Endocrinol Metab 27(1):98-104, March 2012 CSE REPORT 역위된문어단지양심근병증으로발현되어진단된악성갈색세포종 1 예 장정은 권혁희 이민정 정창희 배성진 1 김홍규 1 이우제 울산의대서울아산병원내과, 건강의학과 1 Case of Malignant Pheochromocytoma Presenting as Inverted Takotsubo-Like Cardiomyopathy Jung Eun Jang, Hyuk Hee Kwon, Min Jung Lee, Chang Hee Jung, Sung Jin ae¹, Hong Kyu Kim¹, Woo Je Lee Department of Internal Medicine, Health Screening and Promotion Center¹, san Medical Center, University of Ulsan College of Medicine, Seoul, Korea Takotsubo cardiomyopathy or stress induced cardiomyopathy is characterized by acute transient left ventricular apical ballooning without significant coronary artery disease. The pathophysiology of Takotsubo cardiomyopathy remains unclear, but it has been suggested that the stress related neurohumoral factors, especially catecholamines, play an important role. Recently, several reports have described an inverted Takotsubo cardiomyopathy, which is characterized by the dysfunction of the basal and mid-ventricular segments sparing the apex of the heart. In this report, we present a case of a 50-year-old female with a transient left ventricular dysfunction in an inverted Takotsubo pattern, that later was diagnosed as a malignant pheochromocytoma. (Endocrinol Metab 27:98-104, 2012) Key Words: Pheochromocytoma, Takotsubo cardiomyopathy 서론 Received: 28 July 2011, ccepted: 9 November 2011 Corresponding author: Woo Je Lee Department of Internal Medicine, san Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-5882, Fax: +82-2-3010-6962, E-mail: lwjatlas@naver.com 갈색세포종은부신수질의크롬친화성세포에서기원하는카테콜라민분비종양으로전체고혈압환자의 1% 미만을차지하는드문질환이다 [1]. 가장흔히동반되는증상으로는두통, 발한, 빈맥등이알려져있다 [1,2]. 갈색세포종의가장흔한임상양상은고혈압이며 [3], 전체갈색세포종환자의약 95% 가고혈압을동반하는데, 그양상은발작성일수도있고지속성일수도있다 [3]. 갈색세포종은고혈압이외에도폐부종, 급성관상동맥증후군, 확장성또는비후성심근병증, 심실상성혹은심실성부정맥등의다양한임상상으로발현할수있다 [3]. 최근들어스트레스유발성심근병증또는 Takotsubo ( 문어단지 ) 심근병증으로불리는가역적인일과성좌심실기능부전이갈색세포종과동반되어나타나는증례가보고되고있다 [4-10]. 이러한 Takotsubo 심근병증은감정적또는신체적스트레스에의해유발되는것으로알려져있으며, 정확한발병기전은알려져있지않지만카테콜라민과같은신경내분비적물질이발병에연관되어있다는가설이제기되고있다 [11,12]. 저자들은최근역위된 Takotsubo 심근병증및심실상성부정맥으로발현되어치료및회복과정중갈색세포종이진단된증례를경험하였기에문헌고찰과함께보고하는바이다. 증례 환자 : 유O O, 여자, 50세주소 : 40분전발생한흉통현병력 : 6-7년전흉통으로타병원에서협심증이라고듣고약물복용하며지냈고이후특별한증상이없었다. 