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1 초음파를이용한간탄력도검사 연세대학교의과대학내과학교실 김승업 Although liver biopsy is the best method for assessing liver fibrosis, it is an invasive procedure, with rare, but potentially life-threatening, complications. Thus, attempts to develop non-invasive methods have led to the use of transient elastography (FibroScan R ; EchoSens, Paris, France) and acoustic radiation force impulse (ARFI) elastography (Acuson S2000; Siemens, Mountain View, USA) for assessment of liver fibrosis. Transient elastography is a novel non-invasive method that has been proposed for the assessment of liver fibrosis in patients with chronic liver diseases, by measuring liver stiffness. Transient elastography is a rapid and user-friendly technique that can be easily performed at the bedside or in the outpatient clinic with immediate results and good reproducibility. Combining transient elastography with serum markers increases diagnostic accuracy and as a result, liver biopsy could be avoided for initial assessment in some patients with chronic liver disease. As transient elastography has excellent patient acceptance, it could be useful for monitoring fibrosis progression and regression in the individual case, but more data are awaited for this application. Recently, ARFI elastography, which uses radiation forced impulses to measure liver stiffness while using B-mode ultrasonography, has been introduced. Transient elastography has a fixed region of interest (ROI) at a fixed insertion depth, whereas ARFI enables elastography inside a flexible ROI of cm diameter at variable insertion depths. Therefore, liver stiffness measurement (LSM) in patients with ascites and obesity is feasible. Furthermore, ARFI elastography has the advantage that it enables LSM during a routine ultrasonographic evaluation of the abdomen. Based on the cumulated knowledge, guidelines are being awaited for the use of transient elastography and ARFI elastography in clinical practice. Key words: Fibroscan, Acoustic radiation force impulse image, Chronic liver disease, Liver cirrhosis, Liver fibrosis, Liver stiffness, Transient elastography 서 론 만성간염에서간세포염증및괴사가지속되면간섬유화가발생하고간섬유화가더욱진행되면결국간경변증으로이행한다. 1 임상적으로만성간질환에서간경변증으로진행을막는것이치료의중요한목 11

2 2013 년대한간학회춘계 Single Topic Symposium 표이며, 이는간세포암을비롯한간경변증의합병증으로인한사망을감소시키므로만성간질환의진행과정에서간섬유화를평가하고간경변증을진단하는것은예후및치료방침의결정에중요한역할을한다. 2 지금까지만성간질환의진행은주로혈액검사와초음파검사등으로확인했지만간섬유화가심하지않은경우에는이러한검사들도간섬유화의예측력에있어한계를보이고있다. 간조직생검은간섬유화를직접적으로검사하는것으로최종적진단방법으로서의역할을했지만침습적인검사로시술과관련된합병증이발생할수있는문제점이있었다. 3 이때문에비침습적으로간섬유화를예측하는많은모델들이개발되어왔다. 4-6 대표적으로혈청표지자를이용한것으로간섬유화의과정에서혈청에서증가하는물질들을이용하는직접적인방법이있으며, aspartate aminotransferase, alanine aminotransferase (ALT), 나이, 혈소판수등을이용하는간접적인방법이있으나복잡한수식, 비용적인문제, 그리고간외적인영향에따라서수치가변할수있는점들이문제점으로지적되고있다. 최근 transient elastography (FibroScan R ; EchoSens, Paris, France) 을이용한간탄력도검사가간섬유화를비침습적으로정확히예측할수있다는많은연구결과가보고되고있다. 이뿐만아니라최근에는초음파의원리를이용하여초음파검사중에실시간으로간탄력도를측정하는 acoustic radiation force impulse (ARFI) elastography (Acuson S2000; Siemens, Mountain View, USA) 도개발되어최근연구결과가보고되고있다. 본강좌에서는현재까지보고된연구결과를토대로 transient elastography와 ARFI elastography를이용한간탄력도검사에대한것을다루고자한다. Transient elastography 1. 원리 Transient elastography를이용한간탄력도검사의원리는간의단단함 (stiffness), 간섬유화 (fibrosis), 그리고간의탄력도 (elasticity) 가서로상관관계가있다는것을이용하는것으로간의탄력도측정으로간섬유화를예측할수있다는것이다. 7 Transient elastography의탐촉자는자체적으로저진동수의탄력파를만들고이렇게만들어진탄력파는늑골사이피부표면을통과하여간으로전파되고변환기 (transducer) 를통하여방출하고되돌아온초음파의이동속도를측정한다. 이동속도가빠를수록간이더단단함을시사하며간섬유화가상대적으로진행했음을알수있다. 2. 검사방법환자의오른팔을머리뒤로들어올리고누운상태에서간위치의우측늑간의피부표면에수직으로탐촉자를위치한다. 검사자는화면상간내혈관구조를피하여적절한 ( 약 6 cm 두께이상 ) 병소를향하여탐촉자의버튼을누른다. 측정하는반복적으로최소한 10회이상반복측정하며탄력파의속도가숫자로표기된다. 10회이상측정하여자동적으로계산된중앙값과오차를기록한다. 최근 transient 12

3 김승업 초음파를이용한간탄력도검사 elastography를이용한간탄력도검사는식사여부및호흡에따라서검사결과가영향을받는것으로보고되어이에대한고려가필요하다. 8,9 3. 결과의해석 Transient elastography를이용한간탄력도검사의결과가신뢰성을유지하기위해서는 10번이상의유효검사, interquartile range (IQR) 값을유효검사결과중중앙값으로나눈값 (IQR/M) 이 0.3을넘으면안되며, 측정성공률이 60% 이상되어야하는조건이필요하다. 하지만최근이러한제조사의권고사항을과학적으로증명하는연구가발표되었다 이들연구에서, 높은 IQR/M, 높은체질량지수, 높은 ALT 값, 그리고간조직생검당시의간섬유화정도등이간탄력도검사의신뢰도에영향을주는것으로보고되었다. 하지만간탄력도검사의임상적인해석은반드시전문가의판단을따라야하며환자의상태, 만성간질환의원인, 혈액검사들을비롯한여러가지검사결과들을토대로종합적으로해석되어야한다. 4. 정상수치최근아시아연구 2개를비롯하여정상간탄력도수치에대한연구가보고되었다 (Table 1 14 ). Table 1를보면알수있듯이정상간탄력도수치들의상한치가일반적으로 7-8 kpa 로보고된의미있는간섬유화 (significant fibrosis, F2) 를예측하기위한 cutoff 값보다낮은것을알수있다. 따라서 transient elastography 을이용한간탄력도검사는잠재적인간질환을가지고있는환자들을일반인들부터구별해낼수있다는것을의미한다. Table 1. Normal liver stiffness values of transient elastography Asian study European study Kim 15 Fung 16 Corpechot 17 Roulot 18 Sirli 19 Colombo 20 Colombo 21 Type Full article Full article Letter Full article Full article Abstract Abstract Number of subjects, n Population Liver and Healthy Medical Healthy Blood Blood Liver donors kidney donors volunteers check-up volunteers donors donors Liver stiffness, kpa 4.6 (mean) 4.6 (median) 4.8 (median) 5.5 (mean) 4.8 (mean) 4.9 (mean) 4.4 (median) 95th percentile, kpa BMI, kg/m (mean) 22.5 (median) 25.8 (mean) Effects on TE Age No No No No No No Gender M = F M > F M > F M > F M = F M > F High BMI No No Increased TE values Metabolic syndrome Increased TE values No Increased TE No values Fatty liver Increased TE values Increase TE values 13

4 2013 년대한간학회춘계 Single Topic Symposium 흥미로운것은아시아의정상치는서양의그것보다약간낮은경향을나타낸다는것이다. 아시아연구의낮은체질량지수, 젊은연령및낮은대사성질환의유병률등으로설명이가능할것으로생각된다. 5. 의미있는간섬유화 (significant fibrosis; F2) 의예측만성 C형간염의경우, area under the receiver operating characteristic curve (AUROC) 가 0.79에서 0.83으로보고되었고, 그에따른 cutoff 값은연구마다조금씩상이하다 (Table 2). 25 만성 C형간염에서간내지방은간탄력도검사결과에영향을주지않는것으로보이나추가연구가필요한실정이다. 최근만성 B형간염에서도연구가활발하다. Marcellin 등이처음으로만성 B형간염에있어서간탄력도검사의유용성을보고하였고이연구에서의미있는간섬유화를예측하기위한 cutoff 값은 7.2 kpa 이었다. 28 그이후아시아권에서도만성 B형간염에서간탄력도검사에대한후속연구들이발표되고있다 (Table 3). 14 만성 B형간염에서도지방간은영향을미치지않는것으로보고되었다. 32 Table 2. Diagnostic performance of transient elastography in patients with chronic hepatitis C Fibrosis score (Metavir) Significant fibrosis Severe fibrosis Cirrhosis Ziol 26 Castera 27 Ziol 26 Castera 27 Ziol 26 Castera 27 Number of patients 163/25, /183, 74 76/152, 30 83/183, 45 49/251, 19 46/183, 25 Cutoff (kpa) Sensitivity Specificity Negative predictive value Positive predictive value Positive likelihood ratio Negative likelihood ratio AUROC Table 3. Histologic distribution and the performance of TE for the diagnosis of liver fibrosis in patients with chronic hepatitis B METAVIR and other scoring system F2 METAVIR and other scoring system F4 AUROC Cutoff (kpa) Se Sp PPV NPV LR (+) LR (-) AUROC Kim Chan Kim Marcellin AUROC, area under the receiver operating characteristic curve; Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; LR, likelihood ratio. 만성 C형및 B형간염이외의원인에의한만성간질환의경우에도간탄력도검사의유용성이보고되 Cutoff (kpa) Se Sp PPV NPV LR (+) LR (-) 14

5 김승업 초음파를이용한간탄력도검사 Table 4. Diagnostic performance of transient elastography for the diagnosis of significant fibrosis according to liver disease etiology Author de Ledinghen 33 Yoneda 24 Vergara 34 Corpechot 35 Kelleher 23 Number of patients Prevalence of significant fibrosis (F 2) Etiology HCV-HIV NAFLD HCV-HIV PBC&PSC NASH Proposed cutoffs (kpa) Sensitivity Specificity Negative predictive value Positive predictive value Positive likelihood ratio Negative likelihood ratio AUROC Table 5. Diagnostic performance of transient elastography for the diagnosis of cirrhosis according to liver disease etiology Authors de Ledinghen 33 Fraquelli 36 Coco Ganne- Gomez- Vergara Carrie 38 Dominguez 39 Yoneda 24 Corpechot 35 Foucher 40 Number of patients Prevalence of cirrhosis Etiology HCV-HIV All HCV&HBV HCV-HIV All All NAFLD PBC&PSC All Proposed cutoff Sensitivity Specificity Negative predictive value Positive predictive value Positive likelihood ratio Negative likelihood ratio AUROC 었다. HIV-HCV 동시감염, 담즙정체성질환및지방간염등이그예이며, 의미있는간섬유화를예측하기위한 AUROC는 이고그에따르는 cutoff 값은 kpa로보고되었다 (Table 4) 간경변증 (cirrhosis) 의예측 Transient elastography을이용한간탄력도검사는간경변증의조기발견에유용한검사이다. 초기에발표된연구에서만성 C형간염에서는간경변증진단에있어서 AUROC는 이었고 cutoff 값은 15

6 2013 년대한간학회춘계 Single Topic Symposium Table 6. Performance of transient elastography in diagnosing liver cirrhosis in studies with chronic hepatitis B Parameter Marcellin 28 Chan 30 Kim 29 Metavir score F0, % F1, % F2, % F3, % F4, % Performance Cutoff, kpa Sensitivity, % Specificity, % Positive predictive value, % Negative predictive value, % kpa ( 양성예측도 77%, 음성예측도 95%) 과 14.6 kpa ( 양성예측도 78%, 음성예측도 97%) 이었다. 26,27 이연구에서간탄력도검사가단독으로도다른비침습적인간섬유화예측모델보다우월한것을확인하였고약 90% 의환자에서간조직생검을피할수있는결과가나왔다. 27 간탄력도검사를이용한간경변증의예측에필요한 cutoff 값은연구에따라다르며 11.8 kpa에서 17.3 kpa까지다양하다 (Table 5). 25 만성 B형간염만을대상으로했을경우는 9.0 kpa에서 11 kpa로 cutoff가보고되었다 (Table 6). 41 만성 B형간염에서간경변증의 cutoff 값은만성 C형간염에서보다낮은경향을나타내는데이는만성 B형간염은대결절성간경변증의가장흔한원인으로간내섬유화의총량이작은경향을보이는것을원인으로설명하고있다. 25 최근만성 B형간염환자 2,772명을대상으로한 meta 분석결과가발표되었다. 이연구에서간경변증을진단하기위한 cutoff는 11.7 kpa로보고되었으며, sensitivity는 84.6%, specificity는 81.5% 로나왔다 한계점 Transient elastography를이용한간탄력도검사의정확성이떨거지거나불가능한경우가있으며, 일반적으로복수가있거나늑골사이간격이좁은경우를들수있다. 7 복수가있는경우는탄력파가간실질에도달하지못하여측정이어렵고늑골사이간격이좁으면탐촉자의위치설정이어렵기때문이다. 이뿐만아니라 Foucher 등은높은체질량지수 (> 28 kg/m 2 ) 를보이는환자에서간탄력도검사의실패가능성이 4.5% 로체질량지수가낮은환자에서보다비교적높다는결과를보고하였다. 43 Kettaneh 등은체질량지수뿐만아니라나이에따라서도간탄력도검사의성공률이달라질수있다고보고하였다. 44 흥미로운점은이러한간탄력도검사의실패가능성은서양의연구 ( %) 에서보다아시아연구에서상대적으로낮은것 ( %) 을알수있으며이는아시아인의상대적으로낮은체질량지수로설명될수있다

7 김승업 초음파를이용한간탄력도검사 이외에도간염바이러스에의한만성간질환환자에서 ALT 값이상승하였을때간탄력도검사가영향을받을수있다고보고되었다. 37,45,46 따라서최근에는높은 ALT 값을보이는경우연구대상에서제외하는경향을보이고있으며 ALT 값의상승정도에따라서 cutoff 값을다르게적용하려는시도도되고있다. 47,48 그외에도총빌리루빈수치에의해간탄력도가영향을받는것을보고한연구도있다 Transient elastography를이용한추적관찰연구최근에는 transient elastography를이용하여측정된간탄력도값을이용해서향후간질환과관련된 event ( 간세포암발생, 비대상성간부전, 간질환과관련된사망등 ) 를예측하려는연구가활발하다. 50 이러한연구들은기존의단면적인연구에서사용하는 AUROC의단순비교의문제점을인지하고조금더견고한 end-point를사용하여 transient elastography의임상적유용성을증명하려는연구들이다. 이뿐만아니라항바이러스치료전후의간탄력도값을추적관찰함으로써항바이러스약물의효과를확인하려는연구도활발하다. 51 또한간세포암으로절제를하는경우수술전에간탄력도값을측정함으로써수술이후의재발을포함한장단기예후를평가하려고하는노력도발표되고있다 ARFI elastography 1. 원리 ARFI elastography의탐촉자는 2.67 MHz의진동수를가지고있는 longitudinal wave인 acoustic push pulse (262 μs) 를만들어내며, 이 push pulse에의해서직각의방향으로간실질로전파되는 shear-waves가이어서발생하게되고초음파시스템에서 ROI 안에있는 shear wave의속도를측정하게된다. 55 이러한 shear wave의속도는조직의탄성에따라달라지게되는것을이용한기계라볼수있다. 이와같은원리로간탄력도는속도의단위인 m/s로표현된다. 2. 검사방법검사의방법은일반적으로복부초음파를시행하는방법과비슷하다. 우측늑간에서측정을하며, 심장의박동에의한영향을피하기위해서일반적으로 segment 8 부위에서측정을한다. 탄력도가측정되는곳은간의 capsule 아래 1cm 하방에서측정하는것이보통이고측정할때에는숨쉬는것을잠깐정지하고측정하는것이일반적이다. 56,57 최근연구에서 ARFI elastography도 transient elastography처럼재현성이우수한것으로보고되었다. 58 하지만, BMI가높은경우, 여자인경우, 복수가있는경우, 간경변이없는경우는재현성이일부떨어지는것도밝혀졌다. 58 일반적으로 ARFI elastography는복수가있는경우에도 ROI를움직여서간탄력도를측정할수있는장점이있다고알려져있지만, 59 앞서연구처럼복수가있는경우재현성이떨어질가능성이있을뿐만아니라복수가있는환자에서복수가있을경우와복수 17

8 2013 년대한간학회춘계 Single Topic Symposium 가없어진후에각각측정된간탄력도값의재현성에대한연구가아직부족하여복수가있는환자에서 ARFI elastography를이용하여측정된간탄력도를신뢰하는것은아직문제점이있다. 최근식사여부가 ARFI elastography에영향을준다는보고가있어서 transient elastography와비슷하게금식을유지하고측정하는것이권유된다 결과의해석 ARFI elastography는 transient elastography처럼널리사용되는유효기준이정립이되지않았지만보통 10번이상을측정하여중앙값또는평균값을대표값으로사용하고있다. 최근 ARFI elastography에영향을주는인자에대한연구가발표되었다. 61 이연구에서 female gender와 IQR/M>0.3이조직검사결과와 ARFI elastography에의해서측정된간탄력도값의불일치에영향을주는독립인자로채택되었다. 또다른연구에서는 transient elastography처럼 ALT에영향을받을수있다는연구도있으며, 62,63 고빌리루빈혈증이있을때에 transient elastography를영향을받는반면, ARFI elastography는영향을받지않는다는보고도있어서, 64 ARFI elastography에영향을줄수있는인자를밝히기위한추가적인연구가필요하고이를통해간섬유화예측에정확성을더욱높이는것이필요할것이다. 4. 정상수치 최근정상 ARFI elastography 에의한간탄력도수치에대한연구가보고되었다 (Table 7). Table 7 를보면 알수있듯이정상간탄력도의상한치는 m/s 의범위를보인다. 흥미로운것은 transient elastography Table 7. Normal ARFI velocity Asian studies European studies Son et al. 65 Kim et al 66 Takahashi Friedrich-Rust Sporea D'Onofrio Horster et al 67 et al 56 et al 68 et al 69 et al 70 Sample size Population Liver and kidney donors Medical check-up Healthy volunteers Healthy volunteers Healthy volunteers Healthy volunteers Healthy volunteers ARFI velocity (m/sec) Mean±SD 1.07± ± ± ± ± ± Range ARFI measurement method Location Right lobe Right lobe Right lobe Right lobe Both lobes Both lobes Both lobes Measurement times 10 At least Effects on ARFI elastography Age No Gender No BMI No - No

9 김승업 초음파를이용한간탄력도검사 의정상치와비슷한양상으로아시아의정상치가서양의그것보다약간낮은경향을나타낸다는것이다. 이역시아시아연구의낮은체질량지수, 젊은연령및낮은대사성질환의유병률등으로설명이가능할것으로생각된다. 5. 의미있는간섬유화 (significant fibrosis; F2) 와간경변증 (cirrhosis; F4) 의예측 ARFI elastography를이용한간섬유화의예측력에대한연구는아직까지연구결과가충분하지않다. 대부분의연구에서등록된환자의수가크지않고만성간질환의원인이섞여있는경우가많아향후더많은후속연구들이필요한실정이다. 지금까지의연구에서 F2 이상의의미있는간섬유화를예측하는 AUROC는 으로보고되었고 cutoff는 m/s로계산되었다 (Table 8). 간경변증의경우에는 AUROC가 정도로보고되고있고, 이에따른 cutoff는 m/s도계산되었다 (Table 9). 최근 ARFI elastography에대한간섬유화예측능력을 meta 분석한결과가발표되었다. 75 8개의연구에서 518명을대상으로하였고, 간경변을예측하는 AUROC는 0.93으로계산되었다. ARFI elastography와 transient elastography를동시에측정받은환자들을대상으로분석했을때에 ARFI elastography의 F2 이상, F3 이상의간섬유화예측능력은 transient elastography의그것과대등한결과를보였지만, 간경변증인 F4의예측력은 transient elastography보다낮은결과를보였다. 6. 한계점 ARFI elastography의임상적용에가장큰문제점은아직 transient elastography처럼많은연구가되어있지않다는점이다. 지금까지몇개의연구에서재현성이좋은것을보고하고있으나가장우선이되어야할것이재현성을확보하는연구가충분히이루어져야할것이다. ROI를움직여서원하는간부위의 Table 8. Diagnostic performance of ARFI elastography for the diagnosis of significant fibrosis Author Yoon 62 Colombo 72 Ebinunma 73 Non-transplanted Transplanted Right Left lobe lobe Crespo 71 Friedrich-Rust 74 Number of patients Etiology Mixed Mixed Mixed Mixed Mixed NAFLD Proposed cutoffs (kpa) Sensitivity Specificity Negative predictive value Positive predictive value Positive likelihood ratio Negative likelihood ratio Diagnostic odds ratio AUROC

10 2013 년대한간학회춘계 Single Topic Symposium Table 9. Diagnostic performance of ARFI elastography for the diagnosis of liver cirrhosis Crespo 71 Friedrich-Rust 74 Author Yoon 62 Colombo 72 Ebinunma 73 Non-transplanted Transplanted Right lobe Left lobe Number of patients Etiology Mixed Mixed Mixed Mixed Mixed NAFLD Proposed cutoffs (kpa) Sensitivity Specificity Negative predictive value Positive predictive value Positive likelihood ratio Negative likelihood ratio Diagnostic odds ratio AUROC 탄력도는측정할수있다는것, 복수가있을경우에도측정이가능하다는점, 일부연구에서비장의탄력도도측정하여간섬유화예측에사용한다는것등이 transient elastography보다우월한장점으로보이지만, 아직까지이것들을증명할수있는연구는불충분하다. 이러한문제점들을극복한다면, 만성간질환환자들의간세포암발생에대한감시방법의하나로복부초음파를시행할경우그자리에서바로간탄력도를측정할수있다는큰장점을가지고있는 ARFI elastography가임상적용에한발다가갈수있을것이라생각된다. 7. ARFI elastography를이용한추적관찰연구 Transient elastography를이용한추적관찰연구가최근많이발표되고있지만, 아직까지 ARFI elastography 에대해서는연구는거의없다. 최근항바이러스치료전에 ARFI elastography를이용해측정한간탄력도가향후항바이러스치료후에만성 C형간염의지속바이러스반응이있는환자군과그렇지않은군에서의미있는차이를보였다는연구결과가발표되었지만, 76 이연구도치료전에한번측정된간탄력도값만사용하는연구여서향후에는치료기간중또는관찰기간중에연속적으로 ARFI elastography를이용하여측정된간탄력도의변화가임상적으로어떤의미를가지는지에관한연구가지속되어야할것이다. 결 론 지금까지간조직생검이간섬유화진단의최종적진단방법으로생각되어왔으나최근, 간조직생검이불완전하다는것이인정되고있다. 따라서 transient elastography나 ARFI elastography를이용한비침습적 20

11 김승업 초음파를이용한간탄력도검사 간탄력도검사에대한관심이증가하고있다. 이상적으로간탄력도검사는정상인들중에서잠재적인간질환을가지고있는환자들을구별해낼수있고, 만성간질환을가진환자중에서는의미있는간섬유화의존재를예측함으로써항바이러스약물의시작여부의판단에도움을줄수있고, 간경변증을예측함으로써간세포암발생의위험을인지하고필요한감시장치를가동하는데도움을줄수있다. 또한간경변이있는환자들에게서는문맥압항진증이진행하는것을확인하거나정맥류의존재여부또는이를내시경적으로진단하기위한적절한시점을잡는목적에도도움을줄수있다. 최근에는이러한단면적인예측뿐만아니라특정시점에서측정된간탄력도를이용하거나일정기간을가지고연속적으로측정된간탄력도값을이용하여미래에발생할간질환과연관되어있는임상적 event를예측하고자하는연구가특히 transient elastography에대해서활발하다. 하지만, ARFI elastography의경우에는아직까지단면적인연구결과도충분하지않은상태로더많은연구결과의축적이필요하며, 동시에추적관찰연구도진행이되어야임상적용에가능성을타진해볼수있을것이다. 향후 transient elastography 와 ARFI elastography를이용한간탄력도검사의임상적역할이기대된다. 참고문헌 1. Poynard T, Mathurin P, Lai CL, Guyader D, Poupon R, Tainturier MH, et al.; PANFIBROSIS Group. A comparison of fibrosis progression in chronic liver diseases. J Hepatol 2003;38: Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101(Suppl. 1):S Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biospy: a multicentre retrospective study on 68,276 biopsies. J Hepatol 1986;2: Forns X, Ampurdanes S, Llovet JM, Aponte J, Quinto L, Martinez-Bauer E, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002;36: Adams LA, Bulsara M, Rossi E, DeBoer B, Speers D, George J, et al. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem 2005;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: 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: Mederacke I, Wursthorn K, Kirschner J, Rifai K, Manns MP, Wedemeyer H, et al. Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection. Liver Int 2009;29: Yun MH, Seo YS, Kang HS, Lee KG, Kim JH, An H, et al. The effect of the respiratory cycle on liver stiffness values as measured by transient elastography. J Viral Hepat 2011;18: Lucidarme D, Foucher J, Le Bail B, Vergniol J, Castera L, Duburque C, et al. Factors of accuracy of transient elastography (fibroscan) for the diagnosis of liver fibrosis in chronic hepatitis C. Hepatology 2009;49: Kim SU, Seo YS, Cheong JY, Kim MY, Kim JK, Um SH, et al Factors that affect the diagnostic accuracy of liver fibrosis measurement by Fibroscan in patients with chronic hepatitis B. Aliment Pharmacol Ther 2010;32: Myers RP, Crotty P, Pomier-Layrargues G, Ma M, Urbanski SJ, Elkashab M. Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy. Liver Int 2010;30:

12 2013 년대한간학회춘계 Single Topic Symposium 13. Calvaruso V, Cammà C, Di Marco V, Maimone S, Bronte F, Enea M, et al. Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy. J Viral Hepat 2010;17: Kim SU, Han KH, Ahn SH. Transient elastography in chronic hepatitis B: an Asian perspective. World J Gastroenterol 2010;16: Kim SU, Choi GH, Han WK, Kim BK, Park JY, Kim DY, et al. What are 'true normal' liver stiffness values using FibroScan?: a prospective study in healthy living liver and kidney donors in South Korea. Liver Int 2009;30: Fung J, Lai CL, Chan SC, But D, Seto WK, Cheng C, et al. Correlation of liver stiffness and histological features in healthy persons and in patients with occult gepatitis B, chronic active hepatitis B, or hepatitis B cirrhosis. Am J Gastroenterol 2010;105: Corpechot C, El Naggar A, Poupon R. Gender and liver: is the liver stiffness weaker in weaker sex? Hepatology 2006;44: Roulot D, Czernichow S, Le Clésiau H, Costes JL, Vergnaud AC, Beaugrand M. Liver stiffness values in apparently healthy subjects: influence of gender and metabolic syndrome. J Hepatol 2008;48: Sirli R, Sporea I, Tudora A, Deleanu A, Popescu A. Transient elastographic evaluation of subjects without known hepatic pathology: does age change the liver stiffness? J Gastrointestin Liver Dis 2009;18: Colombo S, Belloli L, Buonocore M, Jamoletti C, Zaccanelli M, Badia E, et al. Liver Stiffness values in the normal population: a studying voluntary blood donors. Hepatology 2008;48 Suppl:A Colombo S, Belloli L, Buonocore M, Jamoletti C, Zaccanelli E, Del Poggio P. True normal liver stiffness measurement (LSM) and its determinants. Hepatology 2009;50 Suppl:741A. 22. Oliveri F, Coco B, Ciccorossi P, Colombatto P, Romagnoli V, Cherubini B, et al. Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases. World J Gastroenterol 2008;14: Kelleher T, MacFarlane C, de Ledinghen V, Beaugrand M, Foucher J, Castera L. Risk factors and hepatic elastography (FibroScan) in the prediction of hepatic fibrosis in nonalcoholic steatohepatitis. Gastroenterology 2006;130:A Yoneda M, Fujita K, Inamori M, Tamano M, Hiriishi H. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut 2007;56: Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48: Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41: Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128: Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Lédinghen V, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int 2009;29: Kim DY, Kim SU, Ahn SH, Park JY, Lee JM, Park YN, et al. Usefulness of FibroScan for detection of early compensated liver cirrhosis in chronic hepatitis B. Dig Dis Sci 2009;54: Chan HL, Wong GL, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. J Viral Hepat 2009;16: Kim SU, Ahn SH, Park JY, Kang W, Kim do Y, Park YN, et al. Liver stiffness measurement in combination with noninvasive markers for the improved diagnosis of B-viral liver cirrhosis. J Clin Gastroenterol 2009;43:

13 김승업 초음파를이용한간탄력도검사 32. Kim SU, Kim do Y, Ahn SH, Kim HM, Lee JM, Chon CY, et al. The impact of steatosis on liver stiffness measurement in patients with chronic hepatitis B. Hepatogastroenterology 2010;57: de Ledinghen V, Douvin C, Kettaneh A, Ziol M, Roulot D, Marcellin P, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2006;41: Vergara S, Macias J, Rivero A, Gutierrez-Valencia A, Gonzalez-Serrano M, Merino D, et al. The use of transient elastometry for assessing liver fibrosis in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2007;45: Corpechot C, El Naggar A, Poujol-Robert A, Ziol M, Wendum D, Chazouilleres O, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology 2006;43: Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007;56: Coco B, Oliveri F, Maina AM, Ciccorossi P, Sacco R, Colombatto P, et al. Transient elastography. A new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007;14: Ganne-Carrie N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology 2006;44: Gomez-Dominguez E, Mendoza J, Rubio S, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. Transient elastography: a valid alternative to biopsy in patients with chronic liver disease. Aliment Pharmacol Ther 2006;24: Foucher J, Chanteloup E, Vergniol J, Castera L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55: Chan HL, Wong GL, Wong VW. A review of the natural history of chronic hepatitis B in the era of transient elastography. Antivir Ther 2009;14: Chon YE, Choi EH, Song KJ, Park JY, Kim DY, Han KH, et al. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: A meta-analysis. PLoS One 2012; 7: e Foucher J, Castera L, Bernard PH, Adhoute X, Laharie D, Bertet J, et al. Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations. Eur J Gastroenterol Hepatol 2006;18: 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 study of 935 patients. J Hepatol 2007;46: Sagir A, Erhardt A, Schmitt M, Häussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2008;47: Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008;47: Jung KS, Kim SU, Ahn SH, Park YN, Kim DY, Park JY, et al. Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan). Hepatology 2011;53: Kim SU, Kim do Y, Park JY, Lee JH, Ahn SH, Kim JK, et al. How can we enhance the performance of liver stiffness measurement using FibroScan in diagnosing liver cirrhosis in patients with chronic hepatitis B? J Clin Gastroenterol 2010;44: Kim SU, Han KH, Park JY, Ahn SH, Chung MJ, Chon CY, et al. Liver stiffness measurement using FibroScan is influenced by serum total bilirubin in acute hepatitis. Liver Int 2009;29:

14 2013 년대한간학회춘계 Single Topic Symposium 50. Kim SU, Lee JH, Kim DY, Ahn SH, Jung KS, Choi EH, et al. Prediction of liver-related events using FibroScan R in chronic hepatitis B patients showing advanced liver fibrosis. PLoS One 2012;7(5):e Kim SU, Park JY, Kim DY, Ahn SH, Choi EH, SeoK JY, et al. Non-invasive assessment of changes in liver fibrosis via liver stiffness measurement in patients with chronic hepatitis B: Impact of antiviral treatment on fibrosis regression. Hepatology Int 2010; 4: Jung KS, Kim SU, Choi GH, Park JY, Park YN, Kim DY, et al. Prediction of recurrence after curative resection of hepatocellular carcinoma using liver stiffness measurement (FibroScan R ). Ann Surg Oncol 2012;19: Kim SU, Ahn SH, Park JY, Kim DY, Chon CY, Choi JS, et al. Prediction of postoperative hepatic insufficiency by liver stiffness measurement before curative resection of hepatocellular carcinoma: A pilot study. Hepatology International 2008; 2: Kim SU, Kim YC, Choi JS, Kim KS, Choi GH, Choi JS, et al. Can preoperative diffusion-weighted MRI predict postoperative hepatic insufficiency after curative resection of HBV-related hepatocellular carcinoma?: a pilot study. MRI 2010; 28: Nightingale K, Soo MS, Nightingale R, Trahey G. Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility. Ultrasound Med Biol 2002;28: Friedrich-Rust M, Wunder K, Kriener S, Sotoudeh F, Richter S, Bojunga J, et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009;252: Goertz RS, Zopf Y, Jugl V, Heide R, Janson C, Strobel D, et al. Measurement of Liver elasticity with acoustic radiation force impulse (ARFI) technology: an alternative noninvasive method for staging liver fibrosis in viral hepatitis. Ultraschall Med 2010;31: Bota S, Sporea I, Sirli R, Popescu A, Danila M, Costachescu D. Intra- and interoperator reproducibility of acoustic radiation force impulse (ARFI) elastography-preliminary results. Ultrasound Med Biol. 2012;38: Lim SM Lim, Kim SU. Acoustic radiation force impulse elastography is useful to exclude nonliver-related ascites. Eur J Gastroenterol Hepatol 2011;23: Popescu A, Bota S, Sporea I, Sirli R, Danila M, Racean S, et al. The influence of food intake on liver stiffness values assessed by acoustic radiation force impulse elastography-preliminary results. Ultrasound Med Biol Feb 13. doi:pii: S (12)00703-X /j.ultrasmedbio [Epub ahead of print] 61. Bota S, Sporea I, Sirli R, Popescu A, Jurchis A. Factors which influence the accuracy of acoustic radiation force impulse (ARFI) elastography for the diagnosis of liver fibrosis in patients with chronic hepatitis C. Ultrasound Med Biol 2013;39: KT Yoon, SM Lim, JY Park, DY Kim, SH Ahn, KH Han, et al.. Liver stiffness measurement using acoustic radiation force impulse (ARFI) elastography and effect of necroinflammation. Dig Liver Dis 2012;57: Chen SH, Li YF, Lai HC, Kao JT, Peng CY, Chuang PH, et al. Effects of patient factors on noninvasive liver stiffness measurement using acoustic radiation force impulse elastography in patients with chronic hepatitis C. BMC Gastroenterol Aug 10;12:105. doi: / X Lim SM, Chung MJ, Han KH, Kim SU. Acoustic radiation force impulse elastography: a better option for patients with extrahepatic cholestasis. Eur J Gastroenterol Hepatol 2012;24: Son CY, Kim SU, Han WK, Choi GH, Park H, Yang SC, et al. Normal liver elasticity values using acoustic radiation force impulse imaging: a prospective study in healthy living and kidney donors. J Gastroenterol Hepatol 2012;27: Kim JE, Lee JY, Kim YJ, Yoon JH, Kim SH, Lee JM, et al. Acoustic radiation force impulse elastography for 24

15 김승업 초음파를이용한간탄력도검사 chronic liver disease: comparison with ultrasound-based scores of experienced radiologists, Child-Pugh scores and liver function tests. Ultrasound Med Biol 2010;36: Takahashi H, Ono N, Eguchi Y, Eguchi T, Kitajima Y, Kawaguchi Y, et al. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study. Liver international 2010;30: Sporea I, Sirli RL, Deleanu A, Popescy A, Focsa M, Danila M, et al. Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients with chronic hepatopathies. Ultraschall Med 2011; 32 Suppl1:S D'Onofrio M, Gallotti A, Mucelli RP. Tissue quantification with acoustic radiation force impulse imaging: Measurement repeatability and normal values in the healthy liver. AJR Am J Roentgenol 2010;195: Horster S, Mandel P, Zachoval R, Clevert DA. Comparing Acoustic Radiation Force Impulse Imaging to transient elastography to assess liver stiffness in healthy volunteers with and without valsalva manoeuvre. Clin Hemorheol Microcirc 2010;46: Crespo G, Fernández-Varo G, Mariño Z, Casals G, Miquel R, Martínez SM, et al. ARFI, FibroScan, ELF, and their combinations in the assessment of liver fibrosis: a prospective study. J Hepatol 2012;57: Colombo S, Buonocore M, Del Poggio A, Jamoletti C, Elia S, Mattiello M, et al. Head-to-head comparison of transient elastography (TE), real-time tissue elastography (RTE), and acoustic radiation force impulse (ARFI) imaging in the diagnosis of liver fibrosis. J Gastroenterol 2012;47: Ebinuma H, Saito H, Komuta M, Ojiro K, Wakabayashi K, Usui S, et al. Evaluation of liver fibrosis by transient elastography using acoustic radiation force impulse: comparison with Fibroscan R. J Gastroenterol 2011;46: Friedrich-Rust M, Romen D, Vermehren J, Kriener S, Sadet D, Herrmann E, et al. Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD. Eur J Radiol 2012;81:e Friedrich-Rust M, Nierhoff J, Lupsor M, Sporea I, Fierbinteanu-Braticevici C, Strobel D, et al. Performance of acoustic radiation force impulse-imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2012;19:e Forestier N, Gaus A, Herrmann E, Sarrazin C, Bojunga J, Poynard T, et al. Acoustic radiation force impulse imaging for evaluation of antiviral treatment response in chronic hepatitis C. J Gastrointestin Liver Dis 2012;21: