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The performance of acoustic radiation force impulse imaging in predicting liver fibrosis in chronic liver diseases
Kaohsiung Journal of Medical Sciences (2016) 32, 362e366
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.kjms-online.com
ORIGINAL ARTICLE
The performance of acoustic radiation force impulse imaging in predicting liver fibrosis in chronic liver diseases Yi-Hung Lin b, Ming-Lun Yeh b,c, Ching-I Huang b, Jeng-Fu Yang b, Po-Cheng Liang a,b, Chung-Feng Huang b,c, Chia-Yen Dai b,c,d, Zu-Yau Lin b,c, Shinn-Cherng Chen b,c, Jee-Fu Huang b,c,d,*, Ming-Lung Yu b,c,d, Wan-Long Chuang b,c,d a
Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan b Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan c Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan d Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Received 14 April 2016; accepted 11 May 2016
Available online 28 June 2016
KEYWORDS Acoustic radiation force impulse imaging; Chronic liver disease; Liver fibrosis
Abstract Sonography-based noninvasive liver fibrosis assessment is promising in the prediction of treatment efficacy and prognosis in chronic liver disease (CLD) patients. Acoustic radiation force impulse imaging (ARFI) is a newly-developed transient elastography (TE) method integrated into a conventional ultrasound machine. The study aimed to assess the performance of ARFI imaging in the diagnosis of liver fibrosis in Taiwanese CLD patients. We also aimed to search for the optimal cut-off values in different fibrosis stages. A total of 60 CLD patients (40 males; mean age, 51.8 11 years) were consecutively included. They received standard ARFI measurement within 2 weeks at the time of liver biopsy. There were eight patients with Metavir fibrosis stage 0 (F0), 16 patients with F1, 20 patients with F2, eight patients with F3, and eight patients with F4, respectively. The mean values among patient with F0, F1, F2, F3, and F4 were 1.17 0.13, 1.30 0.17, 1.31 0.24, 2.01 0.45, and 2.69 0.91, respectively (p < 0.001). The optimal cut-off ARFI value for significant fibrosis (F 2) was 1.53 with the accuracy of 0.733, while it was 1.66 for advanced fibrosis (F 3) with the accuracy of 0.957. Our
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. E-mail address: [email protected] (J.-F. Huang). http://dx.doi.org/10.1016/j.kjms.2016.05.008 1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
ARFI and liver fibrosis
363 study demonstrated that ARFI imaging is competent for fibrosis diagnosis, particularly in CLD patients with advanced fibrosis. Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Introduction Chronic liver disease (CLD) of various etiologies, such as chronic hepatitis B (CHB) or chronic hepatitis C (CHC), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), is the leading cause of hepatocellular carcinoma (HCC) globally. The main pathogenic mechanism underlying hepatocarcinogenesis is necroinflammation and its subsequent fibrogenesis [1,2]. Therefore, severity estimation of liver fibrosis is important for treatment efficacy, prognosis, HCC surveillance and determining the best treatment strategies in CLD patients [3,4]. Liver biopsy, as the gold standard method for the assessment of liver fibrosis, is an invasive method associated with patient discomfort and sometimes with serious complications [5,6]. Biopsy is associated with a bleeding risk of 1% and a mortality rate of w0.01% [3,5]. Additionally, liver biopsies are often considered “imperfect” surrogate markers for liver fibrosis assessment because of inherent limitations. These include invasiveness, risk of life-threatening complications, intra- and inter-observer variability, and sampling error. In addition to serum biomarkers, several ultrasoundbased methods have been vigorously developed and validated for assessing the degree of fibrosis and cirrhosis by measuring liver stiffness in the past decade. These ultrasound-based methods shed a new light in the aspect of noninvasive evaluation of liver fibrosis. They have provided good diagnostic accuracy in a clinical setting [7,8]. Acoustic radiation force impulse (ARFI) imaging is a newly-developed transient elastography (TE) method integrated into a conventional ultrasound machine and can be performed with ultrasound probes during an abdominal ultrasound examination [8]. Previous studies have indicated that it is a good predictor of liver fibrosis stages in CLD patients, particularly in CHC patients [8,9]. However, the performance of ARFI in Asians across different etiologies remains to be clarified and validated. The aim of the study was to assess the performance of ARFI in the diagnosis of liver fibrosis in Taiwanese CLD patients. The optimal cut-off values were also evaluated according to different fibrosis stages in a clinical basis.
Kaohsiung, Taiwan, approved the study before it began. The study was conducted according to the Declaration of Helsinki. Written informed consent for anthropomorphic measurements, ARFI measurement, blood sampling, and medical record review were obtained from patients prior to enrollment.
ARFI measurement ARFI measurement was performed with curved-array transducer (6CI probe) of the Siemens ACUSON S2000 ultrasound system (Siemens Medical Solutions, Erlangen, Germany). The 10 mm 5 mm region of interest was focused on the right liver lobe via an intercostal approach. All patients were measured on the right lobe at a depth of w2e3 cm below the capsule during relaxed breath-holding. Food intake increased shear wave values significantly, especially when consumed < 3 hours prior to measurements. Therefore all patients had enough fasting time (> 10 hours). The mean shear wave velocity (m/s), standard deviation, and number of effective measurements were recorded. At least 10 successful acquisitions were measured for each patient. ARFI-failure was defined as no successful ARFI measurement after 10 attempts and an interquartile range greater than 30%. The interquartile range is defined as the difference between the 75th percentile, essentially the range of the middle 50% of the data.
Histology grading and staging Liver biopsy was performed within 2 weeks of ARFI measurement using an echo-assisted method. For each patient, a liver biopsy specimen of at least 1.5 cm in length was taken and fixed in 10% formalin buffer. Biopsy samples were stained with hematoxylin-eosin and the results were then reported by a dedicated liver pathologist blinded to each patient. Histological grading was performed based on the histological activity index (HAI) by Knodell et al. [10]. Fibrosis score (F0eF4) was determined according to the Metavir scoring systems [11]. Significant fibrosis and advanced fibrosis are defined as F2, and F3e4, respectively.
Methods Statistical analyses Patients Between October, 2013 and November, 2014, a total of 60 CLD patients were consecutively included in this study. All patients received a liver biopsy aiming to elucidate their histopathological manifestations in a clinical setting. The Ethics Committee of Kaohsiung Medical University Hospital,
The demographic data were expressed as mean values standard deviation (SD). ARFI results were expressed as mean values SD and were compared between groups using analysis of variance. The diagnostic performances of ARFI in the diagnosis of fibrosis stages were evaluated by receivereoperator characteristic (ROC) curves. The area
364
Y.-H. Lin et al.
under the ROC curves (AUROC) and the 95% confidence interval were used as indexes of accuracy. All statistical analyses were based on two-sided hypothesis tests with a significance level of p < 0.05. Quality control procedures, database processing, and analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA).
Results A total of 60 CLD patients (40 males; mean age, 51.8 11 years) were consecutively investigated. There were four patients in the CHB group, 67 patients in the CHC group, and 10 patients in the NASH group, respectively. All ARFI measurements were successfully achieved. There were eight patients with a score of F0, 16 patients with F1, 20 patients with F2, eight patients with F3, and eight patients with F4, respectively (Table 1). The mean ARFI measurement value among all patients was 1.57 0.64. The mean values among F0, F1, F2, F3, and F4 were 1.17 0.13, 1.30 0.17, 1.31 0.24, 2.01 0.45, and 2.69 0.91, respectively (p < 0.001; Figure 1). The optimal cut-off ARFI value for significant fibrosis (F 2) was 1.53. The sensitivity, specificity, positive predictive value, negative predictive value, and the accuracy were 0.528,
Table 1 Basic demographical and clinical features of the patients. n Z 60 Age (y) Sex. n (%) Male Female Etiology n (%) HBV HCV NASH Body weight (kg) BMI (kg/m2) WBC (/mL) Hb Platelet (1000/mL) AST (IU/L) ALT (IU/L) Bilirubin Alkaline-P Albumin Creatinine Fibrosis stage, n (%) F0 F1 F2 F3 F4
51.8 (11.0) 40 (67) 20 (33) 3 47 10 72.8 26.7 5742.9 14.3 178.6 68.7 92.1 1.1 104.3 4.3 0.8 8 16 20 8 8
(5) (78) (17) (12.0) (3.5) (1616.2) (1.5) (61.2) (57.2) (72.0) (0.4) (107.3) (0.4) (0.2) (13) (27) (33) (13) (13)
Data are presented as mean standard deviation, unless otherwise indicated. ALT Z alanine aminotransferase; AST Z aspartate aminotransferase; BMI Z body mass index; F Z Metavir fibrosis stage; HBV Z hepatitis B virus; HCV Z hepatitis C virus; NASH Z nonalcoholic steatohepatitis; WBC Z white blood cell.
