도플러와조영증강초음파 Doppler Ultrasonography and Contrast Enhanced Ultrasonography in Liver Diease 연세대학교원주의과대학내과학교실 김문영 Ultrasonography (US) is simple, safe and repeatable in bedside, so it is the most popular diagnostic method in the field of hepatology. However, conventional grey scale US has limitations in estimation of portal hypertension (PHT) and the severity of liver disease as well as delicate differentiation of focal liver lesions (FLL). Because of advantage of Doppler US such as noninvasiveness and ability to evaluate blood flow in vasculature, several attempts using Doppler US have been made to investigate the hemodynamic changes and medical treatment response in cirrhosis and PHT. Commonly used Doppler indices for the evaluation of PHT include portal and splenic venous blood velocity and flows, and the resistive and pulsatility index at hepatic, splenic, renal, superior mesenteric artery. In spit of many positive evidences, its clinical usefulness in portal hypertension has still controversy because of lacking of reproducibility and intra- and inter-observer variation. Recently, 2nd generation microbubble contrast agents, SonoVue R and Sonazoid R are newly launched and drawing new attention beyond the simple differentiation of focal liver lesions; the estimation of effective tumor responses to anti-angiogenic drugs or local ablation therapy, the noninvasive measurement of hepatic fibrosis or PHT. Especially, because of the progression of intrahepatic shunts along with the progression of cirrhosis and PHT, hepatic vein arrival time (HVAT) of microbubble contrast agents in contrast enhanced Ultrasonography (CEUS) get shorter according to the severity of disease. Therefore, application of CEUS can be prospective for the assessment of the severity of PHT. Therefore, this report briefly reviewed the clinical usefulness of Doppler US and CEUS in assessing the severity of portal hypertension and its response to treatment. Key words: Doppler Ultrasonography, Contrast enhanced ultrasonography, Portal hypertension, Cirrhosis 서 론 초음파는소위 21 세기의청진기로서전의학분야에서광범위하고손쉽게이용이되고있으며, 특히, 간장학분야에서의이용은이미필수적이다. 간경변증환자에서발생하는문맥압항진증은식도및위정맥류출혈과같은중요한합병증을일으키며, 환자의생존예후에영향을미친다. 1-3 따라서문맥압항 1
2013 년대한간학회춘계 Single Topic Symposium 진증의정확한진단과평가는간경변증환자의치료와예후판정에중요하다. 문맥압항진증을평가하는가장정확한방법은간정맥압력차 (hepatic venous pressure gradient) 를측정하는것이나, 침습적이고특별한시설과기술을필요로하는것으로임상에서쉽게반복적으로사용할수있는방법은아니다. 4-6 간정맥압력차를대신하여비침습적으로문맥압항진증의진단과정도를평가하고자하는연구들이있어왔고, 대표적인방법이도플러초음파검사를이용하는것이다. 5-8 우리몸의혈액은혈관을통해서지속적으로움직이기에이러한성질을이용한도플러초음파는혈관질환의검사에아주유용한방법이며, 비침습적으로복부혈관의혈역학을정량적으로측정할수있다는장점이있어그동안간경변증및문맥합항진증을평가하는검사법으로서그유용성에대한많은연구가있었다. 초음파조용제 (microbubble ultrasonography contrast) 를이용한조영증강초음파 (contrast enhanced ultrasonography) 는실시간으로초음파를시행하면서정맥을통해서투여된조영제가혈관및장기조직에확산되면서나타나는여러가지조영양상을통해서질환의감별을하는방법으로, 기존의일반회색조초음파 (conventional grey scale ultrasonography) 나 2D color Doppler 기술에비해장기나종양내의혈관조영의특징적인소견을더잘나타내어진단적역량이한층강화된초음파기법이다. 특히, 최근에 2세대미세기포초음파조영제의도입으로인해이전에비해훨씬안정적으로다양한질환에대해서검사가가능해졌으며, 최근에는간내종괴의감별뿐아니라간조직검사및 radiofrequency ablation나 percutaneous ethanol injection 등의시술시좋은 guide 역할을하고있고, 간이식전의간혈관상태의평가에도이용되고있으며, 항암치료 (anti-angiogenic therapy, target therapy) 후의반응평가및간섬유화및문맥압항진증의중증도평가방법으로서의가능성에대한연구들이진행되고있다. 9,10 이에본문에서는간경변증및문맥압항진증평가에있어서도플러초음파와조영증강초음파의임상적유용성에대하여정리해보고자한다. 본 론 1. Measurement of Doppler ultrasonographic indices for portal hemodynamics 도플러초음파를이용해서측정이가능한문맥압항진증의지표에는정맥에서측정하는혈류속도 (blood velocity) 및혈류량 (Blood flow) 과동맥에서측정하는저항지수 (resistive index) 및박동지수 (pulsatile index) 등이있으며, 최근에는간정맥의도플러파형이문맥압항진증과유의한상관성이있음이보고되기도하였다. 5,7 1) Blood velocity and flow in vein 정맥의혈류속도와혈류량측정은비교적쉽고재현성이높아간문맥과비정맥에서손쉽게측정될수있으나, 도플러빔과혈관사이의입사각이 60도이하의예각을이루어야만정확한검사가가능하다. 11 간문맥의평균혈류속도 (mean portal vein velocity, PVV) 와혈류량 (portal blood flow) 를측정하기위해서는 2
김문영 도플러와조영증강초음파 간문맥을종축으로보이게하고간문맥과간동맥이만나는부위에서측정한다. 간문맥평균혈류속도가측정되면간문맥혈류량은혈류속도와단면적을이용한정해진공식 ( 간문맥의단면적 X mean PVV X 60) 에의해자동으로계산된다. 정상인의간문맥혈류속도는 20 cm/sec 내외이나문맥압항진증환자는간내혈관저항이증가되어있어서있어, 혈류속도가 15 cm/sec 이하로낮은경향이있다 (Figure 1). 12,13 문맥압항진증의경우비정맥의확장과함께비정맥 Figure 1. The measurement of portal vein velocity (PVV) and 의혈류속도 (splenic vein velocity) 와혈류량 blood flow (PBF). (splenic blood flow) 의증가를관찰할수있는데, 비정맥혈류량이간문맥혈류량보다많은경우에정맥류의형성과정맥류출혈의위험도의증가와관련이있다는보고가있다. 14 그러나일부연구에서는실제문맥압항진증을대변할수있는간정맥압력차를측정한결과, 간문맥혈류속도및혈류량은간정맥압력차와연관성이없고, 약물투여에따른반응에서도간문맥혈류속도는간정맥압력차의변화와비례하지않아, 문맥압항진증의평가에있어서도플러초음파는유용하지않다는것이현재의대체적인평가이다. 6,11 문맥압과도플러간문맥혈류측정이상관관계를보이지않는이유는간경변증환자대부분이문맥-전신단락 (portosystemic shunt) 을갖는데환자마다단락이매우다양하고복잡하게존재하기때문이다. 즉, 같은정도의문맥압항진증을갖더라도각환자의경우에갖는단락위치가각기다르므로, 약속으로정해진부위 ( 간동맥과문맥이만나는부위 ) 에서측정하는환자들의도플러문맥혈류는다를수있다. 8 또한, 혈류속도측정에있어서 inter- 또는 intraobserver variance 및장비간의차이도이러한측정값의임상적유용성에제약이되고있다. 2) Resistance by measuring resistive and pulsatility index 혈관저항을반영하는저항지수 (resistive index, RI) 와박동지수 (pulsatile index, PI) 는 color 도플러로혈관이확인되면입사각에상관없이측정이가능하여간동맥과비장동맥, 상장간동맥그리고신동맥등에서측정할수있다. 간동맥의경우 color 도플러의늑간스캔을통해서 portal hilus 부근의간동맥을확인하고이곳에도플러 sample volume을위치시켜서시간-속도파형 (time-velocity wave) 을기록하고최고수축기속도 (peak systolic velocity) 와이완기말속도 (end diastolic velocity) 와평균혈류속도 (mean velocity) 를구할수있다 (Figure 2). 이측정값들로부터저항지수 (RI)=[(peak systolic velocity-end diastolic velocity)/ peak systolic velocity], 박동지수 (PI)=[(peak systolic velocity-end diastolic velocity)/mean velocity] 의공식을통해서저항지수와박동지수를구할수있다. 동맥의저항성이클수록최고수축기속도가증가하고이완기말속도는감소하기때문에저항지수와박동지수는커지게된다. 15 박동지수와저항지수의차이점은 3
2013 년대한간학회춘계 Single Topic Symposium A B C Figure 2. The difference of renal resistive index (RI) and pulsatile index (PI) according to the severity of liver disease. (A) Child-Pugh s class A patients with RI 0.533, PI 0.778 (B) Child-Pugh s class B patients with RI 0.714, PI 1.302 (C) Child-Pugh s class C patients with RI 0.798, PI 1.763 (D) Hepatorenal syndrome patients with RI 0.937, PI 2.324. D 박동지수는분모가평균혈류속도라는점으로, 동맥의저항성이매우높아서이완기말혈류속도가 0에가깝게되는경우에는박동지수가저항지수보다더정확한값을나타낼수있다. 6 신동맥의경우에는 interlobar artery에서측정되며, 간경변증이심한경우특히신동맥의저항지수와박동지수가증가하게되는데, 이는간경변증에따른유효혈류량의감소와교감신경계의항진에따른신동맥의수축에의한것이다. 13 그러나이러한저항지표는환자마다똑같은위치의동맥분지에서저항을측정하는것이불가능하므로환자간에동일한조건에서검사가이루어지기어려우며, 동일환자내에서도반복검사의재현성또한떨어질수있다는제한을가지고있다. 6,16 3) Hepatic vein waveform analysis 일반적으로도플러에의한간정맥의파형은정상인의경우 3위상 (3phasic, two negative and one positive) 을가지며, 이는심장박동주기와연관된중심정맥압의변화에의한것이다 (Figure 3A). 그러나, 이러한 3위상파형이간경변증환자의경우에는 2위상또는단위상파형으로변화됨이이미여러연구를통해서알려져있다. 5,17-20 늑간스캔을통해서간정맥은쉽게종축으로확인할수있고, 이때 color 도플러를시행하게되면혈류의흐름이탐촉자로부터멀어져대정맥으로흘러들어감에따라푸른색으로나타나는간정맥을쉽게확인할수있고, 대정맥으로부터 3-6 cm 떨어져있는곳에서도플러파형을확인하게된다. 간정맥파형과간정맥압력차의관계를직접확인한국내연구에따르면, 단위상의파형이 15 mmhg 이상의중증의문맥압항진증과유의한상관성을보여주었다. 또한, 간정맥파형의정량화를위 4
김문영 도플러와조영증강초음파 A B Figure 3. Hepatic vein wave form classification (A) and measurement of damping index (DI) (B). DI is calculated by the minimum velocity/maximum velocity of the downward hepatic vein wave. (a) A patient with liver cirrhosis showed 0.26 of DI with 7mmHg of hepatic venous pressure gradient (HVPG). (b) Another patient with liver cirrhosis showed 0.72 of DI with 15mmHg of HVPG. This was quoted in reference number 7. Table 1. Alterations of hemodynamic parameter in cirrhosis found on Doppler Ultrasonography Hemodynamic parameters Cirrhosis with PH (compared with normal) Clinical usefulness PVV Decreased PVV < 15 cm/s is associated with a sensitivity and a specificity of 88 and 96%for PH PVF Increased Mainly due to increase PV diameter SVV Increased SPI threshold of 3.0 predict presence of EV in 92% of SVF Increased patients HA resistance (RI, PI) Increased or no change Controversial SA resistance (RI, PI) Increased or no change Controversial RA resistance (RI, PI) Increased Renal PI > 1.14 is associated with poor prognosis Higher than normal renal RI and PI have a high PPV (84-100%) for detection of severe PH SMA resistance (RI, PI) Decreased With liver dysfunction and cirrhosis progress, SMA SMA flow Increased resistance decrease while SMA flow increase. HV waveform Flattened Monophasic wave form is associated with severe PH, with a sensitivity of 74% and a specificity of 95%. DI of HV Increased DI40.6 predict severe PH (HVPG412 mmhg) with a PPV of 91% CV, coefficient of variation (calculated by dividing the standard deviation by the mean and multiplying by 100); DI, damping index; HA, hepatic artery; HV, hepatic vein; PH, portal hypertension; PVV, portal venous velocity; PVF, portal venous flow; RA, renal artery; SA, splenic artey; SMA, superior mesenteric artery; SPI, splenoportal index; SVF, splenic venous flow; SVV, splenic venous velocity; -, no data. 해서 damping index (DI) 를측정한결과, DI가중증의문맥압항진증을예측함에있어서매우유용하여, DI 0.6 이상의경우약 75.9% 의민감도와 81.8% 의특이도를보고하였다 (Figure 3B). 약물치료전후의반 5
2013 년대한간학회춘계 Single Topic Symposium 응평가에있어서도, DI 0.23 감소에따라간정맥압력차가 33.6% 감소함을보여, DI가비선택적베타차단제와같은문맥압항진증치료의반응을평가함에도유용할수있음을제시하였다. 7 이러한혈관수축물질투여한후에간정맥압력차와간정맥파형이변화의확인은간정맥파형변화의원인이단순히간섬유화에따른간내구조적인변화에의한것뿐만아니라간경변증의혈역학적변화에이해서도영향을받음을시사하는중요한소견이라할수있다. 5,7 그러나간정맥파형의측정도초음파자체에의한여러한계를가지고있고, 임상적유용성및재현성에있어서도여타의도플러초음파지표와같이잘계획된전향적연구를통한검증이필요하다. 2. Clinical application of Contrast-enhanced Ultrasonogrphy 조영증강초음파는우리나라에 1990년대말에지금은판매가중단된 1세대조영제인 Levovist R (Shering, Berlin, Germany) 를통해서처음소개되었으며, 일부연구자들을중심으로간종괴의감별에대해서연구결과들이보고되었지만, 높은조영제가격과한참성장하고있던일반회색조초음파에의해많은관심을끌지못하고임상에널리활용되지못했다. 그러나 2000년대중반부터새로운 2세대미세기포초음파조영제인 SonoVue R (Bracco, Milano, Italy) 의한국내출시와더불어점차임상현장에서의적용및응용이증가하는추세에있다. 1) 초음파조영제의종류와특성초음파조영제에는여러가지가있으며, 현재우리나라에서사용이가능한것은 2세대초음파조영제로서앞서언급한 SonoVue R 와최근 2012년에처음국내출시되어한국과일본에서만사용이되기시작한 Sonazoid R (Daiichi Sankyo, Tokyo, Japan) 가간질환에이용이가능하다. 이들은모두기체와이를담고있는지방질의 bubble로구성되어있으며, harmonic image 기법에의한미세기포의공진또는붕괴현상을이용하고있다. 이들기체를싸고있는지질막은조영제에따라다소차이가있으며, 미세기포는대부분이 2-10 µm 전후의크기로적혈구와비슷하거나약간작아서, 모세혈관을잘통과하기때문에일반정맥으로주사하더라도우심계와폐를통과해서좌심계를통해서전신순환이가능하게되어목표장기에까지도달하게된다 (Figure 4). (1) SonoVue R SonoVue R 는 2001년이탈리아의 Bracco사에의해처음개발및시판되기시작하였으며, 특징적으로물및혈액에잘녹지않고매우안정적인 sulfur hexafluoride (SF6) gas Figure 4. The flow of microbubble contrast with blood stream after peripheral injection. 6
김문영 도플러와조영증강초음파 를 2-10 µm의 phopholipidic monolayer shell 안에담고있는미세기포이며, 다른조영제와달리주변세포에의한탐식이적고주로혈관내에머물러있어, 혈관상의특성을평가하는데도움이된다. 간내에서 SonoVue R 는투여된후혈류도달속도의차이에의해 arterial (10-20sec), portal (30-45 sec) 및 late phase (> 120sec) 의 3개의 phase로나뉘게되는데, 이들각 phase에나타나는특징적초음파조영상을토대로병변을감별하게된다. (2) Sonazoid R Sonazoid R 는 2011년까지는전세계적으로일본에서만사용이가능하였던조영제로, 2012년부터국내에서도출시가되어조금씩그저변을넓혀가고있다. Sonazoid R 는 lipid shell내에 perflubutane gas를담고있으며, 크기는 SonoVue R 와유사하다. Sonazoid R 는정맥투여후조영증강이특징적으로두개의 phase 즉, 처음약 1-2분간의 vascular imaging phase(arterial phase ~30sec, portal phase ~120sec) 와약 10-15 분후의 Kupffer imaging phase로나눌수있다. 이는 SonoVue R 와다르게 Sonazoid R 는투여약 10분이후에간실질내의 Kupffer cell에의해탐식되어나타나는것으로, 간세포암과같이정상적인 Kupffer cell이존재하지않는경우에는이러한탐식효과가없어서 Kupffer phase에병변이조영증강이없이검게결손으로나타나기때문에, 간세포암의감별에유용하다. (3) Safety 초음파조영제는신독성이없다는큰장점을가지고있어, 일반적인 dynamic CT를시행하기어려운경우에도안전하게시행할수있고, 기타부작용도거의없는것으로알려져있다. 다만, 관상동맥질환을가지고있는경우에는주의가필요하며, 신결석에대한체외충격파쇄석술을시행하는경우에는최소한 24시간의간격을둘것을권하고있다. 또한임산부나수유부에게서는가능한사용하지않도록한다. 2) 조영증강초음파를이용한간섬유화및문맥압항진증의진단최근에미세기포조영증강초음파를이용하여측정한간내간정맥, 간동맥및간문맥에의조영제도달시간및이들혈관간의이동시간의측정이간섬유화의중증도를평가함에유용하다는연구들이보고되고있다. 9,21,22 간정맥도달시간 (hepatic vein arrival time) 은말초에초음파조영제를주입한후에간정맥에서조영제에의한혈관의조영이일정기준이상으로나타날때까지의시간 (sec) 를나타내는것으로 (Figure 5), 간섬유화및간경변증이진행됨에따라간내에동양혈관 (sinusoid) 의모세혈관화 (capillarization) 와동맥-정맥 (arteriovenous) 또는문맥-정맥 (portovenous) 단락들 (shunts) 의형성과이로인한간내혈역학의변화 (hemodynamic change) 가심화됨에따라말초정맥에서주입된초음파조영제가간동맥및간문맥을통해서간정맥에도달하는시간이빨라지게된다. 즉, 이러한초음파조영제의간정맥도달시간은간섬유화의조직학적중증도와유의한상관관계를갖는다. 9,22-24 또한최근국내의대상성간경변증환자에대한연구에서는초음파조영제의간정맥도달시간이간정맥압력차를통해측정한문맥압항진증의중증도와도유의한상관관계가있으며 (r 2 =0.558, P<0.001), 임상적으로유의한문맥압항진증 (clinically significant portal hypertension, CSPH; HVPG 10 mmhg) 를진단함에있어서 AUROC 0.973의매우우수한 7
2013 년대한간학회춘계 Single Topic Symposium A B C Figure 5. HV enhancement with microbubble CEUS and measurement of HVAT. (A and B) US images showing the HV (white arrows) before the contrast injection (A) and the arrival of microbubble contrast agent in the HV after contrast enhancement (B). (C) After a 10-second lead time to estimate baseline value, a 2.4-mL bolus of SonoVue R was injected into the left antecubital vein, and the TIC of the signal was recorded from the right HV. HVAT was calculated as the time (in seconds) from injection to a sustained increase in signal in the TIC to more than 10% above baseline. The recorded TIC profile shows early HVAT (11.0 seconds; the 10-second lead time was subtracted from 21.0 seconds) in a patient with cirrhosis with HVPG of 20 mmhg. (D) The recorded TIC profile shows an HVAT of 27.0 seconds (37.0 minus 10 seconds) in a healthy control. HV, hepatic vein; CEUS, contrast enhanced Ultrasonography; HVAT, hepatic vein arrival time; TIC, time intensity curve. This was quoted in reference number 10. D 결과를보고하여조영증강초음파를이용한간내혈역학의변화에대한측정이향후비침습적으로문맥압항진증을평가함에있어서유용한하나의방법이될수있음을제시하였다. 10 물론이와같은새로운방법에는여러가지해결해야할문제들이있다. 우선, 모든초음파검사가갖는재현성의문제와객관성의문제가남아있다. 특히, 일정정도이상의조영증강을보이기까지의시간을측정함에있어서좀더객관적이고보편적인측정프로그램이필요하며, 이에대한전향적인검증연구들이필요하다. 그러나, 그럼에도불구하고조영증강초음파가기존의일반초음파및도플러초음파와는차원을달리하는새로운 paradigm을제시할것으로기대되며, 현재진행중인또는향후관련된많은연구를통해좀더정밀하고잘디자인된검사기법이곧우리앞에선보일것으로기대된다. 8
김문영 도플러와조영증강초음파 맺음말 이제까지간략히살펴본바와같이비침습적으로문맥압을평가하고자하는노력이지속되어왔으나아직까지간정맥압력차를대신할만한방법은개발되지못했다. 도플러초음파에대한연구가많이이루어졌으나재현성등의문제로널리모두에게받아들여져이용되지는못했다. 조영증강초음파는초음파자체가갖는한계를역시가지고있으나기존의일반초음파나도플러초음파에비하면좀더정확하게혈관및혈류의흐름을평가할수있다는장점을가지고있고, 다양한분야에서응용이될수있는여지를가지고있다. 그러나조영증강초음파도향후임상적유용성에대한검증의과정이필요하며, 재현성과객관성을높이기위한연구가지속되어야한다. 참고문헌 1. Kim MY, Cho MY, Baik SK, et al. Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension. J Hepatol 2011;55:1004-9. 2. Kim MY, Baik SK, Yea CJ, et al. Hepatic venous pressure gradient can predict the development of hepatocellular carcinoma and hyponatremia in decompensated alcoholic cirrhosis. Eur J Gastroenterol Hepatol 2009;21:1241-6. 3. Kim MY, Baik SK, Suk KT, et al. Measurement of hepatic venous pressure gradient in liver cirrhosis: relationship with the status of cirrhosis, varices, and ascites in Korea. Korean J Hepatol 2008;14:150-8. 4. Lebrec D. Methods to evaluate portal hypertension. Gastroenterol Clin North Am 1992;21:41-59. 5. Baik SK, Kim JW, Kim HS, et al. Recent variceal bleeding: Doppler US hepatic vein waveform in assessment of severity of portal hypertension and vasoactive drug response. Radiology 2006;240:574-80. 6. Choi YJ, Baik SK, Park DH, et al. Comparison of Doppler ultrasonography and the hepatic venous pressure gradient in assessing portal hypertension in liver cirrhosis. J Gastroenterol Hepatol 2003;18:424-9. 7. Kim MY, Baik SK, Park DH, et al. Damping index of Doppler hepatic vein waveform to assess the severity of portal hypertension and response to propranolol in liver cirrhosis: a prospective nonrandomized study. Liver Int 2007;27:1103-10. 8. Merkel C, Sacerdoti D, Bolognesi M, et al. Doppler sonography and hepatic vein catheterization in portal hypertension: assessment of agreement in evaluating severity and response to treatment. J Hepatol 1998;28:622-30. 9. Lim AK, Taylor-Robinson SD, Patel N, et al. Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C. Gut 2005;54:128-33. 10. Kim MY, Suk KT, Baik SK, et al. Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis. Hepatology 2012;56:1053-62. 11. Baik SK. Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review. Liver Int 2010;30:1403-13. 12. Zironi G, Gaiani S, Fenyves D, et al. Value of measurement of mean portal flow velocity by Doppler flowmetry in the diagnosis of portal hypertension. J Hepatol 1992;16:298-303. 13. Baik SK, Jee MG, Jeong PH, et al. Relationship of hemodynamic indices and prognosis in patients with liver cirrhosis. Korean J Intern Med 2004;19:165-70. 9
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