내원당일건강검진위 Copyright 2012 Korean Endocrine Society This is an Open ccess article distributed under the terms of the Creative Commons ttribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Takotsubo-like Cardiomyopathy caused by Pheochromocytoma 99 해수면위내시경, 대장내시경시행하면서 midazolam 4.5 mg, lidocaine 40 mg, buscopan 20 mg를정맥투여하였고, 시술이후 flumazenil 0.5 mg를정맥투여하였다. 1시간가량지나회복실에서대기하던중흉통, 발한있어시행한심전도에서 V 4-6 의 ST 분절하강소견보여응급실에내원하였다. 과거력 : 협심증으로타병원에서항혈소판제복용중이던것외특이사항없었다. 가족력 : 부친이뇌졸중진단받은것외특이사항없었다. 사회력 : 특이사항없었다. 진찰소견 : 키 156 cm, 체중 48.8 kg으로체질량지수는 20.05 kg/ m 2 이었다. 응급실이송중니트로글리세린설하정을복용하였고응급실내원당시혈압은 96/65 mmhg, 맥박 85회 / 분, 호흡수 24회 / 분, 체온 36 C, 산소포화도 79% 였다. 흉통은소실된상태였으며산소공급을시작하였고산소포화도는 95% 이상으로회복되었다. 환자는외견상의식상태는명료하였으나급성병색을보이고있었고약간의호흡곤란을호소하였다. 흉부청진상심음은규칙적이며심잡음은청진되지않았고, 양폐기저부에서수포음이청진되었다. 복부진찰상간과비장의비대소견은없었으며, 그외신체진찰에서특이소견은없었다. 검사소견 : 응급실에서시행한말초혈액검사에서혈색소 13.3 g/dl, 헤마토크리트 40.4%, 백혈구 7,900/mm 3, 혈소판 292,000/mm 3 으로정상범위였고, 혈청생화학검사에서혈당 106 mg/dl, 혈액요소질소 7 mg/dl, 크레아티닌 0.7 mg/dl, Na/K/Cl 143/3.7/84 mmol/l, ST 32 IU/L, LT 23 IU/L, 알칼리인산분해효소 (alkaline phosphatase) 78 IU/L, 총콜레스테롤 148 mg/dl, 고밀도지단백콜레스테롤 55 mg/dl, 저밀도지단백콜레스테롤 81 mg/dl로정상범위였다. 심장효소검사에서는미오글로빈 220 ng/ml ( 정상범위, 110 ng/ml 미만 ) 로상승되어있었으나크레아틴키나아제 (creatine kinase, CK) 108 IU/L ( 정상범위, 50-250 IU/L), CK-M 3.7 IU/L ( 정상범위, 5 ng/ml 미만 ), troponin I () 0.360 ng/ml ( 정상범위, 1.5 ng/ml 미만 ) 는정상범위였다. 이후추적관찰한심장효소검사치는 Table 1 과같다. 요검사에서는케톤 (+++) 이외에특이소견은관찰되지않았다. 심전도및방사선학적소견 : 증상발생전본원건강검진에서촬영한단순흉부 X-선검사에서는정상소견이었으나 (Fig. 1), 증상발생후응급실에서촬영한단순흉부 X-선검사에서는양측폐야에폐문부를중심으로증가된간유리음영이관찰되는급성폐부종소 견을보였다 (Fig. 1). 증상발생 3 시간전본원건강검진에서시행한 12 전극심전도에서는분당 65 회의정상동율동리듬이었으며, ST 분 절및 T 파의이상소견은관찰되지않았다. 흉통이발생한다음응급 실내원하여촬영한 12 전극심전도에서는 V 4-V 6 와 lead II, III, avf 에 걸쳐 ST 분절의하강이새롭게관찰되었다. 심초음파소견 : 응급실내원당일시행한경흉부심초음파검사에 서좌심실구혈률은 42% 였고, 좌심실첨부를제외한중부에서기저 좌심실전중격및하후벽과외벽의대칭적인무운동 (akinesia) 소견 을보여관상동맥주행과맞지않는좌심실벽운동장애와역위된 Takotsubo 심근병증의심초음파소견의한형태로알려진심기저부 확장소견을보였다 [13]. 하지만기저하벽 (infero-basal wall) 에 thinning 을동반한무운동이관찰되어우관상동맥주행의허혈성손상 가능성을배제할수없는소견이었다. 승모판은 tethering 과경증내 지중등증의승모판역류소견을보였으며, 좌심실 - 좌심방압력차는 29 mmhg 로폐동맥고혈압소견은관찰되지않았다 (Fig. 2). 관상동맥조영술소견 : 입원다음날관상동맥조영술을시행하였 고정상소견을보였다. 관상동맥조영술시행후일반병동으로전 동된상태에서갑자기심계항진을호소하였고심박수 150 회 / 분가 량으로심전도에서발작성심실상성부정맥소견을보여 adenosine 6 mg 을정맥으로주사하였고, 이후정상동율동으로전환되었다. 내원 4 일째추적관찰한경흉부심초음파검사에서는기저중격 (midseptal wall) 과기저하벽의저운동 (hypokinesia) 은여전히관찰되었 으나, 이전에관찰된심기저부확장소견은호전되었으며좌심실구 혈률또한 58% 로회복된소견을보여퇴원하였다. 이후특별한증 Fig. 1. The chest X-ray before () and after the symptom developed ().. chest X-ray without cardiomegaly and pulmonary congestion.. Increased pulmonary vascular marking and pulmonary edema around perihilar area. Table 1. Serial follow-up of cardiac enzymes during hospitalization t presentation fter 3 hr fter 24 hr fter 36 hr fter 3 day CK (IU/L) 108 148 276 189 69 CK-M (ng/ml) 3.7 5.6 21.5 5.3 2.2 Troponin-I (ng/ml) 0.36 2.32 - - -
