PG 1 PG Course 2012 Portal Hypertension 문맥압항진증의진단 연세대학교원주의과대학내과학교실 박소연 백순구 Diagnosis of Portal Hypertension So Yeon Park Soon Koo Baik Division of Gastroenterology and Hepatology, Department of Internal Medicine, Wonju Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea 서 론 문맥압항진증이란문맥압의비정상적인상승을의미하며, 문맥 (portal vein) 과하대정맥 (inferior vena cava) 간의압력경사 (portal pressure gradient) 가 6mmHg 이상일경우를일컫는다. 정상문맥압 (portal pressure gradient) 은 1-5 mmhg 이며, 10 mmhg 이상일때정맥류나복수가발생되어임상적인의의를갖는다. 1-2 문맥압항진 증은문맥계로유입되는혈류에대한혈관의저항이증가함으로써발생한다. 문맥압항진증은간경변증환자의대부분에서필연적으로발생하는데, 문맥압의상승이역으로전파되어문맥과전신혈관사이의단락 (porto-systemic shunt) 을형성하며, 측부혈관의발달을유도한다. 이는심박출량과내장혈류량의증가를이끌어내고, 결국문맥계유입혈류량 (portal venous inflow) 이증가되어지속적인문맥압항진상태가유지된다. 이와같은문맥압항진증의발생과과역동적혈역학 (hyperdynamic circulation) 변화는정맥류출혈, 복수등과 같은환자의예후와연관된심각한합병증을일으킨다. 1-4 혈관의저항증가는동양혈관 (sinusoid) 부위또는 동양혈관의전, 후 (pre-sinusoid, post-sinusoid) 에서발생하여문맥압항진증을일으킬수있다. 본글에서는주 로동양혈관위치에서저항이증가하여발생하는간경변증즉, B 형및 C 형간염바이러스와알코올에의한 간경변증으로부터생기는문맥압항진증의진단에대해언급하고자한다. 진단및평가 1. Hepatic venous pressure gradient (HVPG), 간정맥압력차 문맥의지류와간정맥의분지사이의 sinusoidal bed 를통하는압력이평형을이루고있음을근거로한간 정맥도자술 (hepatic vein catheterization) 을이용한문맥압측정법이다. 우측대퇴정맥이나경정맥을통하여 7
Postgraduate Course 2012 카테터를간정맥에위치한후압력을재면간정맥자유압 (free hepatic venous pressure) 을구할수있다. 여기 서간정맥의작은가지까지더깊숙이삽입한후압력을재면, 간내문맥혈관의압력을반영하는간정맥쐐 기압 (wedged hepatic venous pressure) 을측정할수있다. 간정맥쐐기압에서간정맥자유압을뺀값이 HVPG 이며, 현재문맥압을재기위해가장널리사용되는침습적측정방법이다 (Figure 1). 1-2,5-7 간정맥쐐기압에서 간정맥자유압을빼주는이유는 HVPG가실제문맥과정맥간의압력경사 (portal pressure gradient) 를의미하고, 문맥압이간내혈관저항뿐만아니라하대정맥을통해간정맥에전달되는압력에의해서도영향을받을수있기때문이다. 즉, 복수의유무나환자혈장량의많고적은상태가문맥압에영향을미칠수있기때문에보정이필요하다. HVPG를측정할때는간내문맥혈관의압력을정확히반영할수있는발룬카테터를사용하고있다. 8-10 HVPG는보통우측간정맥에서재는데쐐기압을측정할때는쐐기 (balloon wedge) 후조영제를주사하여쐐기가완전히이루어졌는지와다른간정맥과단락이존재하는지확인해야한다. 만약쐐기가불완전 (insufficient inflation of the balloon) 하게되었다든지, 다른간정맥과단락 (venous-to-venous shunt) 이있으면쐐기압이저평가된다. 반복측정한 HVPG 값들의 coefficient variation이 7-8% 이면재현성과정확성이 좋다고할수있다. 11-15 시술시간은보통약 20 분이소요되며, 정맥을통해시술을하므로심각한합병증은 없다고할수있다. 정상인의간정맥쐐기압은 10 mmhg 이하이고, 간정맥자유압은 5 mmhg 이하로, HVPG 는정상인에서 5 mmhg 이하이다. 문맥압항진증의심한정도는 HVPG가 5-10 mmhg는 mild, 10-15 mmhg는 moderate, 그리고 15 mmhg 이상은 severe로나눈다. HVPG가보통 10 mmhg 이상이되면정맥류가생기고, 12 mmhg 이상일때정맥류출혈이발생하므로정맥류출혈을예방하기위해서는 HVPG 를 12 mmhg 이하로감소시켜야한다. 1,2,7-8 그러나간혹우회혈류의발달정도에따라 12 mmhg 이하에서도출혈이발생할수있어, 이같은수치가정맥류출혈을반영하는데절대적이라고할수는없다. 정맥류출혈이있었던 138명의한국인 간경변환자를대상으로측정하였던평균 HVPG 는 15.1±5.4 mmhg 였다. 16 현재이시술은문맥압항진증에 대해보험적용 ( 건강보험심사평가원고시제 2000-73 호 ) 을받을수있어임상에서사용하는데유용하다. A B Figure 1. Measurement of hepatic venous pressure gradient by right hepatic vein catheterization. Seven French balloon catheter is placed in the right hepatic vein to measure the free hepatic venous pressure (A). Wedged hepatic venous pressure is measured by inflating the balloon catheter at the right hepatic vein (B). Hepatic venous pressure gradient is determined by subtracting the free hepatic venous pressure from the wedged hepatic venous pressure. 8
박소연 백순구 문맥압항진증의진단 2. Doppler and contrast enhanced ultrasonography(us), 도플러및조형증강초음파검사초음파영상진단에서문맥압항진증을시사하는소견으로는측부혈관의발달, 위-신장또는비장-신장정맥의단락, 비장종대, 담낭벽비후, 복수등을꼽을수있다. 여기에, 도플러초음파검사는복부혈관의혈역학을정량적으로평가할수있는장점이있어, 그동안간경변증과문맥압항진증의병태생리에대한임상연구에이용되었으며, 문맥압항진증을평가하는검사법으로서그유용성에대해많은연구가있었다. 도플러초음파는혈류속도와직경을통해문맥의혈류량을측정할수있고, 동맥에서는저항지수 (resistive index) 와 박동지수 (pulsatility index) 를통해저항을측정할수있다. 17 문맥압항진증환자는간내혈관의저항이크므 로문맥의혈류속도가낮은경향이있어, 일반적으로정상인은 20 cm/sec 내외이나, 문맥압항진증환자는 15 cm/sec 이하이다. 또한, 상장간막동맥과같은내장동맥혈관의저항지수는감소해있고, 혈류량은증가되 어있다. 18 간경변증환자는말기간경변증으로진행할수록유효혈장량 (effective circulatory volume) 이부족 하여기능적신기능장애를가지므로신장동맥의저항이증가한다. 따라서, Child-Pugh C 군이나간신증후군 환자의신장동맥저항지수와박동지수는정상인이나대상성간경변증환자보다높다. 19 정상인에서간정맥 (hepatic vein) 의정상도플러파형은두개의큰전향적혈류 (antegrade flow) 와심방의수축과관련된한개의후향적혈류 (retrograde flow) 에의한삼위상파형 (triphasic waveform) 이다. 간경변증과문맥압항진증환자에서는정상삼위상도플러파형에변화가일어나, 역류가없어지거나파형의진폭이감소되어이위상파형 (biphasic waveform) 을보이거나, 파형에진폭이없는단위상파형 (monophasic waveform) 을보이는데, 환자의약 75-92% 에서비정상적인간정맥파형을보인다. 특히단위상파형을보이는경우는 15 mmhg 이상의심각한문맥압항진증을보일가능성이높다 (Figure 2). 11,12 이렇듯도플러초음파검사가문맥압항진증을어느정도반영할수있다하나, 아직도플러초음파검사의한계점은이검사법이주관적으로그결과가관찰자에따라영향을받으며, 환자가초음파창이좋지않은경우는정확한평가가이루어지기어려울수있다. 조영증강초음파는그간간질환에서는주로간내종괴의감별진단에이용되어왔다. 하지만, 간경변증으로인한문맥압항진증환자는문맥과전신혈관사이에문맥-전신단락 (porto-systemic shunt) 을가짐으로써, 혈행순환시간 (circulatory time) 이감소한다는원리에착안하여, 조영제를이용하여혈행순환시간을측정하여문맥압항진증의정도와비교하였다. 혈행순환시간은조영제를정맥주사한후간정맥에도달하는시간인간정맥도달시간 (Hepatic vein arrival time, HVAT) 으로측정하였다. HVAT는실제 HVPG로측정한문맥압을매우 A B Figure 2. Hepatic vein waveform on Doppler ultrasonography. Normal triphasic waveform is composed of two forward flows and one reverse flow (A). In patients with liver cirrhosis and portal hypertension, abnormal flat hepatic vein waveform (monophasic pattern) is observed (B). Monophasic pattern of hepatic vein waveform is associated with the presence of severe portal hypertension and advanced liver cirrhosis. 9
Postgraduate Course 2012 A B C D Figure 3. Hepatic vein (HV) enhancement with microbubble contrast-enhanced ultrasonography and the measurement of the HV arrival time (HVAT). Ultrasonographic 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). After a 10-sec lead time to estimate baseline value, a 2.4 ml bolus of SonoVue was injected into the left antecubital vein, and the time-intensity curve (TIC) of the signal was recorded from the right HV. HVAT wascalculated as the time (in seconds) from injection to a sustained increase in the signal in the TIC to more than 10% above baseline. The recorded TIC profile shows early HVAT of 11.0sec (the 10-sec lead time was subtracted from 21.0sec) in a cirrhotic patient with hepatic venous pressure gradient (HVPG) of 20 mmhg (C). The recorded TIC profile shows an HVAT of 27.0sec (37.0sec minus 10) in a normal control (D). 잘반영하여, HVAT가낮을수록문맥압항진증의정도가심하였다 (Figure 3). 또한, HVAT값이낮을수록 Child-Pugh score값이높았으며, 정맥류도진행된상태를보여주었고, HVAT <14sec인경우에 HVPG>10 mmhg (clinically significant portal hypertension) 일민감도와특이도가매우높다. 따라서, HVPG를시행할수없는경우이를보조적방법으로사용할수있겠다. 20 3. Liver stiffness measurement (LSM) by transient elastography(te), 간탄력도검사 LSM 은탄성파가간실질을통과하는속도를이용하여간의단단한정도 (stiffness) 를측정하는방법이다. 초음파변환기를포함하는탐촉자를사용하여저주파 (50MHz) 의진동과진폭이간으로전달되면, 이진동에의해발생한탄력파동은간으로파급되며이때발생하는초음파의이동속도는조직의단단한정도를반영하게된다. 즉, 이동속도가빠를수록간섬유화가진행되었다는정보를제공해주며, 결과는 kilopascals(kpa) 로표시된다. 21-23 이상적인간탄력도검사는반복적으로최소한 10회이상반복하여측정하며, 이에따라자동적으로계산된중앙값으로기록된다. 임상적으로검사결과의신뢰성을위해 10회이상의유효검사, interquartile range (IQR) 값이 30% 미만, 성공률이 60% 이상을권고하고있다. 23 간의섬유화정도는문맥압항진증과연관성을보여준다는가정하에시행된연구에서, LSM이 HVPG와의 연관성을나타내어, 문맥압항진증을평가할수있는비침습적인방법의가능성이제시되었다. 24 또한, 전향 적인연구에따르면만성간질환환자에있어서간질환의비대상성과관련된위험도를예측하는데있어서 HVPG 만큼유용한결론을보여주었으며, LSM 이정맥류크기와도연관이있음을보고하였다. 25,26 간탄력도 검사는통증이없고, 비침습적이며쉽고빠른검사가가능하며, 재현성이높은검사방법으로알려져있으나, 일부제한점이있다. 탄력도의측정은비만, 복수가있거나늑골사이간격이좁은경우정확성이떨어지거나검사가불가능할수있으며, 급성간손상이있는경우혼란변수로작용할수있다. 27 또한, 심부전이있는환자들이나알콜성간질환환자에있어 steatohepatitis가동반되어있는경우본검사의측정치에영향을미칠 10
박소연 백순구 문맥압항진증의진단 수있어해석에주의를요한다. 28,29 4. Magnetic Resonance Elastography (MRE), 자기공명영상탄성측정법 MR elastography (MRE) 는환자의등이나전벽을통해서간으로 low frequency vibration을보내 MRI spin-echo sequence를측정함으로써간섬유화정도를재는방법이다. Standard MRI에 MRE protocol을적용하면사용가능하다는장점이있고, acoustic window에대한요구가적기때문에전체간을비교적잘스캔할수있으며, 비만이나복수유무에관계없이적용가능한방법이다. 그간의연구에서간섬유화를평가하는데있어서진 단적정확도가높은안전하고, 비침습적인방법으로알려져있다. 30-32 MRE 가정상과경변성간을구분하 는데있어서 97% 의높은음성예측도를보여주어, 간경변가능성이있는환자의감별진단에간조직검사를대신하여적용할수있다는보고가있었다. 31 그외자기공명영상을이용한비장탄성도의측정을이용하여문맥압항진증을평가하고자한연구가있었고, 간과비장의탄력도에있어서유의한상관관계를보여주면서비장의탄력도값이 10.6 kpa 이상일경우 정맥류를동반한다는결과를보였다. 33 또한, 담즙정체성간질환과동반된문맥압항진증의동물연구에서 HVPG 와 MRE 를통한비장의탄력도측정값사이에의미있는상관관계가있음이보고되었다. 34 MRE 는비 침습적이면서도, 비만이나복수유무에관계없이간섬유화정도를측정가능하다는잇점이있어, 향후간섬 유화및문맥압항진증의정도판정에그유용성이기대되며더많은연구가필요하다. 5. 13C-methacetin breath test (MBT) Breath tests는간에서섭취및대사되는표지물질 (labeled substrates) 의호기동안대사산물을측정하는방법으로, 호기동안발생하는대사물질의양과발생률은간의활성도를반영해주며, 이의감소는간손상을의미하게된다. 13C-methacetin는간에서유일하게대사되는물질로서, 호기동안대사되는 13 C/ 12 C isotope의비율을통해측정된값을간질환의정도판정에이용하는방법이 13 CO 2 13C-methacetin breath test (13C-MBT) 이다. 35 13C-MBT방법은정상 ALT수치를보이는만성 C형간염환자에서염증과섬유화정도를측정하는데도 움이되며, 간경변증환자의생존률과관련이있다고보고되었다. 36 하지만, 13C-MBT 는진행된간경변증의 진단에는유용하게쓰일수있으나간경변증이없는경우와간경변증의다양한단계를구분하는데있어서 신뢰성이적다고하며, 아직까지문맥압항진증과의연관성을보여준연구결과는없어, 향후이에대한연구가 필요하겠다. 맺음말 현재문맥압항진증의평가에정확성을인정받아널리이용되고있는방법은간정맥압력차 (hepatic venous pressure gradient) 의측정이다. 이시술은간정맥도자술을이용하는방법으로비교적간편하며안전하나, 침 11
Postgraduate Course 2012 습적인방법이라는제한점이있다. 비침습적방법으로는도플러및조영증강초음파, 자기공명영상탄성측 정법, 간탄력도검사등이있으며, 간정맥압력차측정이불가능할경우, 제시된비침습적진단법들은문맥 압항진증의진단및평가에도움을주는보조적방법이될수있다. 참고문헌 1. Baik SK. Assessment and current treatment of portal hypertension. Korean J Hepatol 2005;11:211-217 2. Baik SK. Pharmacological therapy of portal hypertension-focused on korean data. Korean J Gastroenterol 2005;45:381-386 3. Kim MY, Baik SK. Hyperdynamic circulation in patients with liver cirrhosis and portal hypertension. Korean J Gastroenterol 2009;54:143-148 4. Kim MY, Baik SK, Lee SS. Hemodynamic alterations in cirrhosis and portal hypertension. Korean J Hepatol 2010;16:347-352 5. Lebrec D. Methods to evaluate portal hypertension. Gastroenterol Clin North Am. 1992;21:41-59 6. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 2004;39:280-282 7. Savader SJ. Angiographic, venographic and hemodynamic evaluation of portal hypertension. In: Savader SJ, Trerotola SO, ed. Venous interventional radiology with clinical perspectives, New York: Thieme 2000;7-31 8. Baik SK, Park DH et al. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol 2003;38:1150-1154 9. Baik SK, Jee MG, et al. Relationship of hemodynamic indices and prognosis in patients with liver cirrhosis. Korean J Intern Med 2004;19:165-170 10. Baik SK, Jeong PH et al. Acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis: a randomized comparison. Am J Gastroenterol 2005;100:631-635 11. Baik SK, KimJW, 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; 240:574-580 12. Kim MY, Baik SK, 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;27:1103-1110 13. Kim MY, Baik SK, 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;1241-1246 14. Kim MY, Choi H, Baik SK, et al. Chang SJ. Portal hypertensive gastropathy: Correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 201055:3561-3567 15. Kim MY, Baik SK, et al. Measurement of hepatic venous pressure gradient in liver cirrhosis: Relationship with the status of cirrhosis, varices, and ascites in Korea. Korean J Hepatology 2008;14:150-158 16. Choi YJ, Baik SK, Kim HS, et al. Comparison of doppler ultrasonography and the hepatic venous pressure gradient in assessing portal hypertension in liver cirrhosis. J Gastroenterol Hepatol 2003;18:424-429 17. Baik SK. Haemodynamic evaluation by doppler ultrasonography in patients with portal hypertension: a review. Liver Int. 2010;30:1403-1413 18. Baik SK, Choi YJ, Kwon SO, et al. Splanchnic and extrasplanchnic vascular hemodynamics in liver cirrhosis. Korean J Gastroenterol 2000; 35: 466-474 19. Baik SK, Kim KH, Jeong YS, et al. Pulsatility index of renal artery in patients with liver cirrhosis. Journal of Korean Society of Ultrasound in Medicine 2000;19:71-76 20. 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 Apr 2. doi: 10.1002/hep.25752. [Epub ahead of print] 21. Kim SU, Jang HW, Cheong JY, et al. The usefulness of liver stiffness measurement using FibroScan in chronic hepatitis C in South Korea: a multicenter, prospective study. J Gastroenterol Hepatol. 2011;26:171-8 12
박소연 백순구 문맥압항진증의진단 22. Sandrin L, Fourquet B, et al. Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705-1713 23. Castera L, Forns X, Alberti A. non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835-847 24. Vizzutti F, Arena U, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology. 2007;45:1290-1297 25. Robic MA, Procopet B, et al. Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study. J Hepatol 2011;55:1017-1024 26. Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. J Hepatol 2012;56:696-703 27. Arena U, Vizzutti F, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008;47:380-384 28. Millonig G, Friedrich S, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol. 2010;52:206-210 29. Mueller S, Millonig G, et al. Increased liver stiffness in alcoholic liver disease: Differentiating fibrosis from steatohepatitis. World J Gastroenterol. 2010;16:966-972 30. Huwart L, Peeters F, et al. Liver fibrosis: Non-invasive assessment with MR elastography. NMR Biomed 2006;19:173-179 31. Yin M, Talwalkar JA, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol 2007;5:1207-1213 32. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology. 2008;134:1670-1681 33. Talwalkar JA, Yin M, Venkatesh S, et al. Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension. AJR Am J Roentgenol 2009;193:122-127 34. Nedredal GI, Yin M, McKenzie T, et al. Portal hypertension correlates with splenic stiffness as measured with MR elastography. J Magn Reson Imaging 2011;34:79-87 35. Dinesen L, Caspary WF, et al. 13C-methacetin-breath test compared to also noninvasive biochemical blood tests in predicting hepatic fibrosis and cirrhosis in chronic hepatitis C. Dig Liver Dis 2008;40:743-748 36. Lalazar G, Ilan Y. Assessment of liver function in acute or chronic liver disease by the methacetin breath test: a tool for decision making in clinical hepatology. J Breath Res 2009;3:047001. PG 1 13