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1 대한소화기학회지 2010;55: DOI: /kjg 식도조직검사상우연히발견된호산구식도염의임상적의의 분당서울대학교병원내과 *, 병리과, 서울대학교의과대학내과학교실 정연무 * ㆍ이혜승 ㆍ이동호 * ㆍ정유정 * ㆍ최태혁 * ㆍ이상협 * 박영수 * ㆍ황진혁 * ㆍ김진욱 * ㆍ정숙향 * ㆍ김나영 * Clinical Significance of Incidentally Detected Eosinophilic Esophagitis with Pathologic Review Youn u Jung,.D.*, Hye Seung Lee,.D., Dong Ho Lee,.D.*, You Jeong Jeong,.D.*, Tae Hyuck Choi,.D.*, Sang Hyub Lee,.D.*, Young Soo Park,.D.*, Jin-Hyok Hwang,.D.*, Jin-Wook Kim,.D.*, Sook-Hyang Jeong,.D.*, and Nayoung Kim,.D.* Departments of Internal edicine* and Pathology, Seoul National University Bundang Hospital, Seongnam, Seoul National University College of edicine, Seoul, Korea Background/Aims: Eosinophilic esophagitis (EE) is a chronic inflammatory disorder characterized by abnormal dense eosinophilic infiltration of esophageal mucosa and results in dysphasia and food impaction. EE is being increasingly recognized in adults. The prevalence is largely unknown. This study was performed to evaluate the detection rate of EE diagnosed based on pathologic criteria and to define the clinical characteristics of EE in Korea. ethods: We reviewed biopsy specimen of the 1,609 patients who underwent esophageal biopsy from January 2006 till August The presence of more than 20 eosinophils per high power field in biopsy specimens was considered cases of EE. Clinical information and endoscopic findings were obtained. Results: 7 (0.4%) patients were diagnosed as EE based on pathologic criteria retrospectively. Clinical symptoms were epigastric pain (43%), regurgitation (29%), dyspepsia (14%), and no symptom (14%). Endoscopic findings were whitish exudates or granules (57%), esophageal polyp (29%), and hyperemic change (14%). Two patients received treatment. One patient with bronchial asthma improved after treatment with inhaled corticosteroid, and one patient improved after 8 week proton pump inhibitor therapy. Conclusions: Eosinophilic esophagitis was found in 0.4% of the total esophageal biopsied cases. Our results suggest that Korean patients with eosinophilic esophagitis showed symptoms mimicking gastroesophageal reflux disease and atypical endoscopic findings. Therefore, regardless of the gross appearance of the mucosa, meticulous diagnostic approaches are needed for patients with swallowing difficulty and lack of response to proton pump inhibitor. (Korean J Gastroenterol 2010;55: ) Key Word: Eosinophilic esophagitis 접수 : 2009 년 8 월 20 일, 승인 : 2009 년 12 월 7 일연락처 : 이동호, , 경기도성남시분당구구미동 300 번지분당서울대학교병원내과 Tel: (031) , Fax: (031) dhljohn@snubh.org Correspondence to: Dong Ho Lee,.D. Department of Internal edicine, Seoul National University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam , Korea Tel: , Fax: dhljohn@snubh.org

6 국외에서호산구식도염의유병률은호주의한후향조사에서인구 198,000명중 19명의성인환자가호산구식도염으로진단되었으며 7 미국의경우 2002년에 0.1% 에서 2005년에는 1.9% 로유병률이꾸준히증가함을보여주었다. 8 이러한유병률의증가는호산구식도염의발생이알레르기반응과관련이있으며 9 다른알레르기질환의발생과더불어질병에대한이해의변화로설명되고있다.

14 이에저자들은단일기관에서심각한식도증상은없었으나내시경으로식도조직생검을받은환자중병리학적기준에의한호산구식도염의발견율과호산구침윤이확인된환자들의임상양상과내시경소견을조사하였다. 대상및방법 1. 대상 상부위장관내시경을받은 26,374명중식도생검을받은환자 1,609명을대상으로하였다.

2 정연무외 10 인. 식도조직검사상우연히발견된호산구식도염의임상적의의 163 서론호산구식도염 (eosinophilic esophagitis) 은 1978년 Landres 등 1 에의해처음보고된이래 1990년대중반까지는주로소아의질환으로발표되었으나 년 Attwood 등 5 이성인의호산구식도염에대한임상및병리소견을처음으로기술한이후최근성인에서도유병률이증가하고있는추세이다. 6 국외에서호산구식도염의유병률은호주의한후향조사에서인구 198,000명중 19명의성인환자가호산구식도염으로진단되었으며 7 미국의경우 2002년에 0.1% 에서 2005년에는 1.9% 로유병률이꾸준히증가함을보여주었다. 8 이러한유병률의증가는호산구식도염의발생이알레르기반응과관련이있으며 9 다른알레르기질환의발생과더불어질병에대한이해의변화로설명되고있다. 10 우리나라의호산구식도염은여러증례보고 11,12 및위식도역류질환과의비교연구 13 가있었고, 최근국내발표에의하면삼킴곤란및음식막힘증상이있거나 PPI에반응이없었던역류성식도질환환자 108명중 2명 (1.8%) 에서최종적으로호산구식도염이진단되었다고그유병률을보고한바있다. 14 이에저자들은단일기관에서심각한식도증상은없었으나내시경으로식도조직생검을받은환자중병리학적기준에의한호산구식도염의발견율과호산구침윤이확인된환자들의임상양상과내시경소견을조사하였다. 대상및방법 1. 대상 상부위장관내시경을받은 26,374명중식도생검을받은환자 1,609명을대상으로하였다. 이들중 706명은건강검진센터에서발견된식도점막이상소견으로조직검사를시행하였고 903명은소화기내과에서식도조직검사를시행하였다. 2. 방법식도생검을받은모든환자의생검보고서를검토하였고호산구 (eosinophil) 란단어가포함된병리보고서의생검조직표본을재확인하여호산구가고배율시야당 20개이상인경우호산구식도염으로진단하였다. 호산구식도염의진단기준을만족하는환자들의진료기록을토대로하여임상양상과혈액소견을조사하였고조직검사시행시의내시경소견은저장되어있는영상을재검토하였다. 악성종양, 급성염증및궤양이있는환자는진단에서제외하였다. 결과 1. 대상환자의일반적인특성식도조직병리보고서에호산구침윤이언급된경우는 31 명이었으며생검조직재확인을통해호산구식도염을만족하는환자는 7명으로전체상부위장관내시경검사를받은 26,374명중 0.03% 및식도조직검사를시행한 1,609명중 0.4% 였다. 환자들의평균연령은 47.7세였고남, 여비율은 6:1로남자의비율이 86% 였다. 7명중 3명 (43%) 이말초혈액에서경한호산구증가증 (500-1,200/mm 3 ) 을보였으며 1명에서알레르기질환의가족력및기관지천식과알레르기성비염이동반되어있었고나머지는특이소견이없었다. 분당서울대학교병원에서 2006 년 1 월부터 2008 년 8 월까지 Fig. 1. Endoscopic findings. (A) It showed white exudates and granules (arrowhead) at 25 cm from upper incisors (UI), (B) esophageal polyp at 28 cm from UI, and (C) hyperemic mucosa (arrow) at 36 cm from UI.

Dysphagia, weight loss (14%) No symptom (14%) GERD, gastroesophageal reflux disease.

