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1 대한내과학회지 : 제 75 권제 1 호 2008 Special Review in Portal Hypertension - 문맥압항진증과합병증 복수및자발세균복막염 고려대학교의과대학내과학교실 서연석 Ascites and spontaneous bacterial peritonitis Yeon Seok Seo, M.D., Ph.D. Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Ascites is the most common complication of liver cirrhosis and the first presentation of hepatic decompensation in most of patients with liver cirrhosis. In addition, the development of ascites is the significant predictor for poor prognosis. The therapeutic modalities for the control of uncomplicated ascites include low sodium diet and diuretics. Spironolactone is the drug of choice for the control of cirrhotic ascites, while furosemide is generally used as an adjunct to spironolactone. In patients with refractory ascites, repeated large-volume paracentesis is the treatment choice. Spontaneous bacterial peritonitis (SBP) is the most common infection in patients with liver cirrhosis. Although inhospital mortality of patients with SBP have significantly reduced with the rapid diagnosis and choice of effective antibiotics, still 15~20% of patients died during hospitalization. Third-generation cephalosporin is the drug of choice for the treatment of SBP, which can cover about 95% of causative organisms. In patients with high-risk of SBP, prophylactic antibiotics should be considered. (Korean J Med 75:15-26, 2008) Key Words : Ascites; Liver cirrhosis; Paracentesis; Peritonitis 복수는간경변증의가장흔한합병증으로서대상성간경변증환자를관찰하였을때반정도에서 10년이내에복수가발생한다 1). 복수가발생하면환자의삶의질이떨어지고감염및신부전등치명적인합병증의발생위험이증가한다 1, 2). 복수의발생유무는간경변증환자의예후평가에서중요한경계로생각되는데, 간경변증환자에서복수가발생한경우간이식을받지않는다면 1년이내에 15%, 5년이내에 50% 가까이사망할정도로예후가불량하다 3). 복수의발생기전복수가발생하는데있어가장중요한역할을하는것은내장동맥혈관확장 (splanchnic arterial vasodilation) 및이로인한유효동맥혈류량 (effective arterial blood volume) 의감소이다 4). 즉, 간경변증으로문맥압이상승하면 nitric oxide 와같은혈관확장물질의국소적생성이증가하여내장동맥 혈관확장이발생한다 5). 간경변증초기에는내장동맥혈관확장의정도가그리심하지않아혈장량및심박출량을증가시킴으로써유효동맥혈류량을정상적으로유지할수있으나 4) 간경변증이점차진행하여내장동맥혈관확장의정도가너무심해지면결국유효동맥혈류량이현저히감소하고동맥압이떨어지게되며, 이에대한보상기전으로교감신경계, renin-angiotensin-aldosterone system ( 이하 RAAS) 및항이뇨인자가활성화되면서신장에서나트륨과수분이저류되어복수및희석저나트륨혈증 (dilutional hyponatremia) 이발생한다 4, 6, 7). 간경변성복수환자의평가간경변성복수는전체복수의 75~85% 를차지할정도로가장흔한원인이며 8, 9), 대부분의환자에서문진이나신체검사만으로도간경변성복수임을확인할수있기는하지만 9),

2 - The Korean Journal of Medicine : Vol. 75, No. 1, Table 1. Recommended tests for the evaluation of the patients with cirrhotic ascites Test Blood tests Ultrasonography Endoscopy Diagnostic paracentesis Purpose Evaluate liver function (AST, ALT, bilirubin, albumin, PT) and renal function (BUN, creatinine) Rule out hepatocellular carcinoma or portal vein thrombosis Assess the esophageal and gastric varices Evaluate the cause of ascites (albumin) and rule out peritonitis (PMN cell count and differential) AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; BUN, blood urea nitrogen; SAAG, serum-ascites albumin gradient; PMN, polymorphonuclear 아무리임상적으로간경변성복수가확실하다고생각되더라도악성종양, 심부전, 결핵및췌장염등다른원인에의한복수를감별해보아야한다. 