100 Jang JE, et al. Fig. 2. Transthoracic echocardiography on admission.. End systole.. End diastole. It shows basal akinesia and thinning at mid to basal inferior wall with apical sparing. C Fig. 3.. Enhanced abdomino-pelvic computed tomography (PCT) scan. & C, I-123 metaiodobenzylguanethidine (MIG) scan.. PCT shows a 5.2 3 cm-sized round, lobulated mass with internal cystic change (arrow) adjacent to the right kidney. & C. Post 4 hour and 1 day after I-123 MIG injection. Increased I-123 MIG uptake at right adrenal gland (circle) and focal increased I-123 MIG uptake in L4 and left ilium (arrows), suggesting right adrenal gland pheochromocytoma with metastatic lesion. 상없이외래에서추적관찰하며지냈고, 1개월가량경과후건강검진에서촬영한조영증강복부컴퓨터단층촬영에서우측부신에 5.2 3 cm 가량의종괴가발견되어 (Fig. 3) 외과외래내원하였으며, 부신우연종에대한호르몬검사가시행되었다. 호르몬검사 : 24시간요카테콜라민검사상에피네프린 112.5 μg/ day ( 정상범위, 0-20 μg/day), 노르에피네프린 157.4 μg/day ( 정상범위, 15-80 μg/day) 이었고, 메타네프린 3.2 mg/day ( 정상범위, 0-1.2 μg/day), 바닐릴만델산 (vanillymandelic acid) 10.7 mg/day ( 정상범위, 0-9 mg/day) 로요중카테콜라민과그대사산물이증가되어있었다. 혈중에피네프린은 612.1 pg/ml ( 정상범위, 0-110 pg/ml), 노르에피네프린은 1,209 pg/ml ( 정상범위, 70-750 pg/ml) 으로상승된소견을보였다. 핵의학검사 : I-123 metaiodobenzylguanethidine (MIG) 스캔을시행하였고복부컴퓨터촬영에서관찰된우측부신의 5 cm 크기의불규칙한종괴에방사성섭취가증가되었으며, 4번요추와왼쪽장골에도부분적인 I-123 MIG 섭취가관찰되어갈색세포종과전이성병변에합당한소견이었다 (Fig. 3, C). 치료및경과 : 복강경하우측부신절제술을시행하였고 3 cm 크기의 2개의종괴가아령형태를이루고있었으며주변하대정맥과의유착및섬유화소견을보여박리술을함께시행하였다. 수술후조직검사에서는부신지지세포에대한 S-100 단백면역염색과, 종양세포에대한 synaptophysin 및 chromogranin 면역염색이양성소견을보여갈색세포종으로확진되었다 (Fig. 4). 병리절편상부신주변연부조직까지암세포의침윤이확인되었으나절제연의침범은없었으
Takotsubo-like Cardiomyopathy caused by Pheochromocytoma 101 C D Fig. 4. Histologic finding of right adrenal gland.. Large and pinkish cells with pleomorphic nuclei and prominent nucleoli (H&E stain, 400).. Immunohistochemistry for chromogranin was positive in tumor cells (chromogranin, 400). C. Synaptophysin staining was positive (synaptophysin, 400). D. Immunohistochemical stain for sustentacular cell, S-100 was positive reaction (S-100, 200). These findings confirmed the diagnosis of pheochromocytoma. 며림프혈관침윤도관찰되지않았다. 