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1 대한내과학회지 : 제 76 권제 5 호 2009 종설 (Review) 통풍의최신지견 한림대학교의과대학내과학교실강남성심병원류마티스내과 정영옥 An update on the management of hyperuricemia and gout Young Ok Jung, M.D. Division of Rheumatology, Department of Internal Medicine, College of Medicine, Hallym Univerisy, Kangnam Sacred Heart Hospital, Seoul, Korea Gout is a common chronic inflammatory arthritis that can lead to significant disability. Gout is one of the few rheumatologic diseases that can be diagnosed with certainty and can be cured with appropriate therapy. Alcohol and dietary consumption are related to hyperuricemia and gout attacks. A moderate intake of purine-rich vegetables or protein is not related to an increased risk of gout. A weight-reducing, calorie-restricted diet with moderate carbohydrate restriction was beneficial for gout patients and reduced the serum uric acid and frequency of gout attacks, although these findings need to be confirmed. Clinicians should consider therapeutic options that do not increase the serum uric acid when treating associated conditions in gout patients. The acute gout attack can be treated appropriately with non-steroidal anti-inflammatory drugs, colchicine, or glucocorticoids. Hypouricemic treatment reduces the uric acid concentration by inhibiting its production (allopurinol) or enhancing its excretion (benzbromarone). Allopurinol is the agent used most commonly, but the recommended dose often fails to control the serum uric acid. Benzbromarone effectively reduces the serum uric acid, but possible hepatotoxicity should be monitored. Febuxostat, a new xanthine oxidase inhibitor, was recently approved by the Federal Drug Administration (FDA). PEGylated uricase, a potent parenteral hypouricemic agent, is under investigation for the treatment of gout. (Korean J Med 76: , 2009) Key Words: Gout; Hyperuricemia; Uric acid 서론통풍은성인남성에서가장흔한염증성관절염이다. 서구에서약 1~2% 의유병률을보이며서양인에비해동양인에서질병빈도가낮은것으로알려져왔으나최근서구화된식생활이나생활습관에의해서구와아시아권모두유병률이증가하는것으로보고되고있다 1,2). 우리나라에서도비만, 고지혈증, 고혈압등대사질환과연관되어발병이점차증가하고있으며건강검진집단을대상으로한보고에서성인의 9.3% ( 남자의 14.3%, 여자의 2.2%) 가고요산혈증 을가지는것으로파악되었다 3). 통풍은그치료법이명확하고성공적으로치료될수있는질병으로알려져있다. 또한치료약이나치료방법에있어크게변화가없는질병이기도하다. 그러나고혈압, 만성신부전등다른질병과동반되는경우가흔하여약제부작용을세심하게고려해야하는경우가많고비약물적치료로서생활습관을변화시키는환자의노력이장기치료의예후를좋게하는데필수적이다. 또한약물치료에잘반응하지않는심한환자들이나부작용으로적절한치료가어려운환자들이많이있다. 잘조절되지않는통풍은만성통풍으로발전

