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Influence of different frequencies and insertion depths on the diagnostic accuracy of liver elastography by acoustic radiation force impulse imaging (ARFI)
European Journal of Radiology 82 (2013) 1207–1212
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Influence of different frequencies and insertion depths on the diagnostic accuracy of liver elastography by acoustic radiation force impulse imaging (ARFI) Andrej Potthoff ∗ , Dina Attia, Sven Pischke, Janina Kirschner, Ingmar Mederacke, Heiner Wedemeyer, Michael P. Manns, Michael J. Gebel, Kinan Rifai Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Article history: Received 17 December 2012 Received in revised form 19 January 2013 Accepted 8 February 2013 Keywords: Acoustic Radiation Force Impulse Imaging Hepatitis C virus infection Transient elastography
a b s t r a c t Background: Acoustic Radiation Force Impulse Imaging (ARFI) is an innovative elastography for staging of liver fibrosis. We evaluated the diagnostic accuracy of different probes to perform ARFI at different insertion depths. Methods: In a prospective study, 89 chronic HCV infected patients underwent ARFI elastography using both available probes (c-ARFI: C4-1-MHz; l-ARFI: L9-4 MHz) in comparison to Fibroscan® . Variability of ARFI elastography at different insertion depths was systematically evaluated in 39 patients (44%). According to Fibroscan® elastography, 32 patients (36%) presented with liver cirrhosis, 23 patients (26%) had significant fibrosis and 34 patients (38%) had no significant fibrosis. Results: Mean propagation velocity with c-ARFI was 1.70 ± 0.67 m/s and 1.91 ± 0.87 m/s with l-ARFI. Results of both probes were correlated to each other (p < 0.001; r = 0.70) and to Fibroscan® (p < 0.001, r = 0.82 and 0.84, respectively). In patients with significant fibrosis or with cirrhosis, mean values by lARFI were significantly higher than by c-ARFI (p < 0.001). For detection of liver cirrhosis, AUROC was 0.97 for c-ARFI (cut-off level 1.72 m/s) and 0.90 for l-ARFI (cut-off 2.04 m/s). Correlation coefficients of c-ARFI with Fibroscan® were highest at an insertion depth of 5–6 cm (r = 0.882 and 0.864, respectively, p < 0.001) and at 3–4 cm for l-ARFI (r = 0.850 and 0.838, respectively, p < 0.001). Conclusions: ARFI elastography with the linear and with the convex probes showed comparable validity and accuracy in the estimation of liver stiffness. The linear probe gave higher ARFI values. The most accurate insertion depth was 5–6 cm for c-ARFI and 3–4 cm for l-ARFI indicating that measurements should not be performed close to the liver capsule. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Liver biopsy is still considered the “gold standard” for assessing hepatic fibrosis or cirrhosis [1]. However, it is an invasive procedure with rare but potentially life threatening complications and limitations [2]. In addition, its diagnostic accuracy is strongly influenced by the quality of the specimen and by inter- or intra-observer variations [3,4]. Thus, there is a need for non-invasive methods that can accurately reflect liver fibrosis. Different multiparametric serum
Abbreviations: ARFI, Acoustic Radiation Force Impulse Imaging; HCV, Hepatitis C virus; kPA, Kilopascals; ROI, Region of interest; TE, Transient elastography; m/s, meters per second. ∗ Corresponding author at: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel.: +49 511 532 9403; fax: +49 511 532 5059. E-mail address: [email protected] (A. Potthoff). 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.02.011
tests (e.g. FibroTest® ) and transient elastography (TE; Fibroscan® , Echosens, France) have been extensively evaluated for grading of liver fibrosis. TE is a rapid, noninvasive, and reproducible method that measures liver stiffness. A strong association between TE and the degree of liver fibrosis has been demonstrated in patients with different causes of chronic hepatitis [5–11]. Moreover, the best diagnostic performance of TE has been reported in patients with significant fibrosis and cirrhosis, two conditions which may frequently cause complications [7,12]. Use of Fibroscan® is limited by ascites, extreme obesity and atrophic right liver lobe [13]. Acoustic Radiation Force Impulse imaging technology (ARFI) is a newer non-invasive method for the estimation of liver fibrosis. ARFI is included in a standard ultrasonography device and may be performed with a standard ultrasonographic convex probe (C4-1 MHz; Siemens Acuson S2000, Virtual TouchTM Tissue Quantification, Siemens Healthcare, Erlangen, Germany). It is based on the measurement of the acoustic shear wave induced by an ultrasonic push
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pulse. [14]. The tissue stiffness correlates closely with the propagation velocity of the shear waves. ARFI is able to assess liver fibrosis in patients with different chronic liver diseases with a diagnostic accuracy comparable to that of Fibroscan® [15–21]. A recent meta-analysis showed that the mean diagnostic accuracy of ARFI expressed as area under receiver operating characteristic curves (AUROC) was excellent with 0.93 for the diagnosis of cirrhosis and good with 0.91 for the diagnosis of severe fibrosis [22]. Recently, a linear probe (L9-4 MHz) has been introduced that is able to perform ARFI, as well. Only very limited data on this probe exist. So far, two experimental studies have been performed investigating the variability of ARFI-elastography of the liver by different frequencies and insertion depths [23,27]. In the first study shear wave velocities measured by the convex probe (c-ARFI) increased when measurements were made close to the liver surface, a limitation which was not shown by the linear probe [23]. Another study found a tendency to higher ARFI values with the linear probe (L9-4 MHz) compared to the convex probe (C4-1 MHz) [24]. The purpose of this prospective clinical study was to investigate the diagnostic accuracy of both probes (C4-1 and L9-4) under clinical conditions in patients with chronic hepatitis C infection. Furthermore, the variability of ARFI values in relation to different insertion depths was evaluated. 2. Patients and methods The study was performed in compliance with the Helsinki declaration and with approval of the local Ethics Committee. Written informed consent was obtained from all patients. All patients with known chronic hepatitis C presenting at our ultrasonography unit between August 2011 and November 2012 were prospectively included in the study with transient elastography by Fibroscan® and liver biochemistry done at the same day. All measurements were done in a fasting condition. In patients with chronic hepatitis C Fibroscan® was used as a reference method, as suggested by the German guidelines on the management of HCV infection [24]. Exclusion criteria were ascites and liver tumors, HIV coinfection, alcohol abuse (>20 g/day), patients receiving antiviral therapy and patients in whom Fibroscan® measurement was not feasible. Fibroscan® and ARFI measurements were done by two independent experienced examiners who were unaware of the results obtained by the two different methods. 2.1. Liver elastography measured by transient elastography (Fibroscan® ) All patients received TE (sample size, 4 × 1 cm) with the FibroScan® using a low-frequency vibrator (50 Hz) with an ultrasonic single-element transducer operating at 5 MHz on the axis of the vibrator as previously described [18]. At least 10 successful measurements were performed in each patient. The results were expressed in kilopascals (kPa). The success rate was calculated as the number of successful measurements divided by the total number of measurements. Only procedures with at least 10 valid acquisitions, a success rate of at least 60%, and an interquartile range of less than 30% of the mean value (IQR) were defined as eligible for the study. Staging of liver fibrosis was assessed as suggested by Roulot [25,26]: <8 kPa: no significant fibrosis; ≥8–<13 kPa: significant fibrosis; ≥13 kPa: cirrhosis. Studies have reported that threshold values of liver stiffness predictive for significant fibrosis (i.e. Metavir F score ≥2) ranged from 7 and 8.8 kPa. 2.2. Liver elastography measured by ARFI Acoustic Radiation Force Impulse Imaging (ARFI) is included in a conventional ultrasonographic system (Siemens ACUSON S2000
Virtual TouchTM Tissue Quantification; Siemens, Munich, Germany) with a standard broad-band 4–1 MHz curved probe (c-ARFI) and a standard broad band 9–4 MHz linear probe (l-ARFI). This allows the placement of the “region of interest” (ROI size: C4-1, 10 × 6 mm; ROI size: L9-4, 6 × 5 mm) under sight in ultrasonographic B-mode. In all 89 patients the insertion depth was variably used up to a maximum of 7 cm for the convex probe and 4 cm for the linear probe (Siemens Acuson S2000), but with a minimum distance of 1 cm below the liver capsule. Ultrasonographic elastography of the liver with ARFI was performed sequentially with the C4-1 and L9-4 probe. In all patients, measurements were performed at the right liver lobe in segment 8. Parameters of quality control were applied as for TE. In 39 of 89 patients (44%) c-ARFI and l-ARFI were performed at defined insertion depths of 3 cm, 4 cm, 5 cm, 6 cm for c-ARFI and 2 cm, 3 cm, 3.5 cm and 4 cm for l-ARFI. In order to prove if the vicinity of the liver capsule has really a strong influence on measurement values the study cohort of 89 chronic HCV-infected patients was extended by 40 additional patients with different chronic liver disease. In these patients only c-ARFI measurements 1 and 2 cm below the liver capsule were performed and data were compared to each other. 2.3. Biochemistry and ultrasonography Serum liver function tests (AST, ALT, bilirubin, gamma-GT, cholinesterase, albumin, prothrombin time, INR and platelets) and abdominal ultrasonographic findings (such as liver and spleen size, liver steatosis, signs of portal hypertension such as diameter of portal and splenic vein and presence of collateral vessels) and signs of relevant right heart insufficiency such as tetra-phasic flow in the right liver vein and highly undulating flow patterns or retrograde flow in the portal vein were noted in all patients. Ultrasonographic signs for hepatic steatosis were an increased echogenicity of the liver in comparison to the kidney parenchyma at the same depth and a decrease in intensity, which lead to a loss of visibility deeper within the liver. 2.4. Statistics SPSS software was used for statistical analysis (version 18.0, SPSS, Chicago, USA). All data are presented as mean ± S.D. p < 0.05 was considered statistically significant. Continuous variables of 2 independent groups were compared with the Student’s t test or Mann–Whitney’s U test depending on the distribution. Categorical variables were tested using Chi-square test (2 ) or Fisher’s exact test, as applicable. Correlations between parameters were expressed with Pearson’s or Spearman’s two-tailed pairwise correlation coefficients, as appropriate. Parameters that were statistically significant in univariate analysis were included in multivariate analysis using linear stepwise regression. Areas under the curve were (AUC) estimated for continuous variables using receiver operating characteristics analysis (ROC). Sensitivity and specificity were calculated from the ROC curves (for ARFI elastography).
3. Results 3.1. Characteristics of the study cohort A total of 89 HCV-infected patients (42 females and 47 males) with a mean age of 54 ± 13.4 years were prospectively included into the study. Table 1 shows basic clinical data of the patients. According to TE, different stages of liver fibrosis were calculated as follows: 34 patients (38%) were without significant fibrosis (group I: TE < 8 kPa), 23 patients (26%) had significant fibrosis (group II: TE
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3.2. Correlation of c-ARFI and l-ARFI with Fibroscan®
Table 1 Characteristics of the study cohort (n = 89). Parameter
Patients N = 89
Gender (female/male) Mean Age ± S.D. (years) ALT (U/L) (Range) Fibrosis stage (according to Fibroscan® ) Group I: No significant fibrosis (<8 kPa) Group II: Significant fibrosis (≥8–<13 kPa) Group III: Cirrhosis (≥13 kPa) Mean Fibroscan® ± S.D (kPa). Mean ARFI (C4-1 MHz) ± S.D. (m/s) Mean ARFI (L9-4 MHz) ± S.D. (m/s)
42/47 54 ± 13.4 81 (9–310) 34 (38%) 23 (26%) 32 (36%) 15.1 ± 13.86 1.70 ± 0.67 1.91 ± 0.87
Abbreviations: ALT, Alanine aminotransferase; kPa, Kilopascals; ARFI, Acoustic Radiation Force Impulse Imaging; m/s, meter per second; S.D., standard deviation.
