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간섬유화 연세대학교의과대학내과학교실, 간경변증임상연구센터 한광협, 김승업 Noninvasive diagnosis using transient elastography Kwang-Hyub Han, Seung Up Kim Department of Internal Medicine, Yonsei University College of Medicine, Seoul,

1 간섬유화 연세대학교의과대학내과학교실, 간경변증임상연구센터 한광협, 김승업 Noninvasive diagnosis using transient elastography Kwang-Hyub Han, Seung Up Kim Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Liver Cirrhosis Clinical Research Center, Seoul, Korea Liver fibrosis is the results of chronic injury and a similar feature of all chronic liver diseases. Beyond being a marker of injury, it appears to play a direct role in the pathogenesis of hepatocellular dysfunction and portal hypertension. Furthermore, the prognosis and treatment plans of chronic liver diseases strongly depend on the degree of liver fibrosis. Thus, from a clinical management viewpoint, accurately assessing the extent and progression of fibrosis is important and clinical interests are being raised in quantifying liver fibrosis. Although liver biopsy has been the gold standard for assessment of liver fibrosis, it has some technical limitations and risks. Accordingly, an increasing need for alternative noninvasive method to quantify liver fibrosis has been a major challenge that has stimulated search for new noninvasive methods. Such methods for diagnosing liver fibrosis have progressed significantly over the last few decades notably with the appearance of several serological markers, which have been reported to predict the presence of significant fibrosis or cirrhosis in patients with chronic liver disease with considerable accuracy. However, complicated calculation and influences of extrahepatic conditions make it less accessible to clinicians. Recently, transient elastography using FibroScan is emerging as a new diagnostic method for liver fibrosis. It is totally noninvasive and reproducible and gives an immediate result with low intra- and inter-observer variability. Here, we review the currently available data on transient elastography for assessing liver fibrosis. Key words: Chronic liver disease; Cirrhosis; Liver fibrosis; Liver stiffness measurement; Transient elastography 서론 1990 년대부터지금까지간섬유화의핵심적인역할을담당하는간성상세포 (hepatic stellate cell) 에대한연구가활발하게이루어진결과간섬유화에대한분자생물학적이해의증진으로여러가지항섬유화약물이대두되고있다. 그뿐만아니라최근만성바이러스성간염에대한항바이러스약물역시항섬유화작용을보인다는보고가있어비침습적인간섬유화예측에대한요구가점차증가되고있다. 1 49

2 만성간질환환자에서질병의진행여부의판단은임상적으로혈액검사및복부초음파검사가주로이용되나, 중증섬유화로의진행이나간경변증의진단에민감도및특이도가낮아정확한예측은어렵다. 2,3 고전적으로정확한간섬유화의진단은간생검을통해이루어져왔지만, 침습적방법으로시술과관련한합병증이발생할수있을뿐만아니라, 검체채취오류 (sampling error), 환자의거부감, 검체해석의다양성 (variability) 등이있어간생검역시문제점을보인다. 4 최근에혈액검사를이용하여간섬유화를예측하려는시도가활발히이루어지고있으나아직간생검을대신할만큼의간섬유화예측정확도가 B형간염의경우 C형간염의경우보다낮고충분한연구결과가미흡하며비용문제등으로국내에서임상에서아직적용하지못하고있는실정이다. 5,6 최근간섬유화스캔 (transient elastography; 이하 TE로약함 ; FibroScan ) 이개발되어비침습적으로간탄력도를측정하여간섬유화를예측한다는많은연구결과들이보고되고있다. 따라서간섬유화의혈청표지자와 TE 등비혈청표지자등을이용하여간생검을대체할수있다면간생검의불편함을줄이고외래에서만성간질환환자의간섬유화의진단, 추적관찰및치료와예후평가에유용하게사용될수있을것이다. 1. 간섬유화의정의및기전간섬유화는만성간내염증으로인한세포외기질 (extracellular matrix) 의과다한침착으로정의될수있으며이러한세포외기질의과다한침착으로만성간질환이지속되는경우결국은간내구조의변형과간세포수의감소로간경변으로진행되게된다. 7 간섬유화에관여하는대표적인세포로는간성상세포 (hepatic stellate cell), 쿠퍼세포 (Kupffer cell), 내피세포 (endothelial cell) 등이있다. 간성상세포는세포외기질을생산하는주생산원으로활성화되며교원질을포함한각종세포외기질의생성증가에관여한다. 쿠퍼세포는간내동모양혈관강 (sinusoidal space) 내에존재하며활성화된쿠퍼세포에서생성된물질들은주위간세포, 내피세포, 그리고간성상세포에영향을주게되어간섬유화를촉진시킨다. 내피세포는간내혈류조절에중요한역할을하는것외에도, 염증이나간섬유화등에의해간성상세포의증식에관여하는성장인자와세포외기질의생성에도관여한다. 간섬유화에영향을미치는사이토카인으로는 transforming growth factor-β (TGF-β), platelet derived growth factor (PDGF) 등이있다. TGF-β 는간성상세포의가장강력한섬유화촉진사이토카인이며간성상세포자체가 TGF-β의주생산원이다. PDGF 는간성상세포의가장강력한분열과증식촉진사이토카인이다. 과거오랫동안간섬유화과정은비가역적현상으로인식되었지만최근가역적으로변화될수있다는사실이보고되어역동적변화가가능하며이러한변화를정확히측정하는것이임상적으로매우중요하게되었다. 2. 간섬유화의진단만성간질환은하나의독립적인질환이기보다는만성간염에서부터섬유화를거쳐간경변증으로진행하는연속적인질환이다. 만성간질환환자의질병진행여부의판단은임상적으로매우유용하여지금까지는간조직생검이가장핵심적표준검사로간섬유화의정도에따라서등급을 F0에서 F4로나누고있다. 그러나간생검은침습적방법으로시술과관련한합병증이발생할수있으며충분한조직채취가이루어지지않을때는간실질전체를대표하지못하여진단에오류가올수도있고관찰자에따라서도오차가있을수있어정확도에대한문제점이제기되고있으며반복적으로권하기어려운점이있어이를대신할검사법이절실히필요한실정이었다. 많은임상의사들이간경변증의진단을임상적소견과영상소견을포함한검사소견으로판단하나주관적견해 50

3 한광협 김승업 간섬유화 에따른기준의모호성으로진단의정확도가떨어지며초기간경변증을간과할위험이높고간섬유화의단계를구분하는데에는한계가있다. 현재까지여러연구에서혈청표지자를이용하여간섬유화및간경변증을예측하고자하는시도가이루어졌지만, 8 실제임상에적용하기힘든고가의검사항목이나복잡한수식등을이용해야하는번거로움으로한계가있다. 3. 간섬유화스캔 (Transient elastography; TE, FibroScan R ). 1) 간섬유화스캔의원리간섬유화는간의탄력도에영향을주게되는데 TE의기본적인원리는간의탄력도 (stiffness) 와간섬유화 (fibrosis) 는깊은상관관계를가지고있어간의탄력도측정으로간섬유화를예측할수있다는것이다. 9,10 TE의탐촉자 (probe) 는자체적으로저진동수의탄력파를만들고이렇게만들어진탄력파는늑골사이피부표면을통과하여간으로전파되고변환기 (transducer) 를통하여되돌아온초음파의이동속도를측정한다. 이동속도가빠를수록간이더단단함을시사하며간접적으로간섬유화가상대적으로진행했음을알수있다. 이처럼 TE의가장큰장점은비침습적이며간생검으로얻은조직의약 100 배이상의용적을이용하여간탄력도를측정하여이론적으로전체간실질의약 1/500 을대표하는간단한검사로재현성이높다는점이다. 10 2) 간섬유화스캔결과의해석상유의사항및제한점 TE로측정된간탄력도수치는압력의단위인 kilopascal (kpa) 로표현된다. 성공적으로측정된측정치중에서중앙값 (median) 을대표값으로취한다. 측정되는간탄력도수치의범위는 2.5~75 kpa 이다. 검사자는 100회정도훈련후쉽게시행할수있다. 11 일반적으로간탄력도수치의다음과같은몇가지의조건을만족해야신뢰성이있는것으로본다. (1) 최소한 10번이상의성공적인측정이있어야하고, (2) Interquartile range (IQR, 성공적으로측정된값들중에서최대값과최소값부터각각 25 percentile 의범위에있는값들을뺀중간의 50 percentile 값의범위 ) 을중앙값 (M) 으로나눈값 (IQR/M) 이 0.3 보다작아야하고, (3) 전체측정횟수중에서성공적인측정횟수가적어도 60% 는넘어야한다고권고하고있다. 최근 TE의정확성을높이기위한적절한 IQR/M 값과성공적인측정횟수에대한연구결과가일부있었으나아직그결과들을검증하기위한후속연구는없는실정이다. 11,12 국내에서도 TE를임상에서활용하고있는 5개병원의만성 B형간염환자들을대상으로 IQR/M 의역할에대해서조사를하였으나만성 C형간염환자를대상으로한이전의연구와는다르게만성 B형간염에서의 IQR/M 은큰의미가없는것으로확인되었으며간생검당시에비교적초기간섬유화 (F2 이하의간섬유화 ) 를보인환자에서 alanine aminotransferase (ALT) 의영향으로간탄력도수치가과대평가되는것을확인하였다. 13 간탄력도검사의정확성이떨거지거나불가능한경우는복수가있거나늑골사이간격이좁은경우, 또는비만인경우 (> 28 kg/m 2 ) 를들수있다. 10,14 복수가있는경우는탄력파가간실질에도달하지못하여측정이어렵고늑골사이간격이좁으면탐촉자의위치설정이어렵다. 그외에최근 ALT 의증가가 TE의결과에영향을줄수있다. 급성간손상이있는경우나간염바이러스에의한급성간손상이있는경우 aspartate aminotransferase (AST) 및 ALT 수치에따라서간탄력도수치가영향을받으며간손상에의한간조직괴사를동반한간조직의병리학적인변화가간탄력도수치를변동시킬수있다. 15,16 이외에도폐쇄성황달이있는경우총빌리루빈수치에의해간탄력도가영향을받는것을보고한연구도 51

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5 한광협 김승업 간섬유화 있다 ) 선별검사로서의간섬유화스캔의역할 TE의간섬유화예측력을알아보기전에 TE가정상군에서만성간질환을가지고있는환자들을구별해낼수있는지확인하는것은중요하다. 비록연구의디자인은조금씩다르지만최근두개의아시아연구를비롯하여간탄력도정상치에대한연구가있었다 ( 표 1) 모든연구에서정상치의상한값은일반적으로중대한간섬유화를예측하는기준인 7~8 kpa 보다작은소견을보였고이러한결과는 TE가간탄력도수치의겹침이없이정확하게일반정상인으로부터간질환의고위험군을선별해낼수있다는것을보여주고있다. 4) 간섬유스캔의임상적유용성및향상방안 TE는 France 에서만들어져만성 C형간염에서유용성연구가유럽인을대상으로활발히이루어져간섬유화가 F3이상의진행된환자에서예측도가매우높은유용한검사로최근인정되며알코올성간질환에도유용하다는보고들이있다. 그러나 B형간염에서는 macro-nodular type 의간경변이많아정확도가다소낮으며간수치의변동이많은점도정확도를낮추어 C형간염에서만큼권장되고있지는않으며연구결과도다소미흡한실정이다. 그러나 2005 년도국내에 TE가처음도입되어만성 B형간질환환자를대상으로 TE의예측력을분석한다른검사들에비해서가장검사예측도가높은것으로밝혀졌으며중국을포함한아시아국가에서최근연구가활발히진행되고있다 아시아연구중에서해외저널이나주요한국제학회에간생검결과를바탕으로 TE 의간섬유화예측력을보고한. 대부분의연구들은 TE가 B형간염에서도유용한것으로발표되었다 ( 표 2, 표 3). 유럽의만성 C형간염을대상으로한연구에서는 F2 이상의간섬유화와 F4의간경변을예측하는데 area under the receiver operating characteristic curve (AUROC) 가각각 0.79~0.83와 0.97~0.95 였다. 27,40 그러나표에서확인할수있듯이만성 B형간염환자들대상으로한아시아연구에서는그값이유럽보다다소낮았다. (F2 이상에서 0.70~0.88, F4에서 0.80~0.93). 아직정확한합의된 cutoff 수치기준은아직없지만 TE는만성간질환의원인과관계없이간경변을비교적정확하게예측하는것으로알려져있다. 논문으로발표된만성 B형간염환자에대한아시아연구만을골라서간경변증에대한 cutoff 수치를보면 9.0~10.1 kpa 로계산되었다. 그리고이값은만성 C형에서계산된 cutoff 수치보다는일관성있게낮은값을보인다. 이렇게아시아의만성 B형간염에서 TE 의간섬유화예측력과 cutoff 수치가유럽의만성 C형간염에서보다다소떨어지는이유는만성 B형간염은대결절형간섬유화를만드는경향이있기때문에전체적인간섬유화조직이적어 cutoff 수치가작다고설명되고있다. 41 아시아의만성 B형간염환자에서 TE의예측력이만성 C형간염에서보다는다소떨어지긴하지만전반적인예측력은만족할만할수준이며특히 F3이상의진행된간질환을예측하는데는더욱유용성이높다. 하지만 TE는간생검을대신하는확진을위한검사라기보다는불필요한간생검을줄이는데유용한 screening 검사로유용성이높을것으로기대한다. 아울러항바이러스약물을투여받게되는환자에서간섬유화진행정도를추적할수있다는점도유용하리라생각되며이에대한추가연구가필요할것이다. TE의임상적유용성을높이기위하여혈청표지자검사들을조합하여검사의예측도를높이고자하는여러연구가있었으며 C형간염의경우에는간조직검사를시행하기전에정해진알고리듬에따라단계적으로비침습적혈청표지자들을분석함으로써 TE의간섬유화예측율을향상시키고, 간생검의대상자를더욱줄여보고자 53

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8 두가지검사가일치하지않는경우에만간생검을권유하는제안도있었다. 40 만성 B형간염에서도 TE와다른간섬유화예측모델의조합시도가검사의예민도를높일수있다는연구들이보고되었다. 33,42,43 만성 B형간질환이만성간질환의대부분을차지하고있는국내에서도 TE의유용성에대한연구가활발하여져약 20여개의연구결과가국내에보고되었을뿐만아니라해외저널에도 10여개의연구가발표되었다. 본교실에서는최근 TE의임상적유용성을확인한결과첫째, 정상인에서간질환의고위험군을가려낼수있으며, 둘째만성간질환환자에서치료를필요로하는간섬유화가진행된환자군을구별하는데유용하며, 셋째간세포암종의발생위험이높은군을예측하는데유용하며, 마지막으로문맥압항진증이동반된진행된간경변증을발견하는데도움을줄수있는것으로보인다. 결론 간섬유화의진행정도를확인하는것은환자의예후와관리에매우중요하며지속적변화를관찰하는것도매우중요하다. 이를확인하는데간생검이아직은가장중요한표준검사이다. 그러나이를비침습적으로진단할수있는검사법이필요하며 TE 는그러한검사법으로최근가장활발히연구가이루어진검사로우리가그장점과한계를정확히알고사용하면임상적유용성은높은검사로여겨진다. 최근간경변의진행을막는치료법이관심이높아지면서이를측정하려는연구가이루어지고있어앞으로보다정확히간섬유화의정도를예측하는검사가나올것을기대한다. 참고문헌 1. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004;99: Aube C, Oberti F, Korali N, Namour MA, Loisel D, Tanguy JY, et al. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol 1999;30: Needleman L, Kurtz AB, Rifkin MD, Cooper HS, Pasto ME, Goldberg BB. Sonography of diffuse benign liver disease: accuracy of pattern recognition and grading. AJR Am J Roentgenol 1986;146: Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986;2: Wong VS, Hughes V, Trull A, Wight DG, Petrik J, Alexander GJ. Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepat 1998;5: Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001;357: Han KH, Yoon KT. New diagnostic methods for liver fibrosis and cirrhosis. Intervirology 2008;51: Kim BK, Kim SA, Park YN, Cheong JY, Kim HS, Park JY, et al. Noninvasive models to predict liver cirrhosis in patients with chronic hepatitis B. Liver Int 2007;27: Rockey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 2006;43:S Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new non-invasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29: Kettaneh A, Marcellin P, Douvin C, Poupon R, Ziol M, Beaugrand M, et al. Features associated with success rate and performance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: a prospective 56

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<30322E535453BABBB9AE2DC6EDC1FD2E687770> 간섬유화의비침습적진단 : transient elastography (FibroScan ) 연세대학교의과대학내과학교실 김승업 Transient elastography (TE, FibroScan ) is a novel non-invasive method that has been proposed for the assessment of liver fibrosis in