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 patients with chronic liver diseases, by measuring liver stiffness. TE 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 TE 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 TE 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. Guidelines are needed for the use of TE in clinical practice. Key words: Fibroscan; Liver cirrhosis; Liver fibrosis, Liver stiffness measurement; Transient elastography 서 론 만성간염에서간세포염증및괴사가지속되면간섬유화가발생하고간섬유화가더욱진행되면결국간경변증으로이행한다. 1 임상적으로만성간질환에서간경변증으로진행을막는것이치료의중요한목표이며, 이는간세포암을비롯한간경변증의합병증으로인한사망을감소시키므로만성간질환의진행과정에서간섬유화를평가하고간경변증을진단하는것은예후및치료방침의결정에중요한역할을한다. 2 지금까지만성간질환의진행은주로혈액검사와초음파검사등으로확인했지만간섬유화가심하지않은경우에는이러한검사들도간섬유화의예측력에있어한계를보이고있다. 간조직생검은간섬유화와간경변증을직접적으로검사하는것으로최종적진단방법으로서의역할을했다. 하지만간조직생검은침습적인검사로시술과관련된합병증이발생할수있다. 3 시술후의통증은비교적흔하며드물지만검사와관련된사망도보고되었다. 이러한문제점들로간조직생검을시행하려는의사나시행받는환자들에게거부감이있으며특히간섬유화의진행및퇴행을확인하기위해반복적인검사가필요할경우에는더욱간조직생검이어렵게된다. 일부진행된간섬유화를가지고있는환자에서는혈소판의저하나응고장애가동반되어있어간조직생검이금기가되는경우도있다. 이 26
김승업간섬유화의비침습적진단 : transient elastography (FibroScan ) 외에도검사자간또는검사자내의간조직생검결과의다양성이문제가되기도한다. 4 간조직생검에서충분한간조직이얻어지지않으면진단이어려운경우도있으며충분한간조직이얻어졌다하더라도간실질의전체를대변하지못할가능성은여전히남아있다. 5 이러한간조직생검의침습적인문제점으로인해비침습적으로간섬유화를예측하는많은모델들이개발되어왔다. 6-8 혈청표지자를이용한것으로간섬유화의과정에서혈청에서증가하는물질들을이용하는직접적인방법이있으며, aspartate aminotransferase, alanine aminotransferase (ALT), 나이, 혈소판수등을이용하는간접적인방법이있으나복잡한수식, 비용적인문제, 그리고간외적인영향에따라서수치가변할수있는점들이여전히문제점으로지적되고있다. 최근 FibroScan 을이용한간탄력도검사가간섬유화를비침습적으로예측할수있다는많은연구결과가보고되고있다. 본강좌에서는현재까지보고된연구결과를토대로 FibroScan 을이용한간탄력도검사의임상적유용성을알아보았다. 원 리 FibroScan 을이용한간탄력도검사의원리는간의단단함 (stiffness) 과간섬유화 (fibrosis) 가연관성을가지고있고간의탄력도 (elasticity) 는간의단단함 (stiffness) 과역시상관관계를가지고있다는것을이용하는것으로결과적으로간의탄력도 (stiffness) 와간섬유화 (fibrosis) 는깊은상관관계를가지고있어간의탄력도측정으로간섬유화를예측할수있다는것이다. 9 간의단단함을측정하기위하여간의조직병리상태에좌우되는탄력도를이용하고압력의단위인 kilopascal (kpa) 을사용하여표현한다. 간탄력도검사의탐촉자는자체적으로저진동수의탄력파를만들고이렇게만들어진탄력파는늑골사이피부표면을통과하여간으로전파되고변환기 (transducer) 를통하여방출하고되돌아온초음파의이동속도를측정한다. 이동속도가빠를수록간이더단단함을시사하며간접적으로간섬유화가상대적으로진행했음을알수있다. FibroScan 을이용한간탄력도검사의장점은통증이없고비침습적이며, 쉽고빠른검사가가능하며, 약 5분만에즉시결과를얻을수있고, 재현성이높으며, 타장기의영향이없이직접간실질의탄력도를측정하고, 간조직생검보다 100배이상많은간실질을대표할수있다는점이다. 검사방법 환자의오른팔을머리뒤로들어올리고누운상태에서간위치의우측늑간의피부표면에수직으로탐촉자를위치한다. 검사자는화면상간내혈관구조를피하여적절한 ( 약 6 cm 두께이상 ) 병소를향하여탐촉자의버튼을누른다. 측정하는간의용적은 3 cm 2 이상이다. 반복적으로최소한 10회이상반복측정하며탄력파의속도가숫자로표기된다. 10회이상측정하여자동적으로계산된중앙값과오차를 27
2011 년대한간학회춘계 Single Topic Symposium 기록한다. 최근 FibroScan 을이용한간탄력도검사는식사여부및호흡에따라서검사결과가영향을받는것으로보고되어검사시이에대한고려가필요하다. 10,11 결과의해석 FibroScan 을이용한간탄력도검사의결과가신뢰성을유지하기위해서는 3가지조건을만족시켜야한다. 즉, 10번이상의유효검사, interquartile range (IQR) 값을유효검사결과중중앙값으로나눈값 (IQR/M) 이 0.3을넘으면안되며, 측정성공률이 60% 이상되어야지간탄력도검사결과를신뢰할수가있다. 하지만이러한조건들은연구결과를토대로한것이아니라 FibroScan 제조사가제시한조건이어서최근이를확인하기위한연구가발표되었다. 12-15 결과를살펴보면, 높은 IQR/M, 높은체질량지수, 높은 ALT 값, 그리고간조직생검당시의간섬유화정도등이간탄력도검사의신뢰도에영향을주는것으로보고되었다. 하지만간탄력도검사의임상적인해석은반드시전문가의판단을따라야하며환자의상태, 만성간질환의원인, 혈액검사들을비롯한여러가지검사결과들을토대로종합적으로해석되어야한다. 한계점및재현성 간탄력도검사의정확성이떨거지거나불가능한경우는일반적으로복수가있거나늑골사이간격이좁은경우를들수있다. 9 복수가있는경우는탄력파가간실질에도달하지못하여측정이어렵고늑골사이간격이좁으면탐촉자의위치설정이어렵기때문이다. 이러한한계점이외에도최근간탄력도검사에영향을미칠수있는요인에대한많은연구가있었다. Foucher 등은높은체질량지수 (> 28 kg/m 2 ) 를보이는환자에서간탄력도검사의실패가능성이 4.5% 로체질량지수가낮은환자에서보다비교적높다는결과를보고하였다. 16 Kettaneh 등은체질량지수뿐만아니라나이에따라서도간탄력도검사의성공률이달라질수있다고보고하였다. 17 흥미로운점은이러한간탄력도검사의실패가능성은서양의연구 (4.3-7.0%) 에서보다아시아연구에서상대적으로낮을것 (1.1-3.5%) 을알수있으며이는아시아인의상대적으로낮은체질량지수로설명될수있다 (Table 1) 18. 이외에도간염바이러스에의한만성간질환환자에서 ALT 값이상승하였을때간탄력도검사가영향을받을수있다고보고되었다. 26-28 따라서최근에는높은 ALT 값을보이는경우연구대상에서제외하는경향을보이고있으며 ALT 값의상승정도에따라서 cutoff 값을다르게적용하려는시도도되고있다. 29,30 그외에도총빌리루빈수치에의해간탄력도가영향을받는것을보고한연구도있다. 31 간탄력도검사가임상에서널리사용되려면재현성은중요한필요조건이다. Sandrin 등이처음으로 28
김승업간섬유화의비침습적진단 : transient elastography (FibroScan ) Table 1. Failure rate of transient elastography measurement Asian study European study Kim 19 Chan 20 Masuzaki 21 Wong 22 Ziol 23 Marcellin 24 Maimone 25 Etiology HBV HBV HCV HBV HCV HBV HBV Total patients, n 74 1,136 876 487 327 202 230 Excluded patients, n 5 30 10 34 76 29 10 Excluded patients due 1 30 10 17 23 14 10 to TE failure, n TE failure rate, % 1.4 2.6 1.1 3.5 7.0 6.9 4.3 Enrolled patients, n 69 1,106 866 453 251 173 220 Age, years 38.9 (mean) 47 (mean) 66.2 (mean) 37 (median) 47.5 (mean) 40.1 (mean) 45.2 (mean) Male, n (%) 35 (50.7) - 398 (46.0) 270 (60.0) 155 (61.8) 115 (66.5) 99 (45.0) BMI, kg/m 2 22.6 (mean) - 22.5 (mean) 22.4 (median) 23.9 (mean) 24.5 (mean) - Failure criteria Success rate < 60% < 60% < 60% < 60% < 60% < 50% < 60% The number of VMs < 10 VMs < 10 VMs < 8 VMs < 10 VMs < 10 VMs < 7 VMs < 10 VMs VM: valid measurement 간탄력도검사의높은재현성을보고하였다 (intra-and inter-operator standardized coefficient of variation: 각각 3.2% and 3.3%). 9 그이후에대규모연구가추가로발표되어간탄력도검사의높은재현성이증명되었다. 32 정상간탄력도수치 FibroScan 을이용한간탄력도검사가만성간질환이있는환자에게간섬유화를예측하는유용성을언급하기전에간탄력도검사가만성간질환이있는환자들과정상인을구별할수있는지확인하는것은중요하다. 이러한것이해결이되지않는다면만성간질환이있는환자들에서간섬유화를예측한다는의미는축소되기때문이다. 하지만최근까지대부분의연구는만성간질환이있는환자들을대상으로진행이되어왔다. 최근정상인을대상으로간탄력도검사를시행하여잠재적인만성간질환을가지고있는환자들을구별해내는것에관심을가지게되면서정상간탄력도수치에대한관심역시증가하였다. 이를반영하듯, 연구의디자인은다르지만최근아시아연구 2개를비롯하여정상간탄력도수치에대한연구가보고되었다 (Table 2). 18 표 2를보면알수있듯이정상간탄력도수치들의상한치가일반적으로 7-8 kpa 39-41 로보고된의미있는간섬유화 (significant fibrosis, F2) 를예측하기위한 cutoff 값보다낮은것을알수있다. 따라서 FibroScan 을이용한간탄력도검사는잠재적인간질환을가지고있는환자들을일반인들부터구별해낼수있다는것을의미한다. 흥미로운것은아시아의정상치는서양의그것보다약간낮은경향을나타낸다는것이다. 조직검사 29
2011 년대한간학회춘계 Single Topic Symposium Table 2. Normal liver stiffness values of transient elastography Asian study European study Kim 19 Fung 33 Corpechot 34 Roulot 35 Sirli 36 Colombo 37 Colombo 38 Type Full article Full article Letter Full article Full article Abstract Abstract Number of subjects, n 69 28 71 429 144 327 746 Population Liver and kidney donors Liver donors Healthy volunteers Medical check-up Healthy volunteers Blood donors Blood 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 4.7 - - 8.6-7.8 6.7 BMI, kg/m 2 22.6 (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 values No - - - Fatty liver - - - - - Increased TE values Increase TE values Table 3. Diagnostic performance of transient elastography in patients with chronic hepatitis C Fibrosis score (Metavir) Significant fibrosis Severe fibrosis Cirrhosis Ziol 23 Castera 43 Ziol 23 Castera 43 Ziol 23 Castera 43 Number of patients (%) 163/25, 65 136/183, 74 76/152, 30 83/183, 45 49/251, 19 46/183, 25 Cutoff (kpa) 8.8 7.1 9.6 9.5 14.6 12.5 Sensitivity (%) 56 67 86 73 86 87 Specificity (%) 91 89 85 91 96 91 Negative predictive value (%) 56 48 93 81 97 95 Positive predictive value (%) 88 95 71 87 78 77 Positive likelihood ratio 6.63 6.09 5.76 8.11 23.05 9.66 Negative likelihood ratio 0.48 0.37 0.16 0.29 0.14 0.14 AUROC 0.79 0.83 0.91 0.9 0.97 0.95 결과가없어서직접비교할수없지만아시아연구의낮은체질량지수, 젊은연령, 및낮은대사성질환의유병률등으로설명이가능할것으로생각되며, 생체이식공여자를대상으로한아시아의연구와는다르게서양연구에서는간탄력도검사수치에영향을줄수있는높은 ALT 값과지방간등을가진연구대상을충분히제외하지않았던것으로도설명이가능하다. 간탄력도검사를이용한의미있는간섬유화 (significant fibrosis) 의예측 만성 C 형간염의경우, area under the receiver operating characteristic curve (AUROC) 가 0.79 에서 0.83 으로 30
김승업간섬유화의비침습적진단 : transient elastography (FibroScan ) 31
2011 년대한간학회춘계 Single Topic Symposium 보고되었고, 그에따른 cutoff 값은연구마다조금씩상이하다 (Table 3). 42 만성 C형간염에서간내지방은간탄력도검사결과에영향을주지않는것으로보이나추가연구가필요한실정이다. 9 최근만성 B형간염에서도연구가활발하다. Marcellin 등이처음으로만성 B형간염에있어서간탄력도검사의유용성을보고하였고이연구에서의미있는간섬유화를예측하기위한 cutoff 값은 7.2 kpa 이었다. 24 그이후아시아권에서도만성 B형간염에서간탄력도검사에대한후속연구들이발표되고있다 (Table 4, 5). 44-46 만성 B형간염에서도지방간은영향을미치지않는것으로보고되었다. 47 만성 B형간염의경우에는항바이러스약물의시작및어떤항바이러스약물을사용할지판단하기위해서는조금더정확한간섬유화의예측이필요하다. 따라서만성 B형간염에서더많은연구결과가요구된다. 만성 C형및 B형간염이외의원인에의한만성간질환의경우에도간탄력도검사의유용성이보고되었다. HIV-HCV 동시감염, 담즙정체성질환, 및지방간염등이그예이며, 의미있는간섬유화를예측하기위한 AUROC는 0.72-0.92이고그에따르는 cutoff 값은 4.5-8.7 kpa로보고되었다 (Table 6). 42 최근메타분석에서간탄력도검사의의미있는간섬유화예측력은높은것으로보고되었다 [ 민감도 70% (95% 신뢰구간, 67-73%), 특이도 84% (95% 신뢰구간, 80-88%), 양성예측도 4.2 (95% 신뢰구간, 2.4-7.2), 음성예측도 0.31 (95% 신뢰구간, 0.23-0.43)]. 51 간탄력도검사를이용한의미있는간경변증 (cirrhosis) 의예측 FibroScan 을이용한간탄력도검사는간경변증의조기발견에유용한검사이다. 초기에발표된연구에서만성 C형간염에서는간경변증진단에있어서 AUROC는 0.95-0.97이었고 cutoff 값은 12.5 kpa ( 양성예측도 77%, 음성예측도 95%) 과 14.6 kpa ( 양성예측도 78%, 음성예측도 97%) 이었다. 23,43 이연구에서 Table 6. Diagnostic performance of transient elastography for the diagnosis of significant fibrosis according to liver disease etiology Author de Ledinghen48 Yoneda41 Vergara49 Corpechot50 Kelleher40 Number of patients 72 67 169 95 129 Prevalence of significant fibrosis (F 2) (%) 61 49 62 60 50.4 Etiology HCV-HIV NAFLD HCV-HIV PBC&PSC NASH Proposed cutoffs (kpa) 4.5 6.6 7.2 7.3 8.7 Sensitivity (%) 93.2 82.7 88 84 81 Specificity (%) 17.9 81.3 66 87 78 Negative predictive value (%) 61 59.1 75 79 Positive predictive value (%) 65 93.5 88 91 Positive likelihood ratio 1.35 4.42 2.59 6.46 3.68 Negative likelihood ratio 0.38 0.21 0.18 0.18 0.24 AUROC 0.72 0.87 0.83 0.92 0.86 32
김승업간섬유화의비침습적진단 : transient elastography (FibroScan ) Table 7. Diagnostic performance of transient elastography for the diagnosis of cirrhosis according to liver disease etiology Authors de Fraquelli 32 Coco 26 Vergara 49 Ganne- Gomez- Yoneda 41 Corpechot 50 Foucher 55 Ledinghen 48 Carrie 53 Dominguez 54 Number of patients 72 200 228 169 775 97 67 95 354 Prevalence of 23.6 12 20.2 38.5 15.5 17 7.5 16 13.3 cirrhosis (%) Etiology HCV-HIV All HCV & HBV HCV-HIV All All NAFLD PBC&PSC All Proposed cutoff 11.8 11.9 14 14.6 14.6 16 17 17.3 17.6 Sensitivity (%) 100 91 78 93 79 89 100 93 77 Specificity (%) 82.7 89 98 88 95 96 98 95 97 Negative predictive value (%) 82 98 82 94 96 98 96 99 92 Positive predictive value (%) Positive likelihood ratio Negative likelihood ratio 100 53 98 86 74 80 64 78 91 13.7 8.27 39 7.75 15.8 22.25 50 18.6 25.66 0 0.1 0.22 0.08 0.11 0.11 0 0.07 0.23 AUROC 0.97 0.9 0.96 0.95 0.95 0.94 0.99 0.96 0.96 간탄력도검사가단독으로도다른비침습적인간섬유화예측모델보다우월한것을확인하였고약 90% 의환자에서간조직생검을피할수있는결과가나왔다. 43 최근메타분석에따르면만성간질환의원인에관계없이간경변증의진단에높은예측력을보인다고발표되었다 [ 민감도 87% (95% 신뢰구간, 84-90%), 특이도 91% (95% 신뢰구간, 89-92%), 양성예측도 11.7 (95% 신뢰구간, 7.9-17.1), 음성예측도 0.14 (95% 신뢰구간, 0.10-0.20). 51 간탄력도검사를이용한간경변증의예측에필요한 cutoff 값은연구에따라다르며 11.8 kpa에서 17.3 kpa까지다양하다 (Table 7). 42 만성 B형간염만을대상으로했을경우는 9.0 kpa에서 11 kpa로 cutoff가보고되었다 (Table 8). 52 이처럼연구마다 cutoff가다른이유는각연구의간경변증의분포가달라서이다. 56 만성 B형간염에서간경변증의 cutoff 값은만성 C형간염에서보다낮은경향을나타내는데이는만성 B형간염은대결절정간경변증의가장흔한원인으로간내섬유화의총량이작은경향을보이는것을원인으로설명하고있다. 42 결 론 지금까지간조직생검이간섬유화진단의최종적진단방법로생각되어왔으나최근, 간조직생검이약점을인정하고있으며그에따라서 FibroScan 을이용한간탄력도검사에대한관심이증가하고있다. 33
2011 년대한간학회춘계 Single Topic Symposium Table 8. Validation of liver stiffness measurement against liver histology in studies with chronic hepatitis B Parameter Marcellin 24 Chan 45 Kim 44 Feature Patients, n 115 161 91 Ethnicity French Chinese Korean Age, years 40.1 (±12.8) 45 (±11) 40 (±13) Body mass index, kg/m 2 25.5 (±4.0) 24 (±4) 23.8 (±4.6) HBeAg positive, % Not reported 43 59 Metavir score 54 (30-85) 93 (±78) 46 (±24) F0, % 9.2 6 0 F1, % 40.5 17 9.9 F2, % 25.4 29 36.3 F3, % 16.8 40 11 F4, % 8.1 25 42.9 LSM F0, kpa 5.1 (2.5-8.5) 5.9 (3.1-8.9) F1, kpa 6.0 (2.7-35.3) 5.9 (2.5-10.2) F2, kpa 7.0 (2.8-17.6) 7.0 (3.9-19.6) 9.1 (±5.4) F3, kpa 12.8 (5.9-45.1) 8.8 (4.8-34.3) F4, kpa 23.7 (6.4-59.3) 14.2 (8.0-36.9) 14.0 (±7.5) Performance Fibrosis stage F4 Cutoff, kpa 11 9 10.3 Sensitivity, % 93 98 59 Specificity, % 87 75 78 Positive predictive value, % 38 57 68 Negative predictive value, % 99 98 72 이상적으로간탄력도검사는정상인들중에서잠재적인간질환을가지고있는환자들을구별해낼수있고만성간질환을가진환자중에서는의미있는간섬유화의존재를예측함으로써항바이러스약물의시작여부의판단에도움을줄수있고, 간경변증환자중에서는문맥압항진증이동반된환자들이나간세포암발생의위험을예측하는데도움을줄수있다. 현재까지는만성 C형간염에대한연구가주를이루었고유럽에서는간탄력도검사가 FibroTest 등과함께처음으로간섬유화를진단하는방법으로사용되고있다. 그에비하여상대적으로만성 B형간염에대한연구는미약했다. 하지만최근아시아를중심으로만성 B형간염에있어서간탄력도검사의역할이서서히규명되고있어서향후에만성 C형뿐만아니라 B형간염에서도 FibroScan 을이용한간탄력도검사의역할이기대된다. 34
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