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1 원저 Korean Circulation J 2003;33(1):52-57 중증간경화환자에서조영심초음파기법으로진단된저산소혈증이동반되지않은폐내우-좌단락의빈도와임상적의의 울산대학교의과대학서울아산병원내과학교실 이승환 양용모 김영학 김준 유희승박재형 강수진 송종민 강덕현 송재관 Prevalence and Clinical Impact of a Subclinical Intrapulmonary Right to Left Shunt Diagnosed by Contrast Echocardiography in Patients with End Stage Hepatic Disease Seung-Whan Lee, MD, Yong-Mo Yang, MD, Young-Hak Kim, MD, Jun Kim, MD, Hee-Seung Yoo MD, Jae-Hyeong Park, MD, Soo-Jin Kang, MD, Jong-Min Song, MD, Duk-Hyun Kang, MD and Jae-Kwan Song, MD Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea ABSTRACT Background and Objectives:The clinical impact of an intrapulmonary right to left shunt, without hypoxia (subclinical IPS), has not been sufficiently evaluated. We investigated the prevalence and clinical impact of a subclinical IPS in patients with end stage hepatic disease. Subjects and Methods:Contrast echocardiography, with hand-agitated saline, was performed in 72 consecutive candidates for a liver transplantation between April 2001 and November A positive contrast echocardiography indicated an intrapulmonary right to left shunt, and was defined as the delayed appearance of microbubbles in the left side of the heart (3 to 6 beats after the initial appearance in the contrast in the right side of the heart). We compared the clinical events of the patients both with and without a shunt, i.e. death, spontaneous bacterial peritonitis, sepsis, hepatic encephalopathy or variceal bleeding. Results:A subclinical IPS was detected in 19 of the 72 candidates for a liver transplantation (26.3%). All these candidates were Child class C liver cirrhosis. There were no differences in the baseline characteristics between the patients and those without a shunt in the Child class C (n=57). The mean PaO2 value of the patients with at least a 3+ left ventricular opacification (3 to 4+, n=6) was significantly lower than those with a 1+ to 2+ left ventricular opacification (n=13) (76±10 mmhg vs. 103±13 mmhg, p< 0.05). The mortality was not significantly difference between the patients with (5%, 1/19) or without (21%, 8/38, p=0.24) a shunt. Also, there were no significant differences in the clinical events during the mean follow-up period of 7±3 months (68.4% vs. 83.5% p=0.12). Conclusion:Subclinical IPS's are not uncommon in patients with end stage hepatic disease. The extent of shunting correlates with the level of arterial 논문접수일 :2002 년 10 월 21 일수정논문접수일 :2002 년 11 월 5 일심사완료일 :2002 년 11 월 28 일교신저자 : 송재관, 서울송파구풍납동 울산대학교의과대학서울아산병원내과학교실전화 :(02) 전송 :(02) jksong@amc.seoul.kr 52

1) 간폐증후군은 Child class C 환자에서 5~13% 의발생률이보고되고있으며, 2) 간이식이유일한치료로알려져있다. 3) 그리고간폐증후군은이식전사망률및이식후사망률과이환률을증가시키는것으로보고되고있다. 4) 이러한간폐증후군환자에서저산소혈증의가장중요한원인은폐내우- 좌단락이다.