Figure 1. The calculated cut-off value and AUROC areas of ARFI elastometry were F3e4 cut-off value Z 1.66, AUROC Z 0.957; F2 cut-off value Z 1.53, AUROC Z 0.733; F1 cut-off value Z 1.44, AUROC Z 0.804. ARFI Z Acoustic radiation force impulse imaging; AUROC Z area under the receivereoperator characteristic curves.
0.958, 0.950, 0.575, and 0.733, respectively. The optimal cut-off ARFI value for advanced fibrosis (F 3) was 1.66. The sensitivity, specificity, positive predictive value, negative predictive value, and the accuracy were 0.875, 0.977, 0.933, 0.956, and 0.957, respectively (Table 2).
Discussion Liver fibrosis is the final result of liver injury of various etiologies. The assessment and prediction of liver fibrosis severity is important in therapeutic decision-making and in prognosis prediction of CLD. Liver biopsy, regarded as the gold standard in this aspect for decades, has been challenged by many newly-developed noninvasive tools in the past decade. Our study demonstrated that ARFI imaging is a competent diagnostic tool for the diagnosis of fibrosis, particularly for the diagnosis of advanced fibrosis in Taiwanese CLD patients. The optimal cut-off values found in this study are therefore proven for clinical use in the Asian population. Precise measurement of the fibrotic lesion is important. First, progressive fibrosis is believed to predict progression to cirrhosis and/or HCC, particularly in CLD patients [12]. The fibrosis stage may predict the likelihood of response to Table 2 Diagnostic performance, optimal cut-offs, and validity of ARFI for the diagnosis of liver fibrosis. Optimal cut-off F0 F1 F2 F3 F4
1.20 1.32 1.53 1.66 1.98
Sensitivity Specificity PPV 0.712 0.596 0.528 0.875 0.583
0.75 0.875 0.958 0.977 0.904
0.949 0.969 0.95 0.933 0.583
NPV Accuracy 0.286 0.25 0.575 0.956 0.904
0.717 0.633 0.733 0.957 0.9
ARFI Z Acoustic radiation force impulse imaging; NPV Z negative predictive value; PPV Z positive predictive value.
ARFI and liver fibrosis antiviral therapeutic interventions in CLD patients [3,13]. In addition, a stage of significant fibrosis implies that an aggressive therapeutic approach is needed for the amelioration of fibrosis progression. Surveillance of portal hypertension such as portal pressure measurement and varices evaluation with esophagogastric endoscope examination is indicated in CLD patients with advanced fibrosis [14]. Our results were in accordance with a previous pooled metaanalysis of ARFI, which reported diagnostic accuracies of 0.93 for the diagnosis of liver cirrhosis, 0.91 for the diagnosis of severe fibrosis and 0.87 for the diagnosis of significant fibrosis [15]. ARFI has been developed as a sonographic-based method involving the mechanical excitation of tissue using short-duration acoustic pulses. These produce propagation of shear waves, generating localized minute displacements in the tissue. The shear wave velocity measured in a region of interest is smaller than that of other TE methods [16]. The major advantage of this technology is that it can be easily implemented on a modified commercial sonographic machine. Previous studies have indicated that its performance was comparable to other TE-based methods, such as FibroScan, in CHC patients [15,17]. In addition, ARFI is easily performed and is rarely failed technically, giving it a promising advantage in clinical application. Despite the fact that TE-based methods provide good diagnostic accuracy, characteristics that limit the use of TE include the high cost of the equipment, the need for regular recalibration, trained operators, and the lack of validated cut-off values for specific fibrosis stages. However, the performance of ARFI might be limited by the narrow range of values. Therefore, validation across different races with CLD is needed to acquire the regional and/or racial optimal cut-off values in clinical practice. Our results further addressed the concern that the narrow metrics of ARFI measurement might undermine its performance. The other limitation of the study was the somewhat heterogeneous composition of the patients, particularly the limited CHB patients. Lack of other noninvasive tools for comparison also limited the clinical application of our results. Meanwhile, whether a high alanine aminotransferase level affects the performance of sonography-based methods remains to be elucidated [18]. The point might not be fully clarified with the limited patient numbers in the study. Further collaborative study with other developing noninvasive tools is needed to gain a wider spectrum of validation to compensate for this disadvantage. In conclusion, the current study demonstrated that ARFI imaging is a good diagnostic tool for noninvasive liver fibrosis assessment, particularly for the diagnosis of advanced fibrosis in CLD patients. The study also provided the optimal cut-off values for clinical use in the Asian population. Further studies to validate the TE-based methods across different etiologies in different regions and races are needed.
