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1 대한내과학회지 : 제 88 권제 3 호 비특이적간질성폐렴의양상으로발생한 IgG4 연관폐질환의 1예 울산대학교의과대학서울아산병원 1 내과, 2 영상의학과, 3 병리과 조동희 1 안지환 1 강유미 1 채은진 2 송준선 3 송진우 1 A Case of IgG4-Related Lung Disease Mimicking Non-Specific Interstitial Pneumonia Dong Hui Cho 1, Ji Hwan An 1, Yu Mi Kang 1, Eun Jin Chae 2, Joon Seon Song 3, and Jin Woo Song 1 Departments of 1 Internal Medicine, 2 Radiology and 3 Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Immunoglobulin (Ig) G4-related disease is a recently described systemic inflammatory disease characterized by high serum IgG4 concentrations and sclerosing inflammation of numerous IgG4-positive plasma cells that responds favorably to steroid treatment. Although initial description of this disorder focused on its pancreatic presentation, it has become apparent that it is a systemic disease. In this report, we describe a case of IgG4-related lung disease presenting as non-specific interstitial pneumonia in a 78-year-old male with interstitial lung disease. Pathological examination through video-assisted thoracic surgery showed a non-specific interstitial pneumonia pattern and numerous (> 50/high-power field) infiltrating IgG4-positive plasma cells. Laboratory tests also revealed a high serum IgG4 concentration. Prednisolone therapy was initiated and his symptoms and reticular opacity improved after two months of treatment. (Korean J Med 2015;88: ) Keywords: IgG4 related disease; Lung involvement; Interstitial lung diseases 서론 IgG4 연관질환 (IgG4 related disease) 은전신을침범하는염증성질환으로침범된장기에 IgG4 positive plasma cell과 T lymphocyte의침윤을보이는것을특징으로한다. 처음에 는 1995년 Yoshida 등 [1] 에의해자가면역성췌장염 (autoimmune pancreatitis) 으로보고되었으나이후이질환이폐를포함한전신의장기들에다양한침범을동반할수있음이알려진후현재는 IgG4의증가를특징으로하는전신질환으로이해되고있다 [2]. Received: Revised: Accepted: Correspondence to Jin Woo Song, M.D. Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul , Korea Tel: , Fax: , jwsong@amc.seoul.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Dong Hui Cho, et al. IgG4-related lung disease 다양한 폐 침범 소견 중 최근에는 간질성 폐 질환(inter- 했기에 문헌고찰과 함께 보고하는 바이다. stitial lung disease)의 형태로 발현한 IgG4 연관 질환의 증례들 증 이 보고되었으나[3-5] 현재까지 국내에서 보고된 바는 없다. 례 저자들은 간질성 폐 질환 중 비특이적 간질성 폐렴(nonspecific interstitial pneumonia)으로 확인된 환자의 조직 및 혈 환 자: 정, 78세 남자 액 검사 소견에서 IgG4 연관 질환으로 확인된 증례를 경험 주 소: 내원 2년 전부터 노작성 호흡 곤란으로 타원에서 A B C D Figure 1. Chest radiography and computed tomography findings. (A) Chest radiograph showing diffusely increased opacity along the periphery of both lower lung zones and decreased volume in both lower lungs. Chest CT revealed diffuse areas of (B) irregular interstitial thickening, (C) reticulation, and (D) traction bronchiectasis with air cysts in the subpleural zone of both lower lungs. Fissural thickening and emphysematous change were also noted. CT, computed tomography

