대한내과학회지 : 제 75 권제 1 호 2008 Special Review in Portal Hypertension - 문맥압항진증과합병증 식도및위정맥류의예방과치료 순천향대학교의과대학내과학교실, 소화기연구소 장재영 Prevention and management of gastroesophageal varices Jae Young Jang, M.D. Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University Medical College, Seoul, Korea Gastroesophageal varices are the most common lethal complication of cirrhosis that result most directly from portal hypertension. Patients with cirrhosis and gastroesophageal varices have an hepatic venous pressure gradient (HVPG) of at least 10~12 mmhg. An increased portal pressure gradient results from both an increase in resistance to portal flow and an increase in portal blood inflow. Patients whose HVPG decreased to < 12 mmhg or at least 20% from baseline levels have a lower probability of developing recurrent variceal hemorrhage. Therefore, a reduction in HVPG is most important. Nonselective β-blockers are the gold standard in the prevention of first variceal hemorrhage in pateints with medium/large varices. Endoscopic variceal ligation (EVL) has been established as an alternative to nonselective β-blockers for the prevention of initial variceal hemorrhage. The combination of vasoconstrictive pharmacological therapy and variceal ligation is the preferred approach to the management of acute variceal hemorrhage. Prophylactic antibiotic therapy is considered standard of care as adjunctive treatment of the acute bleeding episode. Both combination pharmacological therapy and EVL have been proven effective for the prevention of recurrent variceal hemorrhage. For failures of medical therapy, TIPS or surgically created shunts are excellent salvage procedures. (Korean J Med 75:6-14, 2008) Key Words : Gastroesophageal varices; Prevention and treatment 서론위식도정맥류는간경변증의가장흔한치명적인합병증으로서문맥압항진증의결과로초래되며위식도정맥류를가지고있는환자들의문맥압은최소한 10~12 mmhg 이상을보인다 1, 2). 간경변증의약 50% 에서위식도정맥류를가지고있으며간질환의심한정도와연관성을보인다. 즉 Child-Pugh A환자의경우 40% 에서만정맥류를가지고있으나 Child-Pugh C환자의경우 85% 에서정맥류를가지고있다 3). 정맥류가없는환자의매년약 8% 정맥류가발생하며, 정맥류발생의가장강한예측인자로는문맥압이 10 mmhg 이상상승한경우로알려져있다 4, 5). 정맥류의진행은매년 약 8% 로알려져있고비대상성간경변증, 알코올성간경변증, 내시경상 red wale marks를보이는경우가진행에중요한인자로알려져있다 5). 정맥류출혈은매년 5~15% 정도로발생하는데가장중요한예측인자로는정맥류의크기이며, 그외비대상성간경변증과내시경소견상 red wale marks 을보이는경우이다 6). 식도정맥류출혈의경우약 40% 에서자연적으로출혈이멈추고, 지난수십년간치료방법의발달에도불구하고 6주내에최소한 20% 의사망률을가지고있다 7-9). 특히문맥압이 20 mmhg 이상에서초기재출혈또는지혈실패및 1년사망률이그렇지않은경우보다높은것으로되어있다 10, 11). 정맥류출혈에서정맥류벽의긴장도는가장중요한인자로서이는정맥류내부의 - 6 -
- Jae Young Jang : Prevention and management of gastroesophageal varices - 압력으로문맥압과직접적으로연관되어있다. 즉, 문맥압을낮추는것이정맥류벽의긴장도를낮추고출혈의위험도를떨어뜨릴수있으며실질적으로문맥압이 12mmHg 이하에서는정맥류출혈이발생하지않는것으로알려져있다 12, 13). 문맥압을 12 mmhg 미만으로떨어뜨리거나기저치에비하여최소 20% 이상감소시정맥류출혈의재발율이줄며 14) 복수, 간신증후군및사망을줄일수있다고 15) 알려져있어정맥류출혈치료의관건은문맥압을낮추는것이가장중요한것으로생각된다. 병태생리문맥압의변화는 Ohm의법칙 ( P=Q R) 에따라문맥의혈류와저항의곱으로표시된다. 정상적인간에서는식사등으로문맥혈류가변하면이에따라간내혈관저항 (intrahepatic vascular resistance) 이변하여문맥압은일정하게유지된다. 그러나간경변증에서는간섬유조직과재생결절에의한이차적인간조직의변형으로혈류에대한저항이증가하여문맥압항진증이발생하며, 이중 20~30% 는내인성 nitric oxide의간내혈관생성저하로인한간내혈관수축이간내저항을증가시키는것으로알려져있다 16-18). 또한간외순환계에서는 nitric oxide가과다하게생성되어내장혈관의확장 (splanchnic vasodilatation) 과이로인한혈류증가가나타난다. 즉, 간내혈관저항증가와내장혈류의증가에의한문맥유입혈류증가로인하여문맥압항진증이나타나게된다 19). 정맥류의진단정맥류진단에는상부소화관내시경검사을비롯하여비침습적인방법으로혈소판수, fibrotest, 비장크기, 문맥직경및 fibroscan 등 20, 21) 이있으나아직까지는상부소화관내시경이가장좋은정맥류의진단방법으로알려져있다. 상부소화관내시경상정맥류의분류는다음과같다 19). 1. 소정맥류 (small varices) : 식도점막위로약간융기된정맥 2. 중정맥류 (medium varices) : 확장된정맥이식도내강 1/3 미만인경우 3. 대정맥류 (large varices) : 확장된정맥이식도내강 1/3 이상인경우간경변증으로진단된환자는정맥류의유무를확인하기위하여반드시상부소화관내시경검사를시행하여야하며 22, 23) 내시경상크기분류와함께정맥류표면에 red signs (red wale marks 또는 red spots) 의유무를반드시기재하여야한다. 내시경검사의시행간격은대상성간경변증에서정맥류가없는경우는 2~3년에한번씩시행하며, 소정맥류인경우는 1~2년에한번씩시행하여야한다 22). 반면, 비대상성간경변증에서는매년내시경검사를시행하여야한다 23, 24). 정맥류출혈의경우도상부소화관내시경검사가진단의가장중요한방법으로서정맥류로부터혈액이분출되거나출혈부위에적색이나흰색의섬유소응괴가보일때또는다른출혈원인이없이정맥류만관찰될때정맥류출혈로진단할수있다 25). 정맥류의치료 1. 정맥류치료와문맥압약물치료는 vasopressin과그유도체 (terlipressin), somatostatin과그유도체 (octreotide) 및비선택적베타차단제와같은내장혈관수축제와 nitrates와같은정맥확장제가있다. 혈관수축제는내장혈관의수축과문맥유입혈류량의감소를유발하며정맥확장제는간내혈관저항을감소시키는역할을하나, 이보다는전신적으로혈압을떨어뜨리는효과에의하여혈류감소를유발함으로서문맥압을감소시키는것으로생각된다 26). 혈관수축제와혈관확장제의병합요법이문맥압감소에상승효과 (synergic effect) 가있는것으로알려져있다 27, 28). 내시경적경화요법이나정맥류결찰요법은문맥혈류나저항에효과가없는국소치료이며방사선또는수술과같은단락치료는저항이증가된부위를우회시킴으로서문맥압을현저히감소시킨다. 2. 비선택적베타차단제비선택적베타차단제 (propranolol) 는심박출량 ( 베타-1효과 ) 감소와내장혈관수축 ( 베타-2효과 ) 을유발함으로서문맥압을감소시킨다. 선택적베타차단제 (atenolol, metoprolol) 는비선택적베타차단제에비하여효과가떨어지며, 정맥류출혈의일차예방에는효과가미미하다. 그러므로다른이유로선택적베타차단제를사용하는정맥류환자에서는비선택적베타차단제로교체하는것이필요하다. 문맥압을 12 mmhg 이하로감소시키는것이출혈의위험을줄이고생존율의향상을가져오는것으로알려져있으며 12) 기저치에서 20% 이상감소시초출혈의위험을의미있게감소시키는것으로알려져있다 29). 대부분의연구에서는심장박동수를분당 55회이하또는기저치의 25% 이상감소시키도 - 7 -
- 대한내과학회지 : 제 75 권제 1 호통권제 575 호 2008 - Figure 1. Prophylaxis of first variceal hemorrhage (Primary prophylaxis). 록, propranolol을충분한용량으로사용하여야하는데, 보통 160 mg 또는그이상을사용해야한다 30). 그러나현실적으로는임상에서 HVPG (hepatic venous pressure gradient) 를측정하고추적검사하는것이용이하지않고맥박수가정확하게문맥압을반영하지못하는단점이있다 31). 무작위연구에서알수있듯이베타차단제를중지했을때정맥류출혈의위험이증가하므로예방적투여를지속적으로시행해야한다 32). 약 15% 의환자에서천식, 인슐린의존성당뇨병 ( 저혈당이있는경우 ) 및말초혈관질환과같은베타차단제의금기를가지고있다 33). 가장흔한부작용으로는두통, 피로및호흡곤란이있으며대부분용량을줄이면호전되나약 15% 의환자에서는이로인하여치료를중단하게된다. 3. 정맥류출혈의예방적치료 ( 일차적예방 ) ( 그림 1) 1) 정맥류가없는간경변증환자에서예방적치료정맥류가없으면서문맥압고혈압 ( 기저치가 5 mmhg 이상 ) 이있는간경변증환자에서비선택적베타차단제를사용하여문맥압을감소시켰을때의미있게정맥류발생을낮추었다고는하나, 비선택적베타차단제를사용한환자의다수에서약물부작용이나타남으로서정맥류가없는간경변증환자에서비선택적베타차단제의사용은권고되지않는다 4, 34). 2) 출혈하지않는소정맥류환자에서예방적치료출혈하지않았던소정맥류환자에서 Child-Pugh B 또는 C의간기능을가지고있거나정맥류표면에 red wale marks 와같은출혈위험인자가있는환자들에서는정맥류의초출혈을예방하기위하여비선택적베타차단제를반드시사용하는것으로되어있다. 반면, 출혈위험인자가없는소정맥류의경우에는비선택적베타차단제의장기적인효과가입증되지는않았지만사용해볼수는있다. 비선택적베타차단제를복용하지않는경우에는내시경을 2년마다시행하며, 비대상성간경변증으로진행시곧바로내시경검사를시행하고, 이후매년내시경검사를시행하여야한다 19). 베타차단제를복용하는환자들에서의추적내시경검사는반드시필요하지는않다. 3) 출혈하지않는중 / 대정맥류환자에서예방적치료출혈하지않았던중 / 대정맥류환자에서 Child-Pugh B 또는 C의간기능을가지고있거나정맥류표면에 red wale marks 와같은출혈위험인자가있는환자들에서는정맥류의초출혈을예방하기위하여비선택적베타차단제를사용하거나내시경적밴드결찰술을시행하는것을권고하고있다. 최근의연구들에서비선택적베타차단제나내시경적밴드결찰술이모두초출혈을효과적으로예방할수있는것으로알려져있어서, 환자의특성이나의사의경험과선호도등에따라서치료방법을결정할수있다 19). 반면, 출혈위험인자가없는경우에는비선택적베타차단제를우선권고하며, 베타차단제에금기이거나복용상태가좋지않은경우내시경적밴드결찰술을고려하여야한다. 베타차단 - 8 -
- 장재영 : 식도및위정맥류의예방과치료 - Figure 2. Management of acute variceal hemorrhage. 제를복용하는경우는최대허용용량 (maximal tolerated doses) 으로사용하여야하며, 내시경적밴드결찰술의경우는정맥류가완전히소실될때까지 1~2주간격으로시행하며, 소실된이후 1~3개월후에내시경검사를시행하고, 이후 6~12개월간격으로내시경검사를시행하여정맥류의재발을확인하여야한다. Nitrates, 우회치료 (shunt therapy) 또는내시경적경화요법은정맥류의일차적예방치료로서권고되지않고있다. 4. 급성정맥류출혈의치료 ( 그림 2) 간경변증환자가토혈이나흑색변을주소로내원했을때는우선적으로응급치료를시행하고부족한혈장량을보충한다. 수혈은헤모글로빈을 8 g/dl정도로유지할정도로하는데 35), 과도한수혈은문맥압을증가시켜서출혈을악화시킬수있다 36, 37). 단기간 ( 최대 7일 ) 의예방적항생제투여는출혈이있는간경변증환자에서반드시사용하여야한다 38). 경구 norfloxacin (400 mg 1일 2회 ) 또는 ceftriaxone 정맥주사가권유되며, 진행된간경변증환자에서특히퀴놀론-내성균주가높은병원에서는 ceftriaxone 정맥주사가선호된다 39). 정맥류출혈이의심되는환자에서 vasopressin과그유도체 (terlipressin), somatostatin 과그유도체 (octreotide) 등의약물치료를가급적빨리시행하여야하며 40) 진단후 3~5 일동안지속적으로사용해야한다. terlipressin은보통 1~2 mg을초기정주하고 4~6시간마다 1~2 mg씩지속적으로주입한다. 