untitled

Transcription

1 대한내과학회지 : 제 72 권제 5 호 2007 만성 B형간염환자에서간탄력도측정에의한간섬유화의비침습적평가 연세대학교의과대학내과학교실 1, 병리학교실 2, 의학통계학과 3, 소화기병연구소 4, 간경변증임상연구센터 김화숙 1 김자경 1 박영년 2, 4 명성민 3, 4 방미선 윤기태 1 이근호 1 백용한 1, 4 이관식 1, 4 안상훈 1, 4 전재윤 1, 4 문영명 1, 4 한광협 1, 4 =Abstract= Non-invasive assessment of liver fibrosis by measuring the liver stiffness and biochemical markers in chronic hepatitis B patients Hwa Sook Kim, M.D. 1, Ja Kyung Kim, M.D. 1, Young Nyun Park, M.D. 2, 4, Sung-Min Myung, M.D. 3, 4, Mi-Sun Pang, Ki Tae Youn, M.D. 1, Keun-Ho Lee, M.D. 1, Yong Han Paik, M.D. 1, 4, Kwan Sik Lee, M.D. 1, 4, Sang Hoon Ahn, M.D. 1, 4, Chae Yoon Chon, M.D. 1, 4, Young Myoung Moon, M.D. 1, 4 and Kwang-Hyub Han, M.D. 1, 4 Departments of Internal Medicine, Pathology 2 and Biostatics 3, Institute of Gastroenterology 4, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea Background : Transient elastography (FibroScan R ) is a rapid and non-invasive method to measure liver stiffness and this allow the assessment of liver fibrosis. The aim of this study was to assess the diagnostic accuracy of measuring the liver stiffness in addition to measuring the other biochemical markers such as the aspartate transaminase to platelet ratio index [APRI] and the AST/ALT ratio. Methods : We enrolled 228 HBsAg positive patients whose liver stiffness was measured by FibroScan R between March 2005 and September Liver biopsy examinations were performed in 34 patients. The fibrosis (F) was staged on a 0-4 scale according to the Ludwig classification. Results : According to the clinical diagnosis, the median values of liver stiffness were 7.0±2.7 kpa for inactive carriers (n=29), 8.3±5.3 kpa for chronic hepatitis patients (n=106), 15.9±8.3 kpa for compensated cirrhosis patients (n=63), 31.8±20.3 kpa for decompensated cirrhosis patients (n=26), and 45.1±34.5 kpa for HCC patients (n=4). The degree of liver stiffness was significantly different between the different disease groups (p). Liver stiffness was well correlated with the fibrosis stages (r=0.726; p< 0.001). The AUROC of FibroScan R, the APRI and the AST/ALT ratio values were of the same order; 0.72, 0.61 and 0.58, respectively, for F 2; 0.92, 0.73, and 0.56, respectively, for F 3; and 0.97, 0.79, and 0.55, respectively, for F=4. FibroScan R offered the best diagnostic performance both for significant fibrosis (F 2) and severe fibrosis-cirrhosis (F3-F4). Conclusions : FibroScan R is a reliable, rapid non-invasive method to diagnose the severity of chronic liver disease and to predict fibrosis in patients with chronic hepatitis B, in addition to using the APRI and AST/ALT ratio.(korean J Med 72: , 2007) Key Words : Hepatitis B, Liver fibrosis, Non-invasive, Diagnosis, Liver stiffness Received : Accepted : Correspondence to : Kwang-Hyub Han, M.D., Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul , Korea gihankhys@yumc.yonsei.ac.kr *This study was supported by a greant of the Korea health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (No.A050021)

2 -The Korean Journal of Medicine : Vol. 72, No. 5, 서론간섬유화는만성간질환환자에서예후를결정하는가장중요한인자이다. 간섬유화의극단인간경변증은간암의독립적위험인자이며, 우리나라에서는만성 B형간염이가장중요한원인 (62.5~73%) 을차지한다 1). 임상적으로만성 B형간염에서간경변증으로의진행을막는것이치료의중요한목표이며, 이는간경변증의합병증과간암으로인한사망을낮출수있으므로 2) 질환의진행경과에서간섬유화의정도를평가하고간경변증을진단하는것은중요하다. 간조직생검은간섬유화의가장정확한진단방법이지만침습적이어서통증, 출혈같은합병증의위험이있다. 간조직생검에서채취된조직의양은간용적의약 5만분의 1정도의적은조직으로전체간실질의섬유화를반영할수없으며, 간섬유화의비균등분포로인하여채취오류 (sampling error) 를초래할수있어섬유화의정도를실제보다낮거나높게평가할가능성이있다. 또한환자의불편감과조직검사를받기힘든상태로인하여반복적으로시행하기엔어려움이있다 3). 이런점에서최근에비침습적으로간섬유화의정도를평가하는진단방법으로혈액을이용한생화학적간섬유화표지자및영상학적진단방법에대한많은연구들이보고되어왔다 4). 세포외기질의변화를측정하는간섬유화의특이적직접표지자들 (Laminin, Procollagen III N-peptide, Hyaluronan, Tissue inhibitors of metalloproteinase, Collagen type IV) 과 Fibrotest R 등은만성 C형간염환자에서심한간섬유화및간경변증의진단에유용성을보였지만실제로임상에서사용하기에는고가이고수식이복잡하다는단점이있다 4-7). 복부초음파검사는검사자간의주관적판단에따른차이가있을수있어, 실제로간경변증의진단과간섬유화의진행을평가하는데에는한계가있다 8, 9). 최근개발된 Transient elastography (Fibroscan R, Echosens, Paris, France) 는비침습적이며신속하게간의탄력도를측정함으로써간섬유화의정도를간단하게평가할수있는진단방법이다 10). 진동자에서발생된저진폭, 저주파수의진동이진동자위에올려진초음파변환기를거쳐탄력파의형태로간조직에전달되고, 초음파변환기는탄력파를포착하여속도를측정하게되는데, 이속도가간탄력도와직접적으로관련이있다. 즉간조 직이단단할수록탄력파의속도가빠르게되는것이다. 최근유럽의만성 C형간염환자들을대상으로간섬유스캔 (Fibroscan R ) 의진단적유용성에관한논문들에서간섬유스캔이간단하고유용한진단방법으로보고되고있다 10-12). 본연구에서는국내최초로만성 B형간염환자에서간섬유스캔을사용하여측정한간탄력도에관한연구로, 간탄력도가간섬유화정도및간경변의진단에유용한지를알아보고자하였다. 또한, 임상질환별각군간의간탄력도의값을비교분석하였으며, 간탄력도와임상에서쉽게측정할수있는간섬유화표지자들 (the aspartate transaminase to platelet ratio index [APRI], AST/ALT ratio) 과의유용성을비교분석하였다. 대상및방법 1. 환자 6개월이상 HBsAg 양성인만성간질환으로 2005년 3월부터 9월까지연세대학교세브란스병원소화기내과에내원한 228명을대상으로하였다. 질환별로는비활동성보유자, 만성간염, 대상성간경변증그리고비대상성간경변증으로구분하였으며, 대상성간경변증은조직학적으로진단된경우, 복강경검사나수술소견상간표면의대결절성변화가뚜렷하게있는경우, 상부위장관내시경검사상식도나위정맥류가관찰된경우, 복부초음파검사상간위축과비장종대등간경변증의소견을보이는경우중한가지소견이라도만족하면진단하였다. 간경변증으로진행된환자에서복부초음파검사상복수가있는경우, 혈청빌리루빈 3.0 mg/dl 이상, 혈청알부민 3.0 g/dl 이하, 프로트롬빈시간이대조군의 40% 이하의기준들중어느한가지소견이라도만족하거나, Child-Pugh 점수가 7점이상인경우비대상성간경변증으로진단하였다 13-16). 심한비만자 (BMI >40) 및다른원인에의한만성간질환은대상에서제외하였다. 2. 간섬유스캔에의한간탄력도의측정간탄력도의측정은새롭게개발된의료기기인 Fibroscan R (Echosens, Paris, France) 을사용하였으며, 간조직검사를시행한경우는조직검사일전후로 1년이내에간탄력도를측정하였다. 방법은환자를앙와위로눕힌후오른팔은머리위로최대한신전시키고탐촉자를환자의

3 -Hwa Sook Kim, et al : Non-invasive assessment of liver fibrosis - 간우엽위치의늑간위피부와수직으로댄다 ( 그림 1). 간섬유스캔의화면에초음파의 TM mode (time-motion) 와 A-mode (amplitude mode) 의이미지를보면서폐또는늑골을피하고, 간우엽의최소한약 6 cm 두께이내에큰혈관구조물이없는병소로탐촉자의방향을정하여탐촉자의진동기버튼을누르면피부아래 25~45 mm 깊이의간실질의탄력도를측정할수있게된다 ( 그림 2A). 10회의측정을반복한후중앙값으로탄력도가나타나며단위는 kpa (kilopascal) 이다. Figure 1. Liver elasticity measurement by FibroScan R. The elasticity was derived from the velocity of the low frequency elastic wave in a ROI located from 2.5 to 4.5cm below the skin surface. 3. 