2 oxygenation. However, a subclinical IPS is not associated with the mortality or clinical events of the patient selected. (Korean Circulation J 2003;33(1):52-57) KEY WORDS:Echocardiography;Cirrhosis, liver. 서 론 간폐증후군 (hepatopulmonary syndrome, HPS) 은간질환환자에서기저심폐질환이없이저산소혈증 (PaO 2< 70 mmhg) 과폐내혈관의확장으로인한폐내우-좌단락의존재로정의되는질환이다. 1) 간폐증후군은 Child class C 환자에서 5~13% 의발생률이보고되고있으며, 2) 간이식이유일한치료로알려져있다. 3) 그리고간폐증후군은이식전사망률및이식후사망률과이환률을증가시키는것으로보고되고있다. 4) 이러한간폐증후군환자에서저산소혈증의가장중요한원인은폐내우- 좌단락이다. 5) 간경화환자에서저산소혈증이동반되지않는폐내우-좌단락 (intrapulmonary right to left shunt, 이하 subclinical IPS) 의빈도는약 30% 까지보고되고있다. 6) 하지만 subclinical IPS가간폐증후군처럼이식전후에사망률을증가시키는지에대해서는알려진바가없어저자들은간이식이요구되는중증간질환환자에서 subclinical IPS 의빈도와그임상적의의에대해서알아보고자하였다. A 대상및방법 대상 2001년 4월부터 2001년 11월까지간경화로간이식예정인환자를대상으로폐내우-좌단락의진단에표준검사인식염수로만들어진미세기포를이용한조영심초음파를시행하였으며동맥혈가스분석과폐기능검사를조사하였다. 저산소혈증이동반되지않은 (PaO 2 70 mmhg) 조영심초음파양성군과음성군을구분하여간이식전사망률과주요임상사건 ( 자발성세균성복막염, 패혈증, 식도정맥류출혈, 간성혼수 ) 의발생을조사하였고간이식이시행된환자에서사망률을조사하였다. 조영심초음파 (Contrast echocardiography) 2개의주사기사이에 3-way 연결관을이용하여 0.5 ml의공기를섞은 5내지 7 ml의생리식염수를 3- B Fig. 1. Contrast echocardiography. The relative opacification of left ventricle in patients with positive contrast echocardiograms was quantitatively assessed on a scale of 1 to 4+. Minimal left ventricular microb-ubbles was graded 1+ (A), extensive microbubbles opacification with clear endocardial definition was graded 4+ (B). way 연결관을통하여 2개의주사기사이에서수회왕복시켜서미세기포 (microbubble) 를제조하였다. 심첨부사심방도 (apical four chamber) 로심초음파영상을고정시킨후제조된미세기포를두정맥 (cephalic vein) 을통하여정주하였다. 미세기포가우심실에서발견한시점부터 3 내지 6 심박동사이에좌심실내미세기포가관찰되는경우를폐내우- 좌단락을시사하는조영심초음파양성으로정의하였으며, 단락의정도는좌심실내 53

3 미세기포의양에따라 1-4+ 로 7) 구분하였다 (Fig. 1). 우심실에서미세기포가발견된후 3 심박동이내에좌심실에미세기포가보이는경우는심장내단락에의한것으로판단하여제외하였다. 통계적분석범주형변수는빈도및퍼센트로나타내었다. 연속형변수는평균표준편차로나타내었다. 두군간의결과치의비교는 non-paired 혹은 paired t test 혹은 Fisher s exact test 를이용하여비교하였다. p 값이 0.05 미만일때통계학적인의미가있다고보았다. 정도를좌심실내미세기포의양에따라구분시 1+는 4명 (4/57, 7%), 2+는 9명 (9/57, 16%), 3+는 4명 (4/57, 7%), 그리고 4+는 2명 (2/57, 4%) 였다. Child class C 간경화의가장많은원인을차지하는 B형바이러스에의한간경화환자 48명중 subclinical IPS 는 31% 인 15명에서진단되었다. Child class C 환자에서조영심초음파양성군과음성군사이의평균연령, 성별, 간경화의원인, 간경화의중증도, 폐기능검사 (FEV1, FVC), 혹은평균동맥산소분압은차이가없었으나, 3+ 이상의단락을보인환자들의평균동맥산소분압은 2+이하의단락을보인환자들보다의미있게 결 과 폐내우-좌단락의빈도 72명 ( 평균 49±9 세, 남자 58명 ) 의간경화환자중 19명 (26.3%, 평균 52±9 세, 남자 14명 Child A;0/6, Child B:0/9, Child C 19/57) 에서 subclinical IPS 가진단되었다. 즉중증간경화인 Child class C 환자에서만 subclinical IPS 가진단되었다. 폐내우-좌단락의정도와동맥혈산소분압과의관계및환자들의특성 Child class C 환자 (n=57) 에서폐내우- 좌단락의 Fig. 2. Relation of arterial oxygenation to extent of left ventricular opacification. PaO 2 Äpartial pressure of oxygen in arterial blood. Table 1. Baseline clinical characteristics of study patients with child class C liver cirrhosis Positive contrast (n=19) Negative contrast (n=38) p Age (years) 51.0± ± Men/Female 14/5 31/ PaO2 (mm Hg) 93.0± ± Bilirubin (mg/dl) 10.0± ± Aspartate aminotransferase (U/liter) 60.0± ±327 <0.05 Alanine aminotransferase (U/liter) 36.0± ± Albumin (g/dl) 02.7± ± Prothrombin time (INR) 02.3± ± Etiology of liver cirrhosis (%) 0.24 Hepatitis B 15(78.9%) 33 (86.8%) Hepatitis C 02(10.5%) Alcohol 01(05.3%) 03 (07.9%) Cryptogenic 01(05.3%) 02 (05.3%) Pulmonary function test FEV1 (% of predicted) 92.0±23% 093.0±020% 0.51 FVC (% of predicted) 89.0±21% 091.0±019% Korean Circulation J 2003;33(1):52-57

4 Table 2. Short-term clinical outcomes of patients with child class C liver cirrhosis Positive contrast (n=19) Negative contrast (n=38) p Mean follow-up (months) Death 01 (05.3%) 08 (21.1%) 0.24 Variceal bleeding 04 (21.1%) 09 (23.7%) 0.82 Encephalopathy 04 (21.1%) 07 (18.4%) 0.81 Spontaneous bacterial peritonitis 02 (10.5%) 03 (07.9%) 0.74 Sepsis 02 (10.6%) 07 (18.4%) 0.18 Transplantation 11 (57.9%) 14 (36.8%) 0.13 Death after transplantation 2/11 (18%) 0/14 (0%) 0.18 낮았다 (76±10 mmhg vs 103±13 mmhg, p<0.05) (Table 1)(Fig. 2). 단기사망률및간이식후사망률간이식전평균 7±3 개월의단기추적관찰기간중조영심초음파양성군과음성군사이에사망률 ( 양성군 5%(1/19), 음성군 21%(8/38), p=0.24) 과주요임상사건 ( 자발성세균성복막염, 패혈증, 식도정맥류출혈, 간성혼수 ) 의발생빈도는차이가없었다 (68.4% vs 83.5% p=0.12)(table 2). Child class C 환자중 25 명 ( 양성군 ;58%(11/19), 음성군 ;37%(14/38), p= 0.13) 에서간이식이시행되었고이식후평균 4±3 개월의추적관찰기간중양성군에서만 2명 (2/11, 18%) 이사망하였으나통계학적유의성은없었다. 고찰 본연구에서저자들은 Child class C 간경화환자에서 subclinical IPS 가상대적으로빈번하며 (19/57, 33%), 단락의정도와동맥혈산소분압과의연관성은있었으나 subclinical IPS 존재유무에따른간이식전후의사망률및주요임상사건의발생은차이가없음을알수있었다. Child class C 환자에서양성조영심초음파의발생빈도는보고자에따라차이가있으나, 약 13~47% 로보고되고있으며이중간폐증후군은 5~13% 로보고되고있다. 간폐증후군환자중간이식을받지않는경우평균 2.5 년내에 41% 가사망한다고보고되고있으며간이식을시행하더라도다른환자에비해사망률과이환률이높은것으로보고되고있다. 8) Subclincal IPS 의자연경과는잘알려져있지않지 만간폐증후군으로의진행가능성을시사하는보고를고려하면임상적으로중요한의미를가진다고할수있겠다. 9)10) 하지만현재까지 subclinical IPS 의임상적의의에대해서는소수의보고만이있다. 6) Child class C 환자 53명 ( 양성군 ;25/53, 47%) 을대상으로한이전의한연구에서는 subclinical IPS 가있는경우오히려단기사망률이감소된다고보고하였으며, 특히동맥혈산소분압 60 mmhg 이하를간폐증후군으로간주하여이중 8명이간폐증후군의범주에속하였음에도불구하고단기사망률이감소한다고보고하여다른연구와상이한결과를보인바있다. 6) 본연구에서는평균 7±3 개월의단기추적관찰기간중 subclinical IPS 양성군과음성군사이에사망률이나주요임상사건의발생빈도에차이가없어사망률에영향을미치는간폐증후군과는달리 subclinical IPS 는환자들의사망률에영향을미치지않는것으로나타났다. 따라서간폐증후군은간이식이유일한치료이며간이식후사망률과이환률을증가시키므로간폐증후군으로의진행가능성이있다고보고되고있는 subclinical IPS 조기진단은중요한임상적의의를가진다고볼수있다 ) Vachiery 등 9) 은저산소혈증이동반된환자와동반되지않은환자의비교에서저산소혈증과폐내우-좌단락은기저간기능의중증도와연관성이있다고보고하였다. 또한 Mimidis 등 14) 은 child A, 혹은 Child B인초기간경화환자에서저산소혈증이동반되지않은폐내우-좌단락이각각 4.5%, 19.5% 가존재하며, 대부분의환자에서폐기능검사에서폐확산능이감소한다고보고하여간기능부전의정도와폐내우-좌단락의연관성을보여주었고간폐증후군으로의진행가능성을시사하였다. 하지만본연구에서저자들은초기간경화환자에서폐내우- 좌단락을관찰할수가없었다. 이 55