복수가 1.5리터이상있는경우에는타진 (percussion) 으로옆구리탁음 (flank dullness) 및이동탁음 (shifting dullness) 을확인함으로써복수의유무를진단할수있다 10). 옆구리탁음이없는경우복수가실제로있을가능성은 10% 미만이다. 10 복수초음파검사의경우복수가 100 ml 정도만있어도진단이가능하다 11). 간경변성복수환자에서는신기능장애가동반되는경우가많으므로간기능뿐아니라신기능도함께평가해야한다 2). 신기능평가의경우이뇨제가결과에영향을줄수있으므로이뇨제를투여하기이전에시행하는것이좋다 2). 또한, 복부초음파검사를통해간세포암종이나문맥혈전증등이동반되지않았는지, 상부위장관내시경검사로식도및위정맥류유무를확인하는것이좋다 12). 간경변성복수환자의평가에필요한검사는표 1과같다. 진단적복수천자 : 복수의원인을진단하는데있어가장신속하고경제적인방법일뿐아니라간경변성복수환자를평가하는데중요한검사의하나이므로복수가처음으로발생하였거나간경변성복수환자에서발열, 복통, 위장관출혈, 간뇌증, 저혈압, 또는신기능부전등이있는경우에는반드시시행해야한다. 또한, 입원하고있는간경변성복수환자의 15% 에서자발세균복막염 (spontaneous bacterial peritonitis, 이하 SBP) 이동반되어있을정도로빈도가높으므 13, 14) 로간경변성복수환자가입원하는경우에도반드시시행해보아야한다. 복수천자는종대된간이나비장을찌르는것을피하기위해좌하복부또는우하복부에서시행하는데, 주로이용되는부위는좌하복부의 counter-macburney point이다 9). 하복벽동맥 (inferior epigastric artery) 이치골 (pubis) 과전상장골극 (anterior superior iliac spine) 의중간부분으로주행하므로이부위는반드시피해야한다 9). 간경변 증으로인한지혈기능저하는복수천자의금기로생각되지않으며출혈위험을줄이기위해복수천자전에신선동결혈장 (fresh frozen plasma) 이나혈소판을수혈하는것은권장되지않는다 15). 복수천자결과의해석 : 복수천자의가장중요한목적은복수의원인감별및복수감염유무의확인이므로검사항목에알부민농도와혈구수및분획 (cell count and differential) 을반드시포함해야한다 : (1) 알부민농도 : 복수의원인감별은혈청알부민농도에서복수알부민농도를뺀값인 serum-ascites albumin gradient (SAAG) 값을이용하는데, SAAG 가 1.1 g/dl 이상이면문맥압항진증에의한복수로진단할수있다 8). 복수의단백질농도 2.5 g/dl을기준으로한여출액 (transudate)/ 삼출액 (exudates) 의분류는 SAAG에비해복수의원인진단에대한정확도가떨어지므로현재는이용되지않는다 8). 간경변성복수환자에서다른복수를형성할수있는원인이동반되더라도 SAAG 는 1.1 g/dl 이상으로유지된다 15) ; (2) 혈구수및분획 : 복수혈구수는복수감염을진단하는데가장유용한검사이다. 감염이없는경우복수의백혈구수는 100/mm 3 미만이며단핵세포가주를이룬다 (>75%) 12). 복수의백혈구수가증가하고다형핵백혈구 (polymorphonuclear leukocyte, 이하 PMN) 비율이높아지는경우복수의감염을시사하며, 장천공및다른복부장기의염증이없으면서복수의 PMN 수가 250/mm 3 이상으로상승한경우에는 SBP로진단할수있다 14). 간경변성복수에서적혈구수는대개 1,000/mm 3 미만이나 2% 정도에서는적혈구수 50,000/mm 3 이상의혈성복수가관찰된다 16). 복수의적혈구수가 10,000/mm 3 이상인경우에는복수로유입된혈액내중성구로인한증가를보정하기위해복수중성구수에서복수적혈구 250개당한개씩을빼주어야한다 14) ; (3) 기타검사 : 복수의총단백질, lactate dehydrogenase ( 이하 LDH) 및포도당수치가자발복막염과이차복막염구분에도움이될수있으므로복수의감염이의심되는경우

3 - Yeon Seok Seo : Ascites and spontaneous bacterial peritonitis - Table 2. Recommended tests in diagnostic paracentesis All patients with ascites Patients with peritonitis Protein Protein Albumin Albumin Cell count and differential Cell count and differential Glucose LDH Amylase Culture LDH, lactate dehydrogenase 에는처음복수검사를할때같이검사하는것이좋다 17). 또한, 복수감염의가능성이있는경우에는원인균의확인및항생제감수성검사를위해세균배양검사를시행한다. SBP에서원인균이동정되는경우는 50% 정도이나복수를천자한후즉시그자리에서혈액배양용기에접종하면원인균동정율을 80% 까지올릴수있다 18, 19). 일반적인복수천자검사항목을표 2에정리하였다. 