이후환자는전이성병변에대해 2차례고용량 (200 mci) I-131 MIG 동위원소치료를시행받고외래에서추적관찰중이다. 고찰 1991년일본에서 Dote 등 [14] 에의해 Takotsubo 양좌심실기능부전 이라는가역적인심근병증이처음보고된이래, 2001년이후일본이외의지역에서 Dote 등 [14] 이보고한질환과같은질환이면서 일과성심첨부확장, 스트레스유발성심근병증 등의다른명칭으로불리는질환의보고가증가되면서이질환에대한관심이높아졌다 [11,15]. Takotsubo 심근병증은심초음파또는좌심실조영술시심첨부의확장으로인해좌심실의모양이일본에서사용하는문어잡이단지를뜻하는단어인 Takotsubo 와그모양이비슷하다고하여명명된심근병증이다 [16]. 이러한 Takotsubo 심근병증은심근경색과비슷한임상양상을보이나, 관상동맥조영술에서설명할만한관상동맥의협착및연축 (spasm) 이관찰되지않고수주이내에 회복되는비교적양호한경과를보이는질환으로알려져있다 [17]. Takotsubo Cardiomyopathy Study Group에서는 Takotsubo 심근병증진단지침을제시하고있는데 [17], 정의상으로는급성좌심실심첨부확장으로인해좌심실이 Takotsubo 라는일본의문어잡이단지와비슷한모양을보이고, 1개월이내에대부분완전히호전되는경과를보이는질환이다. 하지만분명한관상동맥병변이있거나, 뇌혈관이상, 갈색세포종또는심근염등이있을경우 Takotsubo 심근병증의진단에서제외할것을추천하며, 이중뇌혈관이상과갈색세포종에서유사한현상을보일경우 Takotsubo 양 (like) 심근병증 으로진단할것을제시하고있다. Takotsubo 심근병증의발병기전은정확히밝혀진바는없으나, 몇가지가설이제기되고있는데, 1) 관상동맥의다발성혈관수축, 2) 관상동맥미세혈관의부전, 3) 카테콜라민심장독성, 그리고 4) 신경학적기절심근등이다 [12]. Wittstein 등 [16] 은 13명의심첨부확장을보이는스트레스유발성심근병증환자와 7명의급성심근경색환자들의입원시카테콜라민수치를비교하였고, 에피네프린과노르에피네프린모두스트레스유발성심근병증환자들에서심근경색
102 Jang JE, et al. 환자들보다상승되어있어, 이러한상승된카테콜라민수치가발병기전중하나일가능성을주장하였다. 하지만스트레스유발성심근병증환자모두에서카테콜라민수치가상승한것은아니기때문에, 발병과정에는여러가지기전이같이작용하는것으로생각되고있다 [16]. 전형적인 Takotsubo 심근병증이심첨부의확장과심기저부의과 운동성을보이는것에비해 [17], 최근들어본증례와같이비전형적 Takotsubo 심근병증, 혹은역위된 Takotsubo 심근병증으로불리는심실중벽 (mid portions of ventricular wall) 및기저하벽 (basal inferior wall) 의확장을보이는증례가보고되고있으며, 이경우신경학적혹은내분비적이상을동반하는경우가많았다 [13,18,19]. Kurowski 등 [15] 은 Troponin T 양성을보인 3,265명의급성관상동맥 Table 2. Clinical characteristics of patients with pheochromocytoma associated Takotsubo-like cardiomyopathy (TTC) in Korea ge/ Sex Type of TTC Clinical feature at presentation Cardiac enzyme 50/F Inverted Chest pain Kim et al. [6] 47/M Inverted Chest pain, dyspnea CK, Kim et al. [7] 40/M Inverted Palpitation CK-M Cho et al. [8] 52/F Inverted Squeezing epigastric pain Tn-T, CK-M Jang et al. [9] 62/F Regular Dizziness CK-M Kim et al. [20] 32/M Inverted Palpitation, sqeezing chest pain, hypertension Kim et al. [20] 47/M Inverted Transient hypertension after subdutaneous epinephrine injection Park et al. [10] 41/M Inverted Dyspnea Park et al. [10] 49/M Global hypokinesia Dyspnea, chest discomfort EKG findings ST depression II, III, avf, V2-6 sinus rhythm, ST depression II, III, avf, V1-6 sinus rhythm, tall T wave, no ST elevation or depression tachycardia, ST depression II, III, avf, V2-5 T wave inversion, ST depression V1-6 