5 러한결과의차이는조영심초음파의방법과해석의차이및연구대상의차이에기인되었을것으로추측된다. 특히간경화의원인질환이두연구에서다른점이주된요인으로평가되는데 Mimidis 등 14) 의연구대상은대부분알코올성간경화가원인질환이었으며, 대부분의조영심초음파양성은알코올성간경화에서관찰되었고, 35명의간염바이러스환자중에서는오직 1명만이양성으로확인되었다. 본연구에서의초기간경화환자 15명중 13명이바이러스성간경화증이원인질환이었으므로이들에게서조영심초음파양성이관찰되지않은것은 Mimidis 등 14) 의연구결과와유사하다고볼수있을것이다. 이등 15) 의보고에의하면한국에서 B형간염에의한 Child class C 환자에서의간폐증후군발생빈도는 17.1%, subclinical IPS는 5.7% 로 Child class C에서는 B형간염에의한간경화도알코올에의한간경화와유사한발생빈도를보임을보고한바있다. 하지만초기간경화환자에서의보고는아직없어향후이에대한연구가필요하겠다. 본연구에서폐내우- 좌단락의정도를좌심실내의미세기포의양에따라 1+에서 4+로구분시 3+ 이상의단락을보인환자의동맥혈산소분압은 2+이하의단락을보인환자에비해유의하게낮았다. 이는폐내우- 좌단락의정도와저산소혈증과의연관성이있음을시사하는것으로이전의 Hopkins 등의연구를재확인할수있었다. 6) 3+ 이상의단락을보인환자와 2+ 이하의단락을보인환자사이에사망률 (17% vs. 0%, p=0.33) 과사망률을포함한임상사건의빈도 (50% vs. 23%, p=0.34) 는양군간에차이가없었다. Lange 등 16) 은간폐증후군이있는환자에서는간이식후사망률이증가함을보고한바있다. 그러나본연구에서는 Child class C 환자중 25명 ( 양성군 ;58% (11/19), 음성군 ;37%(14/38), p=0.13) 에서간이식이시행되었고, 추적관찰기간중양성군에서만 2명 (18%) 이사망하였으나통계학적유의성은없었다 (p= 0.18). 결과적으로 subclinical IPS 환자에서간이식전이나후모두사망률의증가는관찰되지않았다. 결론적으로저자들은본연구를통해저산소혈증이없는폐내우-좌단락, 즉 subclinical IPS 는이식전후단기간의사망률이나주요임상사건에는영향을미치지않는다는것을알수있었다. 하지만 subclinical 56 IPS 가사망률의증가가뚜렷한것으로알려진간폐증후군으로의진행될수있다는점을고려한다면적극적인진단이필요하다고생각된다. 또한향후장기간의임상추적관찰을통해간폐증후군으로의진행및임상적의의의규명이중요한과제로남아있다고생각된다. 본연구의제한점은첫째, 대상환자수가적어폐내우- 좌단락과사망률의연관성이없음을확정짓기에미흡하며, 둘째, 간이식예정인환자를대상으로조영심초음파를시행하였으므로표본추출상의오류 (selection bias) 가있을수있으며셋째, 폐내우- 좌단락의진단에예민도가가장높다고보고된경식도초음파를이용하지않아실제폐내우- 좌단락의빈도가더높았을가능성이있다는점이다. 17) 요약 배경및목적 : 간폐증후군은사망률을증가시키는것으로알려져있으나, 폐내우- 좌단락의임상적의의에대해서알려진바가드물다. 저자들은 Child class C 간경화의합병증으로기술되는저산소혈증이동반되지않은폐내우- 좌단락의빈도와임상적의의를알아보고자하였다. 방법 : 2001년 4월부터 2001 년 11월까지간이식예정자 72명을대상으로식염수로만들어진미세기포를이용한조영심초음파를시행하였다. 우심방에서미세기포를확인한후로 3 내지 6 심박동사이에관찰되는좌심실내미세기포의존재를조영심초음파양성으로정의하였다. 양성군과음성군사이의임상사건 ( 사망, 자발성세균성복막염, 패혈증, 식도정맥류출혈, 간성혼수, 이식후사망 ) 을비교하였다. 결과 : 72명의간경화환자중 19명 (26.3%, 남자 14) 에서저산소혈증이동반되지않은폐내우-좌단락이존재하였다. 양성환자들의평균나이는 52±9 세였고 Child class C 환자에서만폐내우-좌단락이존재하였다. Child class C 환자 (n=57) 에서양성군과음성군사이에평균연령, 성별, 간질환의중증도, 폐기능검사 (FEV1, FVC) 혹은평균동맥산소분압은차이가없었으나, 폐내우-좌단락의정도를좌심실내의미세기포의양에따라 1+에서 4+로구분시 3+ 이상의단락을보인 Korean Circulation J 2003;33(1):52-57

6 환자의동맥혈산소분압은 2+이하의단락을보인환자에비해유의하게낮았다 (76±10 mmhg vs 103± 13 mmhg, p<0.05). 간이식전평균 7±3 개월의추적관찰기간중양성군과음성군사이의사망률 ( 양성군 ; 5%(1/19), 음성군 ;21%(8/38), p=0.24) 과주요임상사건의발생빈도 ( 양성군 ;68.4% 음성군 ;83.5% p=0.12) 는유의한차이가없었다. 결론 : 저산소혈증이동반되지않은폐내의우- 좌단락은중증간질환환자에서빈번하며, 조영심초음파에의한단락의정도는저산소혈증과연관성이있었다. 그러나저산소혈증이동반되지않은폐내의우-좌단락은사망률및임상사건의발생에는영향을미치지않았다. 