대한안신경의학회지 : 제 6 권제 2 호 Clin Neuroophthalmol 6(2):19-26, December 2016 ISSN: REVIEW 갑상선안병증 윤진숙 연세대학교의과대학안과학교실 Graves Orbitopathy Jin Sook Yoo

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1 대한안신경의학회지 : 제 6 권제 2 호 ISSN: REVIEW 갑상선안병증 윤진숙 연세대학교의과대학안과학교실 Graves Orbitopathy Jin Sook Yoon, MD Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea Graves orbitopathy (GO) is an autoimmune disease associated with Graves hyperthyroidism and affecting the orbital and periorbital tissues. Although the pathogenesis of GO is not clearly understood, thyroid-stimulating hormone receptor antigen expressed on orbital fibroblasts and thyroid follicular cells is considered to be a target co-antigen. Manifestation of GO is proptosis, conjunctival chemosis, periorbital edema, altered ocular motility, and vision-threatening compressive optic neuropathy, all of which bear significant functional, social, and cosmetic consequences. Therefore, appropriate timely therapeutic management should be applied depending on the phase of GO. Keywords: Graves Orbitopathy; Thyroid; Eye 서론갑상선안병증은그레이브스항진증환자의약 25-50% 에서발생하는자가면역질환으로, 눈꺼풀의뒤당김과부종, 안구돌출및복시와같은증상이발생하며초기에적절한항염증치료가시행되지않으면영구적인후유증을남길수있고삶의질을심각하게저하시킬수있는질환이다. 1 남자보다여자에서더흔하게나타나며가장많이발생하는연령대는여자에서는 40-44세와 60-64세, 남자에서는 45-49세와 65-69세이며, 진단받는나이의중간값은 43세이다. 2 연령이높은경우, 남자, 흡연자의경우더심하게나타난다고알려져있다. 1 한국의갑상선기능항진증환자는매년 4.4% 씩지속적으로증가하는추세로나타났으며국내영남지역의건강검진자를대상으로알아본갑상선기능항진증의유병률은인구천명당남자 4.4명, 여자 12.0명이었고서울경기지역의건강검진수진자를대상으로알아본갑상선기능항진증유병률은인구천명당남자 2.9명, 여자 5.3명으로매우높았다. 3-5 최근보고에서, 갑상선항진증의발생률을인구천명당 0.72명, 유 병률을 3.4명으로보고하였으며갑상선안병증이갑상선항진증환자의약반수에서발생하기때문에갑상선안병증의유병률또한그만큼높을것으로생각된다. 6 갑상선안병증의발생기전아직까지갑상선안병증의발생기전은명확히밝혀지지않았으나, 안와섬유모세포 (fibroblast) 의활성화가질병의발생에핵심적역할을하는것으로알려져있다 (Fig. 1). 현재까지가장유력한병리기전은, 갑상선여포내피세포와안와섬유모세포에공통으로발현되는갑상선자극호르몬수용체 (thyrotropin receptor) 가자가항원으로, 항원표출세포에의하여인식되어 T cell, B cell을자극함으로써염증성싸이토카인및자가항체가생성되는것으로생각되고있다. 활성화된안와섬유모세포는림프구처럼염증성매개체를생성하고, 뿐만아니라, 하이알루로난 (hyaluronan) 을생산하며, 질병이진행함에따라지방세포 (adipocyte) 및근섬유모세포 (myofibroblasts) 로분화한 Correspondence to: Jin Sook Yoon, MD Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: , Fax: , yoonjs@yuhs.ac Received: Oct. 6, 2016 / Accepted: Oct. 10, 2016 Copyright 2016 The Korean Society of Neuro-Ophthalmology 19