Acknowledgments This study was supported partly by grants from the Ministry of Science and Technology, Taiwan (102-2314-B-037-019,
365 102-2314-B-037-024-MY3). The authors thank the secretary and serum processing assistants from Taiwan Liver Research Foundation. The foundation did not influence how the study was conducted or the approval of the manuscript.
References [1] Huang JF, Huang CF, Yu ML, Dai CY, Huang CI, Yeh ML, et al. Serum visfatin is correlated with disease severity and metabolic syndrome in chronic hepatitis C infection. J Gastroenterol Hepatol 2011;26:530e5. [2] Yu ML, Huang CF, Dai CY, Huang JF, Chuang WL. Long-term effects of interferon-based therapy for chronic hepatitis C. Oncology 2007;72(Suppl 1):16e23. [3] Huang JF, Yu ML, Lee CM, Dai CY, Hou NJ, Hsieh MY, et al. Sustained virological response to interferon reduces cirrhosis in chronic hepatitis C: a 1,386-patient study from Taiwan. Aliment Pharmacol Ther 2007;25:1029e37. [4] Omata M, Kanda T, Yu ML, Yokosuka O, Lim SG, Jafri W, et al. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int 2012;6:409e35. [5] Huang JF, Hsieh MY, Dai CY, Hou NJ, Lee LP, Lin ZY, et al. The incidence and risks of liver biopsy in non-cirrhotic patients: An evaluation of 3806 biopsies. Gut 2007;56:736e7. [6] Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001; 344:495e500. [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 meta-analysis. Gastroenterology 2008;134:960e74. [8] Cassinotto C, Lapuyade B, Mouries A, Hiriart JB, Vergniol J, Gaye D, et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan. J Hepatol 2014;61:550e7. [9] Goertz RS, Sturm J, Zopf S, Wildner D, Neurath MF, Strobel D. Outcome analysis of liver stiffness by ARFI (acoustic radiation force impulse) elastometry in patients with chronic viral hepatitis B and C. Clin Radiol 2014;69:275e9. [10] Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1: 431e5. [11] The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994;20: 15e20. [12] Yu ML, Dai CY, Lee LP, Hsieh MY, Hou NJ, Huang JF, et al. Outcome of chronic hepatitis C patients who required early termination of pegylated interferon-alpha plus ribavirin combination therapy. Antivir Ther 2006;11:1015e9. [13] Huang JF, Yu ML, Huang CF, Chiu CF, Dai CY, Huang CI, et al. The efficacy and safety of pegylated interferon plus ribavirin combination therapy in chronic hepatitis C patients with hepatocellular carcinoma post curative therapies - a multicenter prospective trial. J Hepatol 2011;54:219e26. [14] Rockey DC. Noninvasive assessment of liver fibrosis and portal hypertension with transient elastography. Gastroenterology 2008;134:8e14. [15] Friedrich-Rust M, Nierhoff J, Lupsor M, Sporea I, FierbinteanuBraticevici C, Strobel D, et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2012;19:e212e9. [16] Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut 2010; 59:861e6.
366 [17] Takahashi H, Ono N, Eguchi Y, Eguchi T, Kitajima Y, Kawaguchi Y, et al. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study. Liver Int 2010;30:538e45.
