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1 대한내과학회지 : 제 76 권제 2 호 2009 알로퓨리놀사용후발생한진성적혈구감소증 1 예 성균관대학교의과대학마산삼성병원내과학교실 이진호 허종훈 권경아 한대희 황종운 조성 김성록 Allopurinol hypersensitivity syndrome and pure red cell aplasia associated with allopurinol treatment Jin Ho Lee, M.D., Jong Hun Heo, M.D., Kyung A Kwon, M.D., Dae Hui Han, M.D., Jong Woon Hwang, M.D., Seong Cho, M.D. and Sung Rok Kim, M.D. Department of Internal Medicine, Masan Samsung Hospital Sungkyunkwan University School of Medicine, Masan, Korea Allopurinol is widely used to reduce serum uric acid levels and, generally, has mild side effects. Rarely, allopurinol hypersensitivity syndrome occurs and this consists of severe systemic skin lesions, fever, reduced kidney and liver function, and leukocytosis with eosinophilia. Extremely rarely, allopurinol-induced pure red cell aplasia is reported. We report a case of allopurinol hypersensitivity syndrome and pure red cell aplasia following allopurinol therapy for eight weeks and the disease response to steroid therapy in a patient with chronic renal insufficiency. (Korean J Med 76: , 2009) Key Words: Allopurinol; Pure red-cell aplasia 서론 Allopurinol은혈중요산농도를조절하기위한 xanthine oxidase inhibitor로 40년에걸쳐큰부작용없이통풍이나고요산증치료에널리사용되어지고있다 1). Allopurinol의부작용은대부분위장관장애이며, 2% 에서경한피부발진이발생하나투약을중지하면곧호전된다 2). 드물게전신적인심한피부발진, 열, 신기능및간기능장애를동반하여생명을위협하는과민반응이보고되고있으며이를 Allopurinol hypersensitivity syndrome이라한다 3). 약물에의한급성진성적혈구감소증은간혹보고되고있으며, Allopurinol에의해발생하는경우는드물게증례보고되고있지만 4-6) 국내에선아직증례보고가없다. 저자들은만성신장병을가진환자에 서 Allopurinol 사용후 Allopurinol hypersensitivity syndrome 과진성적혈구감소증이병발한사례와투약중단과부신피질호르몬사용후임상적호전된증례를경험하였기에보고하는바이다. 증례 69세의남자로평소고혈압, 심장질환및후천성다발성낭종을동반한만성신기능장애로타병원에서고혈압약복용및경과관찰하다가본원에오게되었으며, 내원당시혈압은 130/80 mmhg, 체온 36.7 로비교적건강한상태였고, 엄지발가락동통을호소하였다. 검사실검사상혈색소 9.2 g/dl, 백혈구 4800/uL, 혈소판 209,000/uL, 혈청크레아티닌 2.5 mg/dl, 뇨산 12.0 mg/dl였다. 내원당시복용중인약물 Received: Accepted: Correspondence to: Jin Ho Lee, M.D., Department of Internal medicine, Masan Samsung Hospital, Sungkyunkwan University School of Medicine, 50 Hapseungdong, Masan , Korea jolinkong@hanmail.net

- Jin Ho Lee, et al. Allopurinol hypersensitivity syndrome associated with Allopurinol treatment - Figure 2.

The state after Allopurinol therapy for 10 weeks.

8 g/dl, 백혈구 3,300 /ul ( 호산구분획13%), 혈소판 171,000/uL, 혈청크레아티닌 2.3 mg/dl, 요산 4.

2 - Jin Ho Lee, et al. Allopurinol hypersensitivity syndrome associated with Allopurinol treatment - Figure 2. Peripheral blood morphology showing normocytic normochromic red blood cells (RBC) with anisopoikilocytosis and a few fragmented RBC (+) (Wright stain, 200). Figure 1. The state after Allopurinol therapy for 10 weeks. 은 Angiotensin II receptor blocking agent 인 Valsartan 80 mg, Calcium channel blocker인 Felodipine 5 mg으로고혈압은잘조절되어그대로사용하고고요산증치료를위해 Allopurinol 을 200 mg/day 사용하였다. 외래경과 2개월째전신적인피부발진이발생하였고검사상혈색소 5.8 g/dl, 백혈구 3,300 /ul ( 호산구분획13%), 혈소판 171,000/uL, 혈청크레아티닌 2.3 mg/dl, 요산 4.4 mg/dl로심한빈혈소견이있었지만입원원하지않아서그대로투약하였고, 2주일후외래내원시더심해진피부발진과 ( 그림 1) 노작성호흡곤란소견이있었고, 이학적검사에서혈압 130/70 mmhg, 심박동수 110 회 / 분, 호흡수 18회 / 분확인되었고, 창백한결막소견과얼굴을포함한전신피부에표피박탈을동반한피부발진이보였다. 검사상혈색소 4.5 g/dl, 망상적혈구수 0.08%, 백혈구 5,300/uL( 호산구분획 18%), 혈소판 208,000/mL, 혈청크레아티닌 2.8 mg/dl, AST 16 IU/L, ALT 17 IU/L 으로더심해진빈혈과피부병변보여입원하였다. 입원전 2~3 개월간상기도감염병력이나다른약물복용력이없었고입원후시행한말초혈액도말검사 ( 그림 2), 골수검사 ( 그림 3) 상진성적 Figure 3. Bone marrow aspirate showing a mildly hypocellular marrow, with a marked decrease in erythroid elements (Wright stain, 400). 혈구감소증소견이보였고, 피부조직검사 ( 그림 4) 는약제유발성박탈성피부질환소견이보였다. Parvovirus B19 에대한검사는 Parvovirus B19 PCR (-), Parvovirus B19 IgG (+) 였다. Allopurinol에의한 Allopurinol hypersensitivity syndrome과급성진성적혈구감소증을생각하고 Allopurinol을중단하고부신피질호르몬을 1 mg/kg 사용하였으며, 노작성호흡곤란호소하여농축적혈구를 2 pints 수혈하였다. 치료일주일후혈액검사에서혈색소 6.5 g/dl, 망상적혈구수 0.14% 확인되었고, 2주일후검사에서혈색소 8.8 g/dl, 망상적혈구수 0.94% 로회복되어부신피질호르몬감량하면서퇴원하였