2 Yoon JS Graves Orbitopathy Fig. 1. Pathophysiology of Graves orbitopathy (The authors would like to thank Dong-Su Jang, MFA, [Medical Illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, Korea] for his help with the illustrations.) 다. 한정된안와뼈공간내에서의연부조직의부피증가는안구돌출을야기하고, 결체조직내콜라겐및글라이코스아미노글라이칸 (glycosaminoglycan) 침착으로인한외안근비대및섬유화는안구운동장애를유발하며, 심한경우안와첨에서의시신경압박으로인한압박성시신경병증을일으키기도한다. 최근에는 insulin-like growth factor-1 수용체가갑상선자극호르몬수용체와더불어안와섬유모세포의활성을유도하는, 갑상선안병증의발생에중요한항원이라는실험적증거가보고되었다. 7 또한갑상선안병증환자의혈액에서골수유래 CD34+ 섬유세포 (fibrocyte) 가증가되어있고, 이세포가안와섬유모세포보다더갑상선안병증의발생과관련이있다는실험적근거들을제시하였다. 8 즉, 골수에서생성된 CD34+ 섬유세포는혈액을통해염증이발생한안와결체조직으로침윤하여 CD34+ 섬유모세포로전환되어안병증을일으킨다는것이다. 9 갑상선안병증의발생에갑상선자극호르몬수용체와결합하는항갑상선자극호르몬수용체항체 (anti-thyrotropin receptor antibody) 의생성이관련됨은잘알려져있다. 10 현재항갑상선자극호르몬수용체항체를정량적으로측정하는방법은, 갑상선자극호르몬수용체와갑상선자극호르몬의결합을방해함으로전체항체의양을측정하는 TSHR binding inhibitory immunoglobulin (TBII) assay 와, 11 수용체가삽입된세포주에서 camp의생성을통하여기능적항체의양을측정하는 thyroid-stimulating immunoglobulin (TSI) assay 가이용되고있다. 12 두가지정량적방법모두처음갑상선안병증으로진단받은환자에서심한질병경과를예측하는데효과적이나, 13 TSI assay 의경우 TBII assay보다갑상선안병증의활동성염증이나제한성근병증등임상적특징을더잘반영한다 갑상선안병증의증상및경과다행인것은, 갑상선안병증은대부분의경우에는심각한합병증을남기지않고경도로발생하며, 대부분은아무치료없이도저절로호전되는특징이있다. 최근영국의한유병률연구에서, 갑상선안병증은그레이브스병을처음진단을받을당시에약 26% 에서동반되었고, 처음진단시갑상선안병증을동반하지않았던 74% 의환자대부분은갑상선안병증이없는상태로유지되고 2.6% 의환자만심한중증도로진행하였음을보고하였다. 17 또한첫진단시경도의갑상선안병증이있던환자의 58.1% 도저절로호전되었고단 1% 의환자만심한중증도로진행하였다. 17 갑상선안병증초기에는안검의부종과발적으로시작되나, 진행될 20

(B) HESS test of this patient shows limited supraduction in the right eye. 경우위눈꺼풀뒤당김 (retraction), 안구돌출및복시가나타날수있다 (Fig. 2). 이러한증상들에의해외모의변형이나타나고눈꺼풀뒤당김과안구돌출은노출에의한안구건조증및각막염을일으킬수있다.