간경변성복수환자의관리에서일반적인주의사항복수는소변등을통해배설되는나트륨의양이체내로유입된양보다적어져서생기므로들어오는양보다배설되는양이많도록하여체내나트륨균형을음성으로만들어주는것이복수치료의기본적인목적이다 20). 그러므로나트륨섭취를제한하여들어오는양을줄이고이뇨제등으로사용하여배설되는양을늘리는것이복수치료의기본이된다. 그러나이보다더기본적이고더중요하게생각되어야할사항은다음과같은것이아닐까생각된다 : (1) 복수를치료할때가장중요한목표로생각해야할것은바로기저간질환의치료이다. 알코올성간경변증환자에서의철저한금주, 만성 B형간염에대한적절한항바이러스치료, 또는자가면역성간염에의한간경변증에서스테로이드치료등으로복수의현저한호전또는소실을기대할수있다 ; (2) 복수를조절할때 과유불급 ( 過猶不及 ) 이라는말을잊으면안된다. 치료를통해환자가불편감을느끼지않도록유지해주면되는것이지, 꼭복수를완전히없애야하는것은아니다. 오히려복수의과다치료는저나트륨혈증, 신부전, 또는간성뇌증등심각한합병증을유발할수있다. 즉, 복수환자는 dry and demented 하게만드는것보다는 wet and wise 한상태로유지하는것이더좋다 11) ; (3) 간경변증 환자에서는식이섭취및영양분흡수가저하되고에너지소비는증가하므로충분한단백질 ( 하루체중 kg 당 1.0~1.2 g) 및칼로리 ( 하루체중 kg 당 25~35 kcal) 의공급이필요하다 12, 21). 그런데복수를조절하기위해저염식을너무강조하다보면일부환자에서는식욕저하가더심해져영양상태를더욱악화시킬수있다. 환자에대한식이교육및주의깊은관찰을통해충분한영양공급이유지되도록항상신경을쓰는것이좋다 ; (4) 간경변증환자에서복수가발생하였다면간이식의가능성에대해심각하게고민해보아야한다. 복수를동반한간경변증환자의경우 5년생존율이 30~40% 에불과하지만간이식을받는경우 70~80% 의생존율을기대할수있다 22, 23). 특히난치성복수, SBP, 또는간신증후군등신기능또는순환기능의심한장애가있는경우에는예후가더욱불량하므로이런합병증이발생한경우에는가능하면간이식이가능한병원으로의뢰하는것이좋다 2). 단순복수환자의치료단순복수는난치성복수, SBP, 또는간신증후군 (hepatorenal syndrome) 등의합병증이발생하지않은경우를말하며이런단순복수환자를어떠한방법으로얼마만큼치료할것인가는복수가얼마나심한가에따라결정된다. 일반적으로이용되는복수의분류및이에대한대표적인치료는표 3과같다 20). 경도 (grade I) 복수는특별한치료를요하지않으나, 경도복수환자의대부분에서중등도복수로진행하므로나트륨섭취를줄이도록충고하는것이좋다. 1. 중등도복수환자의치료중등도 (grade II) 복수환자에서는복수가차는속도가그리빠르지않기때문에나트륨섭취를너무많이하지않는경우라면대량복수가발생하는경우는거의없으며복수가발생하고도상당한시간이지난후에야불편감을느껴병원을찾게된다. 대부분유리수분배설이나사구체여과율 (glomerular filtration rate, 이하 GFR) 은정상으로유지되므로혈청나트륨이나 creatinine ( 이하 Cr) 농도는정상이다. 대부분에서복수는나트륨섭취제한과이뇨제투여로잘조절된다 24-26). 1) 식이요법복수조절을위해나트륨섭취를하루 90 mmol 이하로제한하는것이권장된다. 그러나나트륨섭취제한만으로

4 - 대한내과학회지 : 제 75 권제 1 호통권제 575 호 Table 3. First-line treatment according to the grades of uncomplicated ascites in patients with liver cirrhosis Grade Sign & symptom First-line treatment Grade I (mild ascites) Detected only by ultrasonography Educate low salt diet Grade II (moderate ascites) Grade III (large-volume ascites) Moderate distension of abdomen & mild/moderate discomfort Marked abdominal distension & significant abdominal discomfort Low salt diet ± diuretics Large volume paracentesis followed by low salt diet & diuretics 복수가조절되는경우는 10% 정도에불과하며대부분은이뇨제치료와병행하게된다 27, 28). 나트륨섭취제한은복수조절을위한이뇨제요구량을줄일수있고, 복수조절속도를더빠르게하며입원기간을단축시킨다 29, 30). 나트륨섭취를더엄격하게제한하면복수조절속도가더빨라질수있기는하지만환자의순응도및영양상태에악영향을줄뿐아니라신기능장애및저나트륨혈증등이뇨제의합병증발생이증가할수있으므로권장되지않는다 29-31). 입원하고있는간경변성복수환자에서는나트륨이포함되어있는수액의사용을피해야하며정맥내로투여하는항생제에도상당량의나트륨이들어있으므로주의를요한다 9). 소시지, 햄, 치즈, 통조림에들어있는음식등보통염분이많다고알고있는것들이외에도과자, 케이크, 아이스크림, 사탕, 밀크초코렛, 탄산음료등에도상당량의나트륨이들어있으므로피해야한다 32). 복수가한번도없었던간경변증환자에서예방적목적으로나트륨섭취를제한하는것은아무런의미가없다. 간경변성복수에서이뇨제치료등을통해나트륨배설을증가시키면수분은나트륨이배설될때함께수동적으로배설되기때문에단순복수환자에서수분섭취를제한할필요는없다. 그러나복수가있으면서혈청나트륨농도가 130 meq/l 미만인희석저나트륨혈증의경우에는수분섭취를하루 1~1.5리터이하로제한하는것을고려해보아야한다 12). 