 종양괴사인자에의한프로그램된세포죽음 (programmed cell death) 등여러기전의가능성이있지만대부분의약제에있어서아직확실히밝혀지지않았다 2, 8-10). 약제에의한독성간염은어린이보다는고령의환자에서위험도가높으며다른위험인자로는여성, 비만, 영양불균형, 만성알코올섭취, 공복상태, 임신, 동시에다른약제복용, 싸이토크롬 P450 산화효소의결핍등이있다 11, 12). 이중에서싸이토크롬 P4502E1 (CYP2E1) 은치료약제들을포함한생체이물 (xenobiotics), 발암전구물질, 뿐만아니라알코올등을대사작용으로분해하는매우중요한역할을하고있다 13). 특히만성적인알코올섭취는 CYP2E1 의활동도를감소시키며 CYP2E1 에의한약물대사의현저한장애를초래할수있다 14). 일반적으로약제에의한독성간염은바이러스간염, 알코올성간질환, 담도폐색, 자가면역성간질환등이배제된상태에서약물투여와임상양상과의시간적연관성 ( 약물투여후첫증상혹은간기능검사치이상소견까지의기간이대개 1주에서 12주 ) 과약물투여중단후자연적인간기능의호전을보이는임상경과를통해진단할수있다 15). 간조직의병리학적검사에서약제에의한손상을시사하는특이소견은없으나, 위의임상경과와더불어간세포의괴사, 미세소낭지방증, 담도손상, 이와동반된호중구, 호산구의현저한침착등의소견이있을경우, 약물에의한간손상을진단하는데도움을줄수있다 16). 알벤다졸은벤지미다졸유도체로써광범위구충제로세계적으로널리사용되고있다. 주로포낭충증과낭미충증에서수주에서수개월동안사용하는약제이며그대사과정이싸이토크롬 P450 산화효소에의존적이다. 따라서간이매우중요한 1차대사장기이므로, 장기간사용될경우에는정기적인간기능의추적관찰이필요하다 17). 그러나, 알벤다졸에의한독성간염의보고는세계적으로도극히드물다. 현재까지 54세남자환자의포낭충증치료와 83세남자의낭미충증의치료에각각 8주와 10주경구알벤다졸 10 mg/ kg/day 사용후나타난독성간염이보고되어있으며, 포낭충증에대해 400 mg 하루두번 28일간복용한후일부환자에게서간효소수치가증가하였다가약제중단후간기능이호전된예가알려져있을뿐이다 5, 6). 모든예가기술한바와같이비교적장기간에걸쳐다량의알벤다졸을복용한경우 들이며, 본증례에서와같이비교적건강한젊은남자에서 1 회 1알 (400 mg) 을예방적으로복용한후독성간염이유발된보고는없었다. 소량을 1회복용한후독성간염이유발된것을미루어보아, 알벤다졸에대한과민성반응의가능성도고려되어야하지만, 현재까지알벤다졸에대한과민성반응이존재하는가에대해서는알려진바가없다. 간조직의병리학적소견에서간문맥내호산구의많은침착은약물에의한과민성반응진단에필수적이지는않지만진단을위한근거로도움이될수있다 18). 하지만본증례에서는과민성반응에합당한조직병리학적소견을찾을수없었으며오히려만성적인알코올의섭취로인한간내싸이토카인 P450 산화효소의기능저하가약제의대사과정에심각한장애를유발했을것으로생각된다 15). 저자들은기저만성간질환의증거가없는비교적건강한젊은남자에게서만성적인알코올섭취로인해약물의대사과정에장애가있을것으로추정되고, 알벤다졸 400 mg 1회복용으로급성간독성이유발된예를경험하였다. 내원후시행한혈청 ST/LT는 748/939 IU/L ( 참고치 : 8-3/4-44) 로증가되어있었으나, ST/LT 비율은 2미만이었으며, LP 와 r-gt는각각241 IU/L ( 참고치 89-273) 과 68 IU/L ( 참고치 11-75) 로정상소견을보여알코올성간질환의가능성이낮았다 19). 또한, 담도폐색, 바이러스성간질환및자가면역간질환등의약물이외원인들을배제하였으며, 간조직의병리학적검사에서는섬유화등알코올에의한만성간손상의증거는없었으며수많은호중구및림프구의침윤, 담즙정체등약물유발간염에합당한소견을확인할수있었다. 또한약물에의한간독성의판단근거로1993년에공인된 RUCM (Roussel Uclaf Causality ssessment Method) Score 에서도 14점만점중 12점으로 Highly Probable 소견을보여약물에의한간독성을더욱시사하였다 20). 따라서간내약물대사에장애가있을것으로판단되는환자에서는소량의단기간알벤다졸사용에도주의가필요할것으로사료된다. 요약전세계적으로알벤다졸에의한독성간염은극히드물게보고되고있으며모두포낭충증에대해알벤다졸을 400 mg 하루두번장기간복용한경우였다. 이에저자들은만성알코올섭취로싸이토카인 P450 산화효소의기능이저하되었을것으로추정되는환자에서알벤다졸 400 mg 1회복용으로급성간독성이유발된 1예를경험하고, 이를보고한다. - 567 -
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