Y.-H. Lin et al. [18] Calvaruso V, Camma ` C, Di Marco V, Maimone S, Bronte F, Enea M, et al. Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy. J Viral Hepat 2010;17:469e74.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.kjms-online.com
ORIGINAL ARTICLE
The performance of acoustic radiation force impulse imaging in predicting liver fibrosis in chronic liver diseases Yi-Hung Lin b, Ming-Lun Yeh b,c, Ching-I Huang b, Jeng-Fu Yang b, Po-Cheng Liang a,b, Chung-Feng Huang b,c, Chia-Yen Dai b,c,d, Zu-Yau Lin b,c, Shinn-Cherng Chen b,c, Jee-Fu Huang b,c,d,*, Ming-Lung Yu b,c,d, Wan-Long Chuang b,c,d a
Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan b Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan c Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan d Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Received 14 April 2016; accepted 11 May 2016
Available online 28 June 2016
KEYWORDS Acoustic radiation force impulse imaging; Chronic liver disease; Liver fibrosis
Abstract Sonography-based noninvasive liver fibrosis assessment is promising in the prediction of treatment efficacy and prognosis in chronic liver disease (CLD) patients. Acoustic radiation force impulse imaging (ARFI) is a newly-developed transient elastography (TE) method integrated into a conventional ultrasound machine. The study aimed to assess the performance of ARFI imaging in the diagnosis of liver fibrosis in Taiwanese CLD patients. We also aimed to search for the optimal cut-off values in different fibrosis stages. A total of 60 CLD patients (40 males; mean age, 51.8 11 years) were consecutively included. They received standard ARFI measurement within 2 weeks at the time of liver biopsy. There were eight patients with Metavir fibrosis stage 0 (F0), 16 patients with F1, 20 patients with F2, eight patients with F3, and eight patients with F4, respectively. The mean values among patient with F0, F1, F2, F3, and F4 were 1.17 0.13, 1.30 0.17, 1.31 0.24, 2.01 0.45, and 2.69 0.91, respectively (p < 0.001). The optimal cut-off ARFI value for significant fibrosis (F 2) was 1.53 with the accuracy of 0.733, while it was 1.66 for advanced fibrosis (F 3) with the accuracy of 0.957. Our
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. E-mail address: [email protected] (J.-F. Huang). http://dx.doi.org/10.1016/j.kjms.2016.05.008 1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
ARFI and liver fibrosis
363 study demonstrated that ARFI imaging is competent for fibrosis diagnosis, particularly in CLD patients with advanced fibrosis. Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Introduction Chronic liver disease (CLD) of various etiologies, such as chronic hepatitis B (CHB) or chronic hepatitis C (CHC), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), is the leading cause of hepatocellular carcinoma (HCC) globally. The main pathogenic mechanism underlying hepatocarcinogenesis is necroinflammation and its subsequent fibrogenesis [1,2]. Therefore, severity estimation of liver fibrosis is important for treatment efficacy, prognosis, HCC surveillance and determining the best treatment strategies in CLD patients [3,4]. Liver biopsy, as the gold standard method for the assessment of liver fibrosis, is an invasive method associated with patient discomfort and sometimes with serious complications [5,6]. Biopsy is associated with a bleeding risk of 1% and a mortality rate of w0.01% [3,5]. Additionally, liver biopsies are often considered “imperfect” surrogate markers for liver fibrosis assessment because of inherent limitations. These include invasiveness, risk of life-threatening complications, intra- and inter-observer variability, and sampling error. In addition to serum biomarkers, several ultrasoundbased methods have been vigorously developed and validated for assessing the degree of fibrosis and cirrhosis by measuring liver stiffness in the past decade. These ultrasound-based methods shed a new light in the aspect of noninvasive evaluation of liver fibrosis. They have provided good diagnostic accuracy in a clinical setting [7,8]. Acoustic radiation force impulse (ARFI) imaging is a newly-developed transient elastography (TE) method integrated into a conventional ultrasound machine and can be performed with ultrasound probes during an abdominal ultrasound examination [8]. Previous studies have indicated that it is a good predictor of liver fibrosis stages in CLD patients, particularly in CHC patients [8,9]. However, the performance of ARFI in Asians across different etiologies remains to be clarified and validated. The aim of the study was to assess the performance of ARFI in the diagnosis of liver fibrosis in Taiwanese CLD patients. The optimal cut-off values were also evaluated according to different fibrosis stages in a clinical basis.
Kaohsiung, Taiwan, approved the study before it began. The study was conducted according to the Declaration of Helsinki. Written informed consent for anthropomorphic measurements, ARFI measurement, blood sampling, and medical record review were obtained from patients prior to enrollment.
ARFI measurement ARFI measurement was performed with curved-array transducer (6CI probe) of the Siemens ACUSON S2000 ultrasound system (Siemens Medical Solutions, Erlangen, Germany). The 10 mm 5 mm region of interest was focused on the right liver lobe via an intercostal approach. All patients were measured on the right lobe at a depth of w2e3 cm below the capsule during relaxed breath-holding. Food intake increased shear wave values significantly, especially when consumed < 3 hours prior to measurements. Therefore all patients had enough fasting time (> 10 hours). The mean shear wave velocity (m/s), standard deviation, and number of effective measurements were recorded. At least 10 successful acquisitions were measured for each patient. ARFI-failure was defined as no successful ARFI measurement after 10 attempts and an interquartile range greater than 30%. The interquartile range is defined as the difference between the 75th percentile, essentially the range of the middle 50% of the data.