2) 이뇨제간경변성복수조절에주로사용되는이뇨제는알도스테론길항제인 spironolactone( 상품명, Aldacton) 과루프이뇨제인 furosemide( 상품명, Lasix) 이다. 간경변성복수의원인인나트륨저류는 RAAS 항진에따른이차성고알도스테론혈증으로신세뇨관에서의나트륨재흡수가증가하기때문에발생하므로 33) 알도스테론길항제인 spironolactone이간경변 성복수치료에가장중요한이뇨제로사용된다. 이에반해 furosemide 는헨레고리 (loop of Henle) 의상행각 (ascending limb) 에서 chloride 의능동적흡수를억제하여원위세뇨관으로운반되는나트륨, chloride 및수분을증가시켜빠르고강력한이뇨작용을유발하여가장대표적인이뇨제로사용되고있으나간경변성복수에서는원위세뇨관으로이동한나트륨의대부분이고알도스테론혈증의영향으로재흡수되어버리므로 furosemide 단독요법으로는큰이뇨효과를보기힘들다 25). Furosemide 로원위세뇨관으로운반되는나트륨을증가시키면서 spironolactone으로원위세뇨관에서의나트륨재흡수를억제하면강력한이뇨효과를기대할수있다 9, 15). 이뇨제사용법 : 이뇨제투여방법은 spironolactone 단독으로시작한후반응에따라 furosemide 를추가하는방법과처음부터 spironolactone과 furosemide 를병용하는요법등두가지로나누어볼수있다. 단독요법의경우 spironolactone을하루 50~100 mg으로시작하여반응에따라 3~4 일간격으로하루 400 mg까지증량한후반응이충분하지않으면 furosemide 를하루 20~40 mg으로시작하여반응에따라증량하는것이다 20, 34). 이렇게치료하는경우대부분의환자에서하루 200~300 mg의 spironolactone 만으로도복수가현저히호전되나 15) spironolactone 단독으로사용하는경우고칼륨혈증이발생할위험이증가할뿐아니라충분한이뇨효과를보일때까지의기간이길어복수가심하지않은환자들에서만사용한다 35). 대부분의경우처음부터 spironolactone과 furosemide 를함께투여하는데, 나트륨뇨배설 (natriuresis) 및이뇨효과를좋게하면서칼륨농도에대한영향을최소화하기위해 spironolactone과 furosemide 를 100:40의비율로사용한다 36). 보통 spironolactone 100 mg과 furosemide 40 mg으로시작하며체중감소또는나트륨뇨배설이충분하지않으면 100:40의비율은유지한상태에서 3~5일간격으로증량한다 15). 복수가어느정도조절된이

5 - 서연석 : 복수및자발세균복막염 - 후에는이뇨제로인한합병증을피하기위해이뇨제를감량해야한다. 이뇨제요구량이감소하여한가지약제만을사용하고자할때에는 furosemide 를먼저끊는것이좋다. 반응의평가 : 환자의체중변화를관찰함으로써사용하고있는이뇨제의용량이적절한가를쉽게평가할수있다. 외래에서치료하는경우에는집에서매일체중을측정하여기록하도록하는것이좋다. 심한부종이있는경우에는하루 1 kg 이상체중을감량하여도문제가없으나, 부종은없이복수만있는경우에는하루 0.5 kg 이상줄지않도록이뇨제의용량을조절해야한다 15, 37). 이뇨가과다한경우신기능장애, 간뇌증및저나트륨혈증이나타날수있으므로체중, 신기능및전해질균형에대한주기적인감시가필요하다 38). 이뇨제치료에도체중이감소하지않는경우에는소변나트륨검사를통해현재사용중인이뇨제의용량이적절한가를평가해보아야한다. 저염식을잘지키고있는경우소변을통해 78 mmol ( 하루섭취량 88 mmol 신장외배설량 10 mmol) 이상의나트륨배설되어야복수가조절된다. 그러므로 24시간동안모든소변에서의나트륨양이 78 mmol 미만인경우에는현재사용중인이뇨제의용량이부족함을의미하며이뇨제의증량을고려해보아야한다. 만약 24시간소변의나트륨양이 78 mmol을넘는경우에는환자가저염식을잘지키지않음을의미하므로환자에게복수조절에서의식이조절의중요성을다시한번잘인식시켜저염식을잘지키도록유도해야한다. 그러나 24시간동안소변을한번도빠뜨리지않고모으기가힘들고번거롭기때문에 24시간소변검사를시행하기는쉽지않다. 임의뇨 (spot urine) 검사의경우나트륨농도자체는의미가없으나나트륨농도가칼륨농도보다크면 (urine Na/K ratio >1) 24시간소변에서의나트륨양이 78 meq 이상일가능성이높아임상에서자주이용된다 15). 이뇨제의부작용및대책 : 대표적인부작용으로는신부전, 간뇌증, 전해질불균형, 여성형유방및근육경련등이있으며이뇨제를투여중인환자의 20~40% 에서나타난다. 각각의부작용과이에따른대책은다음과같다. (1) 신기능이상 : 대부분과도한이뇨제투여로인한혈관내유효혈류량부족때문에발생하므로이뇨제를투여하고있는환자들은신기능이상에대한감시가필요하다. 혈청 Cr이 2.0 mg/dl 이상인경우에는이뇨제투여를중단해야한다 15). 이뇨제를중단하고혈류량을증가시켜주면대부분회복된다. (2) 간뇌증 : 이뇨제에의한 hypokalemic alkalosis로신장 에서의암모니아생산이증가되어혈장암모니아농도가증가하거나이뇨제가 urea cycle에장애를일으켜간에서의암모니아의 urea로의전환을감소시키기때문으로생각된다. 경도의간뇌증이발생한경우에는이뇨제를유지하여도무방하나, 심한간뇌증에서는이뇨제를일시적으로중단해야한다 20). (3) 고칼륨혈증 : spironolactone 사용시나타날수있으며, 특히난치성복수환자나고용량의이뇨제가요구되는신기능저하환자에서잘일어난다. 칼륨수치가 5.5 meq/l 이상인경우에는 spironolactone 용량을감량해야하며 6 meq/l 이상인경우에는 spironolactone을중단해야한다 20). (4) 저칼륨혈증 : furosemide 를사용할때나타날수있으며칼륨수치가 3.5 meq/l 미만인경우에는 furosemide 를감량하거나중단해야한다 20). (5) 저나트륨혈증 : 이뇨제치료를받는간경변증복수환자에서흔히관찰되며, 대부분의경우나트륨저하정도가경하고증상이없으며특별한치료가필요없다. 그러나혈청나트륨농도가 120~125 mmol/l 미만으로지속되는경우에는이뇨제투여를중단하고수분섭취량을제한해야한다 15). 저나트륨혈증을빨리교정하기위해고장식염수 (hypertonic saline) 를투여하는것은저나트륨혈증자체보다더많은합병증을유발할수있으므로권장되지않는다 39). (6) 여성형유방 : spironolactone 사용시흔히볼수있는부작용으로 spironolactone의항남성호르몬작용 (antiandrogenic activity) 으로인해성호르몬대사의변화가일어나거나증폭되기때문이다. Amiloride로교체하면증상이완화또는소실된다. (7) 근육경련 : 이뇨제를복용하는환자에서근육경련이흔히발생한다 40). 대부분의경우복수가나타나기이전부터나타났던경우가많으나 34) 이뇨제를사용하면빈도및강도가증가한다. 유효혈장량의감소가근육경련의발생에관여하는것으로생각된다 20). 근육경련이너무심한경우에는이뇨제를감량하거나중단해야하며 20), 알부민투여가증상호전에도움이될수있다 34, 40). 2. 대량복수환자의치료대량 (grade III) 복수는많은양의복수로인해복부불편감이심해일상생활에지장을받는경우이다. 대부분신장에서의나트륨저류가매우심하기때문에저염식을하여도복수가빠른속도로차게된다. 대부분유리수분배설능및혈청나트륨농도는정상이다. 그러나일부에서는유리

6 - The Korean Journal of Medicine : Vol. 75, No. 1, 수분배설능이저하되어많은양의수분을섭취하는경우희석저나트륨혈증이발생할수있다. 혈청 Cr 농도는정상이거나약간증가되어있으며 GFR은정상이거나약간감소되어있다. 대량복수환자에서는우선대량 (5리터이상 ) 복수천자를하는방법이선호되는데, 이방법이이뇨제를복수가소실될때까지증량해나가는방법에비해환자의복수로인한불편감을더신속하고효과적으로해결하면서도부작용의발생은더적기때문이다 38, 41-44). 그러나대량복수환자의경우나트륨저류가매우심할뿐아니라 ( 소변나트륨농도, <10 meq/l) 복수천자가이를호전시켜주는것은아니므로복수천자후복수의재발을막기위해서는나트륨섭취제한과함께이뇨제를사용해야한다 38, 45, 46). 알부민과같은혈장확장제를투여하지않으면서대량복수천자를하면유효동맥혈류량감소로인한혈관수축인자및항이뇨인자의활성화를유발하는순환장애가발생할수있다. 대량복수천자후순환장애가발생한경우복수가빠르게다시차고, 20% 에서는간신증후군이나희석저나트륨혈증등이발생하며, 생존기간이감소한다 47-49). 이와같은심각한합병증은대량복수천자도중또는직후에혈장확장제를투여하여혈관내혈장량을증가시켜주면예방할수있다 47, 49). 혈관확장제로가장선호되는것은알부민으로서, 복수천자로제거된복수 1리터당 8 g의알부민 ( 복수천자 2.5리터당 20% 알부민 100 ml) 을투여한다 47, 50, 51). 알부민주입시체내에서알부민분해가현저히증가하고 52, 53) 알부민의체내합성이저하될수있으므로 54) 복수천자처럼유효동맥혈류량감소가우려되는경우이외에알부민을투여하는것은권장되지않는다. 복수천자에는특별한금기증이없다고인정되고있다 20). 그러나예전에수술을받아복막유착이심한환자의경우에는복수천자에의한장천공의위험이높을수있으므로복수천자를주의해서시행하거나시행하지않는것이좋다 20). 복수천자부위로복수가계속누출되는경우에는환자에게천자부위가가장위로가도록두시간정도돌아누워있도록하고, 필요한경우에는천자부위주변에봉합 (purse-string suture) 을해주면도움이될수있다 20). 난치성복수환자의치료저염식과함께이뇨제를최대용량까지증량하였으나 (spironolactone 하루 400 mg 및 furosemide 하루 160 mg을일주일이상투여 ) 복수가충분히조절되지않거나간뇌증, 저나트륨혈증, 고칼륨혈증, 또는신기능장애등이뇨제에대한심한부작용이반복적으로발생하여이뇨제를충분한용량으로증량할수없는경우를난치성복수라고정의하며복수환자의 5~10% 에서발생한다 55). 난치성복수환자는대량복수천자를하여도복수가빠른속도로재발하고간신증후군의발생위험이높을뿐아니라, 50% 가 6개월이내에사망하고 75% 가 1년이내에사망할정도로예후가매우불량하다 56). 비스테로이드성항염제등 prostaglandin 억제제는간경변증환자에서나트륨의뇨배설을감소시키고고질소혈증 (azotemia) 을유발하여단순복수를난치성복수로전환시킬수있으므로 57, 58) 이러한약제를사용하고있다면이를중단하여야한다. 난치성복수의대표적인치료법으로는반복적복수천자와경경정맥간내문맥-전신단락술 (transjugular intrahepatic portosystemic shunt, 이하 TIPS) 이있다. 복강-정맥단락술 (peritoneovenous shunt) 은복수를조절하는데있어반복적대량복수천자보다더효과적이지도않으면서단락폐쇄, 감염및파종성혈관내응고 (disseminated intravascular coagulation) 등의합병증이흔하여권장되지않는다 59). 1. 반복적대량복수천자알부민을보충해주면서반복적대량복수천자를하는방법이난치성복수에대한가장안전하고효과적인치료이다. 난치성복수환자가저염식을잘지키고있다면복수천자는 2~4주간격으로시행하게되므로외래에서치료가가능하다. 즉, 복수의나트륨농도는혈장과비슷한 130 meq/l 정도이므로 6리터의복수를제거하면 780 meq 의나트륨이체내에서제거된다 15). 저염식 ( 하루나트륨 88 mmol) 을잘지켰다고가정하면하루 78 mmol( 저염식의 88 mmol -신장외나트륨배출량 10 mmol) 이상의나트륨이제거되면복수는악화되지않을것이므로 6리터의복수천자를하였다면소변으로나트륨이전혀배설되지않더라도복수천자이전의상태로돌아오는데까지는 10일이걸린다. 소변으로나트륨이조금이라도배설된다면다음복수천자까지의기간은더욱연장될것이다. 만약빠른복수의재발로이보다더자주복수천자를시행해야한다면환자가나트륨섭취제한을잘지키지않고있음을의미하며, 이런경우복수조절에서저염식의중요성을다시한번설명하여저염식을잘지킬수있도록하는것이좋다