- 대한내과학회지 : 제 76 권제 2 호통권제 582 호 2009 - Figure 4. Skin biopsy showing marked inflammation in the papillary dermis and some atrophic changes with basal disruption of the epidermis (H&E stain, 100). 다.

고 진성적혈구감소증은심한빈혈을보이며골수검사에서적아세포만없고나머지는정상이며, 말초혈액검사상백혈구, 혈소판은정상이나적혈구및망상적혈구가감소하는소견을보이는흔하지않은혈액질환이다 7). 성인에서발생한진성적혈구감소증은대부분특발성이나감염, 악성종양, 전신성홍반성낭창, 약제사용등에의해서도생길수있으며, 급성형태의진성적혈구감소증의 80% 는감염후 20% 는약제사용후발생한다.

3 - 대한내과학회지 : 제 76 권제 2 호통권제 582 호 Figure 4. Skin biopsy showing marked inflammation in the papillary dermis and some atrophic changes with basal disruption of the epidermis (H&E stain, 100). 다. 퇴원 10일후외래검사상혈색소 9.5 g/dl, 요산 10.3 mg/dl, 혈청크레아티닌 2.1 mg/dl 확인되어현재까지외래경과관찰중이며, 피부병변은표피박탈후서서히회복중이고 ( 그림 5) 고요산혈증에대해서는 Benzbromarone을 Allopurinol 대신사용하고있다. 고 진성적혈구감소증은심한빈혈을보이며골수검사에서적아세포만없고나머지는정상이며, 말초혈액검사상백혈구, 혈소판은정상이나적혈구및망상적혈구가감소하는소견을보이는흔하지않은혈액질환이다 7). 성인에서발생한진성적혈구감소증은대부분특발성이나감염, 악성종양, 전신성홍반성낭창, 약제사용등에의해서도생길수있으며, 급성형태의진성적혈구감소증의 80% 는감염후 20% 는약제사용후발생한다. 감염후발생한진성적혈구감소증의경우대부분 Parvovirus B19와연관이있으며, 약제에의한경우는다양하나항경련제, 항생제, 갑상선치료제등이가장흔한약제이다 8, 9). 급성형태의진성적혈구감소증의발병기전은확실하지않으며 anti-erythroblast antibody, anti-erythropoietin antibody, T cell mediated-erythropoietin inhibition 등이관여할것이라는보고가있으며 10), Watts 등 11) 은 Valproate 가직접골수세포들의군체형성을억제한다는실험실보고를하였지만, 약제에의한진성적혈구감소증의정확한발병기전은아직까지알려져있지않다. Allopurinol에의한진성적혈구감소증발생은현재까지 3예가증례보고되고있다. 증례모두약물투 찰 Figure 5. The approved state after steroid therapy. 여하고 6~8 주경과후발생하였고, 2예의경우는정상적인신기능을가진경우였고, 1예는신기능장애 ( 혈청크레아티닌 : 2.5 mg/dl, 사구체여과율 : 35 ml/min) 가있는경우였다. 이들 3예의임상경과를보면신기능의장애가없는 2예 4, 5) 의경우약물중단만으로곧빈혈이호전되었지만신기능의장애를가진 1예 6) 에서는약물중단과부신피질호르몬및조혈호르몬사용후 11주에걸쳐서서서히회복되었다. 본증례의경우는혈청크레아티닌이 2.5 mg/dl, 사구체여과율은 14.9 ml/min였고, Allopurinol 사용후 8주때진성적혈구감소증이발생하였고, 부신피질호르몬사용후 2주때부터말초혈액수치가회복되었다. Allopurinol에의한진성적혈구감소증의발생기전은모르나 Fox 등 12) 의보고에따르면복용된 Allopurinol은흡수된후 Oxypurinol로대사되어요산생성을억제하는주된역할이외에도 allopurinol ribonucleotide로변환하면서적혈구내 phosphoribosylpyrophosphate (PRPP) 를소모시킨다. PRPP는핵산인퓨린과피리미딘생성에중요한역할을하므로 Allopurinol이퓨린생성을억제하는기능을가질것이라고하였다. 이러한기능은조혈작용을억제하는항대사성항암제기능과비슷하다고하겠다. 항암제로치료중인환자에대한임상연구들 13, 14) 에서 Allopurinol을항암제와병용한경우에항암제단독으로사용한경우보다도의미있게골수억제가많이발생하였다고한다. Allopurinol로치료중인환자에서위장관장애, 피부발진같은경한부작용은약물중단후좋아지며경한피부발진발생빈도는 1.8~2% 정도로보고되고있다 2, 15). 드물게박탈피부염을포함하여간장, 신장기능장애와고열을동반하는