≥8 and <13.0 kPa), and 32 patients (36%) presented with cirrhosis (group III: TE ≥ 13.0 kPa). In all 89 chronic HCV-infected patients, ARFI measurements were successfully performed with both probes. Shear wave velocity with c-ARFI ranged from 0.75 to 3.51 m/s (mean 1.70 ± 0.67 m/s). Shear wave velocities measured with l-ARFI were between 0.82 and 4.71 m/s (mean 1.91 ± 0.87 m/s). In the 40 additional patients (female/male 18/22, mean age 53 ± 14.4 years) with different chronic liver diseases mean c-ARFI values 1 cm and 2 cm below the liver capsule were 1.78 ± 0.87 m/s and 1.69 ± 0.75 m/s, respectively.
There was a statistically significant correlation between c-ARFI and TE as well as between l-ARFI and TE (p < 0.001; r = 0.82; r = 0.84, respectively; Fig. 1). Moreover, c-ARFI and l-ARFI were correlated to each other (r = 0.70, p < 0.001). Fig. 2 shows the distribution of the c-ARFI and l-ARFI values according to their fibrosis stages as measured by TE (described above). In patients without significant fibrosis, mean c-ARFI-and l-ARFI values were comparable (1.16 ± 0.28 m/s and 1.16 ± 0.20 m/s, respectively; n.s.). In contrast, patients with significant liver fibrosis showed significant difference between c-ARFI and l-ARFI (1.53 ± 0.40 m/s vs 2.02 ± 0.93 m/s; p < 0.001). In patients with liver cirrhosis, c-ARFI and l-ARFI values were significantly different as well (2.39 ± 0.50 m/s vs 2.63 ± 0.55 m/s; p < 0.001). Moreover, mean c-ARFI versus l-ARFI values were significantly different in the different fibrosis groups (group I-III, p < 0.001). ALT values were significantly correlated with c-ARFI as well as l-ARFI elastography results (r = 0.36, p = 0.001; r = 0.31, p = 0.007, respectively). 3.3. Influence of different insertion depths of the ROI and the liver capsule Mean c-ARFI and l-ARFI values at different insertion depths are shown in Fig. 3. Mean c-ARFI values at insertion depths of 3 cm, 4 cm, 5 cm and 6 cm were not significantly different (1.77 ± 0.79 m/s, 1.71 ± 0.71 m/s, 1.71 ± 0.64 and
Fig. 1. Comparison of Fibroscan® with ARFI elastography results using the convex (C4-1 MHz) and the linear probe (L9-4 MHz) (n = 89 with chronic HCV-infection). A: Correlation of Fibroscan® and c-ARFI. B: Correlation of Fibroscan® and l-ARFI. C: Correlation of c-ARFI and l-ARFI.
Fig. 2. ARFI for the different stages of liver fibrosis as estimated by Fibroscan® (n = 89 with chronic HCV-infection). A: c-ARFI: Boxplot analysis using the convex probe (C4-1 MHz) B: l-ARFI: Boxplot analysis using the linear probe (L9-4 MHz). Box plots show median values with 25th and 75th percentiles of shear wave velocity determined by ARFI. For boxplot analysis, liver fibrosis was graded according to Fibroscan® results as follows: <8 kPa, no significant fibrosis; ≥8 kPa and <13 kPa, significant fibrosis; ≥13 kPa, cirrhosis.
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Fig. 3. Influence of different insertion depths of the ROI (n = 39 with chronic HCV infection). Graphs show mean ARFI values and the standard error of mean (SEM). c-ARFI values showed no significant difference when using different insertion depths. l-ARFI results were significant lower when using an insertion depth of 4 cm. Correlation coefficients of c-ARFI with Fibroscan® were as follows: 0.768 for 3 cm, 0.841 for 4 cm, 0.882 for 5 cm, 0.864 for 6 cm (p < 0.001). Correlation coefficients of l-ARFI with Fibroscan® were as follows: 0.791 for 2 cm, 0.850 for 3 cm, 0.802 for 3.5 cm, 0.838 for 4 cm.
1.72 ± 0.71 m/s, respectively). Mean l-ARFI values were 1.87 ± 0.94 at 2 cm, 1.89 ± 0.81 m/s at 3 cm, 1.87 ± 0.76 m/s at 3.5 cm and 1.67 ± 0.66 m/s at 4 cm. Thus, significantly different values were observed for l-ARFI measurements at 4 cm insertion depth in comparison to the other depths (p = 0.003 compared to 3.5 cm; p < 0.001 compared to 3.0 cm and p = 0.009 compared to 2 cm). Correlation coefficients of c-ARFI with TE were highest when using insertion depths of 5 and 6 cm (r = 0.882, r = 0.864, p < 0.0001, respectively). Correlation coefficients of l-ARFI with TE were highest when using insertion depths of 3 and 4 cm (r = 0.850, r = 0.838, p < 0.0001 respectively). In the 40 additional patients with different chronic liver disease mean c-ARFI value obtained 1 cm below the liver capsule was significantly different to mean c-ARFI value 2 cm below the liver capsule (1.78 ± 0.87 m/s vs. 1.69 ± 0.75 m/s, p < 0.001, respectively). 3.4. ROC analysis of ARFI using both probes The diagnostic value (ROC curves) of liver stiffness measurement for patients with a Fibroscan® value of at least ≥8 kPa (groups II and III) is shown in Fig. 4a. Corresponding AUROC values were 0.91 for c-ARFI and 0.95 for l-ARFI. Based on the ROC curves the optimal cut-off value for c-ARFI and l-ARFI were chosen to maximize the sum of sensitivity and specificity. These cut-off levels were 1.41 m/s for c-ARFI (sensitivity 84%, specificity 85%) and 1.34 m/s for l-ARFI (sensitivity 89%, specificity 82%). The diagnostic value (ROC curves) of liver stiffness measurement for patients with “cirrhosis” (TE ≥ 13.0 kPa) is shown in Fig. 4b. Corresponding AUROC values were 0.97 for c-ARFI and 0.90 for l-ARFI. Cut-off levels for the detection of cirrhosis were 1.72 m/s (sensitivity 94% and specificity 98%) for c-ARFI and 2.04 m/s (sensitivity 84% and specificity 85%) for l-ARFI, respectively. 4. Discussion Acoustic Radiation Force Impulse Imaging (ARFI) as a new ultrasound based method of tissue elastography is increasingly used to assess liver stiffness. Clinical feasibility, diagnostic accuracy and validity of ARFI elastography have been recently summarized in a meta-analysis showing that ARFI using the convex probe (c-ARFI) is at least as effective as Fibroscan® (TE) to discriminate between liver fibrosis and cirrhosis [22]. In our study, l-ARFI elastography was as accurate as c-ARFI when compared to Fibroscan® . We observed a high significant correlation between l-ARFI elastography and TE in particular for detection of liver cirrhosis. l-ARFI achieved a high sensitivity (84%) and specificity (85%) for the detection of liver
cirrhosis. These results were comparable with previous studies using the C4-1 MHz transducer [15–18,22]. Furthermore, hepatic necroinflammatory activity indicated by elevated ALT levels showed significant changes of liver stiffness determined by ARFI in our study cohort. This is in line with a recently published study showing that ALT levels ≥2 upper the limit of normal (ULN) led to higher ARFI values [27]. In our study, box plot analysis of c-ARFI and l-ARFI showed significant difference within the different groups of fibrosis despite of some outlier patients. All of the outlier patients presented with slightly elevated ALT levels (<2-folds). Steatosis or relevant right heart insufficiency was excluded by ultrasound examination. Thus, we could not find an obvious explantation for the failure of accurate measurements of these patients. Our calculated optimal cut-off value for the detection of liver cirrhosis with l-ARFI was significantly higher (2.04 m/s) in comparison to c-ARFI (1.74 m/s) (p < 0.001). Another important finding of our study was that diagnostic accuracy of c-ARFI and l-ARFI was the highest when using insertion depths of 5–6 cm and 3–4 cm, respectively. Thus, our observations are in line with the previously described study by Chang and co-workers [28], in which measurements were performed in an elasticity phantom and in the liver of 8 healthy volunteers. As well as in our study they found a tendency to higher ARFI values with the linear probe (L9-4 MHz) compared to the convex probe (C4-1 MHz) at the same insertion depth and a variability of mean ARFI when using different insertion depths. Variability of ARFI elastography was lower when using insertion depths of 2–3 cm for the linear probe and 4–5 cm for the convex probe [28]. Moreover, our data are in accordance with the experimental study by Zhao, who recommended c-ARFI measurements at a distance of at least >4 cm from the liver capsule. The different cut-off values for c-ARFI and l-ARFI and the variability of ARFI values when using different insertion depths can be explained by the different physical properties of the transducers (intensity field of the push beam, the size of the true measurement ROI and the aperture size). The tolerance of transducers of ±20% contributes to the spread of measurement values and the standard deviation, respectively, within the literature. The vicinity of the liver capsule plays another important role in the diagnostic accuracy of ARFI. In our study significant difference of mean c-ARFI was found between the different insertion depths close to the liver capsule (1 cm and 2 cm below the liver capsule). Our results confirmed the observations made by Sporea and coworkers [12], who recommended to perform ARFI elastography at least 1–2 cm below the liver capsule.
A. Potthoff et al. / European Journal of Radiology 82 (2013) 1207–1212 Fig. 4. AUROC curves for both ARFI methods in the detection of liver fibrosis estimated by Fibroscan® (n = 89 with chronic HCV infection). A: Area under the curve for the detection of significant fibrosis (Fibroscan® ≥8 kPa). B: Area under the curve for the detection of cirrhosis (Fibroscan® ≥13 kPa).
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Thus, for comparison of c-ARFI and l-ARFI a correction factor is needed and depth-dependent changes in the shear wave velocities must be taken into account to provide accurate measurements of c-ARFI and l-ARFI in clinical practice. In conclusion, our study suggested that diagnostic accuracy of ARFI elastography of the liver using the linear probe (L9-4 Mhz) is comparable to the convex probe (C4-1 MHz). However, l-ARFI gives higher values than c-ARFI. Furthermore, the best diagnostic accuracy can be achieved when using insertion depths of 3–4 cm for l-ARFI, 5–6 cm for c-ARFI and a distance below the liver capsule of at least 1 cm. Conflict of interest Declaration of interest: Andrej Potthoff, Michael Gebel and Kinan Rifai have participated in studies and received lecture fees supported by Siemens Healthcare AG (Munich). References [1] Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008;134:1670–81. [2] Dienstag JL. The role of liver biopsy in chronic hepatitis C. Hepatology 2002;36:S152–60. [3] Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. American Journal of Gastroenterology 2002;97: 2614–8. [4] Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–57. [5] Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology 2008;48:835–47. [6] 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;55:403–8. [7] Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Gastroenterology 2008;134:960–74. [8] Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Ledinghen V, Douvin C, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. Journal of Hepatology 2008;49:1062–8. [9] de Ledinghen V, Ratziu V, Causse X, Le Bail B, Capron D, Renou C, et al. Diagnostic and predictive factors of significant liver fibrosis and minimal lesions in patients with persistent unexplained elevated transaminases. A prospective multicenter study. Journal of Hepatology 2006;45:592–9. [10] Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Ledinghen V, et al. Noninvasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver International 2009;29:242–7. [11] Sporea I, Sirli RL. Hepatic elastography for the assessment of liver fibrosis – present and future. Ultraschall in der Medizin 2012;33:550–8. [12] Sporea I, Sirli RL, Deleanu A, Iulia R, Tudora A, Dan I, et al. What did we learn from the first 3,459 cases of liver stiffness measurement by transient elastography (FibroScan(R))? Ultraschall in der Medizin 2011;32:40–5.
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Influence of different frequencies and insertion depths on the diagnostic accuracy of liver elastography by acoustic radiation force impulse imaging (ARFI) Andrej Potthoff ∗ , Dina Attia, Sven Pischke, Janina Kirschner, Ingmar Mederacke, Heiner Wedemeyer, Michael P. Manns, Michael J. Gebel, Kinan Rifai Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Article history: Received 17 December 2012 Received in revised form 19 January 2013 Accepted 8 February 2013 Keywords: Acoustic Radiation Force Impulse Imaging Hepatitis C virus infection Transient elastography
a b s t r a c t Background: Acoustic Radiation Force Impulse Imaging (ARFI) is an innovative elastography for staging of liver fibrosis. We evaluated the diagnostic accuracy of different probes to perform ARFI at different insertion depths. Methods: In a prospective study, 89 chronic HCV infected patients underwent ARFI elastography using both available probes (c-ARFI: C4-1-MHz; l-ARFI: L9-4 MHz) in comparison to Fibroscan® . Variability of ARFI elastography at different insertion depths was systematically evaluated in 39 patients (44%). According to Fibroscan® elastography, 32 patients (36%) presented with liver cirrhosis, 23 patients (26%) had significant fibrosis and 34 patients (38%) had no significant fibrosis. Results: Mean propagation velocity with c-ARFI was 1.70 ± 0.67 m/s and 1.91 ± 0.87 m/s with l-ARFI. Results of both probes were correlated to each other (p < 0.001; r = 0.70) and to Fibroscan® (p < 0.001, r = 0.82 and 0.84, respectively). In patients with significant fibrosis or with cirrhosis, mean values by lARFI were significantly higher than by c-ARFI (p < 0.001). For detection of liver cirrhosis, AUROC was 0.97 for c-ARFI (cut-off level 1.72 m/s) and 0.90 for l-ARFI (cut-off 2.04 m/s). Correlation coefficients of c-ARFI with Fibroscan® were highest at an insertion depth of 5–6 cm (r = 0.882 and 0.864, respectively, p < 0.001) and at 3–4 cm for l-ARFI (r = 0.850 and 0.838, respectively, p < 0.001). Conclusions: ARFI elastography with the linear and with the convex probes showed comparable validity and accuracy in the estimation of liver stiffness. The linear probe gave higher ARFI values. The most accurate insertion depth was 5–6 cm for c-ARFI and 3–4 cm for l-ARFI indicating that measurements should not be performed close to the liver capsule. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Liver biopsy is still considered the “gold standard” for assessing hepatic fibrosis or cirrhosis [1]. However, it is an invasive procedure with rare but potentially life threatening complications and limitations [2]. In addition, its diagnostic accuracy is strongly influenced by the quality of the specimen and by inter- or intra-observer variations [3,4]. Thus, there is a need for non-invasive methods that can accurately reflect liver fibrosis. Different multiparametric serum
Abbreviations: ARFI, Acoustic Radiation Force Impulse Imaging; HCV, Hepatitis C virus; kPA, Kilopascals; ROI, Region of interest; TE, Transient elastography; m/s, meters per second. ∗ Corresponding author at: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel.: +49 511 532 9403; fax: +49 511 532 5059. E-mail address: [email protected] (A. Potthoff). 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.02.011
tests (e.g. FibroTest® ) and transient elastography (TE; Fibroscan® , Echosens, France) have been extensively evaluated for grading of liver fibrosis. TE is a rapid, noninvasive, and reproducible method that measures liver stiffness. A strong association between TE and the degree of liver fibrosis has been demonstrated in patients with different causes of chronic hepatitis [5–11]. Moreover, the best diagnostic performance of TE has been reported in patients with significant fibrosis and cirrhosis, two conditions which may frequently cause complications [7,12]. Use of Fibroscan® is limited by ascites, extreme obesity and atrophic right liver lobe [13]. Acoustic Radiation Force Impulse imaging technology (ARFI) is a newer non-invasive method for the estimation of liver fibrosis. ARFI is included in a standard ultrasonography device and may be performed with a standard ultrasonographic convex probe (C4-1 MHz; Siemens Acuson S2000, Virtual TouchTM Tissue Quantification, Siemens Healthcare, Erlangen, Germany). It is based on the measurement of the acoustic shear wave induced by an ultrasonic push
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pulse. [14]. The tissue stiffness correlates closely with the propagation velocity of the shear waves. ARFI is able to assess liver fibrosis in patients with different chronic liver diseases with a diagnostic accuracy comparable to that of Fibroscan® [15–21]. A recent meta-analysis showed that the mean diagnostic accuracy of ARFI expressed as area under receiver operating characteristic curves (AUROC) was excellent with 0.93 for the diagnosis of cirrhosis and good with 0.91 for the diagnosis of severe fibrosis [22]. Recently, a linear probe (L9-4 MHz) has been introduced that is able to perform ARFI, as well. Only very limited data on this probe exist. So far, two experimental studies have been performed investigating the variability of ARFI-elastography of the liver by different frequencies and insertion depths [23,27]. In the first study shear wave velocities measured by the convex probe (c-ARFI) increased when measurements were made close to the liver surface, a limitation which was not shown by the linear probe [23]. Another study found a tendency to higher ARFI values with the linear probe (L9-4 MHz) compared to the convex probe (C4-1 MHz) [24]. The purpose of this prospective clinical study was to investigate the diagnostic accuracy of both probes (C4-1 and L9-4) under clinical conditions in patients with chronic hepatitis C infection. Furthermore, the variability of ARFI values in relation to different insertion depths was evaluated. 2. Patients and methods The study was performed in compliance with the Helsinki declaration and with approval of the local Ethics Committee. Written informed consent was obtained from all patients. All patients with known chronic hepatitis C presenting at our ultrasonography unit between August 2011 and November 2012 were prospectively included in the study with transient elastography by Fibroscan® and liver biochemistry done at the same day. All measurements were done in a fasting condition. In patients with chronic hepatitis C Fibroscan® was used as a reference method, as suggested by the German guidelines on the management of HCV infection [24]. Exclusion criteria were ascites and liver tumors, HIV coinfection, alcohol abuse (>20 g/day), patients receiving antiviral therapy and patients in whom Fibroscan® measurement was not feasible. Fibroscan® and ARFI measurements were done by two independent experienced examiners who were unaware of the results obtained by the two different methods. 2.1. Liver elastography measured by transient elastography (Fibroscan® ) All patients received TE (sample size, 4 × 1 cm) with the FibroScan® using a low-frequency vibrator (50 Hz) with an ultrasonic single-element transducer operating at 5 MHz on the axis of the vibrator as previously described [18]. At least 10 successful measurements were performed in each patient. The results were expressed in kilopascals (kPa). The success rate was calculated as the number of successful measurements divided by the total number of measurements. Only procedures with at least 10 valid acquisitions, a success rate of at least 60%, and an interquartile range of less than 30% of the mean value (IQR) were defined as eligible for the study. Staging of liver fibrosis was assessed as suggested by Roulot [25,26]: <8 kPa: no significant fibrosis; ≥8–<13 kPa: significant fibrosis; ≥13 kPa: cirrhosis. Studies have reported that threshold values of liver stiffness predictive for significant fibrosis (i.e. Metavir F score ≥2) ranged from 7 and 8.8 kPa. 2.2. Liver elastography measured by ARFI Acoustic Radiation Force Impulse Imaging (ARFI) is included in a conventional ultrasonographic system (Siemens ACUSON S2000
Virtual TouchTM Tissue Quantification; Siemens, Munich, Germany) with a standard broad-band 4–1 MHz curved probe (c-ARFI) and a standard broad band 9–4 MHz linear probe (l-ARFI). This allows the placement of the “region of interest” (ROI size: C4-1, 10 × 6 mm; ROI size: L9-4, 6 × 5 mm) under sight in ultrasonographic B-mode. In all 89 patients the insertion depth was variably used up to a maximum of 7 cm for the convex probe and 4 cm for the linear probe (Siemens Acuson S2000), but with a minimum distance of 1 cm below the liver capsule. Ultrasonographic elastography of the liver with ARFI was performed sequentially with the C4-1 and L9-4 probe. In all patients, measurements were performed at the right liver lobe in segment 8. Parameters of quality control were applied as for TE. In 39 of 89 patients (44%) c-ARFI and l-ARFI were performed at defined insertion depths of 3 cm, 4 cm, 5 cm, 6 cm for c-ARFI and 2 cm, 3 cm, 3.5 cm and 4 cm for l-ARFI. In order to prove if the vicinity of the liver capsule has really a strong influence on measurement values the study cohort of 89 chronic HCV-infected patients was extended by 40 additional patients with different chronic liver disease. In these patients only c-ARFI measurements 1 and 2 cm below the liver capsule were performed and data were compared to each other. 2.3. Biochemistry and ultrasonography Serum liver function tests (AST, ALT, bilirubin, gamma-GT, cholinesterase, albumin, prothrombin time, INR and platelets) and abdominal ultrasonographic findings (such as liver and spleen size, liver steatosis, signs of portal hypertension such as diameter of portal and splenic vein and presence of collateral vessels) and signs of relevant right heart insufficiency such as tetra-phasic flow in the right liver vein and highly undulating flow patterns or retrograde flow in the portal vein were noted in all patients. Ultrasonographic signs for hepatic steatosis were an increased echogenicity of the liver in comparison to the kidney parenchyma at the same depth and a decrease in intensity, which lead to a loss of visibility deeper within the liver. 2.4. Statistics SPSS software was used for statistical analysis (version 18.0, SPSS, Chicago, USA). All data are presented as mean ± S.D. p < 0.05 was considered statistically significant. Continuous variables of 2 independent groups were compared with the Student’s t test or Mann–Whitney’s U test depending on the distribution. Categorical variables were tested using Chi-square test (2 ) or Fisher’s exact test, as applicable. Correlations between parameters were expressed with Pearson’s or Spearman’s two-tailed pairwise correlation coefficients, as appropriate. Parameters that were statistically significant in univariate analysis were included in multivariate analysis using linear stepwise regression. Areas under the curve were (AUC) estimated for continuous variables using receiver operating characteristics analysis (ROC). Sensitivity and specificity were calculated from the ROC curves (for ARFI elastography).
3. Results 3.1. Characteristics of the study cohort A total of 89 HCV-infected patients (42 females and 47 males) with a mean age of 54 ± 13.4 years were prospectively included into the study. Table 1 shows basic clinical data of the patients. According to TE, different stages of liver fibrosis were calculated as follows: 34 patients (38%) were without significant fibrosis (group I: TE < 8 kPa), 23 patients (26%) had significant fibrosis (group II: TE
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3.2. Correlation of c-ARFI and l-ARFI with Fibroscan®
Table 1 Characteristics of the study cohort (n = 89). Parameter
Patients N = 89
Gender (female/male) Mean Age ± S.D. (years) ALT (U/L) (Range) Fibrosis stage (according to Fibroscan® ) Group I: No significant fibrosis (<8 kPa) Group II: Significant fibrosis (≥8–<13 kPa) Group III: Cirrhosis (≥13 kPa) Mean Fibroscan® ± S.D (kPa). Mean ARFI (C4-1 MHz) ± S.D. (m/s) Mean ARFI (L9-4 MHz) ± S.D. (m/s)
42/47 54 ± 13.4 81 (9–310) 34 (38%) 23 (26%) 32 (36%) 15.1 ± 13.86 1.70 ± 0.67 1.91 ± 0.87
Abbreviations: ALT, Alanine aminotransferase; kPa, Kilopascals; ARFI, Acoustic Radiation Force Impulse Imaging; m/s, meter per second; S.D., standard deviation.
≥8 and <13.0 kPa), and 32 patients (36%) presented with cirrhosis (group III: TE ≥ 13.0 kPa). In all 89 chronic HCV-infected patients, ARFI measurements were successfully performed with both probes. Shear wave velocity with c-ARFI ranged from 0.75 to 3.51 m/s (mean 1.70 ± 0.67 m/s). Shear wave velocities measured with l-ARFI were between 0.82 and 4.71 m/s (mean 1.91 ± 0.87 m/s). In the 40 additional patients (female/male 18/22, mean age 53 ± 14.4 years) with different chronic liver diseases mean c-ARFI values 1 cm and 2 cm below the liver capsule were 1.78 ± 0.87 m/s and 1.69 ± 0.75 m/s, respectively.
There was a statistically significant correlation between c-ARFI and TE as well as between l-ARFI and TE (p < 0.001; r = 0.82; r = 0.84, respectively; Fig. 1). Moreover, c-ARFI and l-ARFI were correlated to each other (r = 0.70, p < 0.001). Fig. 2 shows the distribution of the c-ARFI and l-ARFI values according to their fibrosis stages as measured by TE (described above). In patients without significant fibrosis, mean c-ARFI-and l-ARFI values were comparable (1.16 ± 0.28 m/s and 1.16 ± 0.20 m/s, respectively; n.s.). In contrast, patients with significant liver fibrosis showed significant difference between c-ARFI and l-ARFI (1.53 ± 0.40 m/s vs 2.02 ± 0.93 m/s; p < 0.001). In patients with liver cirrhosis, c-ARFI and l-ARFI values were significantly different as well (2.39 ± 0.50 m/s vs 2.63 ± 0.55 m/s; p < 0.001). Moreover, mean c-ARFI versus l-ARFI values were significantly different in the different fibrosis groups (group I-III, p < 0.001). ALT values were significantly correlated with c-ARFI as well as l-ARFI elastography results (r = 0.36, p = 0.001; r = 0.31, p = 0.007, respectively). 3.3. Influence of different insertion depths of the ROI and the liver capsule Mean c-ARFI and l-ARFI values at different insertion depths are shown in Fig. 3. Mean c-ARFI values at insertion depths of 3 cm, 4 cm, 5 cm and 6 cm were not significantly different (1.77 ± 0.79 m/s, 1.71 ± 0.71 m/s, 1.71 ± 0.64 and
Fig. 1. Comparison of Fibroscan® with ARFI elastography results using the convex (C4-1 MHz) and the linear probe (L9-4 MHz) (n = 89 with chronic HCV-infection). A: Correlation of Fibroscan® and c-ARFI. B: Correlation of Fibroscan® and l-ARFI. C: Correlation of c-ARFI and l-ARFI.
Fig. 2. ARFI for the different stages of liver fibrosis as estimated by Fibroscan® (n = 89 with chronic HCV-infection). A: c-ARFI: Boxplot analysis using the convex probe (C4-1 MHz) B: l-ARFI: Boxplot analysis using the linear probe (L9-4 MHz). Box plots show median values with 25th and 75th percentiles of shear wave velocity determined by ARFI. For boxplot analysis, liver fibrosis was graded according to Fibroscan® results as follows: <8 kPa, no significant fibrosis; ≥8 kPa and <13 kPa, significant fibrosis; ≥13 kPa, cirrhosis.
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Fig. 3. Influence of different insertion depths of the ROI (n = 39 with chronic HCV infection). Graphs show mean ARFI values and the standard error of mean (SEM). c-ARFI values showed no significant difference when using different insertion depths. l-ARFI results were significant lower when using an insertion depth of 4 cm. Correlation coefficients of c-ARFI with Fibroscan® were as follows: 0.768 for 3 cm, 0.841 for 4 cm, 0.882 for 5 cm, 0.864 for 6 cm (p < 0.001). Correlation coefficients of l-ARFI with Fibroscan® were as follows: 0.791 for 2 cm, 0.850 for 3 cm, 0.802 for 3.5 cm, 0.838 for 4 cm.
1.72 ± 0.71 m/s, respectively). Mean l-ARFI values were 1.87 ± 0.94 at 2 cm, 1.89 ± 0.81 m/s at 3 cm, 1.87 ± 0.76 m/s at 3.5 cm and 1.67 ± 0.66 m/s at 4 cm. Thus, significantly different values were observed for l-ARFI measurements at 4 cm insertion depth in comparison to the other depths (p = 0.003 compared to 3.5 cm; p < 0.001 compared to 3.0 cm and p = 0.009 compared to 2 cm). Correlation coefficients of c-ARFI with TE were highest when using insertion depths of 5 and 6 cm (r = 0.882, r = 0.864, p < 0.0001, respectively). Correlation coefficients of l-ARFI with TE were highest when using insertion depths of 3 and 4 cm (r = 0.850, r = 0.838, p < 0.0001 respectively). In the 40 additional patients with different chronic liver disease mean c-ARFI value obtained 1 cm below the liver capsule was significantly different to mean c-ARFI value 2 cm below the liver capsule (1.78 ± 0.87 m/s vs. 1.69 ± 0.75 m/s, p < 0.001, respectively). 3.4. ROC analysis of ARFI using both probes The diagnostic value (ROC curves) of liver stiffness measurement for patients with a Fibroscan® value of at least ≥8 kPa (groups II and III) is shown in Fig. 4a. Corresponding AUROC values were 0.91 for c-ARFI and 0.95 for l-ARFI. Based on the ROC curves the optimal cut-off value for c-ARFI and l-ARFI were chosen to maximize the sum of sensitivity and specificity. These cut-off levels were 1.41 m/s for c-ARFI (sensitivity 84%, specificity 85%) and 1.34 m/s for l-ARFI (sensitivity 89%, specificity 82%). The diagnostic value (ROC curves) of liver stiffness measurement for patients with “cirrhosis” (TE ≥ 13.0 kPa) is shown in Fig. 4b. Corresponding AUROC values were 0.97 for c-ARFI and 0.90 for l-ARFI. Cut-off levels for the detection of cirrhosis were 1.72 m/s (sensitivity 94% and specificity 98%) for c-ARFI and 2.04 m/s (sensitivity 84% and specificity 85%) for l-ARFI, respectively. 4. Discussion Acoustic Radiation Force Impulse Imaging (ARFI) as a new ultrasound based method of tissue elastography is increasingly used to assess liver stiffness. Clinical feasibility, diagnostic accuracy and validity of ARFI elastography have been recently summarized in a meta-analysis showing that ARFI using the convex probe (c-ARFI) is at least as effective as Fibroscan® (TE) to discriminate between liver fibrosis and cirrhosis [22]. In our study, l-ARFI elastography was as accurate as c-ARFI when compared to Fibroscan® . We observed a high significant correlation between l-ARFI elastography and TE in particular for detection of liver cirrhosis. l-ARFI achieved a high sensitivity (84%) and specificity (85%) for the detection of liver
cirrhosis. These results were comparable with previous studies using the C4-1 MHz transducer [15–18,22]. Furthermore, hepatic necroinflammatory activity indicated by elevated ALT levels showed significant changes of liver stiffness determined by ARFI in our study cohort. This is in line with a recently published study showing that ALT levels ≥2 upper the limit of normal (ULN) led to higher ARFI values [27]. In our study, box plot analysis of c-ARFI and l-ARFI showed significant difference within the different groups of fibrosis despite of some outlier patients. All of the outlier patients presented with slightly elevated ALT levels (<2-folds). Steatosis or relevant right heart insufficiency was excluded by ultrasound examination. Thus, we could not find an obvious explantation for the failure of accurate measurements of these patients. Our calculated optimal cut-off value for the detection of liver cirrhosis with l-ARFI was significantly higher (2.04 m/s) in comparison to c-ARFI (1.74 m/s) (p < 0.001). Another important finding of our study was that diagnostic accuracy of c-ARFI and l-ARFI was the highest when using insertion depths of 5–6 cm and 3–4 cm, respectively. Thus, our observations are in line with the previously described study by Chang and co-workers [28], in which measurements were performed in an elasticity phantom and in the liver of 8 healthy volunteers. As well as in our study they found a tendency to higher ARFI values with the linear probe (L9-4 MHz) compared to the convex probe (C4-1 MHz) at the same insertion depth and a variability of mean ARFI when using different insertion depths. Variability of ARFI elastography was lower when using insertion depths of 2–3 cm for the linear probe and 4–5 cm for the convex probe [28]. Moreover, our data are in accordance with the experimental study by Zhao, who recommended c-ARFI measurements at a distance of at least >4 cm from the liver capsule. The different cut-off values for c-ARFI and l-ARFI and the variability of ARFI values when using different insertion depths can be explained by the different physical properties of the transducers (intensity field of the push beam, the size of the true measurement ROI and the aperture size). The tolerance of transducers of ±20% contributes to the spread of measurement values and the standard deviation, respectively, within the literature. The vicinity of the liver capsule plays another important role in the diagnostic accuracy of ARFI. In our study significant difference of mean c-ARFI was found between the different insertion depths close to the liver capsule (1 cm and 2 cm below the liver capsule). Our results confirmed the observations made by Sporea and coworkers [12], who recommended to perform ARFI elastography at least 1–2 cm below the liver capsule.
A. Potthoff et al. / European Journal of Radiology 82 (2013) 1207–1212 Fig. 4. AUROC curves for both ARFI methods in the detection of liver fibrosis estimated by Fibroscan® (n = 89 with chronic HCV infection). A: Area under the curve for the detection of significant fibrosis (Fibroscan® ≥8 kPa). B: Area under the curve for the detection of cirrhosis (Fibroscan® ≥13 kPa).
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Thus, for comparison of c-ARFI and l-ARFI a correction factor is needed and depth-dependent changes in the shear wave velocities must be taken into account to provide accurate measurements of c-ARFI and l-ARFI in clinical practice. In conclusion, our study suggested that diagnostic accuracy of ARFI elastography of the liver using the linear probe (L9-4 Mhz) is comparable to the convex probe (C4-1 MHz). However, l-ARFI gives higher values than c-ARFI. Furthermore, the best diagnostic accuracy can be achieved when using insertion depths of 3–4 cm for l-ARFI, 5–6 cm for c-ARFI and a distance below the liver capsule of at least 1 cm. Conflict of interest Declaration of interest: Andrej Potthoff, Michael Gebel and Kinan Rifai have participated in studies and received lecture fees supported by Siemens Healthcare AG (Munich). References [1] Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008;134:1670–81. [2] Dienstag JL. The role of liver biopsy in chronic hepatitis C. Hepatology 2002;36:S152–60. [3] Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. American Journal of Gastroenterology 2002;97: 2614–8. [4] Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–57. [5] Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology 2008;48:835–47. [6] 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;55:403–8. [7] Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Gastroenterology 2008;134:960–74. [8] Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Ledinghen V, Douvin C, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. Journal of Hepatology 2008;49:1062–8. [9] de Ledinghen V, Ratziu V, Causse X, Le Bail B, Capron D, Renou C, et al. Diagnostic and predictive factors of significant liver fibrosis and minimal lesions in patients with persistent unexplained elevated transaminases. A prospective multicenter study. Journal of Hepatology 2006;45:592–9. [10] Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Ledinghen V, et al. Noninvasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver International 2009;29:242–7. [11] Sporea I, Sirli RL. Hepatic elastography for the assessment of liver fibrosis – present and future. Ultraschall in der Medizin 2012;33:550–8. [12] Sporea I, Sirli RL, Deleanu A, Iulia R, Tudora A, Dan I, et al. What did we learn from the first 3,459 cases of liver stiffness measurement by transient elastography (FibroScan(R))? Ultraschall in der Medizin 2011;32:40–5.
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