간섬유스캔의원리 One-dimensional transient elastography를기본원리로 shear elasticity probe 를사용하여간조직으로전달 A B C D Figure 2. (A) Ultrasonic signal envelop is displayed in the A mode display and also as a function of time with a grayscale in the TM mode display. The operator, assisted by a TM and A mode image, located a liver portion that was at least 6 cm thick and free of large vascular structures. (B) The Fibroscan is composed of a probe, the dedicated electronic system and the control unit. The probe acts as a generator of shear waves and as an ultrasound transducer. (C) Propagation of low frequency excitation (acquisition sequence); radiofrequency lines are acquired at a repetition frequency of 4000 HZ during the propagation of the low-frequency elastic wave. (D) The strain rate image displays the strain rates induced in the liver by the propagation of the elastic wave as a function of time and depth. The elastic wave velocity Vs, is the slope of the wave pattern

4 - 대한내과학회지 : 제 72 권제 5 호통권제 561 호 Table 1. Characteristics of the study patients All n=228 Biopsy n=34 F3,F4 n=18 Gender (M:F) Age (years) BMI (kg/m 2 ) AST (IU/L) ALT (IU/L) Total bilirubin (mg/dl) Platelet (10 3 /mm 3 ) Prothrombin time (%) Albumin (g/l) 177: ± ± ± ± ± ± ± ±0.5 31:3 39.4± ± ± ± ± ± ± ±0.5 17:1 48.3± ± ± ± ± ± ± ±0.6 Diagnosis Fibrous stage * Inactive Carrier Chronic hepatitis LC compensated LC decompensated HCC 29 (12.7%) 106 (46.5%) 63 (27.6%) 26 (11.4%) 4 (1.8%) F0 F1 F2 F3 F4 NOTE. Results are means±sd or n(%) BMI, body mass index; AST, aspartate aminotransferase ALT, alanine aminotransferase; LC, liver cirrhosis; HCC, hepatocelluar carcinoma * Ludwig fibrous stage 0 4 (11.8%) 12 (35.3%) 2 (5.9%) 16 (47.1%) 되는탄력파의속도 (shear velocity) 를측정함으로써간탄력도를측정한다. 간섬유스캔은탐촉자 (probe), 전자시스템 (dedicated electronic system), 중앙조절장치 (control unit) 로구성이되며, 탐촉자는진동기 (vibrator) 와그위에올려진초음파변환기 (ultrasonic transducer) 로이루어져있다 ( 그림 2B). 순간적인진동이저주파수 (50Hz) 의탄력파 (shear wave) 를발생시키고, 피부를거쳐간조직에전달되는동안초음파변환기에서 4000Hz, 256개의 radiofrequency line들을반복적으로형성한다 (pulse-echo ultrasound acquisition) ( 그림 2C). 이러한초음파신호를사용하여간조직내에전달되는탄력파의속도를측정하고피부아래약 25~45 mm 깊이의병소에서탄력파의속도로부터간탄력도를계산할수있다 (E = 3pV 2 s, p=mass density). 그림 2D는초음파펄스진단장치의화면상에탄력파의속도를간실질의절단면깊이와시간의경사로표시한그림이며경사가급할수록간탄력도는높다. 4. 간조직생검간탄력도를측정한지 1년이내에시행한환자를대상 으로초음파유도하에경피적으로얻어진간조직은 Hematoxylin-eosin과 Masson's trichrome 염색을한후두명의병리학자가판독하였다. 간조직생검을시행한환자 (32명) 의조직학적인간섬유화의정도는 Ludwig 분류에따라 0~4단계즉, 0단계 (no fibrosis), 1단계 (portal fibrosis), 2단계 (periportal fibrosis), 3단계 (septal fibrosis) 그리고 4단계 (cirrhosis) 로구분하였다. 5. 혈액, 생화학적검사및혈청간섬유화표지자의측정혈소판수, 알부민, AST, ALT, 총빌리루빈및프로트롬빈시간등간기능을나타내는검사를시행하였으며, AST/ALT 비및 APRI를다음과같은공식으로계산하였다. APRI: [AST (x upper limit of normal) x 100/platelet count (10 9 /L) ] 통계통계적분석은 SPSS 11.0 (SPSS, Version 11; Chicago, IL, USA) 을사용하였다. 각결과의값은평균및표준편

5 - 김화숙외 12 인 : 만성 B 형간염환자에서간섬유화의비침습적평가 - Table 2. Liver stiffness according to the clinical diagnosis Disease group Stiffness (kpa) p value Inactive carrier Chronic hepatitis LC compensated LC decompensated HCC 7.04± ± ± ± ± NOTE. Results are means±sd LC, liver cirrhosis; HCC, hepatocelluar carcinoma Figure 3. Liver stiffness values for the clinical diagnosis. The top and bottom of the boxes are the 25 th and 75 th percentiles, respectively. The length of the box represents the interquartile ranges (IQR) within which 50% of the values are located. The lines through the middle of each box represent the median. The error bars show the minimum and maximum values. Figure 4. Liver stiffness values for each fibrosis stage. The top and bottom of the boxes are the 25 th and 75 th percentiles, respectively. The length of the box represents the interquartile ranges (IQR) within which 50% of the values are located. The lines through the middle of each box represent the median. The error bars show the minimum and maximum values. 차로표시하였으며, 각군의비교는분산분석법 (ANOVA) 혹은 t-test를사용하였다. 각변수들간의상관관계의분석에는 Spearman 상관계수및회귀분석을사용하여검증하였으며, 각통계의유의수준 p 값은 0.05 미만으로정의하였다. 간탄력도및생화학적표지자들의진단적유용성을검증하기위하여 ROC (receiver operating characterastic) 곡선을이용하였다. 결과 1. 환자의임상적특성총 228명의환자가연구에등록되었다. 대상환자군 228명의평균연령은 45.9세였으며남녀비는 177명 :51명이었다. 임상진단별로비활동성보유자 29명 (12.7%), 만 성간염 106명 (46.5%), 대상성간경변증 63명 (27.6%), 비대상성간경변증 26명 (11.4%) 그리고간세포암 4명 (1.8%) 이었다. 조직검사를시행한환자들의평균연령은 39.4세였고간섬유화정도 1단계 (portal fibrosis) 는 4명 (11.8%), 2단계 (periportal fibrosis) 는 12명 (35.3%), 3단계 (septal fibrosis) 는 2명 (5.9%) 그리고 4단계 (cirrhosis) 는 16명 (47.1%) 이었다 ( 표 1). 2. 임상질환군별간탄력도의분포간탄력도는비활동성보유자 7.0±2.7 kpa, 만성간염 8.3±5.3 kpa, 대상성간경변증 15.9±8.3 kpa, 비대상성간경변증 31.8±20 kpa 그리고간세포암 45.1±34.5 kpa 이었으며, 각군간에통계학적으로유의한차이를보였다 (p) ( 표 2, 그림 3)

6 -The Korean Journal of Medicine : Vol. 72, No. 5, Table 3. Correlations between liver stiffness and the biochemical parameters AST ALT Total bilirubin Platelet Prothrombin time Albumin Correlation coefficient * p value * Spearman's correlation coefficient AST, aspartate aminotransferase; ALT, alanine aminotransferase Table 4. Liver stiffness in the patients with complications of cirrhosis Varix History of ascites History of variceal bleeding Splenomegaly Child-Pugh class A B C Stiffness (kpa) Yes/None Yes None p value / ± ± / ± ± / ± ± / ± ± ± ± ± 섬유화정도별간탄력도의분포 ( 그림 4) 간조직검사상의섬유화정도에따른간탄력도의평균값은 1단계는 7.95±1.9 kpa, 2단계는 8.2±3.8 kpa, 3 단계는 10.2±5.6 kpa, 4단계는 29.5±22.9 kpa이었다. 간탄력도는섬유화의정도에따라통계학적으로유의한양의상관관계를보였으며 (r=0.726, p)( 그림 4), 섬유화 1, 2단계와 3, 4단계를두군으로묶어간탄력도를비교하였을때 1, 2단계 (16명) 에서 8.1±3.4 kpa, 3, 4단계 (18명) 에서 27.3±22.54 kpa로두군간에통계학적으로유의한차이를보였다 (p). 4. 혈액및생화학적인자들과간탄력도의관계간기능을나타내는혈액학적인자들중 AST, 총빌리루빈의상관계수는각각 (p) 와 (p< 0.001) 로유의한상관관계를보였다. 혈소판, 프로트롬빈시간, 알부민의상관계수는각각 (p), (p), (p) 로유의한상관관계를보였 고, 이중알부민의감소가간탄력도와가장강한상관관계를보였다 ( 표 3). 5. 간경변증의중증도를나타내는인자들과간탄력도의관계문맥압항진으로인한합병증들중에서복수의과거력과비장종대의유무에따라환자군을나누었을때간탄력도의평균값이두군사이에서통계학적으로유의한차이를보였으며 (p=0.002, p=0.015), Child-Pugh 분류에따라나누었을때 A, B, C 군간에통계학적으로유의한차이를보였다 (p). 하지만식도정맥류유무나정맥류출혈의과거력에따른환자군과비교에서는간탄력도의유의한차이가없었다 ( 표 4). 6. 간탄력도와조직학적간섬유화정도의관계 (ROC 곡선 ) 그림 5는간섬유화및간경변증에대한간탄력도의진단적정확도를나타내는 ROC 곡선이다. 간섬유화 2단

7 -Hwa Sook Kim, et al : Non-invasive assessment of liver fibrosis - Table 5. AUROC and the 95% CI for Liver Stiffness, and the APRI and the AST/ALT Ratio, according to the Fibrosis stages F 2 F 3 F=4 Stiffness APRI AST/ALT 0.72 ( ) 0.61 ( ) 0.79 ( ) 0.92 ( ) 0.73 ( ) 0.56 ( ) 0.97 ( ) 0.79 ( ) 0.55 ( ) APRI, aspartate transaminase to platelet ratio index AST, aspartate aminotransferase; ALT, alanine aminotransferase Table 6. Correlation of liver fibrosis and the liver stiffness, the APRI and the AST/ALT ratio Correlation coefficient * Sitffness APRI AST/ALT * Spearman's correlation coefficient APRI, aspartate transaminase to platelet ratio index AST, aspartate aminotransferase; ALT, alanine aminotransferase p value Figure 5. ROC curves for Fibroscan R, the APRI and the AST/ALT ratio for different fibrosis thresholds: (A) F0-F1 vs. F2-F4 (F 2), (B) F0-F2 vs. F3-F4 (F 3), (C) F0-F3 vs. F4 (F=4). 계이상 (F 2;F0-F1 vs. F2-F4), 간섬유화 3단계이상 (F 3;F0-F2 vs. F3-F4), 간섬유화 4단계, 즉간경변증 (F=4;F0-F3 vs. F4) 을구분하기위한간탄력도의 area under the curve (AUC) 값은각각 0.72 (95% CI, 0.58~ 0.86), 0.92 (95% CI, 0.86~0,99), 0.97 (95% CI, 0.93~ 1.0) 로 3단계이상의간섬유화및간경변증에서높은진단정확도를보였다 ( 표 5). 7. 간탄력도와혈청간섬유화표지자들의비교간섬유화의정도와간탄력도, AST/ALT 비및 APRI 와의상관관계를각각비교하였을때간탄력도가가장높은양의상관관계를보였다 ( 표 6). 간탄력도, AST/ ALT 비및 APRI를 ROC 곡선을이용하여비교하였을때, AUC 값은간섬유화 2단계이상에서각각 0.72 (95% CI, 0.58~0.86), 0.61 (95% CI, 0.39~0.82), 0.58 (95% CI, 0.36~0.80) 이었으며, 간섬유화 3단계이상에서각각 0.92 (95% CI, 0.86~0,99), 0.73 (95% CI, 0.61~0.87), 0.56 (95% CI, 0.42~0.70) 이었으며, 간섬유화 4단계 ( 간경변증 ) 에서각각 0.97 (95% CI, 0.93~1.0), 0.79 (95% CI, 0.67~0.90), 0.55(95% CI, 0.49~0.69) 를보였다. 간탄력도의 AUC 값이 AST/ALT 비및 APRI와비교했을때조직학적간섬유화의진단에서가장높은진단율을보였다 ( 표 5, 그림 5)

8 - 대한내과학회지 : 제 72 권제 5 호통권제 561 호 고찰본연구에서는최근개발된간섬유스캔을사용하여측정한간탄력도가만성 B형간염환자에서간섬유화의정도및간경변의진단에유용한지를알아보고자하였다. 또한, 임상질환별각군간의간탄력도의값을비교분석하였으며, 간탄력도와생화학적간섬유화표지자들 (AST/ALT 비및 APRI) 의유용성을비교하였다. 간섬유스캔으로측정된간탄력도는섬유화가심할수록높은값을보였으며경증간섬유화군 (1단계, 2단계 ) 보다심한섬유화군 (3단계, 4단계 ) 에서유의하게높은값을보여주었다. 간탄력도는간기능을나타내는생화학적인자들중만성적인간손상을반영하는인자인혈청알부민의감소와강한상관관계를보였으며혈소판과도다소높은상관관계를보였다. 임상질환별각군간에간탄력도의값이유의하게차이가있었다. 즉, 진행된간질환에서유의하게높은간탄력도를보였는데, 진행된간질환에서섬유화의정도가심하다는것을보여주는결과이다. 이전의연구들에서간섬유화의각단계별로향상된민감도와특이도를보이는 cut-off 치를정하여보고한바있으나 10-12) 본연구에서간섬유화를확진할수있는간조직생검의수가적어앞으로섬유화의단계의 cut-off 치를얻기위해더많은환자를대상으로한연구가필요할것으로생각된다. 간경변증환자에서문맥압항진에의한합병증들이발생한다. 위식도정맥류및출혈, 복수, 비장종대등인데, 특히식도정맥류출혈은간경변증환자에서사망률을증가시키는요인으로조기발견을위한상부위장관내시경검사가시행되고있다 12). 하지만침습적이며환자의불편감이문제가되므로, 현재까지비침습적으로혈액학적인자들을이용하여정맥류를예측하는보고들이있었다 17). Juliette 등의보고에서는총 758명의만성간질환환자를대상으로조직검사와간섬유스캔을시행하여간경변증합병증을가진환자에서현저히높은간탄력도를보였으며, 이러한합병증들을예측할수있는 cut-off 값을정하였다 12). 본연구에서간경변증의문맥압항진에의한합병증중복수의과거력및비장종대에서만그렇지않은군과비교하여유의한차이를보여주었는데, 환자의수가많아지면간경변증의합병증을예측할수있는간탄력도의 cut-off 값을정할수있을것으로생각된다. 또한, 본연구에서간암환자들의간탄력도가현저히높았는데, 환자의간암병소를피해간탄력도를측정하였으므로간암자체의영향은받지않았다고가정할수있는결과이다. 간섬유화가심할수록간암의발생위험성이높다고보고된바있어 18), 간탄력도의간암발생에대한예측은더많은연구가필요할것으로생각된다. 간탄력도는심한간섬유화 (F 3) 및간경변증 (F=4) 에서간탄력도의 AUC가각각 0.92, 0.97이었으며, 혈청간섬유화표지자들 (AST/ALT 비, APRI) 과비교하여가장높은 AUC 값을보였는데이는심한간섬유화와간경변의진단에간탄력도가매우유용한진단방법이될수있다는것을보여주는결과이다. 최근만성 C형간염환자에서간섬유화스캔을이용하여간섬유화의정도와간경변의진단에그유용성을증명한연구들중, Laurent 등은간탄력도의 AUC가간섬유화 2단계이상, 3단계이상, 4단계에서각각 0.83, 0.90, 0.95로본연구와비슷한결과를보여주었다. 또한이들의연구에서간섬유스캔은 Fibrotest R, APRI와비슷한진단적유용성을보였으며, 간섬유스캔과 Fibrotest R 를조합하였을때가장높은진단적정확도를가진다고보고하였다 10). 본연구에서비교한간섬유화표지자인 AST/ALT 비는이미만성바이러스성간질환에서간섬유화의정도와직접적인상관관계를나타냈으며, AST/ALT 비가 1이상일때민감도 78%, 특이도 97% 로간경변증을예측할수있었다 2, 19, 20). AST/ALT 비에대한상반된보고에서진행된간질환환자에서점차적으로증가하여 Child-Pugh 점수와비슷하게사망률을예측할수있었지만, 무증상의간경변증과초기단계의간섬유화를예측하기에는한계점이있고간섬유화의정도와약한상관관계를보여주었다 21-23). 본연구에서 AST/ALT 비는간섬유화의정도와상관관계는통계학적으로유의하지않았으며진단적유용성도낮았다. APRI (the aspartate transaminase to platelet ratio index) 는심한간섬유화및간경변증의예측에가장중요한인자인, 혈소판과 AST를이용하여만든수식으로, 간섬유화각단계의환자에서두인자들의차이를최대화한수식이다 7). 여러연구에서 APRI는간섬유화의정도와높은상관관계를보이며 (r=0.60, p=0.001), 높은진단적정확도 (AUC 0.88(F>2), 0.94(F=4)) 를보고한바있다 1, 24, 25). 본연구에서 APRI는간섬유화의정도와유의한양의상관관계를보였으며 (r=0.379, p=0.027), APRI

9 - 김화숙외 12 인 : 만성 B 형간염환자에서간섬유화의비침습적평가 - 의 AUC는간섬유화각단계별로 0.61, 0.73, 0.79를보였으나, 간탄력도의 AUC는 0.72, 0.92, 0.97을보여간탄력도의진단적유용성이더우수함을보여주었다. 최근개발된간섬유스캔 (FibroScan R, Echosens, Paris, France) 은비침습적으로신속하게간탄력도를측정하는진단방법이다. 앞에서설명하였듯이진동자에서발생한탄력파동을이용하므로첫째, 통증이없으며신속하고, 합병증의위험이없어환자가편하게검사를받을수있다. 둘째, 재현성이있어검사자간의간탄력도의수치에차이가거의없다. 셋째, 간섬유스캔에의해측정되는간실질의양은지름 1 cm, 길이약 4 cm의원통형용적으로, 간조직생검으로채취되는조직의양의약 100배이므로, 좀더정확히간실질전체의섬유화를반영할수있다. 넷째, 검사후즉시결과를알수있고간격을두고반복적으로추적검사가가능하다. 다섯째, 간의탄력도를물리적으로측정하므로혈청검사에영향을주는간외질환들에의해영향을받지않는다 10-12). 그러나간섬유스캔은탄력파가액체를통하여전파될수없기때문에복수를가진환자에서는검사가불가능하며, 환자의늑간이좁을때검사가어렵고, 지방층이탄력파동과초음파를증강시키기때문에비만자에서는검사값이달라질수있다. 현재늑간이좁은환자를위한특수탐촉자가개발중이다 26). 만성 B형간염과 C형간염은원인, 자연경과, 검사실소견, 조직학적간섬유화의양상등이다르다. 조직학적으로지방변성은만성 C형간염에서중요한특징이고, 거대결절이 B형간경변증의특징으로, 간탄력도가 collagen 과 collagen의현미경적구조인격막 (septa) 에의해결정되기때문에간섬유화의서로다른양상이간탄력도에영향을줄수있다고예상하였지만 11, 27) 본연구에서는만성 B형간염환자에서간섬유스캔의간섬유화의예측과진단적정확도는만성 C형간염과크게차이가없음을볼수있었다. Marianne 등의연구에의하면간탄력도는간염활성도 (activity) 또는지방성변화 (steatosis) 정도에영향을받지않으며간섬유화만이간탄력도와유의한상관관계를보인다고하였지만 10-12) 심한지방성변화 (steatosis >60%) 의환자에서간실질이연하여간탄력도가낮게나온다는보고도있다 10, 11, 26). 간탄력도의측정에서문제점은간섬유화정도와불일치를보이는예들인데, 간경변증이면서낮은간탄력도를보이는예는비활동성간경변증, 거대-미세결절의혼합성간경변증, 항섬유화제 제의복용등이알려져있다 28). 본연구에서간경변증환자에서간탄력도의범위는 5~75 kpa로넓었는데아마도간문맥압항진의정도, 간섬유화의비균등분포, 항바이러스제제의사용등의영향으로생각되며, 개개인별로간섬유화에대한여러인자들을밝히는연구들이필요할것이다. 간섬유화뿐만아니라조직학적으로간경변증인경우에도가역적이라는많은연구결과가보고되고있다 29-31). 심한간섬유화및간경변증뿐만아니라경미한섬유화의정도를비침습적으로측정할수있는새로운진단방법들이개발된다면항바이러스제제및항섬유화제제의치료효과들을조직검사없이손쉽게추적관찰할수있을것이다. 본연구의제한점은간조직생검의수가적고, 환자중항바이러스제제를사용중이거나최근에사용한경력이있는환자를포함시킨점이다. 앞으로대상환자가많아지면임상적특성에따라환자군을나누어대규모의전향적연구를시행하고, 혈청학적표지자들과조합하여간섬유화에대한진단적정확도를높인다면, 간섬유스캔이간조직검사를대신할수있는비침습적방법으로사용될수있을것이다. 요약목적 : 최근개발된간섬유스캔은비침습적이며신속하게간의탄력도를측정하여간섬유화의정도를평가하는진단방법이다. 본연구는만성 B형간염환자에서간탄력도의측정이간섬유화의평가에유용한지를알아보고자하였으며, 간탄력도와혈청간섬유화표지자들 (APRI 및 AST/ALT 비 ) 의유용성을비교하였다. 방법 : 2005년 3월부터 9월까지간섬유스캔검사를받은 B형간염환자 228명을대상으로하였다. 간조직검사를시행한환자 34명의조직학적인섬유화의정도는 Ludwig의분류에따라 0단계에서 4단계까지분류하였다. 결과 : 간탄력도는임상질환별로비활동성보유자 (29 명 ) 7.0±2.7 kpa, 만성간염 (106명) 8.3±5.3 kpa, 대상성간경변증 (63명) 15.9±8.3 kpa, 비대상성간경변증 (63명) 31.8±20.3 kpa, 간암 (4명) 45.1±34.5 kpa이었으며각군별로유의한차이를보였다. 간탄력도는간섬유화의정도와유의한상관관계를보였다 (r=0.726; p). 간탄력도, APRI 및 AST/ALT 비를 ROC 곡선을이용하여

10 -The Korean Journal of Medicine : Vol. 72, No. 5, 비교하였을때, AUC (area under the curve) 값은간섬유화 2기이상에서각각 0.72, 0.61, 0.58 이었으며, 간섬유화 3기이상에서각각 0.92, 0.73, 0.56이었으며, 간섬유화 4기에서각각 0.97, 0.79, 0.55를보였다. 간탄력도의 AUC 값이 APRI 및 AST/ALT 비와비교했을때가장높은진단적정확도를보였다. 결론 : 만성 B형간염환자에서간섬유스캔으로측정한간탄력도는신속하고비침습적인방법으로, 진행된간질환을예측할수있으며간섬유화의정도를예측하는데유용하였다. 중심단어 : B형간염, 간섬유화, 비침습적, 진단, 간탄력도 REFERENCES 1) Myers RP, Tainturier MH, Ratziu V, Piton A, Thibault V, Imbert-Bismut F, Messous D, Charlotte F, di Martino V, Benhamou Y, Poynard T. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol 39: , ) 김동준. 간섬유증의약물치료. 대한간학회지 7:6-11, ) Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 344: , ) Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 99: , ) Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with chronic hepatitis C virus infection: a prospective study. Lancet 357: , ) Poynard T, Imbert-Bismut F, Munteanu M, Messous D, Myers RP, Thabut D, Ratziu V, Mercadier A, Benhamou Y, Hainque B. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis(actitest) in patients with chronic hepatitis C. Comp Hepatol 3:1-8, ) Fontana RJ, Lok AS. Noninvasive monitoring of patients with chronic hepatitis C. Hepatology 36:S57-S64, ) Nishiura T, Watanabe H, Ito M, Matsuoka Y, Yano K, Daikoku M, Yatsuhashi H, Dohmen K, Ishibashi H. Ultrasound evaluation of the fibrosis stage in chronic liver disease by the simultaneous use of low and high frequency probes. Br J Radiol 78: , ) Aube C, Oberti F, Korali N, Namour MA, Loisel D, Tanguy JY, Valsesia E, Pilette C, Rousselet MC, Bedossa P, Rifflet H, Maiga MY, Penneau-Fontbonne D, Caron C, Cales P. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol 30: , ) Castera L, Vergniol J, Foucher J, le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, de Ledinghen V. Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 128: , ) Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, de Ledinghen V, Marcellin P, Dhumeaux D, Trinchet JC, Beaugrand M. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 41:48-54, ) Foucher J, Chanteloup E, Vergniol J, Castera L, le Bail B, Adhoute X, Bertet J, Couzigou P, de Ledinghen V. Diagnosis of cirrhosis by transient elastography (fibroscan): a prospective study. Gut 55: , ) Park BK, Park YN, Han KH, Ahn SH, Lee KS, Chon CY, Moon YM, Park CN. Long-term outcome of chronic hepatitis B according to the new histological classification. Korean J Hepatol 6: , ) Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, Moorat A, Gardner S, Woessner M, Bourne E, Brosqart CL, Schiff E. Adefovir difivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 126:81-90, ) Cha BG, Kim JW, Kim SJ, Han SP, Kim HJ, Do JH, Kim JG, Chang SK. Risk factors for hospital acquired infections in patients with decompensated liver cirrhosis. Korean J Med 69:69-75, ) Moon W, Choi MS, Moon YM, Paik SW, Lee JH, Koh KC, Yoo BC, Rhee JC, Shim SG. Efficacy and safety of adefovir dipivoxil in patients with decompensated liver cirrhosis with lamivudine resistance compared to patients with compensated liver cirrhosis. Korean J Hepatol 11: , ) Pilette C, Oberti F, Aube C, Rousselet MC, Bedossa P, Gallois Y, Rifflet H, Cales P. Non-invasive diagnosis of esophageal varices in chronic liver diseases. J Hepatol 31: , ) Nanashima A, Tanaka K, Yamaguchi H, Shibasaki S, Morino S, Yoshinaga M, Sawai T, Nakagoe T, Ayabe H. Fibrosis and inflammatory activity in noncancerous

11 -Hwa Sook Kim, et al : Non-invasive assessment of liver fibrosis - tissue and mitotic index of cancer tissue in patients with hepatocellular carcinoma: relationship to clinicopathological factors and prognosis after hepatic resection. Dig Dis Sci 48: , ) Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, Romagnoli P, Testa E, Ceppa P, Testa R. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 163: , ) Park SY, Kang KH, Park JH, Lee JH, Cho CM, Tak WY, Kweon YO, Kim SK, Choi YH. Clinical efficacy of AST/ALT ratio and platelet counts as predictors of degree of fibrosis in HBV infected patients without clinically evident liver cirrhosis. Korean J Gastroenterol 43: , ) Reedy DW, Loo AT, Levine RA. AST/ALT ratio > or =1 is not diagnostic of cirrhosis in patients with chronic hepatitis C. Dig Dis Sci 43: , ) Sim SJ, Cheong JY, Cho SW, Kim JS, Lim TY, Shin DH, Lim SG, Kim YB, Lee KM, Yoo BM, Lee KJ, Hahm KB, Kim JH. Efficacy of AST to platelet ratio index in predicting severe hepatic fibrosis and cirrhosis in chronic hepatitis B virus infection. Korean J Gastroenterol 45: , ) Park GJ, Lin BP, Ngu MC, Jones DB, Katelaris PH. Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? J Gastroenterol Hepatol 15: , ) Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 38: , ) Cales P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet MC, Konate A, Gallois Y, Ternisien C, Chevailler A, Lunel F. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology 42: , ) Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 29: , ) Hui AY, Chan HL, Wong VW, Liew CT, Chim AM, Chan FK, Sung JJ. Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model. Am J Gastroenterol 100: , ) AASLD. Accuracy of liver stiffness measurement (LSM) for the diagnosis of cirrhosis in patients with chronic liver disease (CLD): a study in 1345 [Abstract]. 56 th annual meeting of the AASLD, ) Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology 122: , ) Friedman SL. The celluar basis of hepatic fibrosis: mechanism and treatment strategies. N Engl J Med 328: , ) Shiratori Y, Imazeki F, Moriyama M, Yano M, Arakawa Y, Yokosuka O, Kuroki T, Nishiguchi S, Sata M, Yamada G, Fujiyama S, Yoshida H, Omata M. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 132: ,