대한내과학회지 : 제 83 권제 3 호 2012 http://dx.doi.org/10.3904/kjm.2012.83.3.363 Methimazole 복용후발생한간부전으로간이식을시행받은 1 예 울산대학교의과대학 1 내과학교실, 2 외과학교실, 3 병리학교실 전성진 1 김태용 1 이승훈 1 강종식 1 최광현 1 이승규 2 황희상 3 A Case Report of Methimazole-Induced Acute Liver Failure Successfully Treated with Liver Transplantation Sung Jin Jeon 1, Tae Yong Kim 1, Seung-Hoon Lee 1, Jong Sik Kang 1, Gwang Hyeon Choi 1, Seung-Gyu Lee 2, and Hee Sang Hwang 3 Departments of 1 Internal Medicine, 2 Surgery, 3 Pathology, Ulsan University College of Medicine, Seoul, Korea Antithyroid drugs inhibit the synthesis and excretion of thyroid hormone from the thyroid gland. Propylthiouracil (PTU) and methimazole are well known as antithyroid drugs. In 2011, the American Thyroid Association and American Association of Clinical Endocrinologists published management guidelines for hyperthyroidism and other causes of thyrotoxicosis, and recommended methimazole as the first-choice antithyroid drug for the treatment of hyperthyroidism. Lower hepatotoxicity is an advantage of methimazole. Fulminant hepatitis rarely occurs in methimazole users, and spontaneous recovery is expected even if it does occur. We describe a rare case of acute liver failure after methimazole intake in a 60-year-old man who underwent liver transplantation. (Korean J Med 2012;83:363-368) Keywords: Liver failure; Liver transplantation; Methimazole 서론갑상선기능항진증의치료제로는크게 thiomidazole (carbimazole, methimazole) 과 propylthiouracil (PTU) 이사용되며이중 carbimazole은체내에흡수되어메티마졸 (methimazole) 로빠르게대사되어작용을나타낸다. 이러한항갑상선제의치료중발생할수있는부작용으로는두드러기나발진, 관절염, 소화불량이있으며, 드물게치명적인부작용으로무과립 구증이나독성간염이발생할수있다 [1]. 최근미국갑상선학회및미국임상내분비의사회 (American Thyroid Association and American Association of Clinical Endocrinologist) 에서 2011 년새로운갑상선기능항진증치료가이드라인을제시하였다. 그가이드라인에따르면 PTU의심각한간독성부작용과관련해특수한두가지경우, 즉임신초기 (first trimester of pregnancy) 나갑상선중독발작 (thyroid storm) 의경우를제외하고는메티마졸을갑상선기능항진증치료제로 Received: 2012. 1. 20 Revised: 2012. 4. 6 Accepted: 2012. 4. 17 Correspondence to Tae Yong Kim, M.D., Ph.D. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-3249, Fax: +82-2-3010-6962, E-mail: tykim@amc.seoul.kr Copyright c 2012 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 363 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 83, No. 3, 2012 - - 364 -
- Sung Jin Jeon, et al. Methimazole induced liver failure - 사용하도록권고하고있다 [2]. 하지만메티마졸에의한간손상도국내외문헌을고찰해본결과지금까지총 30여개의증례 ( 국내에서 10예 (Table 1), 해외에서 20여개의증례 ) 가보고되고있는데, 이중세증례를제외하고는메티마졸투약을중지한후간기능이회복되었던증례들이었다. 세증례 ( 국내 1예, 국외 2예 ) 에서만치명적인간독성을초래하였는데, 국내증례 [3] 는이미 B형바이러스간염에의한간경화를기저질환으로가지고있었던환자였다. 국외의한증례 [4] 는독성간염과동반한감염증으로입원 18일째사망하였던증례였고, 다른증례 [5] 는간이식까지시행받았으나위장관출혈로사망하였던증례로처음시행한초음파에서간위축이관찰되어다른기저간질환이있었을가능성이있는환자였다. 특히나메티마졸에의한간부전으로, 간이식을시행한예는지금까지앞에서언급한증례외에는보고된바가없다. 저자는다른기저질환이없던 60세의한남성이그레이브스병을진단받고메티마졸을복용한후, 간부전이발생하여간이식까지시행받은증례를경험하였기에문헌고찰과함께보고하고자한다. 증례환자 : 60세, 남자주소 : 내원한달전부터발생한황달현병력 : 정확히언제부터인지모르는 6 kg의몸무게감소, 손떨림, 식은땀이흐르는증상이있었던환자이다. 내원 2 개월전회전근개손상으로개인병원에서수술을준비하며, 상기증상에대해혈액검사를시행하였고갑상선자극호르몬 (TSH) 0.01 miu/l 미만 ( 정상, 0.4-5.0), 유리 T4 3.2 ng/dl ( 정상, 0.8-1.9), 항갑상선과산화효소항체 (anti-thyroid peroxidase antibody) 가 1,849 U/mL ( 정상, 0-60) 로양성이었다. 갑상선초음파검사에서갑상선에결절은없으나미만성으로갑상선이커져있었다. 그레이브스병으로진단받고, 베타차단제와메티마졸 10 mg을하루두번씩복용하기시작하였다. 당시시행한혈액검사에서 aspartate aminotransferase (AST) 23 IU/L, alanine transferase (ALT) 29 IU/L, 총빌리루빈 1.2 mg/dl로간기능검사에서특이소견은관찰되지않았다. 메티마졸을하루두번 10 mg씩 15일간복용하다가이후하루세번 15 mg으로증량하여 8일간더복용하였으나, 전신쇠약감과 황달증세가있어외부병원을방문하였다. 메티마졸복용을중단하고한달간경과관찰하였으나황달증세가호전되지않아본원으로전원되었다. 한약이나다른약물의복용력은없었다. 과거력및가족력 : 특이소견없었다. 이학적소견 : 내원당시만성병색을보였으며활력증후는혈압 106/64 mmhg, 맥박 100회 / 분, 호흡수 16회 / 분, 체온은 36.5 였다. 의식은명료했고, 공막의황달소견이관찰되었으나안구돌출은관찰되지않았다. 경부에서저명한갑상선비대나압통은없었으며, 만져지는경부림프절도없었다. 호흡음과심음에서특이소견관찰되지않았고, 복부검사에서우상복부에간비대나압통은관찰되지않았다. 검사실소견 : 전원당시본원에서시행한갑상선기능검사상갑상선자극호르몬 0.05 miu/l 미만, 유리 T4 3.9 ng/dl, 갑상선자극호르몬결합억제면역글로불린 (Thyrotropin Binding Inhibiting Immunoglobulin, TBII) 19.2 IU/L ( 정상, 0-2), 항갑상선과산화효소항체 860 U/mL, 항갑상선글로불린항체 (antithyroglobulin antibody) 는 19.2 U/mL ( 정상, 0-60) 였고, 갑상선스캔은시행하지않았다. 간기능검사상 AST 90 IU/L, ALT 81 IU/L, alkaline phosphatase 211 IU/L 총빌리루빈 41.4 mg/dl, 직접빌리루빈 24.3 mg/dl, 알부민 2.5 g/dl, 프로트롬빈시간 11.9초 (INR 1.03초 ) 였다. 간염표지자검사에서 HAV IgM Ab 음성, HBsAg 음성, anti- HBsAg 양성, anti-hcv 음성으로확인되었고, EBV와 CMV Figure 1. High magnification images show inspissated bile in bile canaliculi, which is predominant in zones 2 and 3, consistent with cholestatic hepatitis ( 400). - 365 -
- 대한내과학회지 : 제 83 권제 3 호통권제 625 호 2012 - PCR도음성이었다. 면역혈청검사에서 anti-nuclear antibody (ANA), anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA) 모두음성이었다. 방사선학적소견 : 단순흉부촬영소견은정상이었고, 복부및골반전산화단층촬영술 (computed tomography, CT) 에서담도확장소견은관찰되지않았다. 치료및경과 : 임상적으로메티마졸에의한독성간염이의심되었으나다른원인들을배제하기위해간조직검사를시행하였다. 조직검사결과담즙울혈성간염소견이 (Fig. 1) 확인되어메티마졸에의한독성간염으로진단하였다. 이후 ursodesoxycholic acid (UDCA) 와베타차단제를복용하면서, 루골용액을 8방울씩하루세번투여하였다. 투약 2주째, 갑상선기능검사에서유리 T4 1.6 ng/dl로정상범위로호전되었으나, 간기능검사에서는 AST 92 IU/L, ALT 103 IU/L, alkaline phosphatase 168 IU/L 총빌리루빈 52.4 mg/dl, 직접빌리루빈 30.5 mg/dl로악화된소견이관찰되었다. 이후환자는간성혼수와간신증후군이발생하면서의식의저하를보이며혼미 (stupor) 해졌고, 질소혈증 (azotemia) 도지속적으로악화되는소견을보여기도삽관및혈액투석을시행하였다. UDCA, N-acetylcysteine, 루골용액, 베타차단제도지속적으로투여하였다. 기도삽관후 10일째, 지속적으로간기능의악화로뇌사자간이식을시행하였다 (Fig. 2). 수술후의식, 간 A B Figure 2. (A) Gross photography of an explanted liver showed diffuse dark brown discoloration without cirrhotic change. (B) The explanted liver showed severe cholestasis with perivenular fibrosis ( 400). Table 2. Biochemical marker changes before and after discontinuation of methimazole Time Free T4 (ng/dl) TSH (miu/l) AST/ALT (U/L) TB/DB (mg/dl) Event D-55 3.22 < 0.11 23/29 1.2/ Took MMZ 10 mg bid D-41 Took MMZ 15 mg tid