tachycardia, ST elevation II, III, avf sinus rhythm tachycardia tachycardia CG, coronary angiography; EchoCG, echocardiography; F, female; LV, left ventricle; M, male;, troponin I. EchoCG or ventriculography findings kinesia of the mid septal and inferoposterior wall, thinning at inferobasal wall EF = 42% kinesia of the LV basal and midventricular segment, hyperkinesia of the apical area Severe basal dyskinesia, sparing of the apical wall motion, significant MR EF = 48.9% pical hyperkinesias, akinesia of the basal and mid portion of LV EF = 53% Impaired wall motion of all basal and mid-ventricular segment of the LV LV akinesia and dilatation of basal and mid ventricular segment, preserved apical motion EF = 35% Dilated LV, akinesia of the basal to mid portions of the LV EF = 28% Severe LV dysfunction, akinesia of the basal and mid ventricular segment, hyperkinesis of the apical segment Severe LV systolic dysfunction, severe hypokinesia of all segment EF = 20% Follow-up EchoCG findings ized LV function and wall motion abrnomalities after 4 days Not mentioned Not mentioned ized LV wall motion after 6 days ized LV wall motion after 2 weeks No regional wall motion, after 3 days ized LV size and systolic function after 2 days ized LV function and regional wall motion after 2 days ized LV function and regional wall motion after 2 days CG findings Not done Not done
Takotsubo-like Cardiomyopathy caused by Pheochromocytoma 103 증후군의심환자중 Takotsubo 심근병증으로진단된환자를대상으로전형적, 비전형적 Takotsubo 심근병증의빈도와기전, 예후에대해전향적분석을시행하였고, 35명의 Takotsubo 심근병증환자중 22명 (60%) 이전형적, 13명 (40%) 이비전형적유형을보였다고보고한바있다. garwal 등 [5] 은현재까지갈색세포종에서 Takotsubo 양심근병증이동반된환자들과 primary Takotsubo 심근병증환자들의유사점과차이점에대한분석을위해, 254건의 primary Takotsubo 심근병증환자와 38건의갈색세포종 -동반 Takotsubo 양심근병증환자의증례보고를분석하였다. 갈색세포종 -동반 Takotsubo 양심근병증환자중 23건 (60.5%) 에서전형적인심첨부확장을보였고, 12건 (31.5%) 이역위된 Takotsubo 양심근병증으로나타났다. 이러한결과는 primary Takotsubo 심근병증에서전형적, 비전형적유형과유사한비율이었다. 또한갈색세포종에서전형적및비전형적 Takotsubo 양심근병증이동반된환자들을비교한결과비전형적 Takotsubo 양심근병증환자에서전형적 Takotsubo 양심근병증에비해남성의유병률이다소높은경향을보였고심전도소견에서도 ST 분절의하강이비교적흔하였다. 합병증측면에서도비전형적 Takotsubo 양심근병증환자에서심인성쇼크 (66.7% vs. 17.4%) 와신부전 (25% vs. 0%) 의발생이유의하게높았고, 승압제의사용 (66.7% vs. 8.7%) 및대동맥내풍선펌프 (intra-aortic balloon pump) 사용 (33.3% vs. 4.3%) 이필요한경우가유의하게많았다. 하지만사망률에서는특별한차이없이오히려전형적 Takotsubo 양심근병증환자에서사망이보고되어, 질병의예후적측면에서는뚜렷한차이를보이지않았다 [5]. 