2 - Young Ok Jung. An update on management of hyperuricemia and gout - 하여관절의파괴를가져올수있으며고혈압, 만성신부전, 관상동맥질환등성인병발생과연관되어환자의전신건강을위협할수있다. 여기서는통풍치료의최근경향과새롭게밝혀진사실들에대해논해보고자한다. 통풍의동반질환및생활습관치료 1. 음식과통풍통풍이비만, 과음, 과식과관계있다는것은오래전부터잘알려져있는사실이다. 서구에서는오랫동안통풍이높은계급의풍요로움을나타내는질병이었다. 20세기중반이후퓨린대사와고요산혈증과의관계가정립되며혈중요산강하제가통풍예방에중요한역할을담당하게되었고, 식이요법의중요성이상대적으로작아지게되었다. 최근에는단순히퓨린함량이낮은음식을섭취하는것보다는고요산혈증과대사성질환을동시에개선시켜환자의장기예후를좋게할수있는식이요법의중요성이강조되고있다. 음식에함유된퓨린은혈중요산농도에영향을끼치며퓨린이제한된식이는혈중요산농도를감소시키는것으로알려져있다. 최근의대규모역학조사에서도퓨린함유량이높은식품인육류와어패류의섭취량과고요산혈증및통풍발병위험도사이에상관관계가있는것으로나타났다 4). 그러나이연구에서버섯, 콩등퓨린이풍부한채소류나, 단백질섭취량은통풍발생과연관이없었고, 유제품의섭취는통풍위험도를낮추는것으로조사되었다. 저퓨린식이는탄수화물함량이높고장기간지속하기힘들고실제로저퓨린식이를엄격하게시행해도요산강하효과가제한적이라는단점이있다. 또한탄수화물섭취가많아지면인슐린저항성을유발하고고지혈증, 당뇨, 혈압, 비만등동반질환의악화요인이될수있다. 또한저퓨린식이에서허용되는과당 (fructose) 은청량음료등에많이들어있는데과당함유식품의섭취량증가는통풍유병률과관계가있는것으로밝혀졌다. 과당은삼인산아데노신 (ATP) 을일인산아데노신 (AMP) 로전환시켜요산의체내생성을촉진시키며인슐린저항성을증가시키는역할을한다. 칼로리를제한하고단백질과불포화지방을증가시킨식단이혈중요산을감소시키고통풍발작빈도를낮추는것으로보고되었다 5,6). 이러한식단은인슐린감수성을증가시켜고지혈증, 비만등동반질환을호전시키며신세뇨관에서의요산배출이증가되어요산을낮추는것으로추정된다. 그러나요산강하제로충분히혈중요산농도가조절되지않는 환자는퓨린함유량이매우높은내장등의식품은제한하는것이좋다. 특히우리나라에서는알코올섭취와더불어안주로고퓨린식품을과식하게되는경우가많아급성통풍발작의원인이될수있으므로주의가필요하다. 알코올섭취는고요산혈증, 통풍과밀접한관련이있다. 알코올은요산의생성을증가시키며동시에배설을감소시키는역할을한다. 또한술을자주마시는환자는그렇지않은환자에비하여더낮은혈중요산농도에서도통풍발작을일으키는것으로나타났다 7). 최근대규모역학조사에서알코올섭취량이많을수록통풍의위험도가증가하고섭취하는알코올의종류도통풍위험도에영향을주는것으로나타났다 8). 퓨린함량이높은맥주가다른주류에비해통풍발생의위험도를증가시키며와인은통풍위험도를증가시키지않는것으로나타났다. 그기전은아직확실치않으나와인에포함된항산화제의역할또는상대적으로적은알코올함유량등이제시되었다. 그러나종류에관계없이많은양의술을마시는것은급성통풍관절염을유발할수있다. 비타민 C의섭취는요산의신장배설을증가시켜요산농도를낮추는데도움을주나 9) 장기간치료성적에대해서는연구가필요하다. 2. 동반질환의관리대사증후군은고혈압, 고지혈증, 혈당증가, 복부비만등의임상양상을보이며동맥경화성심질환과제2형당뇨병등의성인병의위험도증가를가져오는복합적인병증이다 10). 통풍과고요산혈증은대사증후군의진단기준에는들어가지않으나대사증후군은밀접한관계를가지는것으로생각된다. 우리나라에서는통풍환자의 44% 에서대사증후군이동반된것으로보고되었는데일반인구에서대사증후군이 5.2% 동반되는것과비교하여매우높은수치이다 11). 서구에서는 63% 동반이보고되었다 12). 대사증후군의중요한질병기전은인슐린저항성으로, 인슐린농도가높으면요산의재흡수를증가시키고체외배설을감소시켜고요산혈증을유발할수있는것으로알려졌다. 환자가고요산혈증또는통풍이진단되면대사증후군이동반되었는지에대해관심을가지고확인하여적절한치료계획을세우는것이바람직하다. 대사증후군이동반되었을경우규칙적인운동과식이조절을통한체중감소가필요하겠다. 높은신체용적지수 (body mass index: BMI) 는독립적인통풍발병의위험인자이며 BMI가증가하면통풍발병도증가하는것으로나타났다 13). Waist-to-hip ratio 의증가즉복부비만정도도통풍의위험도와상관관계가

3 - 대한내과학회지 : 제 76 권제 5 호통권제 585 호 있다. 따라서과체중인환자들의경우체중감소를유도하는것이좋으며정상체중일경우는이를유지할수있도록식이와운동의조절이필요할것이다. 그러나급격한체중감소를위한금식이나심한운동은오히려통풍발작을유발할수있으므로이에대한주의가필요하다. 통풍환자에서고혈압과고지혈증이동반되었을경우치료제선택에서요산농도에미치는영향을고려하는것이좋다. 고리이뇨제나 thiazide계통이뇨제는요산을높이는반면안지오텐신ii전환효소길항제로살탄, 칼슘통로차단제암로디핀등은요산농도를낮추는역할을한다 14,15). 아토바스타틴과페노피브레이트 (fenofibrate) 도요산을낮추는것으로보고되었다 16,17). 통풍의약물치료 1. 통풍발작치료통풍관절염은대개급성단관절염형태로나타나나소수관절또는드물게다관절을침범하기도한다. 급성통풍성관절염통풍의치료에쓰이고있는비스테로이드성항염제 (non-steroidal anti-inflammatory drugs: NSAIDs), 콜키친 (colchicine), 스테로이드는모두통풍발작을효과적으로치료할수있는약제이다. 통풍치료는무작위대조임상실험에대한개념이정립되기전에이미완성되었기때문에사실상이에대한임상실험은적고실제치료는경험에의한것이많다 18). 비스테로이드성항염제는최대용량으로사용하면종류에관계없이치료효과는비슷하다. 신기능장애, 소화성궤양, 심기능저하등동반질환이있을때위험이증가하므로사용에주의해야한다. 이런경우가아니라면통풍발작치료에처음선택되는치료제이다 19). 선택적 cyclooxygenase (COX) 2 억제제역시기존의비스테로이드성항염제와같은효과가있는것으로보인다. 189명의급성통풍환자를대상으로한 임상실험에서에토리콕시브와인도메타신은비슷한치료효과를보였다 20). 콜키친은과거로부터사용되어왔던약물로비교적통풍에특이적으로작용하여통풍진단이확실하지않은경우진단겸치료목적으로많이사용된다. 보통한시간간격으로 0.5~0.6 mg을복용하여증상이좋아지거나구토, 설사등위장관부작용이나타날때까지증량후끊는방식으로준다. 최대용량 (10회복용 ) 을복용할때까지증상호전이없다면통풍진단에대해의심해볼필요가있다 21). 부작용빈도가높아다른약을사용할수있고진단이확실한경우우선사용하지는않는다. 특히신기능저하가동반된경우 22), 스타틴계통약물과병용한경우 23) 근독성이증가하는것으로알려져주의가필요하다. 스테로이드는경구, 정주, 관절강내주사모두사용할수있고, ACTH 도효과적인것으로보고되었다 24). 약을먹을수없는환자나신기능저하, 소화성궤양이있는경우스테로이드를비경구적으로주는것이유용하다. 스테로이드를갑자기끊었을때통풍발작이다시악화되기도하므로예방적으로저용량콜키친 (0.6~1.2 mg/day) 을함께사용하기도한다 23). 이외에난치성다발성통풍발작에종양괴사인자억제제인에타너셉트를사용하여호전을보고하기도하여 25) 난치성인경우고려해볼만하나아직이에대한정보는많지않은실정이다. 2. 요산강하치료혈중요산농도를포화상태이하로장기간유지하면급성통풍성관절염의예방뿐아니라이미생긴통풍결절 (tophi) 의크기를줄일수있다 26). 요산저하제복용할때요산농도 <6.0 mg/dl 로유지하는것이권장된다 27). 요산저하제는기전에따라 xanthine oxidase (XO) 저해제와요산배설촉진제 (uri- Table 1. Pharmacological options for hypouricemic therapy Drug Dosage Precautions Comments Allopurinol 50 to 300 mg/day (Maximum dose 800 mg/day) Potentially fatal hypersensitivity syndrome Drug interactions with azathioprine and Dose must be reduced according to renal function according to guidelines warfarin Benzbromarone 50~125 mg/day Potentially fatal hepatotoxicity Effective in patients with renal impairment (CCr >25 ml/min) Febuxostat 80~120 mg/day Lack of long-term safety and efficacy data Metabolized in the liver; need to be avoided in patients with hepatic impairment CCr, Creatinine clearance

