Postgraduate Course 2011: The Liver and Other Organs 간폐증후군과문맥폐고혈압 대구가톨릭대학교의과대학내과학교실 이창형 Hepatopulmonary syndrome and portopulmonary hypertension Chang

Postgraduate Course 2011: The Liver and Other Organs 간폐증후군과문맥폐고혈압 대구가톨릭대학교의과대학내과학교실 이창형 Hepatopulmonary syndrome and portopulmonary hypertension Chang-Hyeong Lee Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea Liver cirrhosis and portal hypertension may present with distinct clinitcal entities such as portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS). The pathophysiology of these two conditions is not fully understood. HPS leads to progressive hypoxiema secondary to intrapulmonary vasodilatation. Imbalance in the pulmonary circulation between vasodilators and vasoconstrictors, intestinal endotoxemia, and activation of alveolar macrophage system may play a roles in pathogenesis of HPS. In POPH, there is excessive pulmonary vasoconstriction and vascular remodeling that cause an increase in pulmonary vascular resistance. Both diseases have a substantial negative impact on survival. There is no evidence for any pharmacologic modalities to successfully treat HPS. Liver transplantation, although associated with increased mortality, is a clear and definitive treatment for HPS. Liver transplantation may be beneficial in only highly carefully selected patients with POPH and is definite contraindication for severe POPH due to high perioperative and postoperative mortality rate. New and evolving medical therapies might change the natural course of POPH, but randomized, controlled multicenter trials are urgently needed. Key words: Portopulmonary hypertension, Hepatopulmonary syndrome, Vasodilators, Vasoconstrictors, Liver transplantation 서 론 간경변증환자가순환기및호흡기증상을동반하는것은매우흔한일이며약 50-70% 에서호흡곤란을호소한다. 복수나흉수에의한폐실질의압박이간경변증에서경한저산소혈증의흔한원인이다. 그러나문맥압항진증에의한간폐증후군 (hepatopulmonary hypertension) 과문맥폐고혈압 (portopulmonary hypertension) 도간경변 증환자에서호흡곤란을유발하는유발하는중요한원인이다. 1 간폐증후군은폐혈관확장으로인해동맥혈가 스교환의장애가발생하고문맥폐고혈압은폐동맥수축 (pulmonary arterial constriction) 과재형성 (remodeling) 이유발되어폐동맥압이증가하는질환이다. 간경변증환자에서간폐증후군의유병율은 4-30% 정도로알려져있고, 2,3 문맥-폐고혈압은만성간질환자의 2-16% 에서관찰되는데폐동맥고혈압을유발하는다른원인들이다제거되어야진단할수있다. 2 58

이창형 간폐증후군과문맥폐고혈압 간폐증후군 간폐증후군은 1977년 Kennedy와 Kundson에의해처음사용되었으며 4 만성간질환을가진환자에서폐혈관확장으로인해실내공기호흡시폐포-동맥산소분압차 (AaD02) 가 15 mmhg (64세이상은 20 mmhg) 이상으로증가되는것을특징으로한다. 5 간이식을위해검사를시행하는간경변증환자의약 15-20% 에서발견되며 1 간이식을시행하지않은간폐증후군환자의 5년생존율은약 23%, 중앙생존기간은 24개월로간폐증후군을동반하지않은간경변증환자의 63% 및 87개월에비해낮은생존율을보이며삶의질도낮은것으로알려져있다. 6,7 간폐증후군은주로간경변증에서관찰되나여러가지다양한다른원인의간질환에서도볼수있다. 8 없으며다. 9,10 최근간경변증을동반하지않는문맥압항진증 (portal vein thrombosis, Budd-Chiari syndrome 등 ) 11,12 과전격성간부전을동반하지않는급만성간염에서도간폐증후군이발생한보고도있다. 13,14 간경변증환자에서간폐증후군이발생하면사망률이증가되고나쁜예후를보인다. 15 병태생리 폐동맥순환내모세혈관확장 (microvascular dilatation) 이가장근본적인병태생리소견이다. 이들변화는 precapillary arteriolar tone 자체만의감소에의하던지혈관신생 (angiogenesis), 혈관재형성 (remodeling) 및혈관발생 (vasculogenesis) 등이부가적인기전으로작용하는것으로생각된다. 16 폐혈관확장물질의생성이증가되고혈관수축물질의생성은억제되며또한손상받은간에서폐혈관확장물질의제거가잘되지않아서간폐증후군환자의혈중에는여러가지혈관확장물질 ( 예, nitric oxide, prostaglandins, vasoactive intestinal peptide, calcitonin, glucagons, substance P 및 antinatriuretic factor 등 ) 의농도가증가되어있으며특히 nitric oxide (NO) 의증가가중요한역할을한다 (Table 1). 17 정상적으로폐실질내모세혈관의직경은 8-15 μm 인데비해서간폐증후군환자에서는 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;11:138. 15-500 μm까지확장되어폐포로부터비정상적으로확장된혈관의중심부에위치한적혈구까지거리가멀어져서산소분자가효과적으로적혈구에도달하지못하기때문에저산소증이생긴다. 동물모델의폐동맥모세혈관계에서 endothelial nitric oxide synthase (enos) 와 inducible nitric oxide synthase (inos) 가증가되어있는것이확인되었다. 18,19 폐혈관내피세포 (pulmonary endothelial cells) 에서는 enos의분비가증가하고폐포대식세포 (alveolar macrophage) 에서는 inos의분비가증가되어간경변증환자의폐포 (pulmonary alveoli) 에서 NO 분비가증가된다 (Fig. 1). 20 간폐증후군환자와실험동물의호기가스내의 NO의농도가증가되어있고 21 간이식후간폐증후군이호전된후에는감소하는것을관찰할수있다. 22 59

Postgraduate Course 2011 1. ET-1/ETRB signaling pathway 정상적인상태에서 endothelin-1 (ET-1) 은혈관내피세포의 endothelial A-type 수용체 (ETRA) 와결합하여혈관수축을유발한다. 그러나혈관내피세포의 endothelial B-type 수용체 (ETRB) 와결합하면 NO의분비를증가시켜혈관확장을작용을한다. 간경변증에서는과역동순환 (hyperdynamic circulation) 으로인해폐혈관에서전단력 (shear stress) 이증가하고이로인해폐혈관내피세포에서 ETRB 발현이증가한다. 간에서생성이증가되어혈중으로분비된 ET-1이 ETRB를자극하여 enos를증가시키고이로인해폐혈관내피세포에서 NO의분 Figure 1. Potential mechanisms in hepatopulmonary syndrome 비가증가되어폐혈관를확장시킨다. 23,24 CBDL (Adapted from Gaines DI, Fallon MB. Hepatopulmonary syndrome. Liver international 2004;24:397). (common bile duct ligation) 을시행한동물모델 ( 쥐 ) 은간폐증후군의생리학적양상을나타내는유일한동물모델이다. 25,26 CBDL 동물모델에서는간경변증과과역동순환이유도되고간내담관상피에서 ET-1의분비가증가되어간및혈장에서 ET-1이증가하고그로인해간폐증후군이유발되는것으로생각된다. 24 CBDL 동물에게 ETRB 특이적억제제를투여하면폐혈관내막의 enos와 ETRB 수용체의수가감소하고간폐증후군은현저하게호전된다. 25 또한 ETRB 결핍쥐에게 CBDL로간폐증후군을유도하였을때혈장 ET-1 의증가가관찰되지않았고 Akt 및 enos 발현의증가를볼수없었으며종국에는간폐증후군이유도되지않았다. 27 그러므로 ET-1/ETRB signaling pathway가실험동물에서간폐증후군을유도하는데가장중요한역할을하는것으로생각된다. NG-nitro-L-arginine methyl ester (L-NAME) 으로 NO의생성을차단하거나 cyclic GMP의저해제인 methylene blue를사용하여 NO의작용을차단하면일시적으로간폐증후군이호전될수있다. 28,29 그러나최근 L-NAME을흡인시켜투여하였을때폐혈관확장을호전시킬수없었다는연구보고가있어 NOS에의한 NO의증가외에다른인자들도간폐증후군의발생에관여하는것으로생각된다. 2. Intestinal endotoxemia and monocyte/macrophage system (IETM) 간경변증에서는간내혈관저항의증가로인해간세포로유입되는문맥혈이감소되어장관의벽에부종이생기고장의운동기능과담즙의분비가감소된다. 이로인해장관내에서특히그람음성균의과대증식이일어나고내독소의산생이증가한다. 장관벽의정상적인점막장벽 (mucosal barrier) 의결함, 정상적인기능을하는간세포와쿠퍼세포의감소및전신문맥단락으로인해혈액내로유입된세균및내독소가효과적으로제거되지못하고균혈증 / 내독소혈증을유발한다. 내독소혈증으로인해쿠퍼세포로부터 TNF-α가과분비되는데이것이간폐증후군의중요한병태생리기전중의하나로작용한다. 30 TNF-α가폐포에서폐포대식세포 (alveolar macrophage) 의축적을유도하고 inos의분비를증가시킨다. 그로인해폐순환계내에서 NO의농도가증가되어폐혈관이확장된다. CBDL 동물에게결찰 (ligation) 직후부터 norfloxacin을투여하면장내세균전위 (bacterial translocation) 와 TNF-α 생성이감소되어폐포대식세포의축적을감소시키고 inos의증가를막을수있다. 31 이로보아 TNF-α가폐포대식세포의축적에관여를함을알수있다. Phosphodiseterase의비특이적억제제인 pentoxiphylline은 TNF-α의활동을억제하여혈관내피세포에서 enos와폐포대식세포의 inos에의한 NO의생 60

이창형 간폐증후군과문맥폐고혈압 성을감소시켜서과역동순환과간폐증후군의정도를호전시킬수있었다. 32 또한최근동물실험에서 TNF-α monoclonal Ab를 CBDL 동물에게사용하였을때 endotoxin, TNF-α 및 NO가감소하였으며폐포-동맥산소분압차도호전되었다. 33 3. HO/CO system Heme oxygenase (HO) 에의해유도되는 carbon monoxide (CO) 가간폐증후군의발생에관여한다. HO는 3가지의 isoenzyme으로구분되는데 HO-1은특별한자극에의해유도되나 HO -2 와 HO -3 는정상적인상태에서세포에구조적으로존재하고있다. CO는혈중에서 hemoglobin과강력하게결합하여 carboxyhemoglobin을형성한다. 34 간경변증환자 34,35 와간폐증후군동물 36 의혈중에 carboxyhemoglobin이현저하게증가되어있다. 간폐증후군을동반한폐포대식세포에서 HO-1이간폐증후군을동반하지않은간경변증에비해증가되어있으며 HO-1 억제제를투여하면동맥내 carboxyhemoglobin이정상화되고폐혈관확장이감소하여간폐증후군증상이호전된다. 36-38 일부환자들에서 NO 억제후에도간폐증후군의호전이없는이유를설명하는데이용되나아직그작용여부에대해서는확실하게확립된상태는아니다. Endogenous NOS/NO 및 HO/CO systems은독립적또는상승적으로 (synergistically) 간폐증후군의발생에관여하는것으로추측된다. 39,40 임상증상 대부분의환자들에서식도정맥류, 복수, 비장비대와같은간경변증의임상소견을관찰할수있다. 41 간폐증후군의임상증상은간경변증의소견과호흡기증상을함께나타낸다. 저산소혈증, 호흡곤란, 거미상혈관종 (spider nevi), 청색증및곤봉지 (digital clubbing) 등의소견이간폐증후군을동반하지않은간경변증환자보다더높은빈도로발견된다. 42 대부분의연구에서볼수있듯이간기능부전의정도를나타내는혈청생화학적검사소견및 Child 분류의정도와저산소혈증또는단락의심한정도는항상비례하지않는다. 43,44 서서히발생하는호흡곤란, 특히운동시호흡곤란이가장흔한증상이다. 중력의작용에의해서폐기저부의확장된혈관으로혈류량이증가함으로서생기는편평호흡 (Platypnea: 앉거나선자세에서심해지고누우면호전되는호흡곤란 ) 과직립성저산소혈증 (orthodeoxia: 세운자세에서심해지는저산소혈증 ) 을관찰할수있다. 45 직립성저산소혈증은 post-pneumonectomy, recurrent pulmonary emboli, atrial septal defects (including patent foramen ovale) 및만성폐질환등다른질환에서도관찰할수있지만간폐증후군을강하게시사하는증상이다. 46 직립성저산소혈증은간경변증환자의약 5% 정도에서관찰되고심한저산소혈증을가지는간폐증후군환자에서더빈도가높다. 한연구에의하면 16명의간폐증후군환자중 14명 (88%) 에서직립성저산소혈증이관찰되었다고보고하고있다. 41 거미상혈관종은간폐증후군환자에서흔히관찰된다. 이병변은간폐증후군과관련된폐혈관확장의표지자로여겨지며거미상혈관종이없는환자에비해전신및폐혈관의확장이더심하고가스교환의장애가훨씬심하다. 47 폐순환혈관계의광범위한확장으로인해우좌단락, 직립성저산소혈증, 저산소혈증에대한폐혈관의수축및저환기부위에과도한혈액의관류가유발된다. 48 100% 산소를공급하면혈중산소농도가부분적으로개선되므로폐내혈관확장은진정한의미의해부학적단락으로볼수없다. 산소에의해부분개선이생기는기전은 61

Postgraduate Course 2011 Figure 2. Proposed mechanism for partial response to oxygen in HPS. 확산-관류장애 (diffusion-perfusion impairment) 또는폐포- 모세혈관산소불균형 (alveolar-capillary oxygen disequilibrium) 으로생각된다. 폐내혈관확장으로인해모세혈관의직경이커지게되면산소분자가폐포로부터확장된혈관의중심부까지확산 (diffusion) 해들어가혈관의중심부의혈류를따라흐르는헤모글로빈을산소화시킬수가없다. 그러나산소의분압을높여서공급하면추진압력 (driving pressure) 이증가하므로확산장애를부분적으로극복할수있다 (Fig. 2). 진단 일반적으로간폐증후군은만성간질환을가진환자에서실내공기호흡시동맥혈산소분압이 80 mmhg 이하이면서폐포-동맥산소분압차가 15 mmhg (64세이상은 20 mmhg) 이상증가되어있고폐내혈관확장 (IPVDs) 이있으면진단할수있다. 간폐증후군을의심하는대부분의환자에서만성간질환 ( 또는문맥압항진증 ) 은이미동반되어있으며폐포-폐동맥산소분압차의측정도동맥혈가스검사로쉽게알수있으므로여기에서는폐내혈관확장을진단하는방법에대해주로설명하겠다. 폐내혈관확장을진단하기위해조영증강심초음파 (contrast-enhanced echocardiography), 99mTc-MAA (technetium-99m-labeled macroaggregated albumin) 을이용한폐관류스캔그리고폐혈관조영술 (pulmonary arteriography) 이사용된다. 1. 조영증강심초음파조영증강심초음파가폐내혈관확장을진단하기위해주로사용되는진단방법이다. 60-150 μm 크기의미세기포 (microbuble stream) 를발생시키기위해인도사이아닌그린 (indocyanine green dye) 혹은발포식염수를정맥주사후심초음파를시행하면정상인경우에는미세기포가직경이 8-15 μm인폐모세혈관를통과하지못하므로우측심장부위에서만관찰되나폐내혈관확장에의한폐내단락이있으면좌측심장부위에서도관찰된다. 49 심장내단락이있는경우에는조영제를주사후미세기포가 3회의심박동내에좌측심장에서관찰되며폐내단락의경우에는 3-6회심장박동후좌측심장에서관찰되므로단락의위치를감별할수있다. 경식도심초음파 (Transesophageal echocardiography) 를사용하면좌심방으로유입되는페정맥에서미세기포를직접적으로관찰할수있으므로폐내혈관확장을보다정확하게확인할수있다. 50 심장초음파상우심방의용적은간폐증후군을진단하는데도움을줄수있다. 우심방의용적이 50 ml 이상이면민감도 86%, 특이도 81% 의확률로간폐증후군을진단할수있다. 51 2. 폐관류스캔 99mTc-MAA은직경 20 μm 이상의대응집알부민 (macroaggregated albumin) 을사용하는데, 정상적으로이들은직경이 8-15 μm인폐모세혈관을통과하지못하지만폐혈관의확장이있는경우에는전신순환으로유입되기 62

이창형 간폐증후군과문맥폐고혈압 때문에동위원소가신장또는뇌에흡수되는소견을보인다. 52 3. 폐혈관조영술폐혈관조영술은침습적이며폐내혈관확장을진단하는데민감도가낮기때문에선별검사로는유용성이떨어진다. 폐색전증또는폐동맥고혈압등저산소혈증의다른원인을배제하는데유용하다. 간폐증후군의폐혈관조영술에서는혈관의양상에따라미만형 (type 1) 과국소형 (type 2) 으로나눌수있다. 극소미만형 (minimal diffuse type) 은폐혈관조영술상그물눈모양의혈관이미만성으로펴저있는양상으로나타나고 100% 산소흡입을하면증상의호전을볼수있다. 진행성미만형 (advanced diffuse type) 은범발성스폰지모양의폐혈관이상을보이며 100% 산소흡입에반응이없다. 국소형은드물게나타나는데작고불연속적인국소적인동-정맥교통으로인해생기며 100% 산소흡입에반응이좋지않다. 4. 흉부영상진단흉부단순촬영에서는특징적인양상을보이는것은드문데일부환자에서양쪽폐하부에간질성음영이증가되는소견을볼수있으며간혹간질성폐질환으로오진되기도한다. 고해상흉부전산화단층촬영 (high-resolution computed tomography) 이새로운진단방법으로사용되고있다. 한연구에의하면고해상흉부전산화단층촬영상관찰되는폐미세혈관의확장정도와가스교환의장애정도가관련성이있게나타나며혈관확장의정도를비침습적으로측정할수있다고하였다. 53 알부민-미세기포복합체 (human serum albumin-air microbubble complex) 를사용하여심초음파로측정한폐내전이시간 (pulmonary transit time) 을이용하여간폐증후군환자에서가스교환의장애정도를측정할수있다는연구보고도있다. 54 5. 폐기능검사폐기능검사의이상소견은간폐증후군환자에서비교적흔히볼수있으며간폐증후군에만나타나는특징적인소견은아니다. 55 폐쇄성또는구속성폐질환 (obstructive or restrictive lung disease) 을동반하고있지않는간폐증후군환자는대개폐활량측정에서는전폐용량 (total lung capacity) 및호기유속 (expiratory flow rates) 은정상이다. Carbon monoxide에대한폐확산능 (DLCO) 은간폐증후군환자에서경도에서부터매우심한정도의장애를나타내며 55 대부분의간폐증후군환자에서비정상적인소견을보인다. 그리고간이식후에도호전이되지않는경우가많다. 56 그러나이검사소견은간폐증후군을동반하지않은간경변증환자의 68% 에서도감소되어있어 55 간폐증후군만의특징적인소견이라고할수는없다. 치료 여러가지치료방법이간폐증후군환자의가스교환과저산소혈증을치료하기위해서사용되고있지만아직까지효과적인치료법은없다 (Table 2). 현재, 간이식이간폐증후군환자의심한그리고치료에반응하지않는저산소혈증을치료하는가장효과적인방법으로생각된다. 63

Postgraduate Course 2011 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. 1. 내과적치료여러가지약물적치료가시도되었지만현재까지동맥혈산소화 (oxygenation) 와단락을효과적으로개선시킬수있는방법은아직없다. 교감신경흥분제 (sympathomimetic agents), 알미트린 (almitrine bismesylate), 인도메사신 (indomethacin), 소마토스타틴유도체 (somatostatin analogues), 면역억제제 ( 예, glucocorticoids, cyclophosphamide), cyclooxynenase inhibitor 및혈장교환술 (plasma exchange) 등이간폐증후군의치료에사용되었지만큰효과는볼수없었다. 1,28,29,42,57 간폐증후군을가진두명의어린이에게아스피린을사용하였을때동맥혈산소화가증가되었다는보고가있다. 58 15명의간폐증후군환자에게마늘분말 (garlic powder) 을최소 6개월이상투여하였을때 6명 (40%) 에서동맥혈산소분압이 10 mmhg 이상상승하였으며 1명의환자는 1년 6개월후저산소혈증이치료되었다. 9 간폐증후군의발생에는 NO와 TNF-α가가장중요한역할을하는것으로알려져있으므로이와관련하여여러가지약물이연구되고있다. 7명의간폐증후군환자에게 soluble guanylyl cyclase 억제제인메틸렌블루 (methylene blue) 를정맥주사하여 NO의작용을억제시켰을때저산소혈중과과역동순환을호전시킬수있었다. 29 NOS 억제제인 L-NAME을흡입제로사용하여동맥혈산소분압과운동능력의향상을관찰할수있었다는증례보고가있다. 28 반면심한간기능장애 (Child C classification) 를동반한간폐증후군환자에게 curcumin, terlipressin, 및메틸렌블루등을사용하여 NO를억제하였을때혈관긴장 (vascular tone) 과과역동순환의호전을관찰할수있었지만저산소혈증과직립성저산소혈증을오히려더악화시켰다는다른증례보고도있다. 59 간폐증후군을유도한 CBDL 쥐에게 norfloxacin을투여하였을때혈청 inos 및 NO가감소하였으며간폐증후군의호전을관찰할수있었다. 31 또한 norfloxacin을사용한간폐증후군환자에서동맥혈산소분압을개선시 64

이창형 간폐증후군과문맥폐고혈압 킬수있었다는증례보고도있다. 60 TNF-α 억제제인 pentoxifylline은동물실험에서폐혈관확장을개선시키고가스교환의이상을호전시켜잠재적인치료 (potential therapy) 로대두되고있다. 61 9명의간폐증후군환자에게 pentoxifylline 400 mg을하루 3회, 3 개월간복용시켰을때심한부작용이나간기능의손상이없이 90% 의환자에서간폐증후군의증상을호전시켰다는보고가있다. 62 복수를동반한간경변증환자를대상으로무작위대조사전임상시험 (pilot randomized controlled study) 에서 pentoxifylline은대조군에비해간폐증후군의발생을유의하게감소시켰다고보고하였다. 63 그러나또다른연구에서는 9명의심한간폐증후군환자에게 pentoxifylline을사용하였을때오심및구토가매우흔하게발생하여 8명의환자에서 400 mg씩하루 3회의용량을투여할수가없었으며저산소혈증을개선할수없었다고보고하고있다. 64 현재까지약물적치료에관한연구보고들은대부분증례보고이거나소규모의비대조연구 (uncontrolled study) 가대부분이다. 앞으로충분한환자수를대상으로하는무작위대조연구가필요하리라생각된다. 간폐증후군은문맥압항진증과관련되어발생하므로 TIPS를시행하여문맥압항진증을개선시켜주면간폐증후군의치료에효과가있을것으로생각되었다. 실제로간폐증후군환자에서 TIPS를시행한후가스교환의호전을보였다는증례보고들이있다. 65-67 그러나동맥혈산소화의개선을볼수없었다는보고도있고 TIPS후에심해지는과역동순환에의해폐혈관의확장이오히려심해져간폐증후군을악화시킬수도있으므로간폐증후군의치료에공식적으로권장되지않는다. 42,68 간폐증후군환자의저산소혈증을호전시키기위해산소공급은매우중요한치료방법이다. 생존율을증가시키는것에관한근거가없음에도불구하고저산소혈증을동반한모든간폐증후군환자에게장기적인산소공급이권장된다. 2. 간이식간폐증후군에대한유일하고확실한치료방법은간이식이다. 간폐증후군으로간이식을시행한환자의 85% 에서저산소혈증의완전한개선또는현저한호전을관찰할수있었다. 69 간경변증의심한정도가비슷한간폐증후군환자를대상으로간이식술을시행한경우에시행하지않은환자보다생존율이유의하게증가하였다. 6 일부연구에서는간이식후단락분율과저산소혈증의개선이수일내에일어난다고보고하고있지만다른연구에서는 2-14개월간서서히개선된다고보고하고있다. 6,69,70 간이식후저산소혈증의개선이지연되어나타나는것은 NO에의한혈관확장보다는혈관재형성 (vascular remodeling) 또는폐내단락 (intrapulmonary shunt) 이가스교환의장애를유발하는주요원인인것을시시하나이러한주장을뒷받침할데이터는아직부족한실정이다. 71,72 이식후에많은환자에서 DLCO의호전이관찰되지않았다. DLCO 장애는저산소혈증과는다른기전에의한것일가능성이많으며무증상의폐혈관변화는지속적으로유지되고있음을시사한다. 56 간폐증후군의치료에간이식의유용성을평가한무작위대조연구는아직까지시행되지않았다. 그러나미국간학회의간폐증후군에대한진료지침 (Practice Guidelines) 에서는즉시간이식이가능한센터로이송할것을권고하고있다. 73 간폐증후군환자에서간이식후 1년생존율이 71% 로간폐증후군이없는환자의일반적인 1년생존율 (90%) 보다낮다. 다기관후향적연구에서도 32명의간폐증후군환자를간이식하였을때수술후병원내 (in hospital) 사망률이 16% (5/32 patients) 로매우높았다고보고하고있다. 74 이들환자들에서간이식후생존율이나쁜원인은심한저산소혈증과현저한폐내단락때문인것으로생각된다. 간폐증후군으로간이식을시행한 24명의환자들을대상으로한전향적관찰연구에서 7명 (29%) 이수술후 10주내에조기사망하였다. 35 수술전실내공기흡입상태에서동맥혈산소분압이 (PaO2) 50 mmhg 이하이며수술전단락분율 (shunt fraction) 이 20% 이상인경우 65

Postgraduate Course 2011 가조기사망과관련한인자로나타났다. 간이식수술후의지연회복과심해지는저산소혈증역시생존율을줄이는데관여하였다. Pulmonary-Hepatic Vascular Disorders Scientific Committee의 ERS Task Force에서는동맥혈산소분압 (PaO 2) 이 50-60 mmhg인경우간이식의절대적인적응증으로권장하고있다. 그러나동맥혈산소분압이 50 mmhg 미만이면간이식의금기증으로규정하고있다. 42 문맥폐고혈압 문맥폐고혈압은문맥압항진증을가진환자에서폐동맥고혈압을유발하는다른원인이없이폐동맥고혈압을가진경우를말한다. 문맥폐고혈압은우심장도관삽입후측정하였을때평균폐동맥압 (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 이상증가하는 3가지기준을모두만족하는경우를말한다. 문맥폐고혈압은 40-50대에호발하며남녀간의발생빈도의차이는보이지않는다. 17,901명의간경변증환자를부검한결과폐동맥고혈압에합당한조직학적변화소견이 0.7% 에서관찰되었으며 75 문맥압항진증을동반한 507명의환자를대상으로전향적관찰을한결과 2% 에서폐동맥고혈압을관찰할수있었다. 76 간이식을위해검사중인간경변환자를대상으로한전향적연구에서폐동맥고혈압의유병율이 5.5-6.3% 로보고되고있 으며 77-79 Child Pugh 분류또는 MELD 에의해평가되는간경변증의심한정도와문맥폐고혈압의발생빈도는 관련성이없는것으로생각된다. 78,79 그러나증상이나신체검사에서특이소견을나타내지않으므로초기의문맥폐고혈압은제대로진단되지않는경우가많다. 문맥폐고혈압의발생에는문맥압항진증이필수요건이다. 문맥압항진증을동반하지않는만성간질환에서는문맥폐고혈압을유발하지않는다. 문맥폐고혈압을유발하는문맥압항진증의원인으로는간경변증, 문맥혈전증, 간정맥경화증 (hepatic vein sclerosis), 선천성문맥순환이상 (congenital portal circulation abnormalities) 및간경변증을동반하지않은문맥주변부섬유화 (periportal fibrosis) 등이있다. 80,81 치료하지않은문맥폐고혈압의예후는중앙생존율이 6개월로매우불량하다. 82 74명의문맥폐고혈압을가진간경변증환자중치료를받지않은 19명의 5년생존율은 14% 였으며 54% 가 1년내사망하였다. 폐동맥고혈압에대한치료를시행한 43명의환자는 5년생존율이 45% 였고 12% 가 1년내사망하였다. 폐동맥고혈압치료및간이식을동시에받은 9명의환자는 5년생존율이 67% 였다. 즉폐동맥고혈압에대한적극적인치료를시행한환자에게서생존율을향상시킬수있었다. 83 병태생리 여러가지가설들이제시되고있지만문맥폐고혈압의원인은아직까지정확하게알려져있지않다. 과역동순환으로인해폐순환으로의혈류의유입이증가되고그로인해증가된전단력 (shear stress) 이혈관내막의손상을유발하는것을시작으로문맥폐동맥고혈압의특징적인혈관병변을유발하는일련의경로가시작된다 (Fig. 3). 그러나전단력이증가되어있는모든환자에서실제문맥폐고혈압이발생하지는않으므로전단력의증가에부가적인인자들이함께작용하여야만혈관손상이유발될것으로생각된다. 부가적인인자로는혈관활동성을유발하는호르몬, 유전적소인및환경적인손상등이관여할것으로추측된다. 66

이창형 간폐증후군과문맥폐고혈압 정상적으로간에서대사되어야하는호르몬 (hormonal substance) 이문맥전신단락으로통해서폐혈관순환계내로유입되어문맥폐고혈압을유발한다는가설이널리받아들여지고있다. 84 serotonin 은평활근의증식과비대를유도하는역할을하며문맥폐고혈압의발생에관여한다. 85 정상적인상태에서는간에서 serotonin을대사시키므로폐에도달할수가없으나간의대사기능에장애가있거나문맥전신단락이발생한경우에는높은농도의 serotonin이폐순환으로유입될수있다. 문맥폐고혈압환자의폐에서 serotonin transporter인 5-HTT 의발현과활성이증가되어있다. 86 문맥압항진증에서는강력한혈관수축제이면서 Figure 3. Possible pathogenetic mechanisms leading to porttopulmonary hypertension (Adapted from Budhiraja R, Hassoun 평활근유사분열 (smooth muscle mitogen) 의작용이 PM. Portopulmonary hypertension. Chest 2003;123:562). 있는 ET-1의생성이증가한다. 87,88 또한문맥폐고혈압을가진비대상성간경변환자에서 ET-1의농도가문맥폐고혈압이없는환자에비해유의하게높다 89 두개의증례보고에서비특이적 ET A/ET B 수용체차단제인 bosentan을사용하였을때문맥폐고혈압환자의폐동맥압과문맥압이감소하는것으로보아 ET-1의증가가문맥폐고혈압의발생에관여한다고생각된다. 90,91 그외 angiotensin 1, thromboxane B2 및 prostaglandin F 2α 등다른혈관수축물질도증가되어있다. 반면, 강력한혈관확장을유발하는 prostacyclin을생성하는 prostacycline synthase는문맥폐고혈압환자의폐에서는감소되어있다. 유전적소인 (genetic predisposition) 도발생에관여한다. 가족성폐동맥고혈압에관여하는유전자는 chromosome 2 (locus 2q33) 에위치하고있으며 bone morphogenetic protein receptor type II (BMPR2) 의기능에결함을초래한다. 이러한결함이문맥폐고혈압을유발하는것과관련이있을것으로생각된다. 92,93 병리소견 문맥폐고혈압과특발성폐동맥고혈압환자에서폐의조직병리학적소견은차이가없으며혈관수축 (vasoconstriction), 폐동맥벽의근육층의재형성 (remodeling of the muscular pulmonary artery walls) 및 in situ thrombosis 등을관찰할수있다. 94,95 초기에관찰되는폐동맥의중막비후 (medial hypertrophy) 는잠재적으로가역적인형태이지만질환이진행하면서점차폐동맥병증 (pulmonary arteriopathy) 의구성요소로된다. 폐동맥병증은두가지아형 (subtypes) 으로나눌수있다. 얼기형성폐동맥병증 (plexogenic pulmonary arteriopathy) 은중막비후, 내막섬유화 (intimal fibrosis) 와혈관의전층을침범하는병변이특징이며혈전성폐동맥병증 (thrombotic pulmonary arteriopathy) 은중막비후, 혈전및편재성의 (eccentric) 결이없는 (nonlaminar) 내막섬유화를특징으로한다. 혈전은주로색전 (emboli) 보다는폐자체내에서유래한것으로생각된다. 각아형은같은질환의다른병기인지또는손상에대한반응의차이인지는확실하지않다. 80 67

Postgraduate Course 2011 임상증상 대부분의문맥폐고혈압환자들은문맥압항진증과폐동맥고혈압의임상적인소견을모두가지고있다. 문맥압항진증의증상은대개폐동맥고혈압의증상보다선행하는데문맥압항진증에의한첫증상발현후폐동맥고혈압증상의발현까지는 2년에서 15년정도간격이있다. 82 폐동맥고혈압은대부분초기에는증상을보이지않지만질환이진행할수록운동시호흡곤란, 흉통, 피로감, 실신 (syncope), 객혈및기좌호흡 (orthopnea) 등이나타날수있다. 82 이학적검사상우심실부전에의한소견으로경정맥압력 (jugular venous pressure) 의증가와의존성함요부종 (dependent pitting edema) 을관찰할수있고제 2 심음의 pulmonic component의증가, 삼첨판역류에의한수축기잡음을흔히관찰할수있다. 30명의문맥폐고혈압, 30명의특발성폐동맥고혈압및 30명의만성간질환만가진간이식대기자를비교한후향적연구결과문맥폐고혈압환자에서평균폐동맥압은특발성폐동맥고혈압과비슷한정도로상승되어있었으나전신혈관저항의감소와심박출계수 (cardiac index) 의증가등은만성간질환만단독으로가진환자와비슷하게나타났다. 96 진단 진단에이용되는방법으로는심초음파, 심전도, 흉부방사선사진또는흉부전산화단층촬영, 폐기능검사, 다원수면검사 (polysomnography), 폐환기관류검사 (ventilation-perfusion scanning), 폐동맥조영술, 자가면역항체검사, HIV 검사및간기능검사 (liver function test) 등이이용된다. 환자의병력과신체검사의소견에따라진단에사용할검사의우선순위가결정된다. 특발성폐동맥고혈압은폐동맥고혈압을유발할수있는여러기저질환을제외함으로서 (diagnosis of exclusion) 진단할수있다. 폐동맥고혈압의확진과심한정도를평가하기위해서는우심장도관삽입이필수적이다. 문맥폐고혈압이의심되는경우에는도관삽입중에폐색간정맥압 (hepatic venous wedge pressure) 을측정하여문맥압항진증의심한정도도함께검사할수있다. 문맥폐고혈압은문맥압항진증을가진환자에서평균폐동맥압, 폐혈관저항과경폐간압력차 (transpulmonary pressure gradient) 가증가되어있으며폐동맥고혈압을유발하는다른원인이발견되지않으면진단을할수있다. 평균폐동맥압의정도에따라경증 (mean PAP 25-35 mmhg), 중등도 (mean PAP 36-45 mmhg), 및중증 (mean PAH 46 mmhg) 으로나눌수있다. 중증의문맥폐고혈압을동반한환자는간이식후사망률이높게증가하므로간이식을준비하는모든환자들은문맥폐고혈압에대한검사를꼭시행하여야한다. 97 1. 심초음파문맥폐고혈압을선별 (screening) 하기위해통상적으로사용되는검사법이다. 삼첨판역류가있을때연속파형도플러법에의해삼첨판역류분사 (tricuspid regurgitant jet) 으로부터수축기폐동맥압 (spap) 을비관혈적으로계측할수있다. 간경변증환자에서계측된수축기폐동맥압이 50 mmhg 이상이면중등도및중증의문맥폐고혈압을가진것으로진단할수있다 ( 민감도 97%, 특이도 77%). 98 2. 우심도자술 문맥폐고혈압을진단하고중증도를평가하는데 gold standard 이다. 심초음파로계측된수축기폐동맥압이 50 68

이창형 간폐증후군과문맥폐고혈압 mmhg 이상이면우심도자술을시행하여평균폐동맥압 (mean pulmonary artery pressure, mpap), 좌심실확장기말압력 (pulmonary capillary wedge pressure, PCWP) 을측정하여이를이용하여폐혈관저항 (pulmonary vascular resistance) 을산출한다. 3. Chest radiography and ECG 흉부방사선사진 (chest radiograph) 상대부분의환자에서뚜렷한폐동맥과심비대의소견을관찰할수있다. 대부분의환자의심전도검사에서는우심실비대, 우측축편위 (right axis deviation) 및우각차단 (right bundle branch block) 의소견을볼수있다. 한연구에서는단지 4% 의환자에서만정상심전도소견을보였다고보고하고있다. 82 치료 진행된단계 (advanced stage) 에서치료를시행하면효과가없는경우가많고증상을완전히해소시키기가불가능하며생존율을향상시킬수없다. 1. 항응고제정맥내저류 (venous stasis), 느려진폐혈류 (slowed pulmonary blood flow) 및우측심장비대는특발성폐동맥고혈압과문맥폐고혈압모두에서제자리폐혈관혈전증 (in situ pulmonary vascular thrombosis) 과혈전색전증질환 (thromboembolic disease) 의위험도를증가시킨다. 99 특발성폐동맥고혈압환자를대상으로한여러연구보고에서항응고치료는생존율을증가시킨다. 100,101 문맥폐고혈압환자에대한연구보고는아직없지만금기증이없다면특히우심실부전으로인해심박출량이감소된환자에서는항응고제치료가필요할것으로사료된다. 2. 진보적치료법 (Advanced therapy) 혈관확장 (vasodilation), 혈관성장 (vascular growth) 및혈관재형성 (remodeling) 에대한진보적치료가시도되고있다. 99,102,103 epoprostenol, bosentan, sildenafil 및 iloprost 등이현재시도되고있는약물이지만아직까지증례보고수준이거나소규모관찰연구의단계로특정치료 (specific treatment) 를위한충분한근거자료는아직부족한실정이다. 일반적으로 NYHA (New York Heart Association) 또는 WHO functional class II, III, 또는 IV인경우에는이러한진보적치료법의적응증이될수있다. 순수혈관확장제는전신혈관확장과우심실충만 (right ventricular filling) 의감소를유발하여심한저혈압을유발할수있으므로사용하지않는것이좋다. 문맥폐고혈압환자들은대개만성간질환환자들이며이들은전신혈관저항이낮으므로이런부작용이매우민감하게유발될수있다. 1) Epoprostenol Epoprostenol은 prostacyclin analogue로강력하게폐혈관및전신혈관을확장시킬수있으며또한강력한혈소판응집억제및항증식성기능을가지고있어운동허용능 (exercise tolerance) 을증가시키며생존율을향상시키는것으로알려져있다. 104,105 epoprostenol을지속적으로정맥주입하면혈행역학 (hemodynamics) 과운동능 (exercise performance) 을개선시키므로간이식때까지가교치료 (bridge treatment) 의역할을할것으로기대된다. 106,107 문맥 69

Postgraduate Course 2011 폐고혈압을가진 7명의환자에게지속적인 epoprostenol 정맥주사를시행하였을때 1년후모든환자에서 NYHA functional class가개선되었다. 108 또한운동시간, 평균폐동맥압및폐혈관저항이치료전에비해현저히개선되었다. 14명의진행성간질환환자와중등도이상의폐동맥고혈압 (defined as a mpap 36 mmhg) 을가진환자에게 epoprostenol을투여하였을때평균폐동맥압의감소, 폐혈관저항의감소및심박출량의증가를볼수있었다. 109 epoprostenol는턱관절통, 설사, 발진, 관절통및심박출량증가등의부작용을유발한다. 99,110 심각한합병증으로는감염, 혈전, 심장수축력이상및비장기능항진등이있다. 111 2) Bosentan Bosentan은경구용 endothelin 수용체길항제로 18명의심한문맥폐고혈압에 3년간사용하였을때 1,2,3년생존율이각각 94, 89, 및 89% 였다. 112 11명의심한문맥폐고혈압을가진환자를대상으로 bosentan을 1년간사용한다른연구에서치료전에비해운동능력의향상이있었고, 폐혈관저항은감소하였다. 약 10% 에서간독성을유발할수있으므로 bosentan 사용중에는간기능을주의깊게모니터하여야한다. 3) Sildenafil 경구용 phosphodiesterase 억제제인 sildenafil 50 mg을 14명의중등도또는중증문맥폐고혈압환자에게하루 3회사용하였을때 3개월후평균폐동맥압과폐혈관저항이치료전에비해감소하였고치료 3개월및 1년후의 six minute walking distance가개선되었다. 113 4) Iloprost Prostacyclin 유사체로흡입제또는정맥주사로사용하였을때효과가있음이보고되고있다. 13명의중증문맥폐고혈압환자에게 iloprost 흡입제를 3년까지사용한결과 1,2,3년생존율이각각 77, 62, 46% 로나타났다. 112 3. 간이식 (liver transplantation) 간이식을문맥폐고혈압환자에게시행하였을때폐동맥고혈압이완전히또는부분적으로호전되었다는보고들이있다. 107,114-116 폐동맥고혈압의심한정도가간이식후의예후에미치는영향에대해서는아직제한적인연구결과만있지만중증폐동맥고혈압은주술기위험도 (perioperative risk) 를높이고임상적인예후가나쁜것으로보고되고있다. 간이식후사망률은평균폐동맥압과폐혈관저항에비례하여증가한다. 대부분의간이식센터에서는평균폐동맥압이 50 mmhg 이상이면간이식의절대적금기증으로규정하고있다. 74 우심실의기능은간이식의성공을결정하는데중요한요소로작용한다. 우심실기능부전이있을경우에는간이식직후이식간에울혈 (congestion) 이생기고이식간의부전 (graft failure) 으로진행될수있다. 그러므로우심실및폐혈관의상태및치료에대한기능회복정도가간이식후생존율에영향을미치는중요한인자로여겨진다. 83 1205 명의간경변증을가진환자를대상으로한후향적연구결과, 폐동맥고혈압이없는환자, 경증의폐동맥고혈압 (systolic PAP 30-44 mmhg), 중등도폐동맥고혈압 (systolic PAP 45-59 mmhg), 및중증폐동맥고혈압 (systolic PAP > 60 mmhg) 의간이식후 3년사망률은각각 28, 33, 35, 및 71% 로보고되고있다. 117 4. TIPS TIPS는문맥폐고혈압치료에도움이되지않고오히려나쁜영향을미친다. 42 TIPS 시행후전부하 (preload) 가증가하여심박출량이증가되는반면전신혈관저항은감소한다. 이로인해과역동적상태에있는좌심실 70

이창형 간폐증후군과문맥폐고혈압 (hyperdynamic left ventricle) 의확장기기능이상 (diastolic dysfunction) 을유발하여 pulmonary capillary occlusive pressure를증가시켰다는보고가있다. 118 그러므로문맥폐고혈압을가진간경변증환자중저항성복수또는재발하는정맥류출혈을위해 TIPS를고려할때도문맥폐고혈압에미칠위험도와합병증치료에대한이득을잘고려하여결정하여야한다. 맺음말 호흡곤란을호소하는간경변증환자는간폐증후군또는문맥폐고혈압을동반하고있는지에대한검사가필요하다. 간경변증환자에서이들폐합병증이발생하면생존율이감소하고삶의질이저하된다. 그러므로이들질환을적극적으로치료하여생존율을향상시키는노력이필요하다. 그러나아직효과적인약물치료는없으며향후효과가기대되는약물에대해서는무작위대조연구가필요할것으로생각된다. 간폐증후군은간이식을시행하면증상의호전과생존율의향상을기대할수있다. 그러나폐동맥고혈압에대한간이식후의예후에대해서는아직제한적인연구결과만있다. 중증폐동맥고혈압은간이식의금기증이기때문에특히간이식을앞둔환자에게서는문맥폐고혈압의동반여부를검사하는것이필요하다. 참고문헌 1. Fallon MB, Abrams GA. Pulmonary dysfunction in chronic liver disease. Hepatology 2000;32:859-865. 2. Dollinger MM. Pulmonary complication of liver disease]. Praxis (Bern 1994) 2006;95:1539-1542. 3. Stoller JK, Lange PA, Westveer MK, Carey WD, Vogt D, Henderson JM. Prevalence and reversibility of the hepatopulmonary syndrome after liver transplantation. the cleveland clinic experience. West J Med 1995;163:133-138. 4. Kennedy TC, Knudson RJ. Exercise-aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 1977;72:305-309. 5. Berthelot P, Walker JG, Sherlock S, Reid L. Arterial changes in the lungs in cirrhosis of the liver-lung spider nevi. N Engl J Med 1966;274:291-298. 6. Swanson KL, Wiesner RH, Krowka MJ. Natural history of hepatopulmonary syndrome: Impact of liver transplantation. Hepatology 2005;41:1122-1129. 7. Fallon MB, Krowka MJ, Brown RS, Trotter JF, Zacks S, Roberts KE, et al. Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates. Gastroenterology 2008;135:1168-1175. 8. Schenk P, Fuhrmann V, Madl C, Funk G, Lehr S, Kandel O, et al. Hepatopulmonary syndrome: Prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences. Gut 2002;51:853-859. 9. Abrams GA, Fallon MB. Treatment of hepatopulmonary syndrome with allium sativum L. (garlic): A pilot trial. J Clin Gastroenterol 1998;27:232-235. 10. Whyte MK, Hughes JM, Peters AM, Ussov W, Patel S, Burroughs AK. Analysis of intrapulmonary right to left shunt in the hepatopulmonary syndrome. J Hepatol 1998;29:85-93. 11. De BK, Sen S, Biswas PK, Sanyal R, Majumdar D, Biswas J. Hepatopulmonary syndrome in inferior vena cava obstruction responding to cavoplasty. Gastroenterology 2000;118:192-196. 12. Gupta D, Vijaya DR, Gupta R, Dhiman RK, Bhargava M, Verma J, et al. Prevalence of hepatopulmonary syndrome in cirrhosis and extrahepatic portal venous obstruction. Am J Gastroenterol 2001;96:3395-3399. 13. Regev A, Yeshurun M, Rodriguez M, Sagie A, Neff GW, Molina EG, et al. Transient hepatopulmonary syndrome in a patient with acute hepatitis A. J Viral Hepat 2001;8:83-86. 14. Teuber G, Teupe C, Dietrich CF, Caspary WF, Buhl R, Zeuzem S. Pulmonary dysfunction in non-cirrhotic patients with chronic viral hepatitis. Eur J Intern Med 2002;13:311-318. 71

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