심혈관계질환의기왕력이있거나고위험군은 vasopressin 또는그유도체를사용할때주의해야한다. somatostatin은보통 250 mcg을초기정주하고하루에 6 mg 을 5% 포도당용액에섞어서정맥을통해지속적으로주입한다 41). octreotide가문맥압을감소시키는지에대해서이론 이있지만문맥측부순환을감소시킨다. octrotide는시간당 0.025~0.05 mg을정맥을통해지속적으로주입한다. 내시경은 12시간이내에진단및치료를위하여시행하여야하며내시경적밴드결찰술이나경화요법을시행할수있다. 내시경적경화요법 (EIS) 은정맥류내주사용경화제인 5% ethanolamine olate 나 5% sodium morrhuate, ethylalcohol 등을주사해서조직의염증과섬유화를일으켜정맥류를치료하는방법이다. 경화제주사법은투입부위에따라서정맥류내주사, 정맥류주위주사그리고병용주사법이있다. 합병증으로는발열과흉통이흔하게발생하나대부분대증적인치료로호전되며, 식도궤양과협착, 재출혈등이발생할수있다. 치료후주사부위궤양에대한예방목적으로위산분비억제제나제산제를투여하고 1~2일간금식하고재출혈여부를관찰한다 42). 내시경적밴드결찰법 (EVL) 은고무밴드를포함한결찰기구를이용하여정맥류를결찰하는방법이다. 시술부위는현재출혈이있거나의심되는부위를먼저결찰하고출혈부위가확실치않은경우에는식도접합부의 critical zone을중심으로상부 5~8 cm까지 4~8개의결찰을시행한다. 시술후에는당일금식하고위산억제제나제산제를투여한다. 시술후 7~14일경에고무밴드탈락에의한궤양발생이흔하므로내시경추적검사를시행한다. 밴드결찰요법은경화요법에비하여환자가느끼는불편감이나합병증이적다. 과거에는 overtube 에의한식도점막손상과같은합병증이흔하였으나, 최근에는 multi-band ligator 를사용하게됨에따라서이러한부작용을줄일수있게되었다 43). 내시경치료에실패하였거나내시경치료가가능하지않은경우 TIPS (transjugular intrahepatic portosystemic shunt) 를시도할수있다 44, 45). 풍선탐폰 (Sengstaken-Blakemore tube) 삽입법은대량출혈의경우에효과적인치료가 - 9 -
- The Korean Journal of Medicine : Vol. 75, No. 1, 2008 - 이루어질때까지일시적 ( 최대 24시간 ) 으로사용할수있으며활동성출혈의 90% 에서효과적인지혈이가능하다. 그러나환자에게심한불편감을주며합병증이있을수있으므로약물치료에반응하지않은경우에효과적인치료가이루어질때까지 교량요법 으로만사용하는것이좋다 41). 5. 위정맥류 ( 그림 4) Figure 3. Classification of gastric varices. 위정맥류는식도정맥류에비하여상대적으로적게발생하는데문맥압항진증이있는환자의 5~33% 에서발견되며출혈의빈도는 2년에 25% 이고, 위저부정맥류 (fundal varices) 의출혈빈도가좀더높은것으로알려져있다 46). 위정맥류출혈의위험인자는위저부정맥류의크기 (10 mm 이상 > 5-10 mm > 5 mm 미만 ), 간기능정도 (Child-Pugh A<B<C) 및내시경상정맥류표면에붉은반점이있는경우로알려져있다 47). 위정맥류의분류는식도정맥류와의관계와위내위치에따라서나누어진다. 가장흔한형태인 GOV (gastroesophageal varices) 1형은식도정맥류가위소만부로연장되는형태로식도정맥류가연장되는것으로생각되어치료또한유사하다. GOV (gastroesophageal varices) 2형은위저부를따라식도정맥류가연장되고 GOV 1형에비하여더심한형태를보인다. IGV (isolated gastric varices) 1형은식도정맥류없이위저부에만정맥류가존재하는형태이며, 이형태에서는비장정맥혈전증의유무를확인하여야한다. IGV (isolated gastric varices) 2형은위체부, 전정부또는유문부주위에정맥류가발생하는형태이다 ( 그림 3) 46). GOV 1형인 Figure 4. Management of acute gastric (fundal) variceal hemorrhage. - 10 -
- Jae Young Jang : Prevention and management of gastroesophageal varices - Figure 5. Prophylaxis of recurrent variceal hemorrhage (Secondary prophylaxis). 경우식도정맥류가위소만을따라서연장되어있는형태로치료는식도정맥류와같으며, IGV 1형의경우비장정맥혈전증이있는경우비장절제술을시행한다. 그러나이외의정맥류형태의치료에대해서는아직연구자료가부족한상태이다 19). N-butyl-cyanoacrylate, isobutyl-2-cyanoacrylate, thrombin과같은조직접착체를이용한내시경적정맥류폐색술은내시경적경화요법또는내시경적밴드결찰술에비하여급성위저부정맥류출혈에서초기지혈율이높고재출혈율이낮아좀더효과적으로알려져있다 45, 48). 본교실에서는 Histoacryl R (N-butyl-cyanoacrylate) 0.5 cc와 Lipiodol 0.5 cc을혼합한용액 1 cc를위정맥류로신속하게주입한후 X-선투시하에위정맥류내 Lipiodol 위치를확인하고곧바로순수 Lipiodol을주입하면서정맥류주사침을정맥류로부터제거하고난다음, 증류수로정맥류주입도관을세척한다. 겸자로정맥류를눌러보아딱딱하게촉지되면시술을마치고, 그렇지않은경우위정맥류내에 3~5차례반복적으로주입한다. 본교실에서 85명의환자들을대상으로시행한결과초기지혈율은 98.6%, 재출혈률은 24.2% 였으며합병증은폐색전증 2예, 비장색전증 1예가있었으나이들모두특별한치료없이회복되었다 49). 즉, N-butyl-cyanoacrylate 등과같은조직접착체를이용한내시경적정맥류폐색술은위저부정맥류출혈의초기지혈및재출혈예방에효과적인치료방법으로생각된다 50). 그러나경우에따라서는내시경적밴드결찰술이치료로서사용될수있으며, N-butyl-cyanoacrylate 와같은치료제가없거나 이치료에경험이없는경우에는 TIPS를반드시초치료로서고려하여야한다. 최근의보고에의하면 TIPS는위정맥류출혈이조절되지않는경우 90% 이상의지혈효과가있는것으로알려져있다. 즉, TIPS 는내시경치료가가능하지않거나내시경치료의일차실패시고려되어야한다 19). 풍선-폐쇄역행성경정맥폐쇄술 (ballon-occluded retrograde transvenous obliteration, BRTO) 은위신단락이있는위정맥류의치료에효과적이며성공적인시술후 5년재발률이 2.7% 로매우낮다. 그러나시술후식도정맥류의악화가있을수있으므로정기적인추적내시경검사가필요하다 41). 6. 정맥류의재출혈예방 ( 이차적예방 ) ( 그림 5) 활동성정맥류출혈에서회복된간경변증환자에서는반드시정맥류출혈의예방치료를시행하여야하며비선택적베타차단제와내시경적밴드결찰술의복합치료가정맥류출혈의이차적예방의최선의방법이다 51, 52). 베타차단제를복용하는경우는최대허용용량 (maximal tolerated doses) 으로사용하여야하며, 내시경적밴드결찰술의경우는정맥류가완전히소실될때까지 1~2주간격으로시행하며, 소실된이후 1~3개월후에내시경검사를시행하고, 이후 6~12개월간격으로내시경검사를시행하여정맥류의재발을확인하여야한다. TIPS 는약물및내시경적치료의복합치료에도불구하고지속적인재발을보이는 Child-Pugh A 또는 B환자들에게서반드시고려하여야하며 53), 경험이있는센터에서는 Child-Pugh A환자에서수술적우회술을 - 11 -
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- The Korean Journal of Medicine : Vol. 75, No. 1, 2008-49) 주현수, 장재영, 은수훈, 김상균, 정인섭, 유창범, 김영석, 김진오, 조주영, 김연수, 이준성, 이문성, 심찬섭, 김부성. 위정맥류치료에서 Histoacryl R (N-butyl-2-cyanoacrylate) 주입술의장기성적보고 -10 년경험 -. 대한소화기학회지 49:320-326, 2007 50) Rengstorff DS, Binmoeller KF. A pilot study of 2-octyl cyanoacrylate injection for treatment of gastric fundal varices in humans. Gastrointest Endosc 59:553-558, 2004 51) Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PI, Lin CK. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 32:461-465, 2000 52) De la Pena J, Brullet E, Sanchez-Hernandez E, Rivero M, Vergara M, Martin-Lorente JL, Garcia Suárez C. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 41: 572-578, 2005 53) Boyer TD, Haskal TJ. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 41:386-400, 2005-14 -