현재까지우리나라에서보고된갈색세포종에서 Takotsubo 양심근병증이동반된증례는본증례를포함하여총 9건으로임상적인특징은 Table 2와같다 [6-10,20]. 아직보고된증례의수가적지만, 일반적으로 primary Takotsubo 심근병증이여성에서흔하고전형적인형태가많은것에비해 [15], 우리나라에서보고된갈색세포종동반 Takotsubo 양심근병증에서는남성에서의발병이흔하였고역위된형태가많았다. 또한 garwal 등 [5] 의보고에서갈색세포종동반 Takotsubo 양심근병증에서도전형적형태가많았던것과달리, 우리나라에서는역위된 Takotsubo 양심근병증의발생이흔하였고, 추적검사에서대체적으로가역적이며양호한결과를보였다. 최근의연구에서는교감신경및 adrenoceptor 의분포차이및생리적농도와독성농도에서의카테콜라민에대한 adrenoceptor 의반응차이등으로심실벽운동이상의다양성을설명하려는시도가있으나아직정립된가설은없다 [2,12]. 따라서향후이러한과도한교감신경항진에대한심실의반응및심실벽운동이상의차이에대한추가적인연구가이루어질필요가있다. 또한현재까지우리나라에서보고된증례들에서역위된형태가흔한것에대한분자생물학적인측면의연구뿐만아니라, 나아가역위된형태의 Takotsubo 심근병증과전형적형태의 Takotsubo 심근병증으로발현되는경우의 임상경과및예후등에대한주의깊은관찰이필요할것으로생각 된다. 본증례는급성폐부종을동반한역위된 Takotsubo 양심근병증 및발작성심실상성부정맥으로표현된환자에서추후에악성갈색 세포종이진단되었던경우로, Takotsubo 양심근병증은갈색세포종 에드물게동반될수있다. 특히고혈압및심계항진등의비교적흔 한동반증상이없이심근병증으로발현한경우진단이어려울수 있지만, 정확한진단및치료를통해완치를기대할수있는질환이 다. 따라서비교적젊은나이에특별한기저질환및설명할만한원 인이없는가역적심부전증상을보일경우감별진단에반드시갈색 세포종을고려할필요가있다. 요약 저자들은흉통을주소로내원한 50 세여자환자가역위된 Takotsubo 심근병증을진단받고대증적치료후호전되어퇴원하였다가 추후에갈색세포종이진단된 1 예를경험하였다. 현재까지우리나라 에서보고된갈색세포종동반 Takotsubo 양심근병증증례는전세 계적으로보고된증례와비교하여남성이더많았고, 대부분역위된 Takotsubo 양심근병증형태를보였다. 본증례또한그동안의우리 나라에서보고된증례와유사한임상양상을보였다. Takotsubo 양 심근병증은갈색세포종에서드물게동반되는질환이지만, 갈색세포 종에대한치료를통해교정가능한질환이라는점에서원인불명의 심부전을보이는환자에서감별할필요가있다고생각되어문헌고 찰과함께보고하는바이다. 참고문헌 1. Sica D: Endocrine causes of secondary hypertension. J Clin Hypertens (Greenwich) 10:534-540, 2008 2. Kim S, Yu, Filippone L, Kolansky DM, Raina : Inverted-Takotsubo pattern cardiomyopathy secondary to pheochromocytoma: a clinical case and literature review. Clin Cardiol 33:200-205, 2010 3. Zuber SM, Kantorovich V, Pacak K: Hypertension in pheochromocytoma: characteristics and treatment. Endocrinol Metab Clin North m 40:295-311, 2011 4. Pfister R, Diedrichs H, Dietlein M, Erdmann E, Schneider C: Typical and atypical takotsubo-like cardiomyopathy as a manifestation of pheochromocytoma. J Endocrinol Invest 31:382-383, 2008 5. garwal V, Kant G, Hans N, Messerli FH: Takotsubo-like cardiomyopathy in pheochromocytoma. Int J Cardiol 153:241-248, 2011 6. Kim HS, Chang WI, Kim YC, Yi SY, Kil JS, Hahn JY, Kang M, Lee MS, Lee SH: Catecholamine cardiomyopathy associated with paraganglioma rescued by percutaneous cardiopulmonary support: inverted takotsubo contractile pattern. Circ J 71:1993-1995, 2007 7. Kim TS, Chu EH, Kang HH, Chun SW, Cho EJ, Kim JH: case of re-
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