D-34 65/114 11.6/9.3 MMZ discontinuation D0 (Admission) 3.9 < 0.04 90/81 41.4/24.3 Transfer to our hospital HD 12 1.6 0.04 51/71 64.4/38.3 Intubation, hemodialysis HD 22 1.4 0.07 33/29 41.6/24.9 Liver transplantation HD 61 (POD 39) 0.39 0.97 13/14 1.2/0.6 Discharge POD 72 1.4 0.04 31/47 1.6/0.5 15 mci RAI POD 107 1.1 0.04 38/68 0.9/0.3 OPD for follow up AST, aspartate aminotransferase; ALT, alanine transferase; TB, total bilirubin; DB, direct bilirubin; D, D-day (admission); MMZ, methimazole: HD, hospital day; ICU, intensive care unit; POD, post-operative day; RAI, radioactive iodine; OPD, out-patient department. - 366 -
- 전성진외 6 인. Methimazole 복용에의한간부전 - 기능이모두회복되었으며, 수술후 39일째퇴원하였다. 퇴원시까지루골용액을지속적으로투여하였고, 퇴원당시의갑상선기능검사는 TSH 0.97 μiu/ml, 유리 T4 0.39 ng/dl로정상범위를유지하였다. 이후갑상선기능항진증에대해서루골용액을복용하다가일주일간중단후 15 mci 방사성요오드를투여하였다. 현재정상갑상선호르몬수치를유지하며외래추적관찰중이다 (Table 2). 고찰최근미국내분비학회및미국임상내분비의사회 (American Thyroid Association and American Association of Clinical Endocrinologist) 에서특수한경우를제외하고, 갑상선기능항진증치료제로메티마졸을사용하도록권고하였다. 이는최근 PTU 사용후심각한간손상을입었던 32건 ( 성인 22건, 소아 10건 ) 의증례와관련해 FDA (Food and Drug Administration) 에서이슈화하였던 PTU의심각한간독성에대한권고를받아들였기때문이다 [2]. 미국장기이식센터의데이터베이스에따르면, 1990년부터 2002년까지미국에서간이식을받은 51,741 명의환자중 15% 가약물과관련한간독성으로이식을받았는데, 그원인약물중 PTU가세번째로흔한원인약물이었다. 그러나메티마졸복용에의해간이식을시행받았던경우는없었다 [6]. 이처럼메티마졸에의한치명적인간손상은극히드문것으로알려져있다. Mikhail 등 [7] 이메티마졸을사용후간독성이발생하였던 20개의증례들을살펴본결과, 가장흔한증상은황달이었고, 다음으로간지럼증, 어두운소변색, 진흙색깔의변순으로모두고빌리루빈혈증과관련된증상들이었다. 메티마졸에노출된후황달이발생하기까지의기간은 2일에서 3개월까지다양한특징을나타내었다. PTU에의한간손상은주로세포독성에의해간세포괴사형태로나타나고, 메티마졸에의한간손상은주로답즙울혈성황달로나타난다 [2]. 그기전은아직명확하지않지만과민반응을시사하는소견이많다. 증상이대개몇주이내로발생하였다가중단하면호전을보인다는점, 다시투약하였을때얼마지나지않아증상이다시발현되는점, 약물의용량과관계없이발생하는점, 그리고약물과민반응의지표인림프구전이검사 (lymphocyte transformation test) 에서양성을보인다는점등을종합해볼때과민반응일가능성이높 겠다 [8]. 항갑상선제에의한간독성은흔하지않기때문에약물복용을시작하기전의간기능검사는권장되나, 약물복용중에정기적인간기능검사는추천되지않는다 [2]. 그러므로앞서언급하였던고빌리루빈혈증증상이발현되는경우에는즉시병원을방문하도록교육하는것이중요하고, 갑상선기능항진증에대해서는약물투약을중단후방사성요오드치료나수술로서치료하도록권고하고있다 [2]. 방사성요오드치료나수술치료전까지는본증례처럼루골용액을사용하여갑상선기능을정상으로유지할수있겠다. 간기능회복에대해서는 steroid가도움이된다는몇몇보고가있었으나 [9], 아직까지는논란이있다. 결론적으로메티마졸은발생빈도는극히드물지만간독성을일으킬수있고, 치명적인간부전까지도일으킬수있으므로, 치료시작몇개월간은주의깊은추적관찰이필요하겠다. 요 최근가이드라인을보면 PTU의간독성부작용과관련하여갑상선기능항진증치료로메티마졸을사용하도록권장하고있다. 그러나매우드물지만메티마졸에의해서간독성이발생할수있고, 본증례처럼간이식이필요할정도로심각한간부전을일으킬수도있다. 저자들은 60세남자환자가메티마졸을복용한후간부전이발생하여간이식을시행한증례를경험하였기에문헌고찰과함께보고하였다. 약 중심단어 : 메티마졸 ; 간부전 ; 간이식 REFERENCES 1. Gallelli L, Staltari O, Palleria C, De Sarro G, Ferraro M. Hepatotoxicity induced by methimazole in a previously healthy patient. Curr Drug Saf 2009;4:204-206. 2. Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011;21: 593-646. 3. Kang H, Choi JD, Jung IG, et al. A case of methimazoleinduced acute hepatic failure in a patient with chronic hepatitis B carrier. Korean J Intern Med 1990;5:69-73. - 367 -
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