내시경적식도및위정맥류치료법 건양대학교의과대학내과학교실 이태희 Variceal bleeding is the most important morbidity in the patients with liver cirrhosis. Several methods including pharmacotherapy, endoscopy, radiologic interventions have been developed for reducing the mortality of variceal bleeding. Endoscopy is the method of choice for the diagnosis of gastroesophageal varices and their bleeding, also has the pivotal role for the treatment of variceal bleeding and prophylaxis. Here I review the data of endoscopic therapy for variceal bleeding and introduce some of new methods or trials. 서 론 식도정맥류는비대상성간경변환자의약 40-80% 에서동반되며약 1/3에서출혈이발생하며가장중요한사망원인이되기도한다. 1-2 최근내시경치료및약물요법의진전으로급성정맥류출혈에의한사망률은 6주내사망률이 1980 년대 40-80% 에서 2000년대에는 20-25% 까지감소하였고가장중요한사망위험인자는기저간기능상태로 Child A, B, C에서 6주사망률은각각 0-3%, 12%, 43-55% 정도였다. 3-5 정맥류출혈에대한치료로는내시경치료와더불어약물치료, 영상의학중재치료등이있고이중에서도내시경치료는급성출혈의치료, 초출혈과재출혈예방을위한가장중요한부분이다. 다연발결찰기구를통한내시경정맥류결찰술 (EVL) 과 N-butyl-2 cyanoacrylate (histoacryl) 를이용한내시경정맥류폐색술 (EVO) 이각각식도및위정맥류출혈의일차내시경치료법으로인정되고있다. 6 이원고에서는두가지주된내시경치료법의성적과이외의내시경치료법에대해소개하고자한다. 본 론 1. 식도정맥류의일차예방으로서의내시경치료 (Fig. 1) 초출혈을예방하기위한방법으로는베타차단제와정맥류결찰술을대표적으로사용하고있으며둘은 40
이태희 내시경적식도및위정맥류치료법 각각의장단점을가지고있다. 대한간학회간경변증진료가이드라인 6 에는 1) 정맥류가없는간경변증환자에게정맥류형성의예방및식도정맥류초출혈예방적으로비선택적베타차단제사용은권고하지않는다 (B1). 2) 출혈한적이없는작은정맥류가관찰되나, 출혈의고위험군 (Child-Pugh class B/C, 내시경적색증후 ) 인경우출혈예방을위해비선택적베타차단제사용을고려한다 (B1). 3) 출혈한적이없는큰정맥류 (F2, F3) 가관찰된경우비선택적베타차단제를사용하거 Figure 1. Primary prophylaxis of esophageal variceal bleeding 나내시경정맥류결찰술시행을권장한다 (World J Gastrointest Endosc 2012;4(7):312-322). (A1). 고하고있다. 최근발표된메타분석 7 에서상부위장관출혈과정맥류출혈에는결찰술이유의하게좋은성적을보였으나생존률에는의미있는차이가없어서베타차단제가다른이유로생존율을향상시키는지에대한연구가더필요할것이라고하였다. 2. 급성식도정맥류출혈의치료에서내시경의역할급성식도정맥류출혈에서내시경검사는진단과더불어치료에서도매우중요한역할을한다. 토혈및혈변등소화관출혈이있는환자로서내시경에서정맥류로부터활동성출혈이관찰되거나정맥류표면에혈괴 (blood clot) 나백태 (white nipple) 가붙어있는경우또는식도정맥류외다른잠재적인출혈의원인이발견되지않으면정맥류출혈로진단할수있다. 8 정맥류출혈로진단된환자는곧바로정맥류결찰술을이용하여치료를시행하여야한다. 만약실패한다면다른시술 ( 정맥류경화술, 풍선탐폰, TIPS 등 ) 을고려해야한다. 3. 식도정맥류의이차예방으로서의내시경치료 (Fig. 2) 급성정맥류출혈을경험한환자는 1-2년이내에평균 60% 정도에서재출혈을경험하며, 이로인한사망률이 33% 에달하는것으로보고되어재출혈방지를위한조치가필요하다. 9 대한간학회진료가이드라인 6 에는 1) 식도정맥류의재출혈방지를위해내시경정맥류결찰술 (endoscopic variceal ligation) 단독또는비선택적베타차단제와의병합요법을고려한다 (B1). 2) 경경정맥간내문맥전신단락술 (transjugular intrahepatic portosystemic shunt) 은 Child-Pugh A 또는 B 등급환자에서상기치료가실패한경우구조치료로고려할수있다 (B1). 3) 간이식의적응증이되는환자는간이식을고려한다 (B1) 고하였다. 41
2013 년대한간학회추계 Single Topic Symposium 베타차단제는의미있게재출혈율의개선과생존율향상을가져왔고 10 정맥류결찰술은경화술에비해재출혈, 사망률, 합병증등이의미있게낮았다. 11 베타차단제와내시경치료의병합이내시경치료단독에비해재출혈율을낮추지만생존율을유의하게개선시키지는못하였다. 12 식도정맥류결찰술의경우에도약물과병용하면약물이나결찰술단독에비해재출혈율은감소하지만생존율에는차이가없었다. 13 한편정맥류결찰술과베타차단제, 나이트레이트제제의 Figure 2. Secondary prophylaxis of esophageal variceal bleeding 병합요법은두가지약물의병합요법에비 (World J Gastrointest Endosc 2012;4(7):312-322). 해정맥류출혈을감소시키지만전체적인출혈과생존율에서는유의한차이를보이지않았다. 14 정맥류결찰술의간격에대해서는현재까지정해진기준은없지만두가지연구에서 3-4주간격이적절할것임을시사하고있다. 15-16 한번에사용하는고무밴드의수에대해서도 6개를넘는경우환자의성적이더좋아지지않고오히려시술시간이더걸리고제대로장착되지않는밴드의수가늘었다. 17 4. 위정맥류출혈의내시경치료 (Fig. 3) 위정맥류는식도정맥류와다르게위신단락이많이발달되어있고하대정맥으로유출이되며점막하층에위치하고있고식도정맥류보다직경이크고혈류가빠르다는차이가있다. 18-19 대한간학회간경변증진료가이드라인 6 에서는위정맥류출혈의치료에대해다음과같이권고하고있다. 1) 위정맥류출혈은동반된식도정맥류가위의소만을따라확장된 GOV1의경우내시경정맥류결찰술 (endoscopic variceal ligation) 이나내시경정맥류폐색술 (endoscopic vaiceal obturation) 을고려한다.(B1) 2) 동반된식도정맥류가위저부로확장된 GOV2나단독위정맥류인 IGV1 출혈의경우우선적으로내시경정맥류폐색술을시행하며, 내시경적치료가불가능한경우경경정맥간내문맥전신단락술 (transjugular intrahepatic portosystemic shunt) 을시도할수있다. 위신단락이동반된위정맥류의경우풍선-폐쇄역행경정맥폐쇄술 (balloon occluded retrograde transvenous obliteration) 을고려한다.(B1) 3) 내시경적치료가불가능한 Child-Pugh A/B 환자의경우수술 ( 원위비신단락술, 맥관절제술 ) 을시도할수있으며, Child-Pugh B/C 환자의경우간이식을고려한다.(B1) 1980년대와 1990년대에걸쳐여러가지경화제를이용한위정맥류출혈의치료성적이다양하게발표되었지만 20 cyanoacrylate와의비교연구에서지혈률, 재출혈률, 사망률에있어확연한차이를보여 1차치 42
이태희 내시경적식도및위정맥류치료법 Figure 3. Treatment of Gastric variceal bleeding. Garcia-Pagáan JC, Barrufet M, Cardenas A, Escorsell ÀA, Management of Gastric Varices, Clin Gastroenterol Hepatol (2013), doi: 10.1016/j.cgh.2013.07.015. 료로는사용하지않는다. 21-23 최근발표된 Mishira 등의위정맥류의초출혈예방을위한연구에서 cyanoacrylate 30명, 베타차단제 29명, 대조군 30명으로약 26개월추적관찰하였고, Cyanoacrlate 군에서다른두군에비해유의하게출혈이감소하였으나 ( 각각 13%, 28%, 45%) 전반적인생존율에는차이가없었다. HVPG값은베타차단제군에서만유의하게감소하였다. 24 Lo 등은급성출혈이있는환자와출혈의병력을가진 60명환자에서 cyanoacrylate주입법과정맥류결찰술의효과를비교하였는데급성출혈의성공적인지혈과재출혈율에서 cayanoacrylate군에서효과가우월하고생존율에서도 caynoacrylate군에서더좋은경향을보인다고하였다. 25 한편 2차예방목적으로 cyanoacrylate 주입법을사용한군과 TIPS를시행한군을비교한연구에서재출혈은 TIPS군에서낮았고생존률은통계적인차이가없었으며합병증은비슷하였지만간성뇌증은 TIPS 군에서유의하게많았다. 26 BRTO와비교한연구에서재출혈은 BRTO군에서낮았지만생존률은차이가없었고구조요법으로 BRTO를사용한경우는 cyanoacrylate 단독치료후구조요법을하지않은군에비해유의하게생존률이향상되었다고보고하였다. 그러나대상환자수가매우작았고무작위대조연구가아닌단점이있다. 27 Cyanoacrylate 사용군과베타차단제를사용한군을비교한연구에서전자에서재출혈율뿐만아니라출혈과관련된사망률, 전반적인사망률이낮게확인되어 HVPG의감소와다르게 cyanoacrylate 주입법이유용하다고하였다. 28 Cyanoacrylate주압법에베타차단제를병용한경우는 cyanoacrylate 단독요법에비해추가적인이득은 43
2013 년대한간학회추계 Single Topic Symposium Table 1. The result of primary prophylaxis of GV bleeding comparing cyanoacrylate injection and beta-blockers 24 Characteristics Cyanoacrylate Group I (n=30) (n, %) Beta-blocker Group II (n=29) (n, %) No treatment Group III (n=30) (n, %) p value GV Bleed 3/30 (10%) 11/29 (38%) 16/30 (53%) 0.003 Bleed from GOV2 2/26 (4%) 11/25 (47%) 13/25 (52%) 0.001 Bled from IGV1 1/4 (33%) 0/4 3/5 (60%) 0.197 Increasee in GV size 0 11/29 (33%) 13/30 (43%) 0.003 Decrease in GV size 25/25 (100%) 0 0 0.002 Appearance of esophageal varix 7/30 (23%) 3/29 (10%) 3/30 (110%) 0.216 Aggravation/appearance of PHG 7/30 (23%) 2/29 (7%) 3/30 (10%) 0.154 Bleed related mortality 0/30 3/29 (10%) 5/30 (24%) 0.034 GOV2 0/26 3/25 (12%) 5/25 (20%) 0.025 IGV1 0/4 0/4 1/5 (20%) 1 Overall mortality 2/30 (7%) 5/29 (17%) 8030 (26%) 0.113 GOV2 2/26 (8%) 5/25 (20%) 6/25 (24%) 0.122 IGV1 0/4 0/4 2/5 (40%) 0.464 Complications 1 (3%) 1 (3%) 2 (7%) 1 Table 2. Summary of treatments for acute gastric variceal bleeding 33 Initial hemostasis Rebleeding Mortality Complication rate Endoscopic treatments Sclerotherapy 67-100 25-90 25 24-82 Band ligation 45-93 44-72 15-48 23-38 Gastric variceal obturation (Cyanoacrylate) 87-93 22-37 11-29 19-22 Thrombin injection 70-100 0-28 0-30 0-8 Radiologic treatments TIPS a 87-100 10-30 1-20 4-82 BRTO b 77-100 0-15 0-23 15-25 없었다. 29 베타차단제대신 50% 고장성포도당을잔여위정맥류에추가로주입하면위정맥류의재발이나진행을유의하게줄일수있었다고보고하였다. 30 후향적연구이지만 GVO, GVL, BRTO를비교한연구에서는재출혈률과생존률이세군간에차이가없다는보고도있다. 31 최근 thrombin을이용한위정맥류의치료가다시주목을받기시작하고있다. 첫보고 32 는 1947년에있었고외과영역에서활발하게사용되다가 1990년대이후연구가활발해지고있다. 소에서추출한것은 prion 병의위험으로사용이금지되었고현재는 human thrombin만이사용되고있다. 이는주입부에궤양이발생하지않는다는장점이있지만지혈율은 70-100%, 재출혈률은 7-50%, 사망률은 0-50% 정도로보고되고있다 (Table 2). 33 44
이태희 내시경적식도및위정맥류치료법 5. 내시경치료의실제 1) 시술전처치 34 진단내시경과는달리정맥류출혈을치료하거나예방하기위해시술해야하기때문에시술이실패하여출혈성쇽이발생할가능성이있으므로반드시시술전에혈관확보와혈액교차시험, Sengstaken- Blakemore tube, 기관삽관등을위한응급카트등을준비한다. 활력징후와환자의전신상태등을자주평가한다. 2) 히스토아크릴주입법 34 준비도구로 2 ml 주사기, Histoacryl, 5% lipiodol, 20-23G 7 mm 주사침을가진천자도관등이필요하고시술자와보조자의눈에우발적으로 Histoacryl이튀어들어가지않도록보안경을착용해야한다. 1. Lipiodol 0.5 ml와 Histoacryl 0.5 ml을혼합한다. 2. 정맥류천자도관에미리생리식염수를통과시킨다. 내시경시술기구주입부및겸자공내, 내시경선단부에실리콘오일을소량흡인하거나겸자공내로주입한다. 3. 출혈인접부정맥류나정맥류최대경의상방을깊게천자하고 Histoacryl 혼합액을빠르게주입한다. 4. 주입후즉시식염수가담긴 2 ml 주사기로바꾸어도관에남은 Histoacryl 혼합액의양만큼 1-2 ml 정도빠르게주입한후천자침을빼낸다. 5. 천자도관은폐색을막기위해계속생리식염수로관류시키면서재주입필요성이있으면동일한방법으로시행한다. 6. 시술후 20여초간내시경으로흡인하지않아야하고충분한송기로내시경과출혈병소의직접접촉을피하고내시경손상도주의해야한다. 7. 1회주입량은 Histoacryl 0.5 ml, 같은정맥류에최대 2 ml까지, 1회 0.5 ml로 2-3회주입으로지혈효과가충분하다. 주입후딱딱하게굳어있는정맥류를도관으로가볍게눌러보아확인할수있다. 합병증으로는 753명을대상으로한연구에서 glue cast의탈락으로인한재출혈 (4.4%), 패혈증 (1.3%), 원위부색전 ( 폐, 뇌, 비장, 0.7%), 위궤양 (0.1%), 위정맥류출혈 (0.1%), 혈복강과연관된복강내혈종과세균성복막염 (0.1%0 등이있었고합병증과관련된사망은 0.5% 였다고보고하였다. 35 3) 정맥류결찰술 34,36 1. 먼저진단내시경을시행하여병변을확인하고상절치로부터의거리를확인하고내시경을회수하여선단에 6-10개의고무링이장착된후드를부착하고당김줄의고정틀을겸자공에고정한다. 2. 내시경의재진입시에는외경이좀더굵어져서처음보다진입이어려울수있으나환자의목을약간골곡시키면조금수월하게진입할수있다. 3. 내시경상에서결찰할부위가후드에정면으로포착되면내시경으로계속흡인하여충분히정맥류를후드내로빨아들인후 red out sign" 이나타나면고정틀의당김줄을회전시켜정맥류기저부를 45
2013 년대한간학회추계 Single Topic Symposium 결찰한다. Red out sign이나타나는충분한흡인을위해서는미세하게내시경을좌우또는상하로움직이면서계속흡인하는것이필요하다. 이후내시경의진입에의해결찰된밴드가탈락될수있어이미결찰한정맥류쪽으로더깊숙이진입하지는말아야한다. 3. 내시경을회수하지않고다른병소를연속결찰한다. 예방적결찰술에서는위식도접합부에서부터시작하여나선상으로 6-8 cm 상방까지결찰한다. 급성출혈시에이상적으로는정맥류의출혈점이흡인되는것이중요하지만시야확보가용이하지않은경우에는물로씻은후흡인을해볼수있다. 출혈점을찾기가어렵거나심한활동성출혈로첫시도에실패하면위식도접합부위에서부터몇개의밴드를우선장착하거나출혈점직하방에서우선결찰하는것도좋은방법이된다. 합병증으로는결찰술후에나타나는궤양에의한출혈이약 5.5% 에서나타날수있으며치명적일수도있다. 37 6. 다양한시도들 1) Hemospray 무기물분말로출혈부위에접촉하면장벽을만들어지혈하고흡착력이있어국소적으로응고인자의농도를높여지혈을촉진하는것으로알려져있으며 38 최근위정맥류환자에대한사례가보고되었다. 39 잠재적인위험으로는색전, 장폐색, 알러지반응등이있을수있다. 38 2) Ankaferd Blood Stopper 다섯가지식물 ( 땅백리향, 감초, 유럽포도, 양강 ( 생강종류 ), 애기쐐기풀 ) 에서추출한재료의혼합물로신속하게단백질망을만들고적혈구의응집을촉진하여지혈효과를보인다하였다. 40 이후 Mallory-Weiss tears, Dieulafoy lesions, gastric antral vascular ectasia, gastric varices, anastomotic ulcers, sphincterotomy sites, postpolypectomy sites, radiation proctopathy, solitary rectal ulcers, tumor bleeding 등다양한분야에서지혈에적용되었다. 41 도포후약 20초이내에지혈이시작되어 2분이내에완전지혈이될수있어식도정맥류의결찰술후출혈이나위저부정맥류의치료에대한보고들이있다. 42-46 3) SEMS (Self-expanding metal stent) 특별하게고안된 self-expandable covered metalic stent (SX-Ella Danis stent; Ella-CS, Hradec Kralove, Czech Republic) 를다른치료에반응하지않는식도정맥류의치료로사용한보고들이있다. 약 2주간장착하고그사이에 TIPS 등의다른치료를시행해볼수도있고제거도식도에손상이없이할수있다고하였다. 47-50 4) APC (Argon plasma coagulation) 식도정맥류치료에정맥류결찰술과아르곤응고술을병합하면정맥류결찰술과경화술을병용한경우와비슷하게정맥류의빠른소실, 낮은재발률을나타냈다. 51 46
이태희 내시경적식도및위정맥류치료법 5) Clipping and detachable snare 비정맥류출혈에사용하던클립과올가미를이용한정맥류지혈술도보고되었다. 식도정맥류 40명환자에서클립과결찰술을비교하여정맥류의소실률 (89% and 76%) 과합병증은비슷하였으나치료횟수는클립을시행한군에서작았다 (3 vs. 4, p=0.013). 시술후발생한궤양은결찰술군에서 90% 에서나타나서유의하게많았다 52. 이후활동성위정맥류출혈을클립으로치료한사례도보고되었다. 53-54 크기가 2 cm 이상으로큰위정맥류의경우 detachable snare를이용하고이보다작은위정맥류는고무밴드를이용하여 41명의환자를치료하였고전체적으로 83% 지혈성공률을보고하였다. 55 6) PDT (Photodynamci therapy) 14명의식도정맥류환자들에게정맥류경화술후광역동치료를시행하여대조군에비해재출혈울감소시킨결과를보고하였다. 이는작은신생혈관들을근절하여나타나는효과로보고있다. 56 요약및결론 위식도정맥류출혈은간경변환자에서주요한사망원인이되어이의치료가간경변환자의생존과연관이된다. 내시경치료는약물과영상의학적인중재술과더불어정맥류출혈의치료에, 특히급성출혈에서매우중요한위치를차지하고있다. 식도정맥류의경우일차예방으로베타차단제에적응증이안되거나견디지못하는환자들을대상으로정맥류결찰술을사용할수있고급성출혈에서는정맥류결찰술이우선적인방법으로시도될수있다. 여의치않거나실패하면정맥류경화술이나정맥류폐색술을고려할수도있다. 이차예방법으로는정맥류결찰술과베타차단제의병합요법이추천되고경우에따라나이트레이트제제의추가가도움이될수있다. 위정맥류의경우에는일차예방으로 GOV1의경우베타차단제, GOV1 또는 IGV1의경우정맥류폐색술을고려할수도있으나아직자료가충분치는않다. 위저부정맥류의급성출혈시에는정맥류폐색술이결찰술이나경화술에비해우선되어야한다. 이차예방을위해서는정맥류폐색술과베타차단제간에는재출혈이나생존률에는차이가없어보이지만두가지의병용요법이다른문맥압항진증에대한합병증도줄일수있을것으로보인다. 이외에도 Thrombin, Hemospray, Ankarferd blood stopper 등의지혈제와비정맥류치료에사용되던 hemoclip, detachable snare, APC, PDT, stent 실험적인다양한방법들이소개되고있다. 향후이들새로운방법들의발전과더불어기존의방법들과의병용용법에대한좋은결과들을기대해본다. 47
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