7 - Yeon Seok Seo : Ascites and spontaneous bacterial peritonitis - 2. TIPS 복수발생의근본적인원인은간경변증에의한문맥압항진증이므로 TIPS가난치성복수의치료에효과적일수있음은쉽게생각할수있다. 즉, TIPS 는간경변증으로인해압력이높아진문맥과이에비해압력이낮은간정맥사이에단락을만들어주는방법으로결국문맥의혈류는단락을통해압력이더낮은간정맥으로유입되므로문맥압은감소하고전신순환혈류량은증가하여신기능및나트륨배설이호전되고복수가소실된다 60). 또한복수의재발방지에도효과적이며 61) 이뇨제에대한신장의반응을호전시킨다 62). 그러나 TIPS에는다음과같은몇가지약점이있다 : (1) 단락의협착이흔하여 TIPS 시행 1년이내에 60% 에서발생한다 63) ; (2) TIPS 를받은환자의 30~50% 에서간뇌증이새로발생하거나기존의간뇌증이악화되는데 12, 64), TIPS 시행전간뇌증이있었거나 65세이상의고령인경우발생할위험이높다 65). 대부분의간뇌증은 lactulose를이용한표준치료에잘반응하나 3~10% 에서는치료에잘반응하지않아단락의폐쇄가필요할수도있다 66, 67) ; (3) TIPS 를통해다량의문맥혈류가간정맥을통해우심방으로유입되므로심장의전부하를증가시켜심장질환이있는환자의경우심부전을유발할수있다 68). 그러므로시행전심장초음파검사를시행하여심박출율 (ejection fraction) 이적어도 55% 이상되는환자들에서만시행하는것이좋다 20) ; (4) 문맥의혈류가대부분간으로가지않고단락을통해전신순환으로빠져나가므로간기능이현저히악화될수있다 20). TIPS 와복수천자의효과를비교한연구에서 Child-Pugh class C 인환자의경우 TIPS군에서예후가더불량하였던결과가이와관련이있을수있다 69). 그러므로 Child-Pugh score가 11점이상인경우에는 TIPS를시행하지않는것이좋다 67). 이와같은약점들과함께 TIPS의높은비용및 TIPS를받거나반복적복수천자를하거나두치료군사이에예후의차이는없음을감안하였을때 70, 71), TIPS 를난치성복수의일차치료로선택하기에는무리가있으며, 심한간부전이나간성혼수가없으면서복수천자가불가능하거나반복적복수천자를거부하는환자들의치료법으로남겨두는것이좋다. 심한복막유착등으로복수천자가힘든경우도적응증이될수있다. 자발세균복막염 SBP는간경변증환자의가장흔한감염으로간경변증 Table 4. Results of diagnostic paracentesis which suggest secondary peritonitis rather than spontaneous bacterial peritonitis PMN count (/mm 3 ) Bacterial culture Total protein LDH Glucose CEA ALP Results Many thousands Multiple organisms isolated > 1 g/dl > ULN of serum LDH level >50 mg/dl >5 ng/dl >250 IU/L PMN, polymorphonuclear leukocyte; LDH, lactate dehydrogenase; ULN, upper limit of normal; CEA, carcinoembryonic antigen; ALP, alkaline phosphatase 환자의 10~30% 에서발생한다 2, 14). 자발 이라는단어에서예상할수있듯이 SBP는다른감염원이없으면서발생하는데, 주로정상적인면역상태에서는전혀문제를일으키지않는장내정상세균총에의해발생한다. 대개단일균주에의해발생하며, Escherichia coli 및 Klebsiella species 등그람음성균이원인균의대부분을차지한다 72). 그러나최근간경변증환자에서의예방적항생제사용이증가하면서그람양성균에의한경우도증가하는추세이다 72, 73). 1. 진단 SBP의주증상은발열, 복통, 구역, 간뇌증또는신기능의악화이나상당수에서아무런증상도없으며입원하고있는간경변성복수환자의상당수에서 SBP가있음을고려할때간경변성복수환자가입원하거나 SBP와관련된증상이나징후가있는경우에는반드시진단적복수천자를시행해야한다. 다른감염원인이없으면서복수의 PMN 수가 250/mm 3 이상인경우 SBP로진단할수있다 14). SBP의원인균을찾고항생제에대한감수성을확인하기위해호기성균및혐기성균혈액배양용기에각각적어도 10 ml의복수를접종한다. 그러나 SBP 환자의 60% 는복수배양검사에서원인균이동정되지않으며 72), 50% 에서균혈증 (bacteremia) 이동반되므로 74) SBP가의심되는경우에는복수뿐아니라혈액에대해서도배양검사를시행해야한다. 이차복막염과의감별 : 대부분항생제치료에잘반응하는 SBP와는달리이차복막염은수술적치료가필요한경우가많으므로신속한진단이필수적이다. 이차복막염은십이지장궤양에서와같은장천공에의한경우와신주위농

