02.STS본문.hwp

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1 간폐증후군과문맥폐고혈압 Hepatopulmonary and portopulmonary syndrome 대구가톨릭대학교의과대학내과학교실 이창형 Abstract Portopulmonary hypertension (PPHTN) and hepatopulmonary syndrome (HPS) are distinct clinical entities that may accompany liver disease with significant mortality after orthotopic liver transplantation. In hepatopulmonary syndrome, patients present with hypoxia secondary to intrapulmonary vasodilatation. In portopulmonary hypertension, there is excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right heart failure and death if left untreated. The pathophysiology of these two conditions is not fully understood. Imbalance in the pulmonary circulation between vasodilators and vasoconstrictors may play a role. In hepatopulmonary syndrome, there is excessive nitric oxide (NO), while portopulmonary hypertension there may be excessive endothelin. These vasoactive substances normally do not enter the pulmonary circulation in significant amounts since they are cleared by the normal liver. However, if there is excessive production of these vasoactive substances from the splanchnic circulation, or by the cirrhotic liver, they may find their way into the pulmonary circulation, which ultimately results in the pulmonary vascular syndromes. Key words: Portopulmonary hypertension; Hepatopulmonary syndrome; Vasodilators; Vasoconstrictors 서 론 간경변증환자에서순환기및호흡기증상을동반하는것은매우흔한일이며약 50~70% 에서호흡곤란을호소한다. 1 복수나흉수에의한폐실질의압박이간경변증에서경한저산소혈증의흔한원인으로생각되나, 2 심한저산소혈증은심폐질환을동반하지않으면관찰하기어렵다. 3,4 여러가지많은호흡곤란의원인중간경변증에의한간문맥압항진증환자에서간폐증후군 (hepatopulmonary hypertension) 과문맥폐고혈압 (portopulmonary hypertension) 이폐혈관을침범하는중요한질환

2 2009 년대한간학회 Single Topic Symposium 으로생각된다. 5 간폐증후군은폐혈관확장에의해동맥혈가스교환의장애가발생하고문맥폐고혈압은폐동맥수축 (pulmonary arterial constriction) 과재형성 (remodeling) 이유발되어폐동맥압이증가하는질환이 다. 6 간경변증환자에서간폐증후군의유병률은 4~30% 정도로알려져있고, 7-10 문맥-폐고혈압은만성간질환자의 2~16% 에서관찰되는데폐동맥고혈압을유발하는다른원인들이다제거되어야진단할수있다. 7 간이식후병원내사망률은간폐증후군환자는약 16%, 문맥-폐고혈압환자에서는 36% 에서관찰된다. 11 간폐증후군 간폐증후군은만성간질환을가진환자에서실내공기호흡시폐포-동맥산소분압차 (AaD02) 가 15 mmhg(64세이상은 20 mmhg) 이상증가되고광범위한폐혈관확장을특징으로하는질환이며, 12,13 폐혈관확장은만성간질환환자에서비교적흔히관찰되는현상으로간이식을받은간경변증환자의 40% 이상에서관찰된다. 10,14,15 이중 8~20% 정도에서산소공급의장애가발생하며간폐증후군으로진단된다. 간폐증후군은주로간경변증에서관찰되나여러가지다양한다른원인의간질환에서도볼수있다. 14 간경변증의심한정도와간폐증후군의발생빈도간에유의한상관관계는알려져있지않으며간경변증의심한정도와는관계없이발생할수있는것으로생각된다. 16,17 최근간경변증을동반하지않는문맥압항진증 (portal vein thrombosis, Budd-Chiari syndrome 등 ) 18,19 과문맥압항진증이없는급만성간염에서도간폐증후군이발생한보고도있다. 20,21 1. 병태생리 폐동맥순환내모세혈관확장 (microvascular dilatation) 이가장근본적인병태생리소견이다. 8 이들변화는 precapillary arteriolar tone 자체만의감소에의하던지혈관신생 (angiogenesis), 혈관재형성 (remodeling) 및혈관발생 (vasculogenesis) 등의추가적인메커니즘이부가적으로영향을줄가능성도있다. 22 발생기전으로는 nitric oxide, prostaglandins, vasoactive intestinal peptide, calcitonin, glucagons, substance P 및 antinatriuretic factor 등혈관확장물질과수축물질간의불균형때문에생긴다는가설이가장널리받아들여지고있다 ( 표 1). 손상받은간에 Table 1. Proposed mediators of the hepatopulmonary syndrome Vasodilators Vasodilator prostaglandins Prostacyclin PGE1 PGI2 Vasoactive intestinal peptide (VIP) Calcitonin Glucagon Substance P Nitric oxide Atrial naturetic factor Platelet activating factor Ferritin Estrogens Vasoconstrictors Tyrosine Serotonin Endothelin Adapted from Krowka, MJ, Hepatology 1990;11:

3 이창형 : 간폐증후군과문맥폐고혈압 Figure 1. Potential mechanisms in hepatopulmonary syndrome. (Adapted from Gaines DI, Fallon MB. Hepatopulmonary syndrome. Liver international 2004;24:397) 서폐혈관확장물질의제거장애, 폐혈관확장물질의생성및혈관수축물질의억제등이관여하는것으로생각된다. 정상적으로폐실질내모세혈관의직경은 8~15 μm인데반해서간폐증후군환자에서는 15~500 μm까지확장되어폐포로부터비정상적으로확장된혈관내의가운데에위치한적혈구까지거리가멀어져서산소분자가효과적으로적혈구에도달하지못하기때문에저산소증이생기는것으로생각된다. 특히폐혈관에서분비되는 NO의증가가폐혈관확장의발생에중요한역할을하는것으로생각된다. 간폐증후군환자의호기가스내의 NO의농도가증가되어있으며 23 간이식후간폐증후군이호전된후에는감소하는것을관찰할수있다. 24 간폐증후군환자에서폐순환계내에서 NO(nitric oxide) 가증가되어있으며 25,26 동물모델에서폐동맥모세혈관계에서 enos(endothelial nitric oxide synthase) 와 inos(inducible nitric oxide synthase) 가증가되어나타나는것이확인되었다. 27,28 특히간경변증환자에서폐포 (pulmonary alveoli) 는 NO 분비가증가되는가장중요한원천으로생각되며폐혈관내피세포 (pulmonary endothelial cells) 에서는 enos의분비증가가폐포대식세포 (alveolar macrophage) 에서는 inos의분비증가가관찰된다 ( 그림 1). 29 폐혈관의 enos의증가가 pulmonary NO 생성을증가시키는가장주원인이다. 27,29-30 간경변증에서의과역동순환으로인해증가된전단력 (shear stress) 으로의해 pulmonary vascular endothelial endothelin B (ETB) receptor의발현이증가하며간에서분비가증가되어혈중으로분비된 endothelin-1(et-1) 이 ETB 수용체를자극하여 enos를증가시켜 NO의분비를증가시키는중요한메커니즘으로작용한다 최근의초기보고 (preliminary report) 에의하면담관상피가간에서 ET-1을생산하는중요한근원으로알려지고있다. 34 CBDL(common bile duct ligation) animal에 selective ETB receptor antagonist를투여하면폐혈관내막의 enos와 ETB 수용체의수가감소하고간폐증후군은현저하게호전된다. 35 L-NAME(NG-nitro

4 2009 년대한간학회 Single Topic Symposium L-arginine methyl ester) 으로 NO의생성을차단하거나 cyclic GMP의저해제인 methylene blue를사용하여 NO의작용을차단하면일시적으로간폐증후군이호전될수있다 그러나최근 L-NAME을흡인시켜투여하였을때폐혈관확장을호전시킬수없었다는연구보고가있어 NOS에의한 NO의증가외에다른인자가간폐증후군의발생에관여할가능성이높게생각되고있다. 간경변증에서생기는장관내독소혈증 (intestinal endotoxemia) 은간폐증후군의발생에중요한역할을한다. 39 간의 mononuclear phagocytic system이문맥내의세균및독소를제거하는데중요한역할을한다. 39 간경변증에서는간내혈관저항의증가로인해간세포로유입되는문맥혈이감소한다. 이로인해장관의벽에부종이생기고장의운동기능과담즙의분비가감소한다. 이런원인들에의해장관내에특히그람음성균의과대증식이일어나고내독소의산생이증가한다. 장관벽의정상적인점막장벽 (mucosal barrier) 의결함, 정상적인기능을하는간세포와쿠펴세포의감소및전신문맥단락으로인해세균및내독소가혈액으로유입되어효과적으로제거되지못하고균혈증 / 내독소혈증을유발한다. 내독소혈증으로인해쿠퍼세포로부터 TNF-α가과분비되는것이간폐증후군의중요한병태생리기전중의하나로작용한다. 39 TNF-α가폐포에폐포대식세포 (alveolar macrophage) 의축적을유도하고 inos의분비를증가시켜 NO의폐순환내농도를증가시킨다. CBDL(Common Bile Duct Ligation) 동물에게결찰 (ligation) 직후부터장내세균전위 (bacterial translocation) 와 TNF-α 생성을저해시키기위해 norfloxacin을투여하면대식세포의축적을감소시키고 inos의증가를막을수있다. 이로보아 TNF-α가대식세포의축적에관여를함을알수있다. Phosphodiesterase의비특이적억제제인 pentoxiphylline은세포내에서 camp 의농도를증가시키는역할외에대식세포에서 TNF-α의생성을저해하여간폐증후군의발생을막거나심한정도를경하게할수있다. 40,41 Heme oxygenase에의해유도되는 carbon monoxide와같은다른물질들도폐혈관확장에관여하며일부환자들에서 NO 억제후에도간폐증후군의호전이없는이유를설명하는데이용되나아직그작용여부에대해서는확실하게확립된상태는아니다 임상증상간폐증후군의임상증상은만성간질환의소견과호흡기증상을함께보인다. 대부분의연구에서간기능부전의정도를나타내는혈청생화학적검사소견이나 Child 분류의정도와저산소혈증또는단락의심한정도는항상비례하는것은아니다. 43,44 서서히발생하는호흡곤란 (insidious onset of dyspnea) 특히운동시호흡곤란이가장흔한증상이다. 중력의작용에의해서폐기저부의확장된혈관으로혈류량이증가함으로서생기는편평호흡 (Platypnea: 앉거나선자세에서심해지고누우면호전되는호흡곤란 ) 와직립성저산소혈증 (orthodeoxia: 세운자세에서심해지는저산소혈증 ) 을관찰할수있다. 45 직립성저산소혈증은 post-pneumonectomy, recurrent pulmonary emboli, atrial septal defects(including patent foramen ovale) 및만성폐질환등다른질환에서도관찰

5 이창형 : 간폐증후군과문맥폐고혈압 할수있지만간폐증후군을강하게시사하는증상이다. 46 직립성저산소혈증은간경변증환자의약 5% 정도에서관찰되고심한저산소혈증을가지는간폐증후군환자에서더빈도가높다. 한연구에의하면 16 명의간폐증후군환자중 14명 (88%) 에서직립성저산소혈증이관찰되었다고보고하고있다. 47 거미상혈관종은간폐증후군환자에서흔히관찰되는것을보고되고있다. 이병변은간폐증후군과관련된폐혈관확장의표지자로여겨지며이병변이없는환자에비해전신및폐혈관의확장이더심하고가스교환의장애가훨씬심한것으로보고되고있다. 48 거미상혈관종을가진환자에서폐포-동맥산소분압차는 20 mmhg로없는환자의 8.0 mmhg에비해높다. measured shunt fraction(qs/qt) 도거미상혈관종을가진환자에서더높다 (7.1 v.s. 2.0 percent) 그러나거미상혈관종은간폐증후군이없는환자에서도많은빈도로관찰된다. 폐순환혈관계의광범위한확장으로인해우좌단락, 직립성저산소혈증, 저산소혈증에대한폐혈관의수축및저환기부위에과도한혈액의관류가유발된다 % 산소를공급하면혈중산소농도가부분적으로개선되므로폐내혈관확장은진정한의미의해부학적단락으로볼수없다. 이러한산소에대한부분개선이생기는기전은확산-관류장애 (diffusion-perfusion impairment) 또는폐포-모세혈관산소불균형 (alveolar-capillary oxygen disequilibrium) 으로생각된다. 50 폐내혈관확장으로인해모세혈관의직경이커지게되면산소분자가폐포로부터확장된혈관의중심부까지확산 (diffusion) 해들어가혈관의중심부의혈류를따라흐르는헤모글로빈을산소화시킬수가없다. 그러나산소의분압을높여서공급하면추진압력 (driving pressure) 이증가하므로확산장애를부분적으로극복할수있다. 3. 진단일반적으로간폐증후군은만성간질환을가진환자에서실내공기호흡시동맥혈산소분압이 80 mmhg 이하이면서폐포-동맥산소분압차가 15 mmhg(64세이상은 20 mmhg) 이상증가되어있고폐내혈관확장 (IPVDs) 이있으면진단할수있다. 대부분의간폐증후군을의심하는환자에서만성간질환 ( 또는문맥압항진증 ) 은이미동반되어있으며폐포-폐동맥산소분압차의측정도동맥혈가스검사로쉽게알수있으므로여기에서는폐내혈관확장을진단하는방법에대해주로설명하겠다. 폐내혈관확장을진단하기위해조영증강심초음파 (contrast-enhanced echocardiography), 99mTc-MAA(technetium-99m-labeled macroaggregated albumin) 을이용한폐관류스캔그리고폐혈관조영술 (pulmonary arteriography) 이주로사용된다. 1) 조영증강심초음파조영증강심초음파가폐내혈관확장을진단하기위해주로사용되는진단방법이다 ~150 μm 크기의미세기포 (microbubble stream) 를발생시키기위해인도사이아닌그린 (indocyanine green dye) 혹은발포식염수를정맥주사후심초음파를시행하면정상인경우에는미세기포가폐모세혈관를통과하지못하

6 2009 년대한간학회 Single Topic Symposium 므로우측심장부위에서만관찰되나우좌단락이있으면좌측심장부위에서도관찰된다. 4 심장내단락이있는경우에는조영제를주사후미세기포가 3회의심박동내에좌측심장에서관찰되며폐내단락의경우에는 3~6회심장박동후좌측심장에서관찰되는것으로단락의위치를감별할수있다. 38명의간이식대기자를대상으로심장초음파를시행한전향적연구에서 13.2% 의환자에서폐내혈관확장을관찰할수있었다. 2 일부정상산소혈증 (normoxemic) 환자에서심장초음파에서관찰되는좌우단락소견으로보아전형적인저산소혈증을발생시키지않은상태의무증상의폐내혈관확장이있음을시사하고있다. 경식도심초음파 (Transesophageal echocardiography) 를사용하면좌심방으로유입되는페정맥에서미세기포를직접적으로관찰함으로서폐내혈관확장을보다정확하게확인할수있다. 52 심장초음파상우심방의용적은간폐증후군을진단하는데도움을줄수있다. 우심방의용적이 50 ml 이상이면민감도 86%, 특이도 81% 의확률로간폐증후군을진단할수있다. 53 2) 폐관류스캔 99mTc-MAA은직경 20 μm 이상의대응집알부민 (macroaggregated albumin) 를사용하는데정상적으로이들은직경이 8~15 μm인폐모세혈관을통과하지못하지만단락이있는경우에는단락을통해서전신순환으로유입되기때문에동위원소가신장또는뇌에흡수되는소견을보인다. 54,55 3) 폐혈관조영술폐혈관조영술은침습적이며폐내혈관확장을진단하는데민감도가낮기때문에선별검사로는유용성이떨어진다. 폐색전증또는폐동맥고혈압등저산소혈증의다른원인을배제하는데유용하다. 간폐증후군의폐혈관조영술에서는혈관의양상에따라미만형 (type 1) 과국소형 (type 2) 으로나눌수있다. 47 극소미만형 (minimal diffuse type) 은폐혈관조영술상그물눈모양의혈관이미만성으로퍼져있는양상으로나타나고 100% 산소흡입을하면증상의호전을볼수있다. 진행성미만형 (advanced diffuse type) 은범발성스폰지모양의폐혈관이상을보이며 100% 산소흡입에반응이없다. 국소형은드물게나타나는데작고불연속적인국소적인동-정맥교통으로인해생기며 100% 산소흡입에반응이좋지않다. 4) 흉부영상진단흉부단순촬영에서특징적인양상을보이는것은드문데일부환자에서양쪽폐하부에간질성음영이증가되는소견을볼수있으며간혹간질성폐질환으로오진되기도한다. 고해상흉부전산화단층촬영 (high-resolution computed tomography) 이새로운진단방법으로사용되고있다. 한연구에의하면고해상전산화흉부단층촬영상관찰되는폐미세혈관의확장정도와가스교환의장애정도가관련성이있게나타나며혈관확장의정도를비침습적으로측정할수있다고하였다. 56 알부민-미세기포복합체 (human serum albumin-air microbubble complex) 를사용하여심초음파로측정한폐내전이시간 (pulmonary transit time) 을이용하여간폐증후군환자에서가스교환의장애정도를측정할수있다는연구보고도있다

7 이창형 : 간폐증후군과문맥폐고혈압 Table 2. Categories of treatment of the hepatopulmonary syndrome Treatment Efficacy for improving gas exchange in the hepatopulmonary syndrome Physically occlude IPVDs Spring coil embolization Modest if technically possible Oppose circulating vasodilators Octreotide (somatostatin analog) Variable Nitric oxide synthase inhibitors Variable Indomethacin Poor Improve V/Q matching Almitrine bismesylate Slight Treat underlying liver disease Chemotherapy and corticosteroids Helpful in one patient Liver transplantation Moderately good but variable response Other (miscellaneous) Methylene blue Helpful in one patient Allium sativum (garlic) Variable Propranolol None Plasma exchange None Sympathomimetics None Adapted from Lange, PA, Stoller, JK, Ann Intern Med 1995;122:521. 5) 폐기능검사폐기능검사의이상소견은간폐증후군환자에서비교적흔히볼수있으며간폐증후군에만나타나는특징적인소견은아니다 (largely nonspecific). 58 6) 폐활량측정 (Spirometry) 폐쇄성또는구속성폐질환 (obstructive or restrictive lung disease) 을동반하고있지않는간폐증후군환자는대개폐활량측정에서는전폐용량 (total lung capacity) 및호기유속 (expiratory flow rates) 은정상이다. 7) 폐확산능검사 (Diffusing capacity) Carbon monoxide에대한폐확산능 (DLCO) 은간폐증후군환자에서경도에서부터매우심한정도의장애를나타낸다. 58 한연구에서는간폐증후군환자의 15~18% 가폐확산능의예측치의약 80% 이하로나타났다고보고하고있다. 47 그러나이검사소견은간폐증후군에만볼수있는특징적인소견은아니다. 4. 치료 여러가지치료방법이간폐증후군환자의가스교환과저산소혈증을치료하기위해서사용된다 ( 표 2). 현재간이식이간폐증후군환자의심한그리고치료에반응하지않는저산소혈증을치료하는가장효

8 2009 년대한간학회 Single Topic Symposium 과적인방법으로생각된다. 51 1) 내과적치료 (Medical therapy) 여러가지약물적치료가시도되었지만현재까지동맥혈산소화 (oxygenation) 와단락을효과적으로개선시키는것은아직없다. 교감신경흥분제 (sympathomimetic agents), 알미트린 (almitrine bismesylate), 인도메사신 (indomethacin), 소마토스타틴유도체 (somatostatin analogues) 와혈장교환술 (plasma exchange) 등이간폐증후군의치료에사용되었지만큰효과는볼수없었다. 5,38,51,59 간폐증후군을가진두명의어린이에게아스피린을사용하였을때동맥혈산소화가증가되었다는보고가있다. 60 마늘분말 (garlic powder) 을최소 6개월이상 15명의간폐증후군환자에게투여하였을때 6명 (40%) 에서동맥혈산소분압이 10 mmhg 이상상승하였으며 1명의환자는 1년 6개월후저산소혈증이치료되었다. 61 Soluble guanylate cyclase 억제제인메틸렌블루 (methylene blue) 를정맥주사하여 NO의작용을억제시켰을때 8명의환자에서동맥혈산소화를일시적으로호전시킬수있었다. 37 NOS 억제제인 L-NAME을흡입제로사용하여동맥혈산소분압과운동능력의향상을관찰할수있었다는증례보고가있다. 37 반면효과가없었다는보고도있다. 38 또한 curcumin, terlipressin 및 methylene blue 등을사용하여 NO를억제하였을때저산소혈증과직립성저산소혈증을더악화시켰다는다른증례보고도있다. 62 Norfloxacin을사용한간폐증후군환자에서동맥혈산소분압을개선시킬수있었다는증례보고도있다. 63 NOS 억제제인 Pentoxifylline은동물실험에서 potential therapy로생각되어지고있다. 41 간폐증후군은문맥압항진증과관련되어발생하므로 TIPS를시행하여문맥압항진증을개선시켜주면간폐증후군의치료에효과가있을것으로생각된다. 실제로간폐증후군환자에서경경정맥간내문맥전신순환단락술 (transjugular intrahepatic portosystemic shunt, TIPS) 을시행후가스교환의호전을보였다는증례보고들이있다 그러나동맥혈산소화의개선을볼수없었다는보고도있고 TIPS 후에심해지는과역동순환에의해폐혈관의확장이오히려심해져간폐증후군을악화시킬수도있으므로간폐증후군의치료에공식적으로권장되지않는다. 51,68 2) 간이식 (Liver transplantation) 미국간학회의간폐증후군에대한 Practice Guidelines에서도즉시간이식이가능한센터로이송후간이식에대한 evaluation을시행하도록권고하고있다. 69 간폐증후군의치료에간이식의유용성을평가한무작위대조연구는아직까지시행되지않았다. 간이식전후에심장및호흡기에대한평가를시행한 74 명의환자를대상으로한관찰연구에서가스교환의개선은대부분에서관찰할수있었다. 70 간이식전에는 50% 의환자에서비정상적인폐포-동맥산소분압차를볼수있었고 30% 에서저산소혈증이있었으나이식후에는현저한호전을보였다. 그러나이식후에도 DLCO는호전이관찰되지않았다. DLCO 장애는저산소혈증과는다른기전에의한것일가능성이많으며무증상의폐혈관변화는지속적으로유지되고있음을시사한다. 71 간폐증후군으로간이식을시행한 24명의환자들을대상으로한전향적관찰연구에서 7명 (29%) 이수

9 이창형 : 간폐증후군과문맥폐고혈압 술후 10주내에조기사망하였다. 72 나머지환자들은최소한 1년이상생존하였다. 조기사망에관련한인자로는수술전에실내공기흡입상태에서동맥혈산소분압이 (PaO 2) 50 mmhg 이하이며수술전단락분율 (shunt fraction) 이 20% 이상이었다. 간이식수술후의지연회복과심해지는저산소혈증역시생존율을줄이는데관여하였다. 간폐증후군환자에서간이식후 1년생존율이 71% 인것은간폐증후군이없는환자의일반적인 1년생존율이 90% 인것을감안하면매우낮은생존율로생각된다. 다기관후향적연구에서도 32명의간폐증후군환자를간이식하였을때수술후병원내 (in hospital) 사망률이 16%(5/32 patients) 로매우높았다고보고하고있다. 73 비슷한정도의간질환 severity를가진간폐증후군환자를대상으로간이식술을시행한경우에시행하지않은환자보다의미있는생존율을나타내고있다. 74 일부연구에서는간이식후단락분율과저산소혈증의개선이수일내에일어난다고보고하고있지만다른연구에서는 2~14개월간서서히개선된다고보고하고있다 간이식후저산소혈증의개선이지연되어나타나는것은 NO에의한혈관확장보다는혈관재형성 (vascular remodeling) 또는폐내단락 (intrapulmonary shunt) 이가스교환의장애를유발하는주요원인인것을시시하나이러한주장을뒷받침할데이터는아직부족한실정이다. 78,79 문맥폐고혈압 문맥폐고혈압은문맥압항진증을가진환자에서폐동맥고혈압을유발하는다른원인이없이폐동맥고혈압을가진경우를말한다. 51 폐동맥고혈압은우심장도관삽입후측정하였을때 80 평균폐동맥압 (mean pulmonary artery pressure, mpap) 이안정시에 25 mmhg 이상이고, 운동시에 30 mmhg 이상이면서좌심실확장기말압력 (pulmonary capillary wedge pressure, PCWP) 이 15 mmhg 이하이고폐혈관저항 (pulmonary vascular resistance) 이 240 dynes -1 cm -5 로증가하는 3가지기준을모두만족하는경우를말한다. 문맥폐고혈압은 40~50대에호발하며남녀간의발생빈도의차이는보이지않는다. 17,901명의간경변증환자를부검한결과폐동맥고혈압에합당한조직학적변화소견이 0.7% 에서관찰되었으며 81 간문맥압항진증을동반한 507명의환자를대상으로전향적관찰을한결과 2% 에서폐동맥고혈압을관찰할수있었다. 82 일부연구에서간이식을위해검사중인말기간경변환자에서폐동맥고혈압의유병률이 3.5~ 16.1% 로매우높게나타났다고보고하고있어 심한간경변을가진환자에서문맥폐고혈압의발생이더높은발생빈도를보이는것으로생각된다. 문맥폐고혈압의발생에는간문맥압항진증이필수요건이다. 문맥압항진증을동반하지않는만성간질환에서는문맥폐고혈압을유발하지않는다. 문맥폐고혈압을유발하는문맥압항진증의원인으로는간경변증, 문맥혈전증, 간정맥경화증 (hepatic vein sclerosis), 선천성문맥순환이상 (congenital portal circulation abnormalities) 및간경변증을동반하지않은문맥주변부섬유화 (periportal fibrosis) 등이있다. 89,

10 2009 년대한간학회 Single Topic Symposium Figure 2. Possible pathogenetic mechanisms leading to portopulmonary hypertension. (Adapted from Budhiraja R, Hassoun PM. Portopulmonary hypertension. Chest 2003;123: 562) 1. 병태생리여러가지가설들이제시되고있지만문맥폐고혈압의원인은아직까지정확하게알려져있지않다. 과역동순환으로인해폐순환으로의혈류의유입이증가되고그로인해증가된전단력 (shear stress) 이혈관내막의손상을유발하는것을시작으로문맥폐동맥고혈압의특징적인혈관병변을유발하는일련의경로가시작된다 ( 그림 2). 그러나전단력이증가되어있는모든환자에서실제문맥폐고혈압이발생하지는않으므로전단력의증가에부가적인인자들이함께작용하여야만혈관손상이시작되는것으로생각된다. 부가적인인자로는혈관활동성을유발하는호르몬, 유전적소인및환경적인손상등이관여할것으로추측된다. 정상적으로간에서대사되어야하는호르몬 (hormonal substance) 이문맥전신단락으로통해서폐혈관순환계내로유입되어문맥폐고혈압을유발한다는가설이널리받아들여지고있다. 91 여기에관여하는호르몬들로는 serotonin, interleukin-1, endothelin-1, glucagon, secretin, thromboxane B2, and vasoactive intestinal peptide 등이있다. 89,92-94 이들호르몬들은문맥압항진증환자의하대정맥또는우심실에서채취한혈액에서증가되어있다. Serotonin은평활근의증식과비대를유도하는역할 95 을하는데문맥폐고혈압의발생에관여하는것으로알려져있다. 93 정상적인상태에서는간에서 serotonin을대사시키므로폐에도달할수가없으나간의대사기능에장애가있거나문맥전신단락이발생한경우에는높은농도의 serotonin 이폐순환으로유입될수있다. 문맥폐고혈압환자의폐에서 serotonin transporter인 5-HTT의발현과활성이증가되어있음이알려져있다

11 이창형 : 간폐증후군과문맥폐고혈압 문맥압항진증에서는강력한혈관수축제이면서평활근유사분열 (smooth muscle mitogen) 의작용이있는 ET-1의생성이간, 장관및비장에서증가하는것으로알려져있다. 97,98 문맥폐고혈압을가진비대상성간경변환자에서 ET-1(endothelin-1) 의농도가문맥폐고혈압이없는환자에비해유의하게높다. 88 두개의증례보고에서비특이적 ETA/ETB 수용체차단제인 bosentan을사용하였을때문맥폐고혈압환자의폐동맥압과문맥압이감소하는것으로보아 ET-1의증가가문맥폐고혈압의발생에관여한다고생각된다. 99,100 유전적소인 (genetic predisposition) 이발생에관여하는것으로생각된다. 일부가족성폐동맥고혈압에관여하는유전자는 chromosome 2(locus 2q33) 에위치하고있으며 bone morphogenetic protein receptor type II(BMPR2) 의기능에결함을초래한다. 이러한결함이문맥폐고혈압을유발하는것과관련이있을것으로생각된다 문맥혈류내의혈전이문맥전신단락을통해폐순환으로유입되어폐동맥고혈압을유발할수있는것으로도생각된다. 105,106 그러나대규모부검을시행한연구에서문맥혈관과폐혈관계에동시에유의한혈전이존재하는것을관찰할수는없었으며일부문맥폐고혈압에서관찰되는폐동맥의혈전은조직병리학적양상으로보아폐동맥자체에서생긴것으로생각된다 병리소견문맥폐고혈압과특발성폐동맥고혈압환자에서폐의조직병리학적소견은차이가없으며혈관수축 (vasoconstriction), 폐동맥벽의근육층의재형성 (remodeling of the muscular pulmonary artery walls) 및 in situ thrombosis 등을관찰할수있다. 106,108 초기에관찰되는폐동맥의중막비후 (medial hypertrophy) 는잠재적으로가역적인형태이지만질환이진행하면서점차폐동맥병증 (pulmonary arteriopathy) 의구성요소로된다. Pulmonary arteriopathy는두가지아형 (subtypes) 으로나눌수있다. 얼기형성폐동맥병증 (plexogenic pulmonary arteriopathy) 은중막비후, 내막섬유화 (intimal fibrosis) 와혈관의전층을침범하는병변이특징이며혈전성폐동맥병증 (thrombotic pulmonary arteriopathy) 은중막비후, 혈전및편재성의 (eccentric) 결이없는 (nonlaminar) 내막섬유화를특징으로한다. 혈전은주로색전 (emboli) 보다는폐자체내에서유래한것으로생각된다. 각아형은같은질환의다른병기인지또는손상에대한반응의차이인지는확실하지않다 임상증상대부분의문맥폐고혈압환자들은문맥압항진증과폐동맥고혈압의임상적인소견을모두가지고있다. 일부환자에서는호흡기증상없이문맥압항진에의한증상만가진경우도있으나 82 문맥압항진증의증상이없이폐동맥고혈압의증상만나타내는경우는매우드물다. 문맥압항진증의증상은대개폐동맥고혈압의증상보다선행하는데문맥압항진증에의한첫증상발현후폐동맥고혈압증상의발현까

12 2009 년대한간학회 Single Topic Symposium 지는 2년에서 15년정도간격이있다. 91,109 폐동맥고혈압에의한증상으로는운동시호흡곤란, 흉통, 피로감, 객혈및기좌호흡 (orthopnea) 등이흔히나타난다. 109 이학적검사상제2심음의 pulmonic component의증가, 수축기잡음및부종을흔히관찰할수있다. 30명의문맥폐고혈압, 30명의특발성폐동맥고혈압및 30명의만성간질환만가진간이식대기자를비교한후향적연구 110 결과문맥폐고혈압환자에서평균폐동맥압은특발성폐동맥고혈압과비슷한정도로상승되어있었으나전신혈관저항의감소와심박출계수 (cardiac index) 의증가등은만성간질환만단독으로가진환자와비슷하게나타났다. 110 삼첨판폐쇄부전증이있는경우호기시증가하는수축기잡음을흉골좌연에서청진할수있다. 우심실부전소견으로의존성함요부종 (dependent pitting edema) 을관찰할수있다. 흉부방사선사진 (chest radiograph) 상대부분의환자에서뚜렷한폐동맥과심비대의소견을관찰할수있다. 대부분의환자의심전도검사에서는우심실비대, 우측축편위 (right axis deviation) 및우각차단 (right bundle branch block) 의소견을볼수있다. 한연구에서는단지 4% 의환자에서만정상심전도소견을보였다고보고하고있다 진단진단에이용되는방법으로는심초음파, 심전도, 흉부방사선사진또는흉부전산화단층촬영, 폐기능검사, 다원수면검사 (polysomnography), 폐환기관류검사 (ventilation-perfusion scanning), 폐동맥조영술, 자가면역항체검사, HIV검사및간기능검사 (liver function test) 등이이용된다. 111 환자의병력과신체검사의소견에따라진단에사용할검사의우선순위가결정된다. 특발성폐동맥고혈압은폐동맥고혈압을유발할수있는여러기질질환을제외함으로서 (diagnosis of exclusion) 진단할수있다. 폐동맥고혈압의확진과심한정도를평가하기위해서는우심장도관삽입이필수적이다. 문맥폐고혈압이의심되는경우에는도관삽입중에폐색간정맥압 (hepatic venous wedge pressure) 을측정하여문맥압항진증의심한정도도함께검사할수있다. 문맥폐고혈압은문맥압항진증을가진환자에서평균폐동맥압, 폐혈관저항과경폐간압력차 (transpulmonary pressure gradient) 가증가되어있으며폐동맥고혈압을유발하는다른원인이발견되지않으면진단을할수있다. 폐동맥압의정도에따라경증 (systolic PAP 30 to 44 mmhg), 중등도 (systolic PAP 45 to 59 mmhg) 및중증 [severe PAH(systolic PAP >60 mmhg)] 폐동맥고혈압으로나눌수있다. 5. 치료 1) 항응고제 (anticoagulation) 정맥내저류 (venous stasis), 느려진폐혈류 (slowed pulmonary blood flow) 및우측심장비대는특발성폐동맥고혈압과문맥폐고혈압모두에서제자리폐혈관혈전증 (in situ pulmonary vascular thrombosis) 과혈전색

13 이창형 : 간폐증후군과문맥폐고혈압 전증질환 (thromboembolic disease) 의위험도를증가시킨다. 112 특발성폐동맥고혈압환자를대상으로한여러연구보고에서항응고치료는생존율을증가시킨다 문맥폐고혈압환자에대한연구보고는아직없지만금기증이없다면특히우심실부전으로인해심박출량이감소된환자에서는항응고제치료가필요할것으로사료된다. 2) 진보적치료법 (Advanced therapy) 혈관확장 (vasodilation), 혈관성장 (vascular growth) 및혈관재형성 (remodeling) 에대한진보적치료가시도되고있다. 112,116,117 Epoprostenol, bosentan, sildenafil 및 iloprost이현재시도되고있는약물이지만아직까지증례보고수준이거나소규모관찰연구의단계로특정치료 (specific treatment) 를위한충분한근거자료는아직부족한실정이다. 일반적으로 NYHA 또는 WHO functional class II, III, or IV인경우에는이러한진보적치료법의적응증이될수있다. 순수혈관확장제는전신혈관확장과우심실충만 (right ventricular filling) 의감소를유발하여심한저혈압을유발할수있으므로사용하지않는것이좋다. 문맥폐고혈압환자들은대개의만성간질환환자에서가지고있는낮은전신혈관저항으로인해이런부작용이매우민감하게유발될수있다. (1) Epoprostenol Epoprostenol(prostacyclin, Flolan) 은강력한혈소판응집억제및항증식성기능을가지고있어운동허용능 (exercise tolerance) 을증가시키며생존율을향상시키는것으로알려져있다 Epoprostenol을지속적으로정맥주입하면혈행역학 (hemodynamics) 과운동능 (exercise performance) 을개선시키므로간이식때까지가교치료 (bridge treatment) 의역할을할것으로기대된다 문맥폐고혈압을가진 7명의환자에게지속적인 epoprostenol 정맥주사를시행하였을때 1년후모든환자에서 New York Heart Association (NYHA) functional class가개선되었다. 123 또한운동시간, 평균폐동맥압및폐혈관저항이치료전에비해현저히개선되었다. 14명의진행성간질환환자와중등도이상의폐동맥고혈압 (defined as a mpap >35 mmhg) 을가진환자에게 epoprostenol을투여하였을때평균폐동맥압의감소, 폐혈관저항의감소및심박출량의증가를볼수있었다. 124 epoprostenol는턱관절통, 설사, 발진, 관절통및심박출량증가등의부작용을유발한다. 112,128 심각한합병증으로는감염, 혈전, 심장수축력이상및비장기능항진등이있다. 129 (2) Bosentan Bosentan은경구용 endothelin 수용체길항제로 18명의심한문맥폐고혈압에 3년간사용하였을때 1, 2, 3년생존율이각각 94, 89 및 89% 였다 명의심한문맥폐고혈압을가진환자를대상으로 bosentan 을 1년간사용한다른연구에서치료전에비해운동능력의향상이있었고, 폐혈관저항은감소하였다. 약 10% 에서간독성을유발할수있으므로 bosentan 사용중에는간기능을주의깊게모니터하여야한다

14 2009 년대한간학회 Single Topic Symposium (3) Sildenafil 경구용 phosphodiesterase 억제제인 sildenafil 50 mg을 14명의중등도또는중증문맥폐고혈압환자에게하루 3회사용하였을때 3개월후평균폐동맥압과폐혈관저항이치료전에비해감소하였고치료 3개월및 1년후의 six minute walking distance가개선되었다. 131 (4) Iloprost Prostacyclin 유사체로흡입제또는정맥주사로사용하였을때효과가있음이보고되고있다. 13명의중증문맥폐고혈압환자에게 iloprost 흡입제를 3년까지사용한결과 1, 2, 3년생존율이각각 77, 62, 46% 로나타났다 ) 간이식 (liver transplantation) 간이식을문맥폐고혈압환자에게시행하였을때폐동맥고혈압이완전히또는부분적으로호전되었다는보고들이있다. 126,127,132,133 폐동맥고혈압의심한정도가간이식후의예후에미치는영향에대해서는아직제한적인연구결과만있지만중증폐동맥고혈압 (systolic PAP >60 mmhg) 는주술기위험도 (perioperative risk) 를높이고임상적인예후가나쁜것으로보고되고있다. 그러나경증및중등증의폐동맥고혈압은수술후사망률에영향을주지않는다 , 명의간경변증을가진환자를대상으로한후향적연구결과, 폐동맥고혈압이없는환자, 경증의폐동맥고혈압 (systolic PAP 30 to 44 mmhg), 중등도폐동맥고혈압 (systolic PAP 45 to 59 mmhg) 및중증폐동맥고혈압 [severe PAH(systolic PAP >60 mmhg)] 의간이식후 3년사망률은각각 28, 33, 35 및 71% 로보고되고있다. 83 4) 경경정맥간내문맥전신순환단락술 (transjugular intrahepatic portosystemic shunts, TIPS) TIPS는문맥폐고혈압치료에도움이되지않고오히려나쁜영향을미친다. 135 TIPS 시행후전부하 (preload) 가증가하여심박출량이증가되는반면전신혈관저항은감소한다. 이로인해과역동적상태에있는좌심실 (hyperdynamic left ventricle) 의확장기기능이상 (diastolic dysfunction) 을유발하여 pulmonary capillary occlusive pressure를증가시켰다는보고가있다. 136 그러므로문맥폐고혈압을가진간경변증환자중저항성복수또는재발하는정맥류출혈을위해 TIPS를고려할때도문맥폐고혈압에미칠위험도와합병증치료에대한이득을잘고려하여결정하여야한다. 6. 예후문맥폐고혈압환자의예후는불량하다. 49명의문맥폐고혈압환자의평균생존율은 15개월이었고약물치료를하지않았을경우 6개월사망률이약 50% 였다. 109 주사망원인은우심부전 (right heart failure) 과감염이었다. 조기진단과치료가임상경과를호전시키는지에대한여부는아직불분명하다. 다만일부데이터에서 epoprostenol과간이식이환자의치료에도움을줄수있는것으로생각된다

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20 2009 년대한간학회 Single Topic Symposium hypertension. Am J Med 2005;118: Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 1994;266:L46-L Eddahibi S, Chouaid C, Sediame S, Housset B, Hamon M, Adnot S. Serotonin uptake and citalopram binding in platelets from patients with chronic pulmonary hypertension[abstract]. Am J Respir Crit Care Med 1999;159:A Nagasue N, Dahr DK, Yamanoi A, Emi Y, Udagawa J, Yamamoto A, et al. Production and release of endothelin 1 from the gut and spleen in portal hypertension due to cirrhosis. Hepatology 2000;31: Gerbes AL, Moller S, Gulberg V, Henriksen JH. Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: a role of splanchinc and renal passage and liver function. Hepatology 1995;21: Halank M, Miehlke S, Hoffken G, Schmeisser A, Schulze M, Strasser RH. Use of oral endothelin-receptor antagonist bosentan in the treatment of portopulmonary hypertension. Transplantation 2004;77: Hinterhuber L, Graziadei IW, Kahler CM, Jaschke W, Vogel W. Endothelin-receptor antagonist treatment of portopulmonary hypertension. Clin Gastroenterol Hepatol 2004;2: Nichols WC, Kotter DL, Slovis B, Foroud T, Terry VH, Arnold ND, et al. Localization of gene for familial primary pulmonary hypertension to chromosome 2q Nat Genet 1997;15: Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, et al. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med 2000;161: Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-ii gene. Am J Hum Genet 2000;67: Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 2000; 275: Naeye RL. Primary pulmonary hypertension with coexisting portal hypertension. A retrospective study of six cases. Circulation 1960; 22: Edwards BS, Weir EK, Edwards MD, Ludwig J, Dykoski RK, Edwards JE. Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Coll Cardiol 1987;10: Pietra GG. Histopathology of primary pulmonary hypertension. Chest 1994;105:2S Schraufnagel DE, Kay JM. Structural and pathologic changes in the lung vasculature in chronic liver disease. Clin Chest Med 1996;17: Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: Analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991;17: Kuo PC, Plotkin JS, Johnson LB, Howell CD, Laurin JM, Bartlett ST, et al. Distinctive clinical features of portopulmonary hypertension. Chest 1997;112: Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352: Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336: Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hyper

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