Clinical Ultrasound REVIEW Clinical Ultrasound 2016;1:1-10 미만성간질환의초음파감별진단 백순구연세대학교원주의과대학내과학교실 Differential Diagnosis of Diffuse Liver Disease Soon Koo Baik Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea Ultrasonographic parameters supporting differential diagnosis of diffuse liver disease such as fatty liver, chronic viral hepatitis and cirrhosis include echo-pattern of liver parenchyme, presence or absence of surface irregularity and splenomegaly. Additionally, Doppler ultrasonographic indices can provide clue to diagnosis diffuse liver diseases. Thanks to develop the antiviral agents leading successful treatment of viral hepatitis and reversibility of hepatic fibrosis, a need for differential diagnosis between chronic hepatitis and early stage of cirrhosis has been increasingly recognized. The presence of surface irregularity of liver is currently accepted ultrasonographic finding with highly accuracy and reproducibility favoring early stage of cirrhosis. Recently, liver stiffness measurement by transient elastography is considered as a promising non-invasive method for assessment of hepatic fibrosis. Keywords: Liver disease; Ultrasonography; Diagnosis, Differential 서론 미만성간질환은간실질, 간내담관또는간혈관등을광범위하게침범하는질환을총칭하며, 다양한대사성, 순환성, 독성, 감염성, 종양성질환에의해초래될수있다 [1-5]. 우리나라에서중요한미만성간질환은지방간과 B, 혹은 C형간염바이러스에의한만성간염그리고간경변증이다. 초음파검사에서미만성간질환유무는간의전체적인윤곽뿐아니라간실질의에코, 간표면의굴곡여부등에대한평가에의거한다. 정상간실질의에코는신장의피질과비교하여약간높거나같으며, 비장과비슷하거나약간낮다 [6-10]. 지방간, 간염, 간경변증과같은미만성간질환에서는일반적으로간실질의에코가증가한다. 또한간표면의요철성변화역시간염, 간경변증으로진행할수록더 명확히관찰된다. 하지만이러한소견들특히, 간실질의에코는초음파기기의종류나설정에영향을받을뿐만아니라, 검사자의주관적인판단에따르게되므로, 검사자간의진단적차이가존재한다 [11-20]. 따라서미만성간질환의초음파진단기준에대한정확한이해가필요하다. 본종설에서는미만성간질환의전형적이고특징적인초음파소견을다루면서특히, 초기간경변증을진단하는데유용한초음파 tip에대해소개하겠다. 본론지방간 지방간은간세포내에중성지방이침착되는현상으로, 간 Address for Correspondence: Soon Koo Baik, M.D., Ph.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 lsan-ro, Wonju 26427, Korea Tel: +82-33-741-1229, Fax: +82-33-745-6782 E-mail: baiksk@yonsei.ac.kr Received : 2016. 4. 20 Revised : 2016. 4. 22 Accepted : 2016. 4. 25 Copyright 2016 The Korean Association of Clinical Ultrasound This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. pissn 2465-7786 eissn 2465-7794
Clinical Ultrasound Vol. 1, No. 1, May 2016 으로들어오는지방의양이많아지거나, 간내지방대사의이상, 간세포로부터지방분비의이상을야기할수있는매우다양한조건이그원인이될수있다. 임상적으로흔히접하는지방간의원인은비만, 당뇨병, 알콜과다섭취등이며, 뚜렷한원인없이초음파검사에서지방간소견을보이는경우도있다. 지방간의예후는대부분양호하여, 임상증상을일으키지않고간기능검사에서정상이거나약간이상소견을보이는정도이다. 그 러나최근심한지방간으로표현되는비알콜성지방간염 (nonalcoholic steatohepatitis) 은간경변증으로진행이가능하여추적검사가필요하다. 지방간의초음파소견은다음과같다. 신장및비장에비해간의에코가높아진다 (bright liver) (Fig. 1A). 간실질의에코가증가하다보니문맥의벽에코가보이지않게된다. 즉, 정상간에서는문맥벽에코가고에코를보이지만지방간의경우간조직의 A B C Figure 1. Ultrasonographic findings for fatty liver: (A) Bright liver parenchymal echo-pattern contrast to renal cortex, (B) Poorly visualization of portal vein wall, (C) Obliteration of diaphragm. Figure 2. Focal fat sparing. Figure 3. Focal fat deposition. 2
Soon Koo Baik. Differential diagnosis of diffuse liver disease Clinical Ultrasound 에코가증가하므로문맥벽의에코가뚜렷이보이지않게된다 (Fig. 1B). 또한, 음향감쇠가증가하여횡격막같은심부구조물이안보이거나희미하게보인다 (Fig. 1C). 그외, 간종대가있을수있다. 초음파검사는지방간유무의진단에유용하며 computed tomography (CT) 보다민감한것으로알려져있으나지방간의진단과그경중의판단에있어초음파의진단정확도에대해서는좀더연구가필요하다. 부분적인지방회피 (focal fat sparing) (Fig. 2) 와국소적지방간 (focal fat deposition) (Fig. 3) 은국소적병변과감별하기어려울수있다. 위치가특징적이고, 주변혈관에종괴효과가없으며, 정상부위와의경계가직선적인것이감별점이다. 국소적비지방침윤이잘생기는부위는간문에서문맥의전방, 담낭와, 간의경계부위이며, 간문에서간문맥의전방에는국한적인지방침윤이잘생긴다 (Figs. 2 and 3). 간염초음파에서특이한소견을보이는공간점유병소와는달리급성간염은특징적인소견으로보이지않는다. 그러나병의시간경과에따라간세포의부종으로간의크기가커지고간실질 Figure 4. Changes in thickening of gall bladder wall by lapse of time in acute hepatitis. Figure 5. Ultrasonographic findings of Chronic hepatitis B. A B Figure 6. Ultrasonographic findings of alcoholic liver disease: Hypertrophic changes of (A) caudate lobe and (B) left lobe of liver. 3
Clinical Ultrasound Vol. 1, No. 1, May 2016 의에코는다소저하되기도하며, 특징적으로담낭벽의비후나수축이관찰된다. 한편급성기에축소되어있던담낭이병의회복에따라담낭의상태가가역적으로되돌아오는것을초음파상으로관찰할수있다 (Fig. 4). 만성바이러스성간염은간실질의에코가거칠어지며, 경우에따라서는작은재생결절들이산재하여그물모양형태 (meshwork pattern) 의간실질을보이기도한다. 그물모양형태는특히, B형만성바이러스성간염에서흔히관찰되며, 이런경우간암의발생률이높으므로자주초음파나 CT 추적이요구된다 (Fig. 5) [17,21]. 알콜성간질환은지방침착으로인해현저히에코가증가하며 CT나 magnetic resonance imaging상에서도지방침착이주소견이다. 또한특징적으로좌엽및 caudate lobe의비대가동반되며 (Fig. 6), 좌측문맥의직경이커지고, ligament teres와담낭사이의거리가좁아진다. 간경변초음파로초기간경변증을어떻게진단할것인가? 증례 (1) 만성 B형간염인 49세남환이담낭절제술중, 수술장에서육안 (Fig. 7) 으로간경변증을확인하게되어소화기내과로전과되었다. 다음은본환자의초음파소견 (Figs. 8 and 9) 과이어촬영한 CT 소견 (Fig. 10) 그리고간경변증을보여준간조직검사소견 (Fig. 11) 이다. 증례 (2) 만성 B형간염의과거력을가지고있는 48세여환으로토혈을주소로내원하여위내시경을시행하였고, 위정맥류출혈소견을보여히스토아크릴주사후지혈에성공하였다 (Fig. 12). 본환자의초음파및간섬유화스캔결과이다 (Figs. 13 and 14). 본두증례의초음파소견을보고, 실제수술장에서확인되었거나, 위정맥류출혈을야기한진행된간섬유화상태인간경변증환자일것으로판단하기는쉽지않을수있다. 즉, 일반적으로우리가초음파로간경변증을진단할때, 간경변증의진단이 Figure 7. Gross finding of cirrhotic liver with surface irregularity. Figure 8. Liver evaluation using 3.5 MHz convex probe. 4
Soon Koo Baik. Differential diagnosis of diffuse liver disease Clinical Ultrasound Figure 9. Liver evaluation using 9 MHz linear probe for estimation of surface irregularity. Figure 10. Liver C-T scan: suspicious early stage of cirrhosis. CT, computed tomography. Figrue 11. Pathologic finding: cirrhosis. 저평가 (underestimation) 되고있을가능성이높다고하겠다. 간경변증과관련된초음파소견은간용적의재배치, 거친에코질감, 결절성표면이있다. Nishiura 등 [21] 은고주파탐촉자와저주파탐촉자를통한초음파로만성간질환환자의섬유화정도를변연부의둔화 (bluntness of edge), 결절성간표면 (irregularity of surface), 거친에코질감 (coarseness of the parenchymal texture) 을점수화하여간조직검사결과와비교하였다. 그결과, 각항목의점수와간섬유화결과는상관관계가있었으며, 특히세항목중 surface score, 즉간표면이얼마나우둘투둘한지가간조직검사로밝혀진섬유화정도와가장상관관계가높다고보고하였다 (Fig. 15) [21]. 그러므로초음파검사때, 간표면을자세히관찰하는것이초기간경변증을진단하는데있어비교적정확하고간단한방법이겠으며, 고주파의 linear probe를사용하여간표면의요철정도를관찰하는것이도움이되겠다 [18]. 본교실의연구에서도초음파로간표면요철정도, 간실질에코변화, 간우엽위축정도, 비장종대여부, 비장정맥의굵기, 간정맥파형의존재유무등을이용한점수화시스템이간조직의섬유화와높은상관관계가있음을보고한바있다 (Table 1) [17]. 간경변증의초음파소견일반적으로간경변증을진단하는초음파소견은다음과같다 [17,18,21]. 저에코부터고에코까지다양한에코의무수히많은재생결절 간실질전체가고에코로조잡하게보인다. 5
Clinical Ultrasound Vol. 1, No. 1, May 2016 A B Figure 12. Esophagogastroscopy: (A) Bleeding gastric varix, (B) Hemostasis after endoscopic treatment. A B C Figure 13. Conventional and Doppler Ultrasonographic findings: (A, B) Coarse parenchymal echo-pattern by 3.5 MHz convex probe, (C) Monophasic waveform of hepatic vein by Doppler ultrasonography suggesting presence of cirrhosis and significant portal hypertension. A B C Figure 14. Ultrasonographic findings and Liver stiffness measurement by transient elastography: (A, B) Visible surface irregularity using 9 MHz linear probe, (C) 10.8 kpa of liver stiffness indicating significant fibrosis. A B C D Figure 15. Ultrasonographic findings of cirrhosis: (A) Coarse parenchymal echo-pattern and surface irregularity, (B) Angle blunting and collateral vessels, (C) Atrophic change of right lobe and ascites, (D) Splenomegaly and gamma gandy nodules. 6
Soon Koo Baik. Differential diagnosis of diffuse liver disease Clinical Ultrasound Table 1. Fibrosis scoring system by ultrasonography: over seven points is more likely to be a significant fibrosis [17] Clinical features Score 0 1 2 Surface and edge Smooth and sharp Mildly irregular and mildly blunted Irregular and blunted Parenchyma echogenicity Fine Mildly coarse Coarse Right lobe atrophy Absent a Present b Spleen size (cm) <10 10-14 >14 Splenic vein diameter (cm) <0.7 0.7-0.9 >0.9 Hepatic vein waveform Triphasic Bi or monophagic Modified from Moon, et al. [17]. The total score from six ultrasonogrphic indices including surface nodularity and edge shape (0-2), parenchyma echogenicity (0-2), right lobe atrophy (0-2), spleen size (0-2), splenic vein diameter (0-2) and hepatic vein waveform (0-1) was calculated. a Right lobe maximal oblique diameter > 7 cm with no subphrenic ascites. b Right lobe maximal oblique diameter < 10 cm with subphrenic ascites. A B Figure 16. Doppler ultrasonography: (A) Splenomegaly and splenorenal shunt, (B) Shunt formation of umbilical vein. 비장종대 우회혈관확장 복수 담낭벽비후 제대정맥 (umbilical vein) 의확장 Figure 17. Low portal venous velocity in cirrhosis by Doppler ultrasonography. 간표면이수많은결절에의해서우둘투둘해진다. 간우엽 ( 특히우후분절 ) 의위축과, 미상엽과간좌엽 ( 특히외 분절 ) 의상대적인비대 주문맥의확장 ( 기준은대개 13 mm) 이상의전형적인간경변증의초음파소견이있으면비교적쉽게진단을내릴수있으나, 실제로간의내부에코의변화와간기능의정도나변화와는반드시일치하지않을수있다. 한편내부에코의변화가별로없는간경변증도있으며, 특히알코올성간경변증에서는심한지방간이동반되어간실질에코변화를뚜렷하게보이지않는경우도있다. 간구역의형태변화와함께혈관의변화도나타나는데, 정상은우문맥지름이좌문맥보다크지만, 간경변증으로인해좌엽외구역이커지고우엽이작아진다. 좌문맥지름이우문맥과같아지거나커진다. 7
Clinical Ultrasound Vol. 1, No. 1, May 2016 A B 비장에서는 Gamma-Gandy 결절이라고하는철침탁결절이 고에코성으로발견되기도한다. 이결절은문맥고혈압에따른 비장소포출혈로인해형성되며, 헤모시데린과칼슘, 섬유화조 직으로구성되어있다 (Fig. 15). 간경변증과도플러초음파 Figure 18. Measurement of renal arterial resistance by Doppler ultrasonography: (A) normal resistive index: 0.533, (B) high resistive index in cirrhosis: 0.714. 문맥고혈압을시사하는초음파소견은먼저간경변증존재의확인과측부혈관의발달, 위-신장정맥의단락, 비장종대와비장-신장정맥의단락 (Fig. 16A), 제대정맥의단락 (Fig. 16B), 담낭벽비후, 복수등을꼽을수있다. 여기에도플러초음파검사는복부혈관의혈역학을정량적으로평가할수있는이점이있어, 간경변증과문맥압항진증에동반된혈역학적변화의관찰을가능하게하여문맥고혈압의진단에도움이된다. 도플러초음파는혈류속도와직경을통해문맥의혈류량을측정할수있고, 동맥에서는저항지수 (resistive index) 와박동지수 (pulsatility index) 를통해저항을측정할수있다. 문맥압항진증환자는간내혈관의저항이크므로문맥의혈류속도가낮은경향이있어, 일반적으로정상인은 20 cm/sec 내외이나, 문맥압항진증환자는 15 cm/sec 이하이다 (Fig. 17) [1,2,6-9,13]. 또한, 상장간막동맥과같은내장동맥혈관의저항지수는감소해있고, 혈류량은증가되어있다 [2,5]. 문맥계가아닌신장동맥에서의저항측정은간경변환자의예후나심한정도를반영한다. Child-Pugh C 군에해당하는진행성간경변증환자의신장동맥저항지수와박동지수는정상인이나대상성간경변증환자보다높은데, 간경변증환자가말기간경변증으로진행할수록유효혈장량 (effective circulatory volume) 이부족하여기능적신기능장애를가지므로신장동맥의저항이증가하기때문이다. 따라서신장동맥에서 Doppler 초음파를이용하여저항지수나박동지수를측정하는것이말기간경변증을감별하는데도움이된 Figure 19. Changes in hepatic vein waveform in cirrhosis. 다 (Fig. 18) [3,4,10]. 또한정상인에서간정맥 (hepatic vein) 의정상도플러파형은두개의큰전향적혈류 (antegrade flow) 와심방의수축과관련된한개의후향적혈류 (retrograde flow) 에의한삼위상파형 (triphasic waveform) 이다. 간정맥은간실질에둘려싸여있으며, 얇은벽을가지고있는데, 간실질에질환이있을때는간정맥혈류에이상이생겨정상삼위상도플러파형에변화가일어나, 역류가없어지거나파형의진폭이감소되어이위상파형 (biphasic waveform) 을보이거나, 파형에진폭이없는단위상파형 (monophasic waveform) 을보인다. 기존의연구에의하면간경변증환자의 75% 까지도이러한이상소견을보인다고한다. 따라서간경변증에서문맥압의상승과이러한파형의이상소견은연관가능성이있어정맥류출혈이있었던환자에서는약 92% 에 8
Soon Koo Baik. Differential diagnosis of diffuse liver disease Clinical Ultrasound Figure 20. Liver stiffness measurement by transient elastography. 서비정상적인간정맥파형을보인다. 특히단위상파형을보이는경우는 15 mmhg 이상의심각한문맥압항진증을보일가능성이높다 (Fig. 19) [14,15]. 따라서도플러초음파검사는비침습적으로간경변증과문맥압항진증의진단및평가에도움이된다 [16]. 간경변증과 fibroscan 간섬유화는만성간질환의중요한예후인자로서, 간섬유화의정도를평가하는것이치료결정과추적관찰에필수적이다. 만성간염환자의섬유화의진단에간조직생검이유용하며간경변증의진단은간조직검사를통해확진되지만, 침습적이며검사와관련된합병증과적절한조직의채취여부, 환자의거부감, 비용문제등여러가지어려움이있다. 따라서간조직생검을대체할수있는비침습적인검사들이지난수년간보고되었다. 혈청학적검사를이용하여간섬유화및간경변증을예측하고자많은연구들이보고되었지만실제로임상에서사용하기에고가이고, 복잡한수식을이용하여야하는번거로움이있다. 최근개발된초음파펄스진단장치는비침습적이며신속하게간탄력도를측정하여간섬유화를평가하는새로운진단방법이다. 진동자와초음파변환기로이루어진탐촉자를환자의늑간에수직으로위치시킨후버튼을누르면, 진동으로유발된탄력파동이조직으로전달되고초음파변환기가포착하여탄력파동의속도를측정하게된다. 여러문헌에서초음파펄스진단장치로측정한간탄력도는간조직검사에의한간섬유화의정도와유의하게상관관계를보였으며, 만성간질환의임상질환별로간탄력도의유의한차이를보였다. 초음파펄스진단장치의장점은첫째, 통증이없고신속하며, 검사에따른합병증이없어쉽게검사할수있다. 둘째, 검사자간의검사치의변수가거의없다. 셋째, 간조직생검시에채취하는간조직의 100배정도의큰용적 의간병소를대상으로검사하므로간전체의섬유화의정도를 반영할수있다. 하지만복수환자에서측정이불가능하고비 만환자에서정확도가떨어지는단점이있다. 일반적으로정상 은 5.4 KPa 이하이고, 간섬유화는 5.5-10.9 KPa, 간경변증은 11 Kpa 이상이다 (Fig. 20) [19,20]. 결론 지방간과만성간염그리고간경변증을감별진단하는주요 초음파기준은간실질의에코패턴, 간표면의요철성변화그리 고비장종대유무이다. 이외도플러초음파검사는간경변증을 진단하는데도움이되는방법이다. 최근, 성공적인바이러스성 간염치료덕분에간섬유화의가역적변화가이루어지고있어, 특히, 만성간염상태와초기간경변증사이의정확한감별진 단이임상에서요구되고있다. 만성간염에비교하여, 초기간경 변증을진단하는데가장민감도가높은초음파소견은간표면 의요철성변화 (surface irregularity) 여부이다. 그외최근개발 되어널리사용되고있는파이브로스캔을이용한간섬유화검 사 (liver stiffness) 가감별진단에도움이된다. 중심단어 : 미만성간질환 ; 초음파 ; 감별진단 REFERENCES 1. Baik SK, Suh JI, Kim JW, et al. Is doppler ultrasonography useful in assessing risk of variceal bleeding? Korean J Gastroenterol 2000;36:515-521. 2. Baik SK, Choi YJ, Kwon SK, et al. Splanchnic and extrasplanchnic vascular hemodynamics in liver cirrhosis. Korean J Gastroenterol 2000;35:466-474. 9
Clinical Ultrasound Vol. 1, No. 1, May 2016 3. Baik SK, Kim KH, Jeong YS, et al. Pulsatility index of renal artery in patients with liver cirrhosis. J Korean Soc Med Ultrasound 2000;19:71-76. 4. Seo JI, Baik SK, Kim JW, et al. Renal function indices predicting the prognosis of patients with liver cirrhosis. Korean J Hepatol 2001;7:140-146. 5. Im DW, Baik SK, Suh JI, et al. Hyperdynamic circulatory changes in liver cirrhosis: comparative evaluation by Doppler ultrasonagraphy with normal subjects. J Korean Soc Med Ultrasound 2001;20:273-277. 6. Baik SK, Kim YJ, Park JW, et al. Effect of terlipressin administration on portal pressure in patients with liver cirrhosis. Korean J Gastroenterol 2002;39;198-203. 7. Baik SK, Choi JC, Kim KH, et al. The effects of propranolol on portal pressure in cirrhotic patients with portal hypertension. Korean J Med 2003;64:639-646. 8. 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;18:424-429. 9. Baik SK, Park DH, Kim MY, et al. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol 2003;38:1150-1154. 10. Baik SK, Jee MG, Jeong PH, et al. Relationship of hemodynamic indices and prognosis in patients with liver cirrhosis. Korean J Intern Med 2004;19:165-170. 11. Baik SK. Assessment and current treatment of portal hypertension. Korean J Hepatol 2005;11:211-217. 12. Baik SK. Pharmacological therapy of portal hypertension -fucoused on Korea data-. Korean J Gastroenterol 2005;45:381-386. 13. Baik SK, Jeong PH, Ji SW, et al. Acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis: a randomized comparison. Am J Gastroenterol 2005;100:631-635. 14. 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;240:574-580. 15. 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;27:1103-1110. 16. Baik SK. Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review. Liver Int 2010;30:1403-1413. 17. Moon KM, Kim G, Baik SK, et al. Ultrasonographic scoring system versus liver stiffness measurement in prediction of cirrhosis. Clin Mol Hepatol 2013;19:389-398. 18. Berzigotti A, Abraldes JG, Tandon P, et al. Ultrasonographic evaluation of liver surface and transient elastography in clinically doubtful cirrhosis. J Hepatol 2010;52:846-853. 19. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41:48-54. 20. Castéra L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-350. 21. Nishiura T, Watanabe H, Ito M, et al. Ultrasound evaluation of the fibrosis stage in chronic liver disease by the simultaneous use of low and high frequency probes. Br J Radiol 2005;78:189-197. 10