8 - 대한내과학회지 : 제 75 권제 1 호통권제 575 호 Table 5. Indications and regimens of prophylactic antibiotics for the prevention of spontaneous bacterial peritonitis Indication Regimen Tx. Duration Patients with GI hemorrhage Patients who recovered from SBP 3rd-generation cephalosporin, IV norfloxacin 400 mg once daily, PO 5~7 days life-long GI, gastrointestinal; IV, intra-venous; SBP, spontaneous bacterial peritonitis; PO, per os 양 (perirenal abscess) 과같은천공이없이농양에의한경우로나눌수있다. 일단환자의증상과징후는 SBP와이차복막염을감별하는데큰도움이되지않는다 17). 이보다는진단당시의복수검사결과와치료에대한반응이감별에큰도움이된다 ( 표 4) 17). 장천공의경우복수의 PMN 수가대개수천개이상으로상승하고그람염색과균배양에서여러개의균주가동정되는경우가많다. 또한, 총단백질이 1 g/dl 이상, LDH가혈청 LDH 정상상한치이상및포도당농도가 50 mg/dl 이상의세가지기준중두가지이상해당되는경우가많다 17). 그러므로복수의 PMN 수가 250 mm 3 이상인경우에는복수의그람염색및세균배양검사이외에도총단백질, LDH 및포도당검사를함께시행하는것이좋다 15). 복수의 carcinoembryonic antigen이 5 ng/ml 이상이거나복수의 alkaline phosphatase 가 250 IU/L 이상인경우에도장천공에의한이차복막염을의심해야한다 75). 그러나이러한기준들은장천공이아닌복강내농양에의한이차복막염을진단하는데에는큰도움이되지않는다 15). 만약적절한항생제를투여한후 48시간에시행한복수천자에서 PMN 수가치료전보다감소하지않은경우에는농양에의한이차복막염을의심해보아야한다 17). 2. 치료항생제 : SBP가진단되면즉시치료를시작해야한다. Cefotaxime 을비롯한 3세대 cephalosporin이 SBP에대한최선의치료선택으로생각되며, SBP에가장많은원인균인 Escherichia coli 및 Klebsiella pneumoniae를포함하여원인균의 95% 를치료할수있다 76). Cefotaxime 2 g을 8~12시간간격으로투여하는용법이가장많이사용된다. Cefotaxime 을 5일간만투여하여도충분하다고인정되고있기는하지만 77, 78) 여러임상연구결과에서의 SBP 소실기간을감안할때 8일정도투여하는것이안전할것으로생각된다 12). Ceftriaxone이나 ceftazidime 같은다른 3세대 cephalosporin 뿐아니라 amoxicillin/clavulanic acid도 cefotaxime 과비슷한치료효과를보인다 14, 79). 치료반응의평가 : SBP가좋아지면증상도좋아지므로증상의호전이없으면치료실패를생각해야한다 9). 항생제투여를시작하고이틀후재시행한복수천자에서 PMN 수가치료시작전보다 25% 이상감소하지않았으면치료실패로간주한다 14). 이런경우이차복막염을의심하여이에대한검사를해보아야하며균이배양된경우에는항생제내수성에따라항생제를교체해야한다 9). 진단당시복수검사결과가 SBP의전형적인소견을보이고항생제치료에잘반응한다면 PMN 수의감소를확인하기위해복수천자를재시행할필요는없다 15). 알부민 : SBP 환자의 30% 에서신기능장애가발생하며이경우높은사망률을보인다 80, 81). 최근보고에따르면 SBP 환자에서항생제치료와함께알부민을함께투여하였을때 (SBP 진단시체중 kg 당 1.5 g 및 48시간후 kg 당 1 g의알부민투여 ) 신기능장애를예방하고생존율을호전시켰다 80). 그러나알부민이워낙고가이므로 SBP 환자들중신기능장애가발생할위험이높은군을선별하여투여하는것이좋을것으로생각된다. SBP 진단시 bilirubin이 4 mg/dl 미만이고 Cr이 1 mg/dl 미만인경우신기능장애가발생할위험은 10% 미만이므로 12, 80) bilirubin >4 mg/dl 또는 Cr >1 mg/dl 인환자에서만선별적으로투여하는것을권장하기도한다 12). SBP 치료중혈청 Cr이점차증가하는경우에도알부민투여를고려하는것이좋다 9). 신기능장애를유발할수있는대량복수천자, 이뇨제및신독성약물은 SBP가심한상태에서는피해야한다 12). 3. 예방최근신속한진단및적절한항생제선택으로 SBP 환자의예후가과거에비해현저히호전되기는하였으나아직 15~20% 의사망률을보인다. 따라서 SBP를예방하는것이간경변증환자의예후를호전시키는데중요할것으로보인다. 그러나장기간경구항생제를투여하다보면항생제내성균주의증가를유발할수있으므로 SBP 발생위험이높은고위험군에대해서만예방적항생제를투여하는것이좋다

9 - 서연석 : 복수및자발세균복막염 - SBP의고위험군및이에대한예방요법은표 5에제시된바와같다. SBP가한번도발생한적이없으면서복수의단백질이 1 g/dl 미만인환자가예방적항생제의대상이될것인가에대해서는아직논란이있는상태이다 14). 정맥류출혈없이내시경적경화요법이나정맥류결찰술을하는경우는예방적항생제의대상이되지않는다 82). 결 간경변성복수환자의대부분은저염식과이뇨제에잘반응하므로단순히복수를조절하는것은그리어려운일이아닐수있다. 그러나단순한복수의조절은복수의근본원인인간경변증을치료하는것은아니므로이와함께원인질환을호전시키기위한노력을지속해야할것으로생각된다. 또한, 자발세균복막염등감염성질환이나신기능부전과같은합병증이발생할위험이높으며이런합병증이발생한경우환자의예후가더욱악화되므로합병증을예방하고합병증이나타났을때빨리진단하여대처하는것이환자의예후를호전시키는데중요할것으로생각된다. 론 중심단어 : 복수 ; 간경변증 ; 복수천자 ; 복막염 REFERENCES 1) Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, Caballeria J, Rodes J, Rozman C. Compensated cirrhosis: natural history and prognostic factors. Hepatology 7: , ) Gines P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and ascites. N Engl J Med 350: , ) Planas R, Montoliu S, Balleste B, Rivera M, Miquel M, Masnou H, Galeras JA, Gimenez MD, Santos J, Cirera I, Morillas RM, Coll S, Sola R. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol 4: , ) Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8: , ) Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 339: , ) Saadeh S, Davis GL. Management of ascites in patients with end-stage liver disease. Rev Gastroenterol Disord 4: , ) Heneghan MA, Harrison PM. Pathogenesis of ascites in cirrhosis and portal hypertension. Med Sci Monit 6: , ) Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 117: , ) Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 55(Suppl 6):vi1-12, ) Cattau EL, Jr., Benjamin SB, Knuff TE, Castell DO. The accuracy of the physical examination in the diagnosis of suspected ascites. JAMA 247: , ) Kuiper JJ, de Man RA, van Buuren HR. Review article: Management of ascites and associated complications in patients with cirrhosis. Aliment Pharmacol Ther 26(Suppl 2): , ) Gines P, Cardenas A. The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis 28:43-58, ) Caly WR, Strauss E. A prospective study of bacterial infections in patients with cirrhosis. J Hepatol 18: , ) Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, Inadomi JM. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 32: , ) Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology 39: , ) Bar-Meir S, Lerner E, Conn HO. Analysis of ascitic fluid in cirrhosis. Dig Dis Sci 24: , ) Akriviadis EA, Runyon BA. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis. Gastroenterology 98: , ) Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic fluid culture technique. Gastroenterology 95: , ) Runyon BA, Antillon MR, Akriviadis EA, McHutchison JG. Bedside inoculation of blood culture bottles with ascitic fluid is superior to delayed inoculation in the detection of spontaneous bacterial peritonitis. J Clin Microbiol 28: , ) Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, Angeli P, Porayko M, Moreau R, Garcia-Tsao G, Jimenez W, Planas R, Arroyo V. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 38: , ) Hepatic cirrhosis. In: In: Sherlock S, Dooley J, eds. Diseases of the liver and biliary system. 11th ed. p , Oxford, England, Blackwell Science, ) Llach J, Gines P, Arroyo V, Rimola A, Tito L, Badalamenti S, Jimenez W, Gaya J, Rivera F, Rodes J. Prognostic value

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