중심단어 : 심초음파 ; 간경화. REFERENCES 1) Rodriguez-Roisin R, Agusti AGN, Roca J. Pulmonary function and liver disease. Curr Opin Gastroenterol 1988;4: ) Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroen-terolgy 1998;114: ) Scott V, Miro A, Kang Y, Dewolf A, Bellary S, Martin M, Kramer D, Selby R, Dolye H, Pavadis I, Ziady G, Thiel VD. Reversability of the hepatopulmonary syndrome by orthotopic liver transplantation. Transplant Proc 1993;25: ) Krowka MJ, Porayko MK, Plevak DJ, Pappas SC, Steers JL, Krom RA, Wiesner RH. Hepatopulmonary syndrome with progressive hypoxemia as an indication for liver transplantation: case reports and literature review. Mayo Clin Proc 1997;72: ) 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: ) Hopkins WE, Waggoner BA, Barzilai B. Frequency and significance of intrapulmonary right-to-left shunting in endstage hepatic disease. Am J Cardiol 1992;70: ) Barzilai B, Waggoner AD, Spessert C, Picus D, Goodenberger D. Two-dimensional contrast echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformation. Am J Cardiol 1991;68: ) Scott VL, Dodson SF, Kang Y. The hepatopulmoary syndrome. Surg Clin North Am 1999;79: ) Vachiery F, Moreau R, Hadengue A, Gadano A, Soupuson T, Valla D, Lebrec D. Hypoxemia in patients with cirrhosis: relationship with liver failure and hemodynamic alterations. J Hepatol 1997;27: ) Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Med 1995;122: ) Laberge JM, Brandt ML, Lebecque P, Moulin D, Veykemans F, Paradis K, Peletier L, Lacroix J, Blanchard H, de Ville de Goyet J. Reversal of cirrhosis-related pulmonary shunting in two children by orthotopic liver transplantation. Transplantation 1992;53: ) Battaglia SE, Pretto JJ, Irving LB, Jones RM, Angus PW. Resolution of gas exchange abnormalities, and intrapulmonary shunting following liver transplantation. Hepatology 1997;25: ) Eriksson LS, Soderman C, Ericzon BG, Eleborg L, Wahren J, Hedenstierna G. Normalization of ventilation/perfusion relationship after liver transplantation in patients with decompen-sated cirrhosis: evidence for a hepatopulmonary syndrome. Hepatology 1990;12: ) Mimidis KP, Karatza C, Spiropoulos KV, Toulgaridis T, Charokopos NA, Thomopoulos KC, Margartitis VG, Nikolopoulou VN. Prevalence of intrapulmonary vascular dilatation in normoxaemic patients with early liver cirrhosis. Scand J Gastroenterol 1998;33: ) Lee JH, Lee DH, Zo JH, Kim TH, Lee KL, Chung HS, Kim CH, Han SK, Sim YS, Lee HS, Yoon YB, Song IS, Kim CY. Hepatopulmonary syndrome in poorly compensated postne-crotic liver cirrhosis by hepatitis B virus in Korea. Korean J Intern Med 2001;16: ) Lange PA, Stoller JK. The heaptopulmoary syndrome: effect of liver transplantation. Clin Chest Med 1996;17: ) Vedrinne JM, Duperret S, Bizollon T, Magnin C, Motin J, Trepo C, Ducerf C. Comparison of transesophageal and transthoracic contrast echocardiography for detection of an intrapulmonary shunt in liver disease. Chest 1997;111:

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar