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1 대한안과학회지 2015 년제 56 권제 2 호 J Korean Ophthalmol Soc 2015;56(2): ISSN (Print) ISSN (Online) Case Report 히알우론산나트륨점안액의장기사용으로인한독성각막염 1 예 A Case of Toxic Keratitis due to Chronic Use of Sodium Hyaluronate Eyedrops 이은정 유인정 현주 임동희 정태영 Eun Jung Lee, MD, In Jeong Lyu, MD, Joo Hyun, MD, Dong Hui Lim, MD, Tae Young Chung, MD, PhD 성균관대학교의과대학삼성서울병원안과학교실 Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Purpose: To report a case of toxic keratitis due to chronic use of sodium hyaluronate eyedrops. Case summary: A 74-year-old female visited our clinic with severe ocular pain and decreased vision in both eyes. She had received refractive surgeries in both eyes 10 years prior. She had been using sodium hyaluronate eyedrops for the treatment of dry eye symptoms for 10 years. Slit-lamp examination revealed inferior punctate erosions in the inferior part of the cornea in both eyes. With her history of chronic use of sodium hyaluronate and after ophthalmologic examination, we suspected keratitis medicamentosa due to sodium hyaluronate eyedrops. We discontinued the eyedrops she was using and prescribed autologous serum. One month later, ocular discomfort and decreased vision were improved and corneal erosions were decreased. Conclusions: In the present case, toxic keratitis was assumed to be associated with the use of sodium hyaluronate eyedrops and corneal erosions improved after the eyedrops were discontinued. We suggest sodium hyaluronate eyedrops are potentially hazardous and recommend a regular follow-up should be performed by a qualified ophthalmologist. J Korean Ophthalmol Soc 2015;56(2): Key Words: Keratitis medicamentosa, Sodium hyaluronate, Toxic keratitis 건성안은 2007년에있었던 International Dry Eye Workshop (DEWS) 에서정의한바에의하면 눈물막의삼투압이증가하고안구표면의염증이유발되어눈의불편감, 시력저하, 눈물막의불안정을일으키는복합성질환 이다. 1 일반적으로건성안환자의유병률은 14-33% 로매우높으며특히동양인과히스패닉계에서더높다. 2-5 국내에서도많은수의환자가건성안으로안과진료를받고있다. 2010년에시행된한국내조사에서는건성안환자가안과진료수진자의 20-30% 를차지하는것으로나타났고 년에시행된연 Received: Revised: Accepted: Address reprint requests to Tae Young Chung, MD, PhD Department of Ophthalmology, Samsung Medical Center, #81 Irwon-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: tychung@skku.edu 구에서는 65세이상의노인인구에서약 33% 의유병률을보이는것으로조사되었다. 6 최근건성안에대한개념이바뀌면서항염증제제들이건성안치료에도입되고있지만 7,8 아직까지범국민적인인식에는도달하지못한상태이다. 특히, 인공누액의부작용에대해서도특별한주의를기울이지않고있다. 인공눈물은과량사용하여도안전하다는인식에따라많은수의환자들이적절한안과진료없이인공눈물을장기점안하고있다. 경미한안병변혹은안증상은경험하고있지만아직까지는국내에서인공눈물의장기점안으로인한직접적이고심각한안병변의합병증은논문으로보고된적이없다. 저자들은건성안으로히알우론산나트륨점안액을장기적으로사용한각막염환자 1예를경험하였고, 이의중단과함께각막염의호전을관찰하였기에히알우론산나트륨점안액에의한독성각막염의가능성을염두에두어이를임상의들에게보고하고자한다. c2015 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 291

- 대한안과학회지 2015 년제 56 권제 2 호 - 증례보고 74세여자환자가내원 1달전부터심해진양안통증과시력저하를주소로내원하였다. 과거력상내원 10년전양안근시로굴절교정수술을시행받았고, 이후발생한건성안증상조절을위하여적절한안과진료없이장기간 0.1% sodium hyaluronate 점안액 ( 히아레인 0.