3 대한내과학회지: 제 88 권 제 3 호 통권 제 655 호 2015 치료를 받아 오던 중 내원 3개월 전 호흡 곤란 악화로 시행한 양측 흉부 아래쪽에서 악설음(crackle)이 청진되었다. 흉부 전산화 단층촬영에서 양측 하엽의 간유리 음영(ground 검사실 소견: 전체 혈구 검사에서 백혈구 8,500/mm3 (호중 glass opacities)의 증가와 임파선 비대가 관찰되어 임파선 조 구 67.1%), 혈색소 15.2 g/dl, 혈소판 226,000/uL였고 혈청 생 직 검사를 시행했으나 특이소견이 없었다. 내원 3주 전 추적 화학 검사에서 총 단백 7.8 mg/dl, 알부민 2.8 g/dl, 총 빌리 검사에서 폐 병변의 악화가 확인되어 본원으로 의뢰되었다. 루빈 0.6 mg/dl, alkaline phosphatase 74 IU/L, AST 21 IU/L, 과거력: 전립선 비대 이외에 특이 병력은 없었다. ALT 10 IU/L, 혈중 요소 질소 9 mg/dl, 크레아티닌 0.94 mg/dl, 개인력: 100갑년의 흡연력이 있었으나 3년 전부터 금연 C-reactive protein은 1.94 mg/dl였다. 결체조직 질환 동반 여 중이었고 음주는 하지 않았다. 부를 확인하기 위해 자가면역항체 검사를 시행했고 모두 음 가족력: 특이사항은 없었다. 성이었다. 동맥혈 가스 검사에서 ph는 7.423, 이산화탄소 분 이학적 소견: 환자는 신장 162 cm, 체중 62.5 kg이었고 혈 압 33.6 mmhg, 산소 분압 77.5 mmhg, bicarbonate 22.2 mmeq/l, 압 114/58 mmhg, 체온 36.2, 맥박 84회/min, 호흡수 22회 산소 포화도 95.8%였다. /min이었으며 만성 병색을 보이고 있었다. 흉부 청진에서는 폐기능 검사 소견: 폐활량 검사에서 노력성 폐활량(forced A B C D Figure 2. Histopathological findings of the lung. (A) A wedge resection specimen shows subpleural and septal thickening with lymphoid follicles (hematoxylin and eosin [H&E], 10). (B) Interstitial inflammation and fibrosis were identified and these changes were temporally uniform, suggestive of non-specific interstitial pneumonia with a mixed pattern (H&E, 40). (C) Plasma cell infiltration (asterisks; H&E, 400), storiform fibrosis (arrow) and obliterative phlebitis (arrow heads; H&E, 200) are indicated. (D) IgG4 immunostaining reveals > 50 IgG4-positive plasma cells per high power field (H&E, 400)

4 - 조동희외 5 인. IgG4 연관폐질환 - vital capacity) 은정상예측치의 68% (2.60 L), 1초간노력성호기량 (forced expiratory volume in one second) 은정상예측치의 65% (1.59 L), FEV 1/FVC 0.61로폐쇄성환기장애를보였고폐용적검사에서총폐용적 (total lung capacity) 은정상예측치의 81% (4.70 L), 폐확산능 (diffusing capacity) 은예측치의 42% (6.9 ml/mmhg/min) 로감소되어있었다. 방사선학적소견 : 외부병원에서시행한흉부전산화단층촬영에서는이전에비해양측폐의중 하엽에간유리음영증가를보였고종격동, 폐문부임파선도크기가증가했다. 치료및임상경과 : 조직검사를위해흉강경하폐쐐기절제술 (video-assisted thoracoscopic surgery) 을시행했고현미경소견에서비특이적간질성폐렴양상으로생각되는간질의미만성염증침윤이관찰되었으나다수의 lymphoplasmacytic infiltration과 storiform fibrosis, obliterative phlebitis도관찰되었다. IgG4 연관질환의가능성을고려하여 IgG4 염색 (anti-igg4 antibody 1:1,600, Binding site, Bermingham, UK) 을시행했고고배율소견에서 50개이상의 IgG4 양성형질세포가관찰되었다. 또한혈청 IgG는 2,990.0 mg/dl ( 정상범위 : 700-1,600 mg/ dl), IgG4 255 mg/dl ( 정상범위 : mg/dl) 로증가되어최종적으로는비특이적간질성폐렴의양상을보이는 IgG4 연관질환의폐침범으로판단했다. 타장기침범여부를확인하기위해복부전산화단층촬영을시행했으나췌장및다른복부장기에이상소견은관찰되지않았다. 이후스테로이드치료 (prednisolone 30 mg/day) 를시작했고 2개월에걸쳐서서히감량했으며환자는증상의호전을보였다. 치료 2개월째에시행한폐활량검사에서노력성폐활량은정상예측치의 74% (2.81 L), 1초간노력성호기량은정상예측치의 74% (1.77 L), FEV 1/FVC 0.63, 폐확산능은예측치의 44% (7.1 ml/mmhg/min) 로호전된소견을보였고치료 6개월째시행한단순흉부방사선사진에서이전에비해망상음영과간유리음영의호전이관찰되었다. 고찰 1995년 Yoshida 등 [1] 이처음으로자가면역성췌장염의개념을제안한이후많은증례보고들을통해이질환이다른장기의침범을동반함이알려졌고결국현재는 IgG4의증가를특징으로하는전신염증성질환으로이해되고있다. 대 표적인침범부위로는췌장, 담도, 침샘, 눈물샘, 간, 신장, 폐및후복막강등이알려져있다 [2]. 병인에대해서는잘알려지지않았으나 T-helper 2 cytokines, regulatory T-cell, interleukin-10, transforming growth factor-β 등이 IgG4 양성형질세포의침윤과섬유화과정에관여할것이라여겨지고있다 [6]. 2004년자가면역성췌장염이있는 63세의남자환자에서처음으로폐침범이보고된후 [7] 폐침범에대한몇몇보고들이있었는데 Zen 등 [8] 은 IgG4 연관질환환자 114명중 16명 (14%) 에서폐침범을동반함을보여주었다. 또한 Inoue 등 [9] 은 IgG4 연관폐질환의방사선학적형태를종괴를포함한단독결절형 (solitary nodular type), 원형의간유리음영 (round-shaped ground glass opacity), 폐포간질음영 (alveolar interstitial), 그리고기관지혈관성 (bronchovascular) 등크게네가지로분류하여폐침범이다양한양상으로나타날수있음을보고하였다. 국내에서는 2009년 Yoo 등 [10] 이최초로폐내다발성결절을동반한 2명의환자에서조직검사를통해 IgG4 연관폐질환으로보고하였으나아직까지간질성폐질환양상으로발현한보고는없었고외국에서도세증례만이보고되었다. Takato 등 [3] 은영상및병리검사상비특이적간질성폐렴양상을보인 59세남자환자에서 IgG4 양성형질세포침윤이있었던증례를보고했고, Tanaka 등 [4] 역시비특이적간질성폐렴양상을보인 75세남자환자에서조직검사결과 IgG4 연관폐질환으로진단한증례를보고했으며두증례모두스테로이드치료후환자의임상경과는호전되었다. 한편 Wibmer 등 [5] 은통상형간질성폐렴 (usual interstitial pneumonia) 양상으로발현한 IgG4 연관폐질환을보고하기도했는데역시스테로이드치료후임상경과가호전되었다. 본증례에서는흉부전산화단층촬영및병리소견상비특이적간질성폐렴양상을보인환자에서 IgG4 면역염색결과고배율소견상 50개이상의 IgG4 양성형질세포가관찰되었고 IgG4/IgG ratio는 80% 에달했으며혈청 IgG4 농도또한증가되어최종적으로는 IgG4 질환의폐침범으로진단했으나기타다른장기의침범은관찰되지않았다. 또한본증례에서는이전에보고되었던 nonspecific interstitial pneumonia 양상으로발현한 IgG4 related lung disease 의증례들과달리 storiform fibrosis, obliterative phlebitis 등다른장기의 IgG4 related disease 에서흔히보이는소견들도관찰되었다

5 - The Korean Journal of Medicine: Vol. 88, No. 3, 요 특발성비특이적간질성폐질환과 IgG4 related lung disease는증상, 폐기능검사, 영상의학소견만으로는감별이어려운질환이다. 하지만 IgG4 related lung disease 는 steroid 치료에좋은치료반응을보이는것으로알려져있어이들의감별은매우중요하다고할수있다. 본증례는특발성간질성폐질환, 특히비특이적간질성폐렴에서혈청 IgG4의증가혹은조직소견상 lymphoplasmacytic infiltration이다수관찰되고 obliterative phlebitis, storiform fibrosis 등이관찰된다면 IgG4 연관질환의폐침범가능성을고려해야함을시사해준다. 중심단어 : IgG4 연관질환 ; 폐침범 ; 간질성폐질환 약 REFERENCES 1. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995;40: Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38: Takato H, Yasui M, Ichikawa Y, et al. Nonspecific interstitial pneumonia with abundant IgG4-positive cells infiltration, which was thought as pulmonary involvement of IgG4- related autoimmune disease. Intern Med 2008;47: Tanaka K, Nagata K, Tomii K, Imai Y. A case of isolated IgG4-related interstitial pneumonia: a new consideration for the cause of idiopathic nonspecific interstitial pneumonia. Chest 2012;142: Wibmer T, Kropf-Sanchen C, Rüdiger S, et al. Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case. Multidiscip Respir Med 2013;8: Nirula A, Glaser SM, Kalled SL, Taylor FR. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol 2011;23: Taniguchi T, Ko M, Seko S, et al. Interstitial pneumonia associated with autoimmune pancreatitis. Gut 2004;53:770; author reply Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010;34: Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology 2009;251: Yoo JW, Roh JH, Lim CM, et al. Two cases of pulmonary involvement of immunoglobulin G4 related autoimmune disease. Tuberc Respir Dis 2009;67:

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