Histology grading and staging Liver biopsy was performed within 2 weeks of ARFI measurement using an echo-assisted method. For each patient, a liver biopsy specimen of at least 1.5 cm in length was taken and fixed in 10% formalin buffer. Biopsy samples were stained with hematoxylin-eosin and the results were then reported by a dedicated liver pathologist blinded to each patient. Histological grading was performed based on the histological activity index (HAI) by Knodell et al. [10]. Fibrosis score (F0eF4) was determined according to the Metavir scoring systems [11]. Significant fibrosis and advanced fibrosis are defined as F2, and F3e4, respectively.
Methods Statistical analyses Patients Between October, 2013 and November, 2014, a total of 60 CLD patients were consecutively included in this study. All patients received a liver biopsy aiming to elucidate their histopathological manifestations in a clinical setting. The Ethics Committee of Kaohsiung Medical University Hospital,
The demographic data were expressed as mean values standard deviation (SD). ARFI results were expressed as mean values SD and were compared between groups using analysis of variance. The diagnostic performances of ARFI in the diagnosis of fibrosis stages were evaluated by receivereoperator characteristic (ROC) curves. The area
364
Y.-H. Lin et al.
under the ROC curves (AUROC) and the 95% confidence interval were used as indexes of accuracy. All statistical analyses were based on two-sided hypothesis tests with a significance level of p < 0.05. Quality control procedures, database processing, and analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA).
Results A total of 60 CLD patients (40 males; mean age, 51.8 11 years) were consecutively investigated. There were four patients in the CHB group, 67 patients in the CHC group, and 10 patients in the NASH group, respectively. All ARFI measurements were successfully achieved. There were eight patients with a score of F0, 16 patients with F1, 20 patients with F2, eight patients with F3, and eight patients with F4, respectively (Table 1). The mean ARFI measurement value among all patients was 1.57 0.64. The mean values among F0, F1, F2, F3, and F4 were 1.17 0.13, 1.30 0.17, 1.31 0.24, 2.01 0.45, and 2.69 0.91, respectively (p < 0.001; Figure 1). The optimal cut-off ARFI value for significant fibrosis (F 2) was 1.53. The sensitivity, specificity, positive predictive value, negative predictive value, and the accuracy were 0.528,
Table 1 Basic demographical and clinical features of the patients. n Z 60 Age (y) Sex. n (%) Male Female Etiology n (%) HBV HCV NASH Body weight (kg) BMI (kg/m2) WBC (/mL) Hb Platelet (1000/mL) AST (IU/L) ALT (IU/L) Bilirubin Alkaline-P Albumin Creatinine Fibrosis stage, n (%) F0 F1 F2 F3 F4
51.8 (11.0) 40 (67) 20 (33) 3 47 10 72.8 26.7 5742.9 14.3 178.6 68.7 92.1 1.1 104.3 4.3 0.8 8 16 20 8 8
(5) (78) (17) (12.0) (3.5) (1616.2) (1.5) (61.2) (57.2) (72.0) (0.4) (107.3) (0.4) (0.2) (13) (27) (33) (13) (13)
Data are presented as mean standard deviation, unless otherwise indicated. ALT Z alanine aminotransferase; AST Z aspartate aminotransferase; BMI Z body mass index; F Z Metavir fibrosis stage; HBV Z hepatitis B virus; HCV Z hepatitis C virus; NASH Z nonalcoholic steatohepatitis; WBC Z white blood cell.
Figure 1. The calculated cut-off value and AUROC areas of ARFI elastometry were F3e4 cut-off value Z 1.66, AUROC Z 0.957; F2 cut-off value Z 1.53, AUROC Z 0.733; F1 cut-off value Z 1.44, AUROC Z 0.804. ARFI Z Acoustic radiation force impulse imaging; AUROC Z area under the receivereoperator characteristic curves.
0.958, 0.950, 0.575, and 0.733, respectively. The optimal cut-off ARFI value for advanced fibrosis (F 3) was 1.66. The sensitivity, specificity, positive predictive value, negative predictive value, and the accuracy were 0.875, 0.977, 0.933, 0.956, and 0.957, respectively (Table 2).
Discussion Liver fibrosis is the final result of liver injury of various etiologies. The assessment and prediction of liver fibrosis severity is important in therapeutic decision-making and in prognosis prediction of CLD. Liver biopsy, regarded as the gold standard in this aspect for decades, has been challenged by many newly-developed noninvasive tools in the past decade. Our study demonstrated that ARFI imaging is a competent diagnostic tool for the diagnosis of fibrosis, particularly for the diagnosis of advanced fibrosis in Taiwanese CLD patients. The optimal cut-off values found in this study are therefore proven for clinical use in the Asian population. Precise measurement of the fibrotic lesion is important. First, progressive fibrosis is believed to predict progression to cirrhosis and/or HCC, particularly in CLD patients [12]. The fibrosis stage may predict the likelihood of response to Table 2 Diagnostic performance, optimal cut-offs, and validity of ARFI for the diagnosis of liver fibrosis. Optimal cut-off F0 F1 F2 F3 F4
1.20 1.32 1.53 1.66 1.98
Sensitivity Specificity PPV 0.712 0.596 0.528 0.875 0.583
0.75 0.875 0.958 0.977 0.904
0.949 0.969 0.95 0.933 0.583
NPV Accuracy 0.286 0.25 0.575 0.956 0.904
0.717 0.633 0.733 0.957 0.9
ARFI Z Acoustic radiation force impulse imaging; NPV Z negative predictive value; PPV Z positive predictive value.
ARFI and liver fibrosis antiviral therapeutic interventions in CLD patients [3,13]. In addition, a stage of significant fibrosis implies that an aggressive therapeutic approach is needed for the amelioration of fibrosis progression. Surveillance of portal hypertension such as portal pressure measurement and varices evaluation with esophagogastric endoscope examination is indicated in CLD patients with advanced fibrosis [14]. Our results were in accordance with a previous pooled metaanalysis of ARFI, which reported diagnostic accuracies of 0.93 for the diagnosis of liver cirrhosis, 0.91 for the diagnosis of severe fibrosis and 0.87 for the diagnosis of significant fibrosis [15]. ARFI has been developed as a sonographic-based method involving the mechanical excitation of tissue using short-duration acoustic pulses. These produce propagation of shear waves, generating localized minute displacements in the tissue. The shear wave velocity measured in a region of interest is smaller than that of other TE methods [16]. The major advantage of this technology is that it can be easily implemented on a modified commercial sonographic machine. Previous studies have indicated that its performance was comparable to other TE-based methods, such as FibroScan, in CHC patients [15,17]. In addition, ARFI is easily performed and is rarely failed technically, giving it a promising advantage in clinical application. Despite the fact that TE-based methods provide good diagnostic accuracy, characteristics that limit the use of TE include the high cost of the equipment, the need for regular recalibration, trained operators, and the lack of validated cut-off values for specific fibrosis stages. However, the performance of ARFI might be limited by the narrow range of values. Therefore, validation across different races with CLD is needed to acquire the regional and/or racial optimal cut-off values in clinical practice. Our results further addressed the concern that the narrow metrics of ARFI measurement might undermine its performance. The other limitation of the study was the somewhat heterogeneous composition of the patients, particularly the limited CHB patients. Lack of other noninvasive tools for comparison also limited the clinical application of our results. Meanwhile, whether a high alanine aminotransferase level affects the performance of sonography-based methods remains to be elucidated [18]. The point might not be fully clarified with the limited patient numbers in the study. Further collaborative study with other developing noninvasive tools is needed to gain a wider spectrum of validation to compensate for this disadvantage. In conclusion, the current study demonstrated that ARFI imaging is a good diagnostic tool for noninvasive liver fibrosis assessment, particularly for the diagnosis of advanced fibrosis in CLD patients. The study also provided the optimal cut-off values for clinical use in the Asian population. Further studies to validate the TE-based methods across different etiologies in different regions and races are needed.
Acknowledgments This study was supported partly by grants from the Ministry of Science and Technology, Taiwan (102-2314-B-037-019,
365 102-2314-B-037-024-MY3). The authors thank the secretary and serum processing assistants from Taiwan Liver Research Foundation. The foundation did not influence how the study was conducted or the approval of the manuscript.
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