3 갑상선안병증 윤진숙 A B Fig. 2. Patient with Graves orbitopathy during active inflammatory period. (A) Eyelid edema with erythema, chemosis with conjunctival injection, limited ocular movement, and proptosis are noted in his both eyes. (B) HESS test of this patient shows limited supraduction in the right eye. 경우위눈꺼풀뒤당김 (retraction), 안구돌출및복시가나타날수있다 (Fig. 2). 이러한증상들에의해외모의변형이나타나고눈꺼풀뒤당김과안구돌출은노출에의한안구건조증및각막염을일으킬수있다. 복시가발생한경우일상생활이매우불편하므로어떤증상보다도심각한삶의질저하를일으킨다. 갑상선안병증의활동성 (activity) 은염증징후의존재유무를의미하며평가는 Clinical Activity Score (CAS) 를통해서이루어진다. CAS에서고려하는항목은 (1) 구후부의자발적인통증, (2) 눈을움직일때의통증, (3) 결막충혈, (4) 눈꺼풀의발적, (5) 결막부종, (6) 눈물언덕 (caruncle) 의부종, (7) 눈꺼풀의부종이며총 7점중에 3점이상일때활동성갑상선안병증 (active GO) 로판단한다. 18 갑상선안병증의중등도 (Severity) 는갑상선안병증으로인한기능적손상정도를의미하며활동성과는별개로증상과징후에기반하여 mild, moderate-to-severe, sight-threatening 세가지로분류된다. 19 눈꺼풀의발적과부종은갑상선안병증의염증을판단하는 CAS 의가장중요한 score 2점이며, 초기에발생하는증상이므로이시기를놓쳐선안된다. 갑상선안병증은초기에 년정도의높은활동성염증시기가있다가시간이지나면서염증이호전된다. 염증이호전된후눈모양의변형또는복시와같은기능적합병증을어느정도남길수있으며이는심각한삶의질저하를일으킬수있다 (Rundle s curve). 19 따라서초기염증시기를놓치지않고염증정도에따라용량은다르겠지만, 고용량스테로이드주사 ( 또는경구 ) 요법또는방사선치료를단독또는병용치료할경우, 활동성염증시기를단축할수있으며추후초래되는외관적또는기능적손상을최소화할수있다. 19 비활동성시기에항염증치료를시행하면, 효과가거의없다. 갑상선안병증의치료방법을선택하기위해서는갑상선안병증의 단계를평가할수있는도구가필요하다. 이를위해 VISA (Vision, Inflammation, Strabismus and Appearance, classification 과 EUGOGO (European Group of Graves Orbitopathy, classification 두가지가마련되어있다. 20 VISA classification은 International Thyroid Eye Disease Society에서제안한, 활동성과중등도를결합한가이드라인으로시력 (1점 ), 염증정도 (10점 ), 사시 (6점) 및겉모습 (3점) 으로최대 20점으로환자상태를평가를하고한장의평가지로요약이되어있기때문에임상에서쉽게시행할수있다. EUGOGO classification은 CAS 를이용하여염증활동성을평가하고 NOSPECS를이용하여 mild/moderate to severe/sight threatening의세분류의중증도로평가하는데, 내용이자세하고방대하여임상연구를하기에는적합하지만임상진료에도입하기에는다소불편함이있다. 갑상선안병증의감별진단 - 복시를호소하는경우복시는신경안과외래를내원하는환자들이호소하는흔한증상중의하나이다. 복시환자를진료할때눈모양을살펴보는것이중요한데, 갑상선안병증환자에서는복시가안구돌출이나눈꺼풀뒤당김과함께나타나는경우가많다. 또한안검하수가있으면서, 내전장애를동반한외사시를보이는경우엔중증근무력증이단독또는동반된경우가드물게있으므로주의가필요하다. 갑상선안병증이단독으로있을경우외사시는매우드물기때문이다. 갑상선안병증에서는안구운동제한의심한정도가안와전산화단층촬영상의외안근의비대와거의반드시비례하므로, 이것이맞지않는경우에도중증근무력증또는그외의다른마비성안구운동장애인지를확인해 21

4 Yoon JS Graves Orbitopathy 야한다. 21 갑상선항진증의 2-3% 에서중증근무력증이, 중증근무력증의 % 에서갑상선중독증이같이나타나며, 역학적으로중증근무력증과갑상선안병증은여성에서많이나타나고 20-40세사이의연령에서많이나타난다는공통점을가진다. 22 갑상선안병증의치료갑상선안병증의치료는질병의병인이확실히규명되어있지않고증상의발현, 치료반응및경과가개인마다차이가많아치료결정에많은어려움이있다. 그러나갑상선안병증환자의상당수가미용및기능적인면에서불편감을느끼고다른면역질환환자보다삶의질이낮기때문에질병의시기와중증도를기반으로환자개개인에따라적합하게치료하는것은매우중요하다. 아래그림은 EUGOGO에서제시한갑상선안병증에대한치료가이드라인이다 (Fig. 3) 보조적대증요법흡연은갑상선안병증에영향을미치는주요한위험인자로, 갑상선안병증의발생유무와관련없이모든갑상선기능이상환자들에게금연은필수적이다. 24 흡연은 1) 비흡연자에비해갑상선안병증의중증도를높이고, 2) 방사성요오드치료후의갑상선안병증의발생및진행을유발하며, 3) 갑상선안병증에대한면역치료의효과를감소 또는지연시키는것으로알려져있다 뿐만아니라흡연은압박성시신경병증의발생위험또한 10배이상높인다고보고되었다. 30 또한갑상선기능항진증또는저하증모두갑상선안병증에부정적인영향을주므로정상갑상선기능을유지하는것이중요하다. 항갑선제와갑상선절제술은갑상선안병증의자연경과에영향을미치지않는것으로밝혀졌으나방사성요오드치료는갑상선안병증을발생시키거나악화시키는것으로알려져있으며, 이는특히흡연자, 심한갑상선기능항진증상태 (high free thyroid hormone levels and/or TSH receptor autoantibodies), 최근발생한갑상선항진증환자에서방사선요오드치료후안병증의악화가더많이나타난다. 25,31-33 방사성요오드치료시에갑상선안병증악화의위험이높은환자들에게는예방적으로경구스테로이드 (prednisone) 를복용하는것을권고하고있다 ( 시작용량 mg prednisone/kg). 위험이낮은경우에는저용량의스테로이드를사용할수있으며다른위험요소가없는비활동성기의갑상선안병증환자는예방스테로이드치료없이방사성요오드치료를시행할수있다. 이밖에갑상선안병증환자에서는많이발생하는안구표면염증과건성안으로인한불편감을줄이기위해인공눈물을자주점안하고취침시겔또는연고형태의점안약을사용하여각막을보호하도록한다. Fig. 3. Management of Graves orbitopathy. 22

5 갑상선안병증 윤진숙 2. 셀레늄 (Selenium) EUGOGO 표준지침에서는환자의눈증상과삶의질호전및갑상선안병증의진행예방을위해경한갑상선안병증환자에게 6개월정도단기간셀레늄 (Selenium) 복용을권장하고있다. 셀레늄 (Selenium, Se) 은항산화작용을주로하는필수미량무기질로서셀레늄단백질 (selenoprotein) 과같은형태로혈장에존재한다. 셀레늄은당뇨병및갑상선호르몬의대사, 조절에영향을미치는것으로알려져있다. 34 대규모다기관무작위임상연구에서경증갑상선안병증을대상으로 sodium selenite를 6개월간 100 μg 하루 2번 (93.6 μg of elemental selenium/day) 매일복용하게하였을때 placebo군에비해, 6개월후눈증상및삶의질이유의하게호전되었고이러한호전은셀레늄복용중단후 12개월동안유지되어갑상선안병증이진행하는것을예방하는효과가있었다 스테로이드고용량전신스테로이드 (Glucocorticoids) 는시신경병증이동반되었거나 CAS 3 점이상의활성기의중등도 -중증갑상선안병증환자에서일차치료로권고된다. 전신스테로이드의경우경구복용보다정주로투여하는것이더효과가좋고 ( 치료반응률 ; 정주 70-80% vs 경구 50%), 부작용또한적다고 ( 부작용발생률 ; 정주 39% vs 경구 81%) 보고된바있어전신스테로이드는정주로투여하는것이선호된다 일반적으로중등도-중증활성기의갑상선안병증환자에서 methylprednisolone 500 mg을 1주에 1회씩 6주간정주투여하고, 이후 250 mg/ 주를 6주투여하여총 4.5 g 투여하는방법 (weekly protocol) 이흔히사용되고있다. 39 대규모다기관무작위임상연구에서활성기의중등도 -중증갑상선안병증환자를대상으로같은기간동안 3가지다른총용량 (7.47, 4.98, 2.25 g) 의 methylprednisolone 을사용한결과, 모든용량에서 CAS가유의하게감소하였으나전반적인안과적증상의유의한호전은높은용량에서많이나타났다 (52, 35, 28%). 40 그러나높은용량에서는스테로이드로인한부작용또한훨씬많이나타나대부분의환자에서 g으로치료하고매우심한경우에만그이상의용량을사용할것을권고하고있다. 단, 시신경병증이동반된경우에는 (Sight - threatening GO) 고용량스테로이드를입원하여하루 500 mg-1 g을매일 3일간정주하고, 이후시력을평가하여스테로이드정주투여를반복하거나응급안와감압술을시행한다. 41 스테로이드에대한반응은대개치료시작 1-2주내나타나며, 시신경침범에의한시력장애, 연부조직변화, 외안근운동장애에는비교적효과가좋지만안구돌출에는효과가적다. 스테로이드치료시작전에간효소, 간염바이러스표지자, 간초음파, 공복혈당에대한검사를시행하는것이좋으며최근바이러스간염이나심각한간기능이상의병력이있거 나, 심각한심혈관계질환및정신질환이있는경우에는스테로이드정주를사용하지않아야한다. 당뇨, 고혈압이있는경우스테로이드치료시작전에혈당, 혈압이잘조절되어야하며치료시작후에도간효소, 혈당, 혈압을매달모니터링할것을권고한다 안와방사선안와방사선치료는안와의림프구감소및비특이적항염증작용으로인해갑상선안병증의활성기에효과를나타내며만성섬유화기에는효과가없는것으로알려져있다. 43 고용량스테로이드치료의효과가부족하거나스테로이드부작용으로인해스테로이드치료를지속할수없는활성기의갑상선안병증환자의치료에이차치료 (second-line treatment) 로주로이용되고있으며총 20 Gy의용량을 2주동안 10번에나누어조사하는방법이일반적이나 1주에 2 Gy씩적은용량을 20주에걸쳐조사해도효과가동일하다는보고도있다. 44 특히활성기의안구운동장애에효과적이며스테로이드와병용치료하였을때면역억제작용의상승으로빠른효과를보일수있을뿐만아니라방사선조사의장기간지속되는효과로안병증의재발을함께줄일수있는장점까지기대할수있다. 최근에저자는활성기의스테로이드와안와방사선병용치료가외안근의부피감소를통해스테로이드만사용한군과비교하였을때안구운동이상및복시가더호전되고압박시신경병증이더적게발생하였으며안와감압술을할경우술후외안근부피증가가감소하였음을보고한바있다. 45,46 방사선망막병증, 당뇨망막병증의병력이있는경우를제외하고는대부분의환자에서안전하게사용할수있으며방사선으로인한이차암발생의위험은매우낮다 수술갑상선안병증의활성기에는스테로이드에반응하지않거나시력감퇴가현저하여시력상실의우려가있는경우긴급으로안와감압술을시행하여야한다. 이염증시기를지나만성섬유화기에진입하였을경우, 미용적문제및기능손상정도, 환자의삶의질을고려하여안와감압술, 사시수술, 눈꺼풀뒤당김교정술및미용적눈꺼풀수술을시행해볼수있다 (Fig. 4). 세가지수술이다필요할경우먼저안와감압술, 그다음으로사시수술, 마지막으로눈꺼풀수술순서로시행하게된다. 23 염증단계가아님을확인하기위해여러번의관찰이필요하며, 갑상선호르몬의정상화 (euthyroid), 항체수치의감소및금연을시행하였는지확인해야하고, 안구돌출수치및사시각의변화는없는지 CAS가 3 미만으로낮게유지되는지를평가한후에재활수술이시행되어야한다. 23

Yoon JS Graves Orbitopathy A B C D Fig. 4. Preoperative (A) and postoperative (B) clinical photographs of a patient with Graves orbitopathy who underwent bilateral orbital decompression.

Rituximab Rituximab은 B세포표면의 CD20과결합하여 B 세포감소효과및기능조절효과를나타내어비호지킨림프종, 류마티스관절염및자가면역질환에서사용되고있다. 스테로이드치료에효과가없는갑상선안병증환자에서 rituximab이효과가있음이 2006년보고된이후다양한연구들이진행되어왔으며아직은치료효과나용량에대해합의된결론없이상반된결과들이보고되어추가적인연구가필요하다.

갑상선안병증의재활성화 (reactivation) 또한 Rituximab 치료군에서적게나타나 (Rituximab 0% vs 스테로이드정주 31%) Rituximab이스테로이드정주에비해효과적인것으로나타났다.

6 Yoon JS Graves Orbitopathy A B C D Fig. 4. Preoperative (A) and postoperative (B) clinical photographs of a patient with Graves orbitopathy who underwent bilateral orbital decompression. Severe protptosis were improved after surgery. Preoperative (C) and postoperative (D) CT scans of the same patient showed reduced amount of proptosis. 최근새롭게시도되는치료법 1. Rituximab Rituximab은 B세포표면의 CD20과결합하여 B 세포감소효과및기능조절효과를나타내어비호지킨림프종, 류마티스관절염및자가면역질환에서사용되고있다. 스테로이드치료에효과가없는갑상선안병증환자에서 rituximab이효과가있음이 2006년보고된이후다양한연구들이진행되어왔으며아직은치료효과나용량에대해합의된결론없이상반된결과들이보고되어추가적인연구가필요하다. 대표적으로 2015년 Salvi 등 48 이발표한무작위연구에서중증도- 중증활성기갑상선안병증환자를대상으로 Rituximab과스테로이드정주의치료효과를비교하였을때두군모두에서 CAS가유의하게감소하였으나, 치료 24주후관찰한결과 Rituximab 치료후에갑상선안병증이좀더유의하게비활성화되었고 (Rituximab 100% vs 스테로이드정주 69%), 갑상선안병증의재활성화 (reactivation) 또한 Rituximab 치료군에서적게나타나 (Rituximab 0% vs 스테로이드정주 31%) Rituximab이스테로이드정주에비해효과적인것으로나타났다. 이와반대로같은해 Stan 등 49 이발표한무작위연구에서는중증-중등도활성기갑상선안병증환자에서 Rituximab 치료군과 Placebo군을 24주후비교하였을때 CAS의감소가두군사이에차이가없었고 (Rituximab 31 % vs Placebo 25%), 안구돌출이나안구운동이상의호전과같은다른안과적증상의호전역시두군사이에차이가없어 Rituximab이치료효과가없다고보고하였다. 기존연구들에서보 고된 Rituximab 치료에따른부작용은대부분의경우주입관련반응 (infusion-related reaction) 이었으며일시적인저혈압, 기침, 가려움이보고된바있으나대부분의연구에서감염률이심각하게높아지지는않았다. 50,51 2. Tocilzumab 주로류마티스관절염, 소아류마티스관절염등에사용되는면역억제제로 interleukin-6 수용체에대한단클론성항체이다. 스테로이드치료에반응하지않는환자들을대상으로시행한연구에서 CAS 및혈중 TSI가감소하였으며 83% 의환자들에서안구운동이상및복시가호전되었다고보고된바있다 기타면역억제치료갑상선안병증의자가면역성병인을토대로안와섬유모세포에발현되는 IGF-1 수용체에특이적인단클론성자가항체를갑상선안병증의치료에시도하려는임상연구가진행중이며이밖에 IGF-1 수용체활성을차단하는 tyrosine kinase 억제제, 지방세포발달을억제하는 peroxisome proliferator-activated receptor-γ (PPAR-γ), 염증을감소시키기위한항시토카인약제등이연구되고있다. 53 요약갑상선안병증은환자마다나타나는증상및경과가매우다양하 24

7 갑상선안병증 윤진숙 고, 아직까지병리기전이완벽하게이해되지않은질환이므로더욱 많은기전에대한연구와치료법개발이절실하다. 특히젊은여성에 서발병하며, 외모의심각한변형을일으킬수있으므로환자들이느 끼는삶의질을고려하여, 의료진의보다빠른초기진단및적극적인 치료가필요하다. REFERENCES 1. Hiromatsu Y, Eguchi H, Tani J, Kasaoka M, Teshima Y. Graves ophthalmopathy: epidemiology and natural history. Intern Med 2014;53: Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc 1994;92: Oh MK CK, Jung SM, Ryu DS, Park MS, Cheong SS, Kim JS, et al. Prevalence of thyroid diseases among adult for health check-up in a Youngdong area of Kwangwon province. J Korean Acad Fam Med 2001; 22(9): Chung JH KB, Choi YH, Shin MH, Kim SH, Min YK, Lee MS, et al. Prevalence of thyrotoxicosis and hypothyroidism in the subjects for health check-up. J Korean Soc Endocrinol 1999;14(2): National Health Insurance Corporation.Patients with hypothyroidism and hyperthyroidism over 500,000 people (press release). 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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R