3 164 The Korean Journal of Gastroenterology: Vol. 55, No. 3, 2010 Table 1. Frequency of Symptoms, Endoscopic Features and Endoscopic Diagnosis with Eosinophilic Esophagitis Symptoms Endoscopic features Endoscopic diagnosis Epigastric pain (43%) Regurgitation (29%) Dysphagia, weight loss (14%) No symptom (14%) GERD, gastroesophageal reflux disease. Whitish exudates or granules (57%) Esophageal polyp (29%) Hyperemic mucosa (14%) GERD, minimal change (57%) Esophageal polyp (29%) Acanthosis (14%) Table 2. Endoscopic Findings and Eosinophil Counts in 7 Cases of Eosionophilic Esophagitis Case Age (years) Sex Endoscopic findings Eosinophil counts/hpf F Whitish exudates of GEJ Esophageal polyp, distal esophagus Whitish nodules, 25 cm from UI Hyperemic mucosa, 36 cm from UI Whitish nodules, cm from UI Esophageal polyps, 28 cm and 36 cm from UI Whitish nodules, cm from UI HPF, high power field; GEJ, gastroesophageal junction; UI, upper incisors:, male; F, female. > Fig. 2. Pathologic findings (H&E stain, 400). (A) Biopsy of the esophageal mucosa showed massive infiltration of eosinophils. (B) It showed more than 20 eosinophils on high power field examination. 2. 임상증상환자의주된임상증상은경한심와부통증 (3명), 역류증상 (2명) 및 2 kg 정도의체중감소와소화불량 (1명) 이었고자각증상이전혀없는경우 (1명) 도있었다. 3. 내시경및조직소견 구진성결절이있었고 2명의용종소견및 1명에서적색색조변화가관찰되었으며 (Fig. 1) 내시경후육안진단은역류성식도염중미세변화가 4예, 식도용종 2예및식도표피비후증 1예였다 (Table 1). 각환자의조직검사소견상식도점막에서고배율시야당최소 23개에서 100개이상의광범위한호산구침윤이관찰되었다 (Table 2, Fig. 2). 내시경검사상 4 명에서백색삼출물혹은여러개의백색

4 Jung Y, et al. Clinical Significance of Incidentally Detected Eosinophilic Esophagitis with Pathologic Review 임상경과진단된 7명의환자중 3명은건강검진센터에서내시경을시행했던환자로특별한치료를하지않았다. 소화기내과에서진단된 4명중 2명은심각한소화기증상을호소하지않아역시경과관찰만하였고, 1명은기관지천식이동반된상태에서분무식기관지흡입기치료후호전되었으며나머지 1명은양자펌프억제제 (omeprazole, 20 mg) 8주투약후호전되어더이상의추가치료는하지않았다. 이후 7명중 1명은검진목적으로 1년후상부위장관내시경검사를시행하였으나이상소견이없었고, 나머지 6명은추적내시경검사를시행하지않았으며식도관련증상으로인한외래방문은없었다. 고찰성인의호산구식도염발생은이전의외국문헌에의하면 % 로유병률이매우낮다고보고되었지만 15,16 최근미국에서 1992년부터 2004년까지검사된식도조직표본을재검토하였을때본래의호산구식도염진단은 1.3% 였으나재조사후 1.7% 로증가되었고초기 9년동안유병률 (0.3%) 에비해후반기 4년동안의유병률 (3.8%) 이의미있게높았다고발표하였으며 17 다른전향연구에서도 7개월동안성인 400명에서내시경검사후 6.5% 까지호산구식도염이진단된보고가 18 있어성인에서만성적인삼킴곤란및식도막힘증세가있고산억제제치료에잘반응하지않는역류성식도염이있을때반드시고려해봐야할질환으로인식되고있다. 19 최근국내에서삼킴곤란과역류관련식도증상이있는환자에서호산구식도염의유병률은 1.8% 였다고보고하였으며 14 이번연구에서는식도점막이상소견이있어식도생검을시행한 1,609명중 0.4% 에해당하는 7명에서호산구식도염에합당하는호산구침윤소견이발견되었다. 호산구식도염은남, 여비율이 3:1 이상으로주로 대의남성에게많이나타나며 6 호산구식도염환자의부모중거의 10% 에서식도협착병력이있었고약 8% 에서조직검사상호산구식도염이진단된보고 15 를포함하여다른문헌에서도호산구식도염이유전성관련질환임을강하게시사하는근거들이발표되었다. 20,21 호산구식도염의발생원인은아직까지확실하지않지만전신또는국소스테로이드제제에대해반응이있고 21 피부단자와첩포검사에근거하여식품알레르기의흔한원인인 6가지단백질을제외한식사요법이후식도조직검사상염증이유의하게개선되었다는보고에서호산구식도염이알레르기반응에의한것으로추측되고있으며 22,23 호산구식도염환자의 51.6% 에서는음 식알레르기, 아토피성피부염및천식질환의다른알레르기질환이동반되어있고성인의약 1/3에서는말초혈액호산구증가증이관찰된다고알려져있다. 6,24 이번연구에서는전체환자 7명중남성이 6명이었고나이는 40대가많았으며, 1명에서알레르기질환의가족력과천식, 비염등의알레르기질환이동반되어있었고 7명중 3명 (43%) 에서경한정도의말초혈액호산구증가증이관찰되었다. 호산구식도염의가장흔한증상은고형식의삼킴곤란, 음식막힘, 흉부작열감등의순으로소아와성인에서비슷하게나타나며덜흔한증상으로성인에서는비심인흉통, 연하통, 구토, 역류증상등이있다. 6,7,25 호산구식도염에서의연하곤란은만성및진행성의경과를갖고산억제치료에도반응을잘하지않으며특히역류성식도염에비해정상식도산도 (ph) 이며, 아토피질환이동반된젊은남자에서는식도운동장애와협착이잘발생한다. 15 이번연구에서진단된호산구식도염환자들은심한연하곤란이나음식막힘은없었고주로덜흔한증상인심와부동통이나역류증상이있었으며식도내침윤된호산구수와증상의심각도도비례하지않았다. 호산구식도염의전형적인내시경소견은동심원모양의주름진식도, 종축방향의골, 백색삼출물혹은구진, 점막의혈관상소실, 크레페종이모양 (crepe paper) 의점막의유약성 (friability), 식도소구경및심한경우식도협착등이있다. 26 이전 24개의연구를종합한보고에서는점막의유약성혹은부종이 59.3% 로가장흔한소견이었고주름진식도가 49.2%, 식도협착 39.7%, 백색점상삼출물 15.7%, 반경이작은식도는 5.3% 였고 8.8% 에서는내시경검사상이상소견이없었다. 6 이와다른보고에서는 30명의호산구식도염환자에서혈관상소실이 93.3% 였고백색삼출이 53.3% 로높았으며, 백색삼출부위에서특히호산구침윤이증가되어있었고백색삼출과삼킴곤란의빈도는유의한관련이있음을보고하였다. 27 이번연구에서는전형적인식도점막취약이나부종및주름진식도소견보다는 7명중 4명에서백색삼출혹은다발성백색구진성결절이가장흔하게관찰되었으며 2명은용종형태였고나머지 1명도적색색조변화외에다른이상이없어, 이전에보고된호산구식도염의전형적인내시경결과와는달리비특이적이고애매한소견을관찰할수있었다. 호산구식도염의진단은병리학적으로확진하며역류성식도염과호산구식도염을구분하는데있어침윤된호산구의숫자가도움이될수있다고하였는데즉, 역류성식도염은원위부식도에국한된고배율 (400배 HPF) 당 6개정도의상대적으로낮은호산구침윤이있으며, 일차성호산구식도염에서는근위부와원위부식도에 20-24개의많은호산구침윤이관찰된다고하였다. 28 또한침윤된호산구의수는통

5 166 대한소화기학회지 : 제 55 권제 3 호, 2010 상적인역류성식도염의치료에대한반응과음의상관관계가있어, 고배율에서 23개이상의호산구침윤은역류성식도염이나만성식도염보다는호산구식도염을의미하며산억제제치료에도반응이약한것으로보고하였다 년미국에서호산구식도염의진단과치료에대해이전의보고들을종합한일치된의견을발표하였는데 1) 성인에서삼킴곤란, 음식막힘등의증상이있거나소아에서는섭취장애, 역류성식도염의증상이있고 2) 식도조직에서고배율당 15개이상의호산구침윤이관찰되며 3) 유사한임상, 병리및내시경소견을보이는다른질환, 특히정상식도산도및고용량양자펌프억제제에반응이없음이증명되어역류성식도염을배제할수있을때일차성호산구식도염을진단할수있다고하였으며 30 고배율당 15개호산구수를기준으로식도조직표본의수가많을수록호산구식도염진단의예민도가증가되었던대규모코호트연구에 31 근거하여진단을위해서는식도의여러부위에서최소 3개이상의조직표본이필요하다고추천하였다. 30 현재호산구식도염의주된치료는식사회피요법, 항염증치료및협착에대한물리적확장치료가있다. 24,25 양자펌프억제제는호산구식도염의일차적인치료제로고려되지는않지만진단목적으로역류성식도염과의감별을위해투약에따른증상반응을관찰하고, 산분비가식도의호산구증을촉발시킬수있기때문에초기에투여해볼수있다. 30 산억제제치료후증상호전은있을수있으나조직학적인호전은일반적으로일어나지않기에원인이되는음식이나항원을피하며일부환자에서는전신및국소스테로이드제제 (flucatisone) 가도움이될수있고 32 이외알레르기와관련된면역치료로항 IL-5 제제 (mepolizumab) 가식도호산구침윤을줄이고증상이호전되었다는보고가있으며 33 조직학적으로호산구감소는증명되지않았지만류코트리엔수용체길항제 (ontelukast), TNF 억제제등이호산구식도염환자의증상소실에효과가있다고하였다. 34 이번연구에서 5명은검사당시심각한증상이없는상태에서상기와같은치료가고려되지않았고 1명은기관지천식, 비염이동반되어흡입기사용후식도증상이호전되었으며 1명은역류성식도염진단하에산억제제복용으로증상호전후더이상의치료는하지않았다. 호산구식도염은흔히위식도역류질환으로진단되어약물치료를계속함에도불구하고효과가전혀없는경우가많고진단의지연으로인해길게는수십년까지연하곤란과음식막힘같은증상을호소한다. 우리나라의호산구식도염에대한광범위하고전향적인연구가없어서일반적으로말하기는어렵지만이번연구를통해본우리나라성인호산구식도염은주로 40대에서발병했고, 외국의경우와비교했을때증상이더욱모호한경우가많으며, 내시경소견 도비특이적이라고말할수있겠다. 따라서내시경병변과임상증상과의관계가뚜렷하지않은환자들에서호산구침윤이확인되었던이번연구의결과를토대로삼킴곤란이나음식막힘등호산구식도염을의심할만한증상을호소하는환자에서호산구식도염의특징적인내시경소견이없더라도적극적으로식도조직검사를시행하여호산구침윤여부를확인할필요가있을것으로생각한다. 결론으로, 이번연구에서 2년 8개월간시행된 1,609명의식도생검을조사한결과 7명 (0.4%) 에서호산구식도염의병리기준에합당하는결과를보였으며우리나라호산구식도염의임상, 내시경특징은외국의그것과다를수있음을알수있었다. 전세계적으로호산구식도염의유병률이증가함을감안할때우리나라도호산구식도염의발생이증가하고있을것으로생각하며향후이에대한잘계획된대규모의전향연구가필요할것으로생각한다. 요약목적 : 호산구식도염은식도에호산구가심하게침윤하여삼킴곤란이나음식막힘등의증상을일으키는만성적인질환이다. 이에저자들은우리나라식도조직검사상호산구식도염의발견율과임상특징을알아보고자하였다. 대상및방법 : 분당서울대병원에서 2006년 1월부터 2008년 8월까지식도생검을받은환자들의조직소견을후향분석하여고배율에서 20개이상의호산구가관찰될때호산구식도염이라정하였고각환자들의임상특징과내시경소견을조사하였다. 결과 : 2년 8개월간내시경식도점막이상으로식도생검을받은환자 1,609명중 7명 (0.4%) 에서고배율당 20개이상의호산구침윤이관찰되었으며이들은심와부동통, 역류증세및소화장애등의비특이적인소화기증상과백색삼출과백색결절, 식도용종및식도비후증등의내시경소견을보였다. 결론 : 생검을시행한환자들의후향적인식도조직재검토결과 0.4% 에서호산구식도염이발견되었고, 임상양상과내시경소견은비특이적이었다. 전세계적으로호산구식도염의유병률이빠르게증가하는것을볼때만성적인삼킴곤란증상이있거나특히산억제제치료에반응하지않는역류성식도염환자에서호산구식도염의가능성을고려하여세심한진단접근및식도생검이요구되며이에대한향후대규모전향연구가필요할것으로생각한다. 색인단어 : 호산구식도염

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<B0E6C8F1B4EBB3BBB0FAC0D3BBF3B0ADC1C E687770> 개원의와함께하는임상강좌 2011 역류성식도질환제대로이해하기 Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea Jae-Young Jang, M.D., PhD. 개원의와함께하는임상강좌 2011 109 최신치료