4 - 이진호외 6 인. 알로퓨리놀사용후발생한진성적혈구감소증 1 예 - Table 1. Singer & Wallace's diagnostic criteria for AHS 3) 1 Clear history of exposure to Allopurinol 2 A. At least two of the following major criteria: 1. worsening fo renal function 2. acute hepatocellular injury 3. a rash including either TEN, erythema multiforme, or a diffuse maculopapular or exfoliative dermatitis B. One on the above major criteria plus at least one of the following minor criteria: 1. fever 2. eosinophilia 3. leukocytosis 3 Lack of exposure to another drug that may cause a similar clinical picture 심한부작용을야기시키는경우가있으며이를 allopurinol hypersensitivity syndrome라한다. Allopurinol hypersensitivity syndrome는드물게증례보고되어 allopurinol 사용환자중에서어느정도발생하는지는모르나 McInnes 등 15) 의보고에따르면 allopurinol 사용중인입원환자 260명중 1명에서발생 (0.4%) 하였다고한다. Allopurinol hypersensitivity syndrome 의임상경과는나빠서증례보고된 101명의환자중 27 명 (26.7%) 의환자가독성표피괴사융해증이나심한간기능부전, 신기능부전등으로사망하였다고보고되고있다 16). Allopurinol hypersensitivity syndrome의진단기준은 Singer and Wallace의진단기준을사용하고있다 3) ( 표 1). Allopurinol hypersensitivity syndrome의발생기전은아직까지모르며유전적특이체질, 면역기전, 약물의축적등이관여할것으로알려져있고, allopurinol hypersensitivity syndrome가발생한환자의대부분이부작용발생전이미만성질환을가진경우가많았고고혈압, 만성신기능장애, 당뇨, 심부전빈도순으로질환을가지고있었다. 특히신기능장애를가진경우는 47% 나되어서 allopurinol 배설장애로인한혈중농도상승이 allopurinol hypersensitivity syndrome의위험인자로여겨진다 16). Allopurinol은복용후 oxypurinol로신속히대사되어지며이물질의혈중농도는신장배설능력에달려있다. Hande 등 17) 은사구체여과율이 10 ml/min 인경우는정상신기능을가진환자에비해반감기가 5배정도길어지며혈중 oxypurinol 농도와 AHS 발생사이에는연관관계가있으므로신기능이감소한경우 allopurinol 용량을감량하여야된다고제안하였고, 실제임상에서도신기능이감소된환자에게사용시용량을감량하여사용하는것이일반적이다. 또한개인적특이체질에의해부작용이잘생긴다고여 겨지나, allopurinol hypersensitivity syndrome 발생대부분이약물투여후 4~6 주후에발생하고조직검사상임파구의침윤과육아종형성이있고 oxypurinol에의한자극실험에서 T 임파구의증가, AHS 환자의말초혈액에서 CD8 항원을표현하는 T 임파구의증가가있으므로세포매개면역체계가 allopurinol hypersensitivity syndrome 발생에관여한다는보고도있다 18). 치료는빠른진단과 allopurinol의중단이우선이며부신피질호르몬의사용에대해서는 4주간 1~2 mg/kg을사용시 50% 정도에서임상적인호전이있다는보고도있지만 16) 서로상반된보고가있어서정립되어있지않다. 본예는만성신장기능장애를기저질환으로가지고있었고부신피질호르몬사용후임상적으로호전을보였다. 요약 Allopurinol은고요산증치료를위해많이사용되고있는약제이며가벼운위장장애및피부발진을유발할수있다. 고혈압, 만성신기능부전등의기저질환이있는경우드물게심한표피박탈성피부발진과간장, 신장장애를동반하는 allopurinol hypersensitivity syndrome을야기시키며이때는신속한진단과약물투여중지를해야한다. Allopurinol은약제사용 6~8 주후급성진성적혈구감소증을드물게유발할수있다. 저자들은만성신기능부전을가진환자에서 allopurinol 사용 8주경부터 allopurinol hypersensitivity syndrome 과진성적혈구감소증이병발한경우를경험하여보고하는바이다. 중심단어 : 알로퓨리놀 ; 진성적혈구감소증

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract