|Year : 2018 | Volume
| Issue : 2 | Page : 538-543
Real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C
Zeinab A Ali1, Ashraf A Zytoon1, Mahmoud M Elsakhawy2, Ramadan M Algamal3
1 Department of Radiology, Faculty of Medicine, National Liver Institute, Menoufia University, Menoufia, Egypt
2 Diagnostic and Intervention Medical Imaging Department, National Liver Institute, Menoufia University, Menoufia, Egypt
3 Department of Radiology, Shebien Elkom Teaching Hospital, Menoufia, Egypt
|Date of Submission||23-Sep-2017|
|Date of Acceptance||05-Nov-2017|
|Date of Web Publication||27-Aug-2018|
Ramadan M Algamal
Department of Radiology, Shebien Elkom Teaching Hospital, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of this study was to evaluate the diagnostic accuracy of real-time shear wave elastography (SWE) in assessment of liver fibrosis in patients with chronic hepatitis C compared with the liver biopsy.
Chronic hepatitis C is a global disease and one of the most intractable clinical problems in Egypt with drastic consequences. Diagnosis and grading of hepatic fibrosis is one of the chief clues in selection of appropriate plan of treatment and follow-up.
Patient and methods
This study included 161 patients (male/female = 112/49) with chronic hepatitis C and 30 healthy control (male/female = 25/5). Liver biopsy and transient elastography were done for all patients before SWE examination.
Different liver fibrosis stages were observed (13.7% F0, 20% F1, 11.2% F2, 23.6% F3, and 31.1% F4); the reference range of liver stiffness in the diseased group by SWE was 5.2–22.5 kPa and control group was 2–4.5 kPa. There was significant discrimination between mild fibrosis (F1), with reference range from 4 to 5.3 kPa, and significant fibrosis of at least F2, with area under the receiver operating characteristic curve of 0.994 and P value of less than 0.0001, and between mild fibrosis F2 (5.7–12.2 kPa) and severe fibrosis F3 (13.2–21.6 kPa) and F4 cirrhosis of at least 22.1 kPa, with area under the receiver operating characteristic curve of 0.995 and P value of less than 0.0001. There was strong correlation between SWE staging of fibrosis and that of liver biopsy (Kendall's τ-b was 0.892).
Being noninvasive and regarding its accuracy SWE can replace liver biopsy with its related complication dilemma. SWE can also replace transient elastography for being a real-time treatment with enhanced accuracy.
Keywords: cirrhosis, elastography, hepatitis C, liver stiffness, ultrasound
|How to cite this article:|
Ali ZA, Zytoon AA, Elsakhawy MM, Algamal RM. Real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C. Menoufia Med J 2018;31:538-43
|How to cite this URL:|
Ali ZA, Zytoon AA, Elsakhawy MM, Algamal RM. Real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C. Menoufia Med J [serial online] 2018 [cited 2019 Jan 18];31:538-43. Available from: http://www.mmj.eg.net/text.asp?2018/31/2/538/239757
| Introduction|| |
The liver is a chief player in the human body and is commonly affected with hepatitis C virus (HCV) infection, which is a global disease. Approximately, 70 million persons are chronically infected with HCV worldwide , with the highest estimated prevalence in Egypt, accounting for 11 to 14% of the population estimated to have chronic infection .
In chronic hepatitis C (CHC), prognosis and management is determined largely by the extent of fibrosis ,.
Currently, the place of liver biopsy as the standard of reference for assessing liver fibrosis has been challenged by the increasing awareness of a number of drawbacks related to its use (invasiveness and sampling error). In parallel with this, noninvasive assessment of liver fibrosis has experienced explosive growth in recent years, and a variety of noninvasive methods ranging from serum assays to imaging techniques have been developed .
Shear wave elastography (SWE) is a new technique that is based on shear waves implemented in a diagnostic ultrasound (US) system. SWE estimates the speed of a shear wave to provide a quantitative estimate of tissue stiffness. SWE has the advantage of being able to image liver stiffness in real time, because the shear waves are generated by US pulses. Additionally, the SWE image is guided by a higher frame-rate B-mode image. This method could result in a more accurate score of fibrosis staging, resulting from the SWE and B-mode image guidance ,.
| Patients and Methods|| |
After approval of the Local Institutional Ethical Committee of National Liver Institute and obtaining written consents from all patients to participate in our study, this study was done in Diagnostic and Intervention Medical Imaging Department at National Liver Institute from March 2015 to October 2016. The study was carried on randomly selected 161 patients presented to the outpatient and Sovaldi project clinics in National liver institute and Shebien Elkom Teaching Hospital and 30 healthy controls who came to liver institute for evaluation of unexplained jaundice, suspected drug reactions, toxicity, and abnormal liver function test result.
The inclusion criteria were patients with CHC (with diagnosis of more than 6 months) and serum HCV-RNA positive.
Patients with congestive heart failure, acute hepatitis, recently diagnosed CHC (<6 months), thyroid disorders, inferior vena cava/hepatic vein thrombosis, previous thermal ablation, previous microwave ablation, previous TACE, younger than 20 years, uncontrolled depression, uncontrolled diabetes mellitus, and having undergone antiviral therapy were excluded from the study.
All patients underwent the following procedures: clinical examination including full history taking, BMI assessment, HCV-RNA assessment, liver biopsy, and transient elastography (TE). Thereafter, all patients underwent US examination which was performed with SWE implemented on a convex probe (C5-1) of Philips iU22 x-Matrix apparatus (Philips Ultrasound, Bothell, WA.98021 USA). Patients were in a supine position. Real-time US examination was done to locate the region of interest (ROI) in the right lobe of liver (especially segment V or VIII) approximately 2 cm beneath and perpendicular to Glisson capsule. The patients were then instructed to hold breath for starting measurement by initiating shear wave pulses through the same convex probe which propagates in the liver tissue, and by using the ultrafast acquisition rate and the Doppler frequency shift, the machine estimates the velocity of the propagated shear wave in the ROI and automatically translates it to stiffness in KPs.
Multiple successful measurements are obtained; the results appear in the final report as the average of all measurements.
Data were analyzed using Stata, version 14.2 (StataCorp LLC, College Station, Texas, USA).
Normality of numerical data distribution was examined using the Shapiro–Wilk test. Non-normally distributed numerical data were presented as median and interquartile, and intergroup differences were compared using the Wilcoxon rank sum test (for two-group comparison) or the Jonckheere-Terpstra trend test (for comparison of multiple ordered group). The Conover test was used for post-hoc comparisons following the Jonckheere-Terpstra test if needed with application of the Bonferroni correction for multiple pairwise comparisons.
Categorical data were presented as number and percentage and differences were compared using Fisher's exact test (for nominal data) or the χ2-test for trend (for ordinal data).
Correlations among ordinal variables were tested using the Spearman rank correlation and Kendall rank correlation.
| Results|| |
The study was carried on 161 patients with CHC and 30 healthy controls. In the patients, 112 (69%) were males and 49 (31%) were females. Their age ranged from 23 to 63 years, with a mean age of 43 years. In the control group, 25 (83%) were males and five (17%) were females, and their age ranged from 24 to 61 years, with mean age of 42 years.
In this study, there was no statistical significance regarding age (P = 0.184) and sex (P = 0.194) on liver stiffness.
In our study, the liver stiffness among participants was as following: 22 F0, 33 F1, 18 F2, 38 F3, and 50 F4, and regarding control group, 28 F0 and 2 F1.
Significant difference were found between patients with CHC virus and controls using liver stiffness measured with SWE (P ≤ 0.0001) and area under the receiver operating characteristic (AUROC) of 0.951.
The reference range of liver stiffness in the diseased group with variable degrees of chronicity and virology by SWE was 5.2–22.5 kPa and that of control group from 2 to 4.5 kPa, with significant discrimination between the healthy and diseased patients (P > 0.0001.
There was a significant discrimination between mild or no fibrosis (F1) and significant fibrosis (≥F2) with AUROCs of 0.994 and P value of less than 0.0001.
There was strong correlation between liver stiffness by SWE and degree of fibrosis by liver biopsy (P ≤ 0.00001) [Table 1].
|Table 1: Correlation and agreement between shear wave elastography and liver biopsy for grading of hepatic fibrosis as measured in the whole study population|
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The most important SWE findings was the ability to differentiate between F2 (mild fibrosis) and F3 (severe fibrosis) in CHC with (P ≤ 0.0001) and AUROC of 0.995 [Table 2].
|Table 2: Receiver operating characteristic curve analysis for discrimination between patients with F2 and F3 chronic hepatitis C using liver stiffness measured with shear wave elastography|
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There was also strong correlation between SWE and TE for grading of hepatic fibrosis in the whole study population, with P ≤ 0.001 and AUROC of 0.934.
This study shows significant discrimination between F3 (severe fibrosis) and F4 (cirrhosis) of at least 22.1 kPa, with AUR OCs of 0.952 and P value of less than 0.0001 [Figure 1], [Figure 2], [Figure 3].
|Figure 1: A 61-year-old female patient, with positive HCV antibodies. HCV PCR. result. is 20 300 000 IU/l. The liver is cirrhotic with no hepatic focal lesions and the spleen is enlarged. The patient is staged F4 by liver biopsy, F3 by transient elastography, and F4 by shear wave elastography.|
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|Figure 2: A 42-year-old male patient with positive HCV antibodies. HCV PCR result is 689 000 IU/l. The liver shows periportal fibrosis, with no hepatic focal lesions, and the spleen is enlarged. The patient was staged F3 by liver biopsy, F3 by transient elastography, and F3 by shear wave elastography.|
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|Figure 3: A 44-year-old male patient with positive HCV antibodies. HCV PCR result is 542 000 IU/l. The liver is enlarged, with no hepatic focal lesions, and the spleen is normal size. The patient is staged F2 by liver biopsy, F2 by transient elastography, and F2 by shear wave elastography.|
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| Discussion|| |
Cirrhosis is one of the major complications of CHC in Egypt. Cirrhosis is a major risk factor for the development of hepatocellular carcinoma .
Liver biopsy was one of the earliest and gold standard approaches to evaluate liver fibrosis/cirrhosis; however, it has complications and pitfalls of being an invasive procedure with preprocedural primary tests, evaluation and preparations, operational complications of pain, infections and bleeding, postprocedural hospital stay, observations, and medications ,. The biopsy sample has own set of difficulties, errors, and limitations from the sample volume to the preservation of the sample, and finally, experience of the pathologist. Biopsy requires multiple lines of sampling, preservation, and interpretations. Nowadays, liver biopsy is certainly not the ideal procedure for assessment of liver fibrosis .
Numerous noninvasive approaches have been developed and evaluated to stage liver fibrosis in the past decade including TE and different MR and US techniques. Only fibroscan (TE) has successfully entered into clinical practice, particularly in most European countries. However, there is considerable variation in the performances reported for TE to predict significant fibrosis . TE is also hindered by the number of noninterpretable measurements, reaching nearly 20% of cases .
Concerning the control group in this study (which represent 30 healthy persons), the aim was to assess the normal liver stiffness range values in healthy controls, without overt causes of liver disease and normal liver enzymes. The study results state 2 to 4.5 kPa as lower and upper limits for normal liver elasticity. The cutoff value is at least 4.4 KPa, and this finding is slightly different from a study by Suh et al. , where the reference range of normal hepatic elasticity was 2.6–6.2 kPa, with 6.2 kPa as a cutoff value.
Few studies have evaluated two-dimensional SWE for the staging of liver fibrosis ,,, one of which used liver biopsy as reference method . This study by Leung et al.  evaluated SWE accuracy in 226 patients with chronic hepatitis B (METAVIR fibrosis stage 17% F0, 23% F1, 25% F2, 20% F3, and 15% F4). 2D-SWE had AUROCs of 0.88 and 0.98 for the diagnosis of significant fibrosis and cirrhosis, respectively; moreover, sensitivities and specificities were 85 and 92%, respectively, for the diagnosis of significant fibrosis, and 97 and 93%, respectively, for the diagnosis of cirrhosis. Another study by Toshifumi and colleagues clarified the diagnostic effect of liver fibrosis using SWE in patients with CHC. The study concluded that SWE has a high ability to diagnose significant liver fibrosis .
In this study, the reference range of liver stiffness in the diseased group with variable degrees of chronicity and virology by SWE was 5.2–22.5 kPa, with significant discrimination between the healthy and diseased patients. Moreover, significant discrimination was found between mild or no fibrosis (F1) and significant fibrosis (≥F2), with AUROCs of 0.994, 95% confidence interval (95% CI) from 0.965 to 1.0, and Youden index J of 0.932. The cutoff value is at least 5.73 KPs, with sensitivity of 100%, specificity of 93.22%, positive predictive value of 95.7%, and negative predictive value of 100%. These results are more assured than a study by Ferraioli et al. , as the AUROCs in differentiating no or mild fibrosis (F1) from significant fibrosis (≥F2) were 0.92 with cutoff value of at least 6.2 KPs.
This study shows significant discrimination between F2 (7.2–10.2 kPa) and F3 (13.2–19.6 kPa) severe fibrosis, with AUROCs of 0.995, 95% CI from 0.965 to 1.0, and Youden index J of 0.974. The cutoff value was at least 11.7 KPs, with sensitivity 97.3%, specificity 100%, positive predictive value 100%, and negative predictive value 97.3%. These results are better than those obtained by a study by Ferraioli et al.  in differentiating F2 from F3, with cutoff value of least 10 KPs and 90% sensitivity and 87% specificity; however, this difference might be because the study was performed on Aixplorer supersonic imagine, which is a very specialized machine, but is not as advanced as Philips iU22 (the one used in our study).
This study shows significant discrimination between F3 (severe fibrosis) and F4 (cirrhosis) of at least 22.1 kPa, with AUROCs of 0.952, 95% CI from 0.904 to 0.981, and Youden index J of 0.835. The cutoff value was at least 22.1 KPs, with sensitivity 99.0%, specificity 93%, PPV 83.7%, and NPP 96.2%. This result is slightly different from a study by Ferraioli et al.  in differentiating F3 from F4, with cutoff value of at least 15.7 KPs and 90% sensitivity and 87% specificity; however, this difference might be because the study was performed on Aixplorer supersonic imagine, which is a very specialized machine, but is not as advanced as Philips iU22 (our study machine).
Another single-center study was conducted to assess the accuracy of SWE in patients with CHC, in comparison with TE, by using liver biopsy as the reference standard, and fibrosis was staged according to the METAVIR scoring system. In the study, the diagnostic accuracy of real-time SWE and TE in estimating liver fibrosis was compared against histology in patients with CHC. Real-time SWE measurements compared favorably with that of TE in assessing severe fibrosis and cirrhosis. Real-time SWE demonstrated a significant improvement in the identification of significant fibrosis, when compared with TE. The study suggests that real-time SWE can be used in the same way as TE in the evaluation of severe fibrosis and cirrhosis, with the benefit of improved assessment of significant fibrosis .
In this study, there was a very strong correlation and agreement between TE and liver biopsy in staging of fibrosis in the diseased group (Kendall's τ-b was 0.857, Spearman's ρ value was 0.917, and weighted κ-test value was 0.749).
In this study, there was a strong correlation and agreement between SWE and liver biopsy in staging of fibrosis in the diseased group (Kendall's τ-b was 0.892, Spearman's ρ value was 0.941, and weighted κ-test value was 0.835).
This study show strong correlation and agreement between SWE and TE in the staging of fibrosis in the diseased group (Kendalls τ-b was 0.902, Spearman's ρ value was 0.947, and weighted κ- test value was 0.873).
The accuracy of SWE in relation to TE was the aim of several previous studies that stated that real-time SWE exhibited a significantly higher ability to identify intermediate stages of fibrosis in comparison with TE. In the study by Ferraioli and colleagues, the AUROCs in differentiating no/mild fibrosis (F0–F1) from significant fibrosis (F > 2) were 0.84 and 0.92 for TE and real-time SWE, respectively. The performances of real-time SWE in identifying severe fibrosis (F ≥ 3) and cirrhosis (F4) were similar to that of TE (0.98 and 0.96, respectively, for severe fibrosis, and 0.98 and 0.96, respectively, for cirrhosis), which were already quite high. These findings suggest that real-time SWE can be used similarly as TE in the assessment of severe fibrosis and cirrhosis, with the benefit of improved assessment of significant fibrosis .
Finally, being in real time, the number of erroneous or extreme results was significantly decreased owing to elimination of sites of hepatic focal lesions from the ROI and also the sites of the ligaments and blood vessels, which give extreme erroneous results.
This study has multiple points of strength. The study was done in a specialized liver institute, with many linked facilities for imaging, laboratory, and biopsy. The imaging facility had the most innovated high-line ultrasound and SWE machine at that time. The study population was large enough, and the procedure was done by a specialist and revised by three consultants. The results correlated with biopsy and histopathology.
The study has one limitation: the relative small number of control subjects owing to difficulty in biopsy in a healthy person.
| Conclusion|| |
SWE overcomes errors of biopsy and limitations of TE, and this study shows high accuracy of SWE in grading of liver fibrosis in patients with CHC. SWE can replace liver biopsy in assessment of liver fibrosis for being noninvasive and having high accuracy. SWE can replace TE in assessment of liver fibrosis for being a real-time technique and having high accuracy. SWE is recommended for screening of liver fibrosis for being a noninvasive outpatient technique with no morbidity or mortality in contrast to liver biopsy.
SWE is recommended for follow-up of liver fibrosis as it can predict the incidence of hepatocellular carcinoma and esophageal varices by measuring liver stiffness in various segments of the liver.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hanafiah K, Groeger J, Flaxman A, Wiersma S. Global epidemiology of hepatitis C virus infection: new estimates of age estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013; 57
Abdelmoneim S, Kamel S, Ahmed M, Naser A, Aly M. Risk factors for progression of chronic hepatitis c infection to cirrhosis in rural Upper Egypt: a retrospective study. AAMJ 2013; 11
Ghani M, Strader D, Ghany MG, Seeff L. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. J Hepatol 2009; 49
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55
Papastergiou V, Tsochatzis E, Burroughs A. Non-invasive assessment of liver fibrosis. Ann Gastroenterol 2012; 25
Bavu É, Gennisson M, Couade M, Bercoff J, Mallet V, FinK M, et al.
Noninvasive in vivo
liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients Ultrasound Med Biol 2011; 37
Ferraioli G, Tinelli C, Lissandrin R, zicchetti M, Dal Bello B, Fillice G. Reproducibility and performance of a new point shear wave elastography technique for assessing fibrosis in chronic hepatitis C. World J Gastroenterol 2014; 20
Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C. Global epidemiology of hepatitis C virus infection: an up-date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol 2016; 22
Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39
Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000; 32
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. Am J Gastroenterol 2002; 97
Castera L, Foucher J, Bernard P, Carvalho F, Allaix D, Merrouche W, et al.
Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010; 51
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
Suh CH, kim SY, Kim KW, Lim YS, Lee SJ Lee MG, et al.
Determination of normal hepatic elasticity by using real-time shear-wave elastography. Radiology 2014; 271
Muller M, Gennisson JL, Deffieux T, Fink M. Quantitative Viscoelasticity Mapping of Human Liver Using Supersonic Shear Imaging: Preliminary In Vivo
Feasability Study. Ultrasound Med Boil 2009; 35
Frulio N, Trillaud H. Ultrasound elastography in liver. Diagn Interv Imaging 2013; 94
Leung V, Shen J, Wong V, Abriqo J, Wong GL, Chim AM, et al.
Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology 2013; 269
Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Okuda S, et al.
Utility of real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C infection without cirrhosis: comparison of liver fibrosis indices. Hepatol Res 2015; 45
Ferraioli G, Tinelli C, Zicchetti M, Above E, Poma G, Di Greqorio M, et al.
Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity. Eur J Radiol 2012; 81
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]