4 - 정영옥. 통풍의최신지견 - Table 2. Guidelines for the allopurinol dose according to renal function Creatinine clearance Allopurinol maintenance dose (ml/min) > mg every 3 days 100 mg every 2 days 100 mg/day 150 mg/day 200 mg/day 250 mg/day 300 mg/day cosuric agent) 로대별된다 ( 표 1). 알로퓨리놀 (allopurinol) 은 XO억제제로서고요산혈증의원인에관계없이효과적으로사용할수있는약물이다. 알로퓨리놀의반감기는 1~2시간으로짧으나활성대사산물인옥시퓨리놀 (oxypurinol) 은정상신기능에서반감기가 18~30시간으로 XO에대한주억제기능을수행한다. 약 20% 의환자에서위장관장애, 피부발진등의부작용이나타내며이들중약 5% 에서약제를중단하게되는것으로보고된다 21). 알로퓨리놀의가장심각한부작용은과민성증후군 (hypersensitivity syndrome) 으로발열, 홍반, 호산구증가, 간염, 신부전등을보이며사망에이를수있다 28). 과민성증후군의발생이신기능저하와이에따른옥시퓨리놀의혈청농도상승과관련이있는것으로생각되어크레아티닌청소율에따라용량을감소시키도록권장하였으나 ( 표 2) 28), 실제임상시험에서는크레아티닌청소율에따른알로퓨리놀유지용량감소가부작용발생을예방한다는것이증명되지는못하였다 29). 최근에는중국인에서 HLA-B* 5801을가진경우심한피부증상부작용발생이증가한다고보고되기도하였다 30). 요산배설촉진제로서국내에서유통되는약제는벤즈브로마론 (benzbromarone) 이있다. 벤즈브로마론은요산의분비후세뇨관재흡수를억제하는기전으로요산을낮춘다. 비교적적은용량으로도요산저하효과가크고신기능이저하된환자에서도비교적안전하고효과적으로요산을낮출수있으며 ( 크레아티닌청소율 >25 ml/min) 31,32), 통풍결절의크기를줄이는속도도알로퓨리놀보다빠른것으로보고되었다 26). 그러나심각한간독성이보고되어있어 33) 이에대한주의를요한다. 페북소스타트 (febuxostat) 는역시 XO억제제이나알로퓨리놀과달리비퓨린계선택적차단제로서주로간에서대사되어글루크로나이드 (glucronide) 를형성한다. 임상시험에서알로 퓨리놀과비교하여요산강하효과가좋고통풍발작억제면에서도좋은성적을보였다 34). 특히신기능저하환자에서도용량을조절할필요가없이사용해도부작용이증가하지않으며신기능저하환자에서도요산강하효과가좋다는장점이있다. 최근미국식품의약국 (FDA) 의승인을받아기존약제를사용하기힘든환자에서사용이증가될전망이다. 사람을비롯한영장류에는요산을알란토인 (allantoin) 으로분해하는우리카아제 (uricase: urate oxidase) 가없다. 우리카아제에의해요산이알란토인으로전환되면용해도가높아쉽게신장을통해배설되며근본적으로고요산혈증이나통풍이라는문제자체가발생하지않게된다. Rasburicase 는재조합우리카아제로종양용해증후군 (tumor-lysis syndrome) 의예방을위한단일사용으로승인을받은약물이다. 주사제로서효과가빠르고신속하게요산을감소시키고통풍결절을녹이는효과가뛰어난것으로보고되었다. 그러나반감기가약 18시간정도로짧고반복사용시에는이약에대한항체가형성되고 35) 아나필락시스위험이있어 36) 통풍환자에서장기간사용하기에는적당하지않다. 이런문제를해결하기위해 polyethylene glycol (PEG) 로처리하여항원성을줄이고반감기를증가시킨약제가페글로티카제이다 (pegloticase, PEGuricase) 이다 37). 페글로티카제는정맥주사로사용하며 38) 난치성통풍환자를대상으로한임상연구에서주사후약 6시간내에요산강하효과를보이고, 8 mg, 2주간격으로사용한군에서가장좋은효과를보였다 39). 가장흔한부작용은통풍발작으로약 88% 의환자에서나타났고 41명의대상환자중 31명에서약에대한항체가형성되었다. 특히결절성통풍환자에서결절의크기를빠르게줄이는데에유용할것으로보이나아직장기적으로사용하였을때의안전성이확보되지않아향후여기에대한연구가더진행되어야할것이다. 결론통풍의치료는의학의역사를아우르는긴전통을가지고있으나최근식이요법의새로운방향이제시되고기존에쓰던약물에저항을보이는환자에서사용될수있는새로운요산강하제가개발되는등변화를보이고있다. 이러한발전과더불어환자개개인의동반질환과약제부작용들을세심하게관찰하고조절하는노력을기울인다면통풍환자의치료결과는더욱좋아질것으로기대된다. 중심단어 : 통풍 ; 고요산혈증 ; 요산

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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