Journal of Hepatology ‘Accepted article’ Journal conference Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study Journal of Hepatology ‘Accepted article’ Giovanna Ferraioli1, M.D., Carmine Tinelli2, M.D., Barbara Dal Bello3, M.D., Mabel Zicchetti1, M.D., Gaetano Filice4, M.D., and Carlo Filice1, M.D. on behalf of the Liver Fibrosis Study Group (Elisabetta Above1, M.D.; Giorgio Barbarini4, M.D., Enrico Brunetti4, M.D., Willy Calderon4, M.D.; Marta Di Gregorio1, M.D.; Raffaella Lissandrin4, M.D.; Serena Ludovisi4, M.D.; Laura Maiocchi4, M.D., Antonello Malfitano4, M.D., Giuseppe Michelone4, M.D., Mario Mondelli4, M.D.; Savino F.A. Patruno4, M.D., Alessandro F. Perretti 4, M.D., Gianluigi Poma1, M.D., Paolo Sacchi4, M.D., Marco Zaramella4, M.D.) 2012.08.20 R1 김재민 / pf 심재준

Introduction In chronic hepatitis C : the extent of fibrosis is important for prognosis & Mx Liver Bx : gold standard for evaluation of liver fibrosis invasive, painful, costly, sampling error, intr- and inter-observer variability → not an ideal method for repeated assessment of Dz progression Non invasive Methods TE(transient elastopraphy) – Fibroscan™ : velocity of elastic shear waves in the liver generated by mechanical push SWE(shear-wave elastography) – Supersonic shear imaging : image liver stiffness in real-time : guided by B-mode image Aim of this study evaluate the diagnostic accuracy of real-time SWE vs TE by using histologic METAVIR scoring system as reference method

<Shear wave-based elastography> TE ARFI SWE 원리 기계적 진동파 -> 일정 지점 M-mode probe로 전단파 탐지 일정부위 높은 강도 초음파 집중 -> detection pulse 탐지 종파진행방향 5개 초점 음파 집중 -> plane wave 2차원 실시간 elastography 영상 특징 B-mode 안됨 10회 반복측정 비만,복수 : 측정불가 5.5~6% 실패율 B-mode보면서 측정 가능 피부에서 8cm 깊이만 가능 ROI : 6x10mm 전체 간 평균탄성 측정위해 5~10회 반복측정 B-mode 넓은 부위 측정 약한 집속파 이용 -> 비만, 호흡조절안되는 경우 3% 실패율 <Shear wave-based elastography> Introduction SWE TE(FibroScan)

Methods single center cross-sectional study confirmed chronic hepatitis C scheduled for liver Bx(2010.06 ~ 2012.01) Inclusion criteria: HCV-RNA, ALT ↑ exclusion criteria: HIV coinfection SWE & TE & Liver Biopsy Rt lobe of liver, same intercostal space, same day : SWE, TE, liver Bx Real-time SWE(shear wave elastography): Aixplorer™ (SuperSonic Imagine) TE(transient elastopraphy) : Fibroscan™ Liver Bx : METAVIR scoring system

Patients and methods TABLE 1. Patients demographics, and their biochemical and histological data at liver biopsy examination Fibrosis score (Metavir) N(%) F0~F1 50(41.3%) F2 33(37.3%) F3 14(11.6%) F4 24(19.8%) 69% Characteristics Mean value n 121(138-17) Sex(men) 87(71.9%) Age(y) 44.8 BMI(kg/m2) 25.4 AST/ALT 41/75 ALP/γGT 130.6/42.5 TB 6.4 Alb 42 PLT 210.5k PT 94.4 Activity grade (Metavir) N(%) A0(none) 3(2.5%) A1(mild) 51(42.1%) A2(moderate) 50(41.3%) A3(severe 17(14.1%) Steatosis N(%) S0(fat 0%) 77(63.6%) S1(<33%) 32(26.4%) S2(33~66%) 6(5.0%) S3(>66%)

Results TABLE 2. Median values, interquartile range, range, outliers, and p values of measurements obtained for each fibrosis stage with shear wave elastography and transient elastography METAVIR stage Method F0-F1 F2 F3 F4 Median value in kPa SWE^ TE+ 6.2 5.6 7.6 6.4 10.0 9.1 15.6 19.8 IQR SWE TE 5.1-6.8 4.5-6.5 7.2-8.3 5.4-8.0 9.2-10.1 8.4-11.6 12.8-18.8 13.4-23.0 Range 4.5-9.3 3.5-8.9 5.6-13.0 3.6-10.2 8.9-12.0 6.1-20.8 8.0-22.5 6.4-36.3 Number of outliers 1 2 p value 0.0001 0.02 0.003 0.002 0.09 0.06 P values refer to differences between consecutive fibrosis stages (*F0-F1 vs. F2; **F2 vs. F3; ***F3 vs. F4). ^:shear wave elastography; +:transient elastography; §:interquartile range

Results TABLE 3. Resulting clinical performance of shear wave elastography and transient elastography using optimal measurements cut-off values. Parameter Method F≥2 F≥3 F=4 Cutoff in kPa SWE^ TE+ 7.1 6.9 8.7 8.0 10.4 11.6 Sensitivity % SWE TE 90.0 (80.5-95.9) 69.6 (57.3-80.1) 97.3 (85.8-99.9) 89.2 (74.6-97.0) 87.5 (67.7-97.3) 91.7 (73.0-99.0) Specificity % 87.5 (74.8-95.3) 89.6 (77.3-96.5) 95.1 (87.8-98.6) 88.8 (79.7-94.7) 96.8 (91.0-99.3) 96.8 (90.9-99.3) PPV % 91.3 (82.0-96.7) 90.6 (79.3-96.9) 90.0 (76.3-97.2) 78.6 (63.2-89.7) 87.5 (67.6-97.3) 88.0 (68.8-97.5) NPV % 85.7 (72.8-94.1) 67.2 (54.3-78.4) 98.7 (93.1-100) 94.7 (86.9-98.5) 97.8 (92.4-99.7) LR+ 7.2 (6.3-8.2) 6.7 (5.6-8.0) 19.7 (18.3-21.2) 7.9 (6.9-9.1) 27.4 (23.5-32.0) 28.4 (25.0-32.3) LR- 0.11 (0.04-0.3) 0.34 (0.1-0.8) 0.03 (0.003-0.2) 0.12 (0.04-0.4) 0.13 (0.03-0.6) 0.09 (0.02-0.5)

Results TABLE 4. Analysis of concordance of shear wave elastography and transient elastography vs.METAVIR stage. METAVIR F0-F1 F2 F3 F4 Total Concordance rate(%) SWE≤7.1kPa 42 7 49 85.7 TE≤6.9kPa 43 19 1 64 67.2 7.1<SWE≤8.7kPa 4 24 29 82.8 6.9<TE≤8.0kPa 3 6 2 11 54.5 8.7<SWE≤10.4kPa 16 68.8 8.0<TE≤11.6kPa 17 41.2 SWE>10.4kPa 21 87.5 TE>11.6kPa 22 25 88.0 Cumulative concordance SWE Weighted K = 0.90 98/118 83.1 TE Weighted K = 0.83 78/117 66.7

<SWE & TE values for each METAVIR stage> Results Box-and-whisker plots of (A) shear wave elastography and (B) transient elastography values for each METAVIR stage in relation to the degree of necro-inflammatory acitivity. Liver stiffness values are reported on the y-axis, and METAVIR grade of necro-inflammatory activity on the x-axis. The central box represents values from the lower to upper quartile (25 to 75 percentile). The line through each box represents the median. Error bars show minimum and maximum non-extreme values. A, necro-inflammatory activity (METAVIR grade); F, fibrosis (METAVIR stage); O, extreme values; *, only 2 patients with A0 grade in F4 stage. 209x296mm (300 x 300 DPI) SWE TE(FibroScan) <SWE & TE values for each METAVIR stage>

<Comparison of ROC curves> Results (B) F0-F2 vs. F3-F4 (F>3) (C) F0-F3 vs. F4 (F=4) Comparison of ROC curves for real-time shear wave elastography (SWE) and transient elastography (TE) 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). 95% Confidence Intervals are shown in parentheses. P values of differences between AUROCs are given. 296x209mm (300 x 300 DPI) (A) F0-F1 vs. F2- F4 (F>2) <Comparison of ROC curves>

Conclusion Assessment of significant fibrosis (F>2) : Real-time SWE was more accurate than TE SWE with respect to TE : imaging liver stiffness in real-time by B-mode inage → anatomical & tissue stiffness information enables identification of artifacts(pulsating vessels or others) difficult patients, can search for an acoustic window in real-time Limitations(ultrasound imaging modes) → user dependencies and patient body habitus can influence Further studies in larger patient populations are needed