2 - 대한안과학회지 2015 년제 56 권제 2 호 - 증례보고 74세여자환자가내원 1달전부터심해진양안통증과시력저하를주소로내원하였다. 과거력상내원 10년전양안근시로굴절교정수술을시행받았고, 이후발생한건성안증상조절을위하여적절한안과진료없이장기간 0.1% sodium hyaluronate 점안액 ( 히아레인 0.1점안액, Taejoon Pharm, Seoul, Korea) 을하루 4회이상매일사용하였다. 내원 8년전좌안백내장수술을시행받았고우안은 Pirenoxine ( 가리유니점안액, Taejoon Pharm, Seoul, korea) 을간혹점안하였다. 이외안과적인과거력및전신질환은없었고, 복용중인약물도없었다. 환자는정기적으로안과진료를받지않고약처방만받아하루 4회이상 10년간지속적으로히알우론산나트륨점안제를사용하였으며내원 2주전양안통증으로인근안과에서표층각막염으로진단받고 Tosufloxacin Tosylate ( 오젝스점안액, Dong-A Pharm, Seoul, Korea) 하루 3회, solcoseryl 120 concentrate ophthalmic gel ( 솔코린점안겔, 한림제약 ) 을하루 2회 2주간사용하며증상의호전이없어서본원으로내원하였다. 히알우론산나트륨점안액은지속적으로사용하고있었으며, 내원당시나안시력은 우안 0.5, 좌안 0.4, 안경교정시력우안 0.7 좌안 0.4로시력저하가있었다. 세극등현미경검사상양안결막의충혈소견과함께각막중심부를포함한아랫부분에표층각막염소견을보였고, 우안보다좌안이더심하였다 (Fig. 1). 교정시력저하를동반한양안각막의중심부및아랫부분을침범한표층각막염소견과히알우론산나트륨점안액의장기점안과거력을고려하여저자들은약물독성각막염을의심하였고히알우론산나트륨점안액및오젝스점안액, 솔코린점안겔을모두중단하도록하였다. 동시에 20% 자가혈청안약을 2시간마다점안하도록하고다른점안약제의사용은없었다. 1달후외래에서추적관찰하였을때나안시력은우안 0.6, 좌안 0.3, 안경교정시력은우안 0.9, 좌안 0.5로상당한증세의호전을보였고, 양안각막염소견의호전도관찰할수있었다 (Fig. 2). 고찰 이론적으로모든점안제는각막상피세포막의생리적작용에영향을끼칠수있고장기점안하는경우문제를일 A B C D Figure 1. Slit-lamp photography of the patient on the first visit under white light (A, B) and cobalt-blue light (C, D). Corneal punctate erosions are found in her both eyes, mostly on the inferior side. 292

- 이은정외 : 히알우론산나트륨점안액독성각막염 - A B C Figure 2. Slit-lamp photography of the patient one month after discontinuation of the eyedrops under white light (A, B) and cobalt-blue light (C, D).

3 - 이은정외 : 히알우론산나트륨점안액독성각막염 - A B C Figure 2. Slit-lamp photography of the patient one month after discontinuation of the eyedrops under white light (A, B) and cobalt-blue light (C, D). The corneal erosion improved in both eyes. D 으킬수있다. 9 따라서어떠한약물이든안과의사의임상적판단에따른처방과지속적인진료를통한관리가권장된다. 일반적으로안합병증을잘유발하지않는인공누액의점안약제는안과의사의정기적인관리없이장기간본인의의도만으로사용하게되는경우가많다. 본증례에서환자는 10여년간지속적으로히알우론산나트륨점안제를점안한과거력이있었고, 양안의각막중심부및아랫부분에점상미란소견과결막충혈소견을종합하여볼때저자들은약물에의한독성각막염을가장의심할수있었다. Pirenoxine 사용에의한독성각막염의가능성은우안에만간헐적으로점안하였고, 우안보다좌안에서각막염소견이더심했다는점에서독성각막염의유발원인으로는배제된다. 이외에장기간사용한점안제는없었고히알우론산나트륨점안제의중단과함께각막염이다소호전된점에서히알우론산나트륨점안제를각막염을일으킨원인으로결론내릴수있었다. 건성안등의안구표면질환이있을때에는독성각막염이쉽게유발되는것으로알려졌다 년에 Schwab and Abbott 13 는 19명의독성각막염환자를대상으로연구를시행하였는데건성안, 이전안구내수술과거력, 헤르페스감 염, 혹은대상포진감염등으로인한안구표면질환을가진환자들이 14명으로다수를차지하였다. 특히방부제가포함된안약제제를장기간사용한경우에각막염이잘발생하며이는점안빈도와기간, 그리고환자의각막상태에크게영향받음이증명되었다. 14 또한 Baudouin and de Lunardo 15 는안과수술을받은과거력, 고령, 안구표면질환등의요소가있을때에도점안제부작용의발현빈도가커진다고하였으며, Ashton et al 16 은각막상피세포층의손상이나기능이저하되어있는경우에는기존에는무해하다고알려진점안제성분들의각막내로의침투가촉진되어독성을야기할수도있다고언급하였다. 건성안치료로사용되는인공누액은윤활작용외에도눈물구성성분대체, 염증성물질희석, 눈물오스몰농도조절등의기능을갖는데눈물층의전해질농도, 오스몰농도, ph, 산소농도등이각막상태에영향을줄수있다. 17 오스몰농도스트레스가있을때각막상피세포는수분을잃게되고전해질농도를올리게되어세포손상을유발한다. 18 미생물번식을억제하기위해첨가되는보존제는계면활성제인벤잘코늄염화물이주로사용되는데이는세포막투과도를변화시켜상피세포독성을나타낼수있고, 녹내장환자에서건성안을유발하 293

4 - 대한안과학회지 2015 년제 56 권제 2 호 - 는주요원인으로작용한다고알려졌다. 19 본증례에서독성각막염이발생한것은환자가 74세의고령여성이었고, 굴절교정수술과백내장수술을받았으며, 건성안으로인하여일반인구보다각막염에취약하다는점이작용하였을것이다. 이러한위험인자를가진환자들이국내에적지않음에도불구하고현재까지보고가없었는데이는독성각막염이나타내는증상이기존의건성안증상과유사하여간과되었을가능성을생각해볼수있다. 환자들이병원에내원하지않고약처방만받아장기간점안제를사용하는경우에도독성각막염을진단하지못하고, 건성안의기존증상이나안합병증으로인한현상으로혼돈할경우가있을것으로저자들은생각한다. 따라서현재까지국내에서는이러한예가보고된바가없었으나, 미미한독성각막염이나건성안의합병증으로인한혼돈으로점안약제에의한각결막염의위험에노출된건성안환자들의수는상당할것으로생각한다. 본증례에서는벤잘코늄염화물등미량함유된요소에의한영향을완전히배제할수는없지만, 히알우론산나트륨점안제를사용하고발생한독성각막염의첫증례보고라는점에서그의미가크다고생각한다. 증례에서와같이히알우론산나트륨점안제특히벤잘코늄염화물같은보존제가포함된경우이를적절한진료및관리없이장기간사용하는경우에시력저하와각막염이발생할수있으며, 특히고령, 굴절교정수술혹은안과수술력등건성안의위험인자를가진환자들에서는더욱주의가필요할것이다. 따라서향후보존제의유무에상관없이임상적으로많이사용되는인공누액점안약제의부작용을줄이기위해서는전문적인지식을갖춘안과전문의의관리및정기적인검진이병행되어야하며부작용에대한지속적인추적관찰이필요할것으로생각한다. REFERENCES 1) Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5: ) Schein OD, Muñoz B, Tielsch JM, et al. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997;124: ) Lin PY, Tsai SY, Cheng CY, et al. Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2003;110: ) Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol 2001;45 Suppl 2:S ) Kim WJ, Kim HS, Kim MS. Current trends in the recognition and treatment of dry eye: a survey of ophthalmologists. J Korean Ophthalmol Soc 2007;48: ) Han SB, Hyon JY, Woo SJ, et al. Prevalence of dry eye disease in an elderly Korean population. Arch Ophthalmol 2011;129: ) Stern ME, Gao J, Siemasko KF, et al. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res 2004;78: ) Dana MR, Hamrah P. Role of immunity and inflammation in corneal and ocular surface disease associated with dry eye. Adv Exp Med Biol 2002;506(Pt B): ) Wilson FM 2nd. Adverse external ocular effects of topical ophthalmic medications. Surv Ophthalmol 1979;24: ) Burstein NL. Preservative cytotoxic threshold for benzalkonium chloride and chlorhexidine digluconate in cat and rabbit corneas. Invest Ophthalmol Vis Sci 1980;19: ) Coster DJ. Superficial keratopathy. In: Tasman W, Jaeger EA, eds. Duane's Clinical Ophthalmology, revised ed. Philadelphia: Lippincott, 1995; v. 4. chap ) Lemp MA. Advances in understanding and managing dry eye disease. Am J Ophthalmol 2008;146: ) Schwab IR, Abbott RL. Toxic ulcerative keratopathy. An unrecognized problem. Ophthalmology 1989;96: ) Ichijima H, Petroll WM, Jester JV, Cavanagh HD. Confocal microscopic studies of living rabbit cornea treated with benzalkonium chloride. Cornea 1992;11: ) Baudouin C, de Lunardo C. Short-term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol 1998;82: ) Ashton P, Diepold R, Platzer A, Lee VH. The effect of chlorhexidine acetate on the corneal penetration of sorbitol from an arnolol formulation in the albino rabbit. J Ocul Pharmacol 1990;6: ) Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5: ) Chen Z, Tong L, Li Z, et al. Hyperosmolarity-induced cornification of human corneal epithelial cells is regulated by JNK MAPK. Invest Ophthalmol Vis Sci 2008;49: ) Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 2002;86:

5 - 이은정외 : 히알우론산나트륨점안액독성각막염 - = 국문초록 = 히알우론산나트륨점안액의장기사용으로인한독성각막염 1 예 목적 : 히알우론산나트륨점안액을장기간점안하여이로인해독성각막염이발생한증례를보고하고자한다. 증례요약 : 74 세여자환자가양안의심한안구통증및시력저하를주소로내원하였다. 내원 10 년전양안굴절교정수술받았으며수술후발생한건성안조절을위하여히알우론산나트륨점안액을장기간사용하였다. 검안상양안각막중심부및하부에표층각막염소견을보였고, 이에과거력과임상소견으로독성각막염을의심하고사용하던점안약제를중단한후자가혈청안약을처방하고 1 개월후추적관찰하였을때안경교정시력의호전, 주관적인불편감의해소및부분적인각막염의호전을관찰하였다. 결론 : 장기간점안하던히알우론산나트륨점안액의사용을중단한후각막염이회복됨을관찰하였기에독성각막염의가능성이높다고생각하며, 본증례를통해히알우론산나트륨점안제를장기간사용하는경우의위험성을일깨우고, 적절한안과진료가동반되어야한다는점을되새겨볼수있겠다. < 대한안과학회지 2015;56(2): > 295

<283732372D3733312920B4D9C3CAC1A120BCD2C7C1C6AEC4DCC5C3C6AEB7BBC1EEC0C720B3EBBEC8C0C720BDC3B7C2BAB8C1A4BFA120B4EBC7D120C0AFBFEBBCBA20C6F2B0A1283035292E687770>

<283732372D3733312920B4D9C3CAC1A120BCD2C7C1C6AEC4DCC5C3C6AEB7BBC1EEC0C720B3EBBEC8C0C720BDC3B7C2BAB8C1A4BFA120B4EBC7D120C0AFBFEBBCBA20C6F2B0A1283035292E687770> 대한안과학회지 제 49 권 제 5 호 2008 J Korean Ophthalmol Soc 49(5):727-731, 2008 DOI : 10.3341/jkos.2008.49.5.727 다초점 소프트콘택트렌즈의 노안의 시력보정에 대한 유용성 평가 김현경 1 김효명 2 정성근 1 가톨릭대학교 의과대학 성모병원 안과학교실 1, 고려대학교 의과대학 안암병원 안과학교실