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Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature
The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx
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Original Article
Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature Rania E. Mohamed a,⇑, Mohamed A. Amin a, Hazem M. Omar b, Mohamed Y. Rabea c, Mona A. Abd Elazeem d a
Radiodiagnosis and Imaging Department, Tanta University, Tanta, Egypt Diagnostic and Interventional Radiology Department, National Liver Institute, Menoufya University, Menoufya, Egypt Tropical Medicine Department, Tanta University, Tanta, Egypt d Pathology Department, Tanta University, Tanta, Egypt b c
a r t i c l e
i n f o
Article history: Received 21 August 2016 Accepted 16 December 2016 Available online xxxx Keywords: Ultrasound Elastography Shear wave Liver Point quantification
a b s t r a c t Introduction: Hepatic fibrosis is the underlying pathological condition in chronic hepatitis C virus (HCV) infection. Shear wave elastography (SWE) with elastography point quantification (ElastPQ) feature is a recently developed method for measuring tissue elasticity. Aim of this study: To evaluate the diagnostic value of SWE with ElastPQ feature for the quantitative assessment of liver fibrosis in patients with chronic HCV infection. Patients and methods: This prospective study included 60 patients with chronic HCV infection and 50 healthy controls. All participants underwent imaging with ElastPQ technique for evaluation of the liver stiffness (LS). All patients underwent ultrasound guided liver biopsy. The METAVIR scores of fibrosis were illustrated. Results: The study participants included 50 controls (mean LS 3.12 ± 0.40 kPa), 5 patients with F0 score (mean LS 3.77 ± 1.44 kPa); 10 patients with F1 score (mean LS 7.50 ± 0.68 kPa), 23 patients with F2 score (mean LS 8.45 ± 0.62 kPa), 17 patients with F3 score (mean LS 9.64 ± 1.20 kPa) and 5 patients with F4 score (mean LS 12.61 ± 1.41 kPa). There was a highly significant correlation between the METAVIR scores of liver fibrosis and LS measurements assessed by ElastPQ SWE (p > 0.0001). Conclusion: The ElastPQ SWE technique appears as a reliable non-invasive tool that can provide an optimal way to monitor liver tissue stiffness in patients with chronic HCV infection with high accuracy (97.6%) in recognition of the earlier fibrosis stage (F2). Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
1. Introduction Chronic viral hepatitis infections are the most important public health problems leading to a significant rate of morbidity and mortality. Hepatitis C virus (HCV) infection in Egypt carries the highest prevalence worldwide [1], which is estimated to be 14.7% in the 15–59 years age group, reflecting a national level epidemic [2]. A wide variety of liver diseases usually ends in hepatic fibrosis which
Abbreviations: SWE, shear wave elastography; ElastPQ, elastography point quantification; LB, liver biopsy; LS, liver stiffness. Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine. ⇑ Corresponding author. E-mail address: [email protected] (R.E. Mohamed).
is responsible for most of the clinical complications in patients with chronic HCV infection. Fibrosis is a dynamic pathological scarring condition in which chronic inflammation leads to the production and accumulation of collagen and extracellular matrix proteins with potential progression to cirrhosis [3]. Furthermore, the clinical management and prognosis in patients with chronic liver disease depend largely on the degree of fibrosis [4]. Liver biopsy (LB) is still considered as the standard reference for the evaluation of liver fibrosis and degree of histo-pathological damage in patients with chronic liver disease [3]. However, this method is not suitable for frequent monitoring due to its invasive nature which may be associated with some complications, in addition to technical limitations derived from small sampling or intra-observers and inter-observer variability in staging of fibrosis. All these limitations have motivated the efforts to search for new
http://dx.doi.org/10.1016/j.ejrnm.2016.12.010 0378-603X/Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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R.E. Mohamed et al. / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx
non-invasive approaches [5,6]. In the last decade, ultrasoundbased techniques have become commercially available to quantify the degree of liver fibrosis [3]. Shear wave ultrasonographic elastography (SWE) with elastography point quantification (ElastPQ) feature is a recently developed, non-invasive method for measuring tissue elasticity, which gives a local assessment and measurement of the shear wave propagation speed at each point of interest of an organ in kilopascals (kPa). This imaging method is operator-independent, reproducible, and quantitative [7–9]. It works by generating electronic voltage pulses, which are transmitted to the transducer. In the transducer, a piezo electric array converts the electronic pulse into an ultrasonic pressure wave [10,11]. The maximum penetration depth of ElastPQ is 8 cm. Therefore, it may offer an ideal way to monitor liver tissue stiffness [10]. The aim of this study is to prospectively evaluate the diagnostic value of SWE with ElastPQ feature as a non-invasive method for the in vivo quantitative assessment of liver fibrosis in patients with chronic hepatitis C virus and compare the results with fibrosis stage assessed by the histological METAVIR scoring system and biopsy samples as the reference methods.
2. Materials and methods 2.1. Study participants and study design The current study is a prospective study, carried out in the period between March 2015 and May 2016. Study participants, recruited from the Hepatology outpatient clinic in our institutions, included sixty consecutive patients with chronic HCV infection, in addition to fifty consecutive healthy volunteers served as a control group. The patients were 38 males and 22 females; their ages ranged between 25 and 69 years, while controls were 32 males and 18 females; their ages ranged between 18 and 65 years. Patients were recognized on the basis of clinical data, and laboratory findings including the liver function tests, and polymerase chain reaction (PCR) for HCV. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) levels were estimated in all subjects. Serum levels of AST and ALT above 37 unit/liter and 40 unit/liter, respectively, were considered abnormal. However, so as to avoid inclusion of transient episodes of acute hepatitis, only patients with stable AST and ALT within the last 6 months and thereafter were included in this study. The patients’ characteristics, epidemiological data and biochemical test results were recorded. Assessment of liver fibrosis with the liver stiffness (LS) measurements was prospectively estimated in all subjects by using ElastPQ SWE. The study criteria excluded patients with history of decompensated liver diseases or co-infection with chronic hepatitis B virus or other liver disease that may have influenced the hepatic parenchyma and the extent of liver stiffness such as; congestive heart disease, liver failure, chronic renal disease, hemchromatosis, hepatolenticular degeneration, biliary obstructive disease and fatty liver. Patients with liver tumor or gross ascites, and patients who received antiviral and/or interferon therapy during the study period were also excluded. The control group consisted of healthy volunteers, who visited the Hepatology outpatient clinic of our institution for medical checkup. They did not receive any medications and did not show history of chronic liver disease. They all had normal B-mode ultrasonographic examination, normal liver function tests, and negative PCR. An official permission to perform this work was achieved from the local medical research ethical committee. A written informed consent was also obtained from all study participants.
2.2. Ultrasound and ElastPQ shear wave elastography technique Initially, all study participants underwent B-mode liver ultrasound scanning with iU22 ultrasound system (iU22, Philips Medical Systems, Bothell, WA, USA), which was adapted to generate shear waves via its ElastPQ feature (Fig. 1A). During ultrasound examination, quantitative evaluation of the LS was performed by ElastPQ using a convex transducer C5-1 (1–5 MHz; C5-1, Philips Healthcare). Sub-costal and intercostals scans were used to reach and visualize the 8 liver segments (I–VIII). The maximum penetration depth of ElastPQ is 8 cm. [10]. Each region of interest (ROI) was simulated by a fixed sample box with predefined size of 15 5 mm, which was placed by moving a trackball, in a hepatic parenchymal area that did not include large vasculature, biliary structures and away from the heart, diaphragm, liver/kidney interface, or liver capsule (at least 1.5–3 cm below the Glisson’s capsule). The study participants were all instructed to suspend their breath during the actual scanning with breathing rehearsals were allowed while measurements were obtained. Furthermore, for all study participants; three 10measurement elastographic cine clips were obtained at each of the following locations in the liver: (a) left lobe, (b) upper right lobe, and (c) lower right lobe. So, to provide a more comprehensive evaluation, total of thirty measurements were obtained across the liver for off line analysis. We considered the median values of LS measurements, which were automatically calculated, were reliable if 10 valid successful measurements (out of the 30 measurements) of both hepatic lobes in each study participant were obtained. These measurements were expressed either in meters/seconds (m/s) or kilopascals (kpa). However, if we could not obtain 10 valid measurements after 20–25 attempts, we considered these cases as invalid failed measurements and they were excluded from the study [3,11]. The means of the median values were then statistically calculated in the group of patients and compared with those of the control group. The median values of LS measurements card (which is displayed to the left of the image; as shown in Fig. 1B) and the bias reference table were automatically calculated and displayed on the screen over a B-mode ultrasound image. The bias reference table is a reference table which describes the potential variation that obtained at different sample depths in m/s and does not vary by patient (Fig. 1C). Finally a sample report was generated at the end of examination (Fig. 1D). The average of these measurements was then used to estimate the degree of liver stiffness, which was correlated with a predicted biopsy METAVIR score. The mean values of each fibrosis stage were statistically calculated and then they were compared with each other. 2.3. Liver biopsy and histopathological evaluation All patients underwent ultrasound guided liver biopsy, which was performed in the same day, immediately after ElastPQSWE. The liver biopsy was carried out through a semi-automatic 18G needle by experienced interventional radiologist. All the biopsy specimens were analyzed by a qualified pathologist using the METAVIR scoring system [12], which evaluates both necro-inflammatory changes as well as degree of fibrosis. The fibrosis score was assessed on a five-point scale (F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = few septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis). 2.3.1. Statistical analysis The SPSS for Windows version 18.0 software package (SPSS Inc, Chicago, IL) was used for statistical data analysis. Data of continuous variables were reported as mean ± standard deviation (SD),
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
R.E. Mohamed et al. / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx
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Fig. I A
Fig.I C
Fig.I B
Fig. I D
Fig. 1. (A–D): Demonstrates the ElastPQ SWE technique and its machine (1 A). The liver stiffness measurement card (1 B) which is displayed to the left of the obtained image. The bias reference Fig. 1C which is shown as a reference table to describe the potential variation in meters/s obtained at different sample depths and does not vary by patient. Fig. 1D shows the automatically generated sample report of 10 valid successful LS measurements of both hepatic lobes. It is displayed on the screen of the ElastPQ SWE machine.
while categorical variables were reported as number of patients and percentages (%). The Chi-square, t-tests and ANOVA tests (with the Fisher exact and Tukey’s subtests) were used to compare and correlate the given data. The P value below 0.05 was considered statistically significant. The final histopathological diagnosis was considered as the reference standard. Additionally, the areas under the curves (AUCs); the receiver operating characteristic (ROC) curves, were built for ElastPQ to evaluate its diagnostic performance in differentiating different stages of liver fibrosis. The optimal cutoff values were used to evaluate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of ElastPQSWE in all study participants.
3. Results Liver stiffness was evaluated by means of ElastPQSWE in sixty consecutive patients with chronic HCV infection; in addition to fifty consecutive healthy volunteers served as a control group. The group of patients consisted of 38 (63.3%) males and 22 (36.7%) females; their ages ranged between 25 and 69 years with a mean age of 48.04 ± 8.54 years. On the other hand, the controls
were 32 (64%) males and 18 (36%) females; their ages ranged between 18 and 65 years with a mean age of 44.72 ± 12.11 years. Table 1 showed a comparison of some patients’ characteristics versus the control. In the current study, the mean age (48.04 vs. 44.72 years) was not significantly higher in patients compared to controls (p > 0.05), while the mean BMI was significantly higher in patients compared to controls (p < 0.05). Additionally, all liver function tests were significantly higher in patients compared to controls (p < 0.05). In all included subjects, technical success was achieved and valid results were obtained. According to the METAVIR score of fibrosis, the patients were categorized as follows: 5 (5/60; 8.3%) patients without liver fibrosis (F0 score), 10 (10/60; 16.7%) patients with mild liver fibrosis (F1 score) and patients with significant fibrosis included 23 (23/60; 38.3%) patients of F2 score, 17 (17/60; 28.4%) patients of F3 score and 5 (5/60; 8.3%) patients of F4 score. Furthermore, the mean liver stiffness measurements of the study participants by ElastPQSWE was 3.12 ± 0.40 kPa for healthy control (Fig. 7), 3.77 ± 1.44 kPa for F0 patients (Fig. 8), 7.50 ± 0.68 kPa for F1 patients (Figs. 9 and 10), 8.45 ± 0.62 kPa for F2 patients (Figs. 11 and 12), 9.64 ± 1.20 kPa for F3 patients (Figs. 13 and 14) and 12.61 ± 1.41 kPa for F4 patients (Figs. 15 and 16). Moreover, we found a highly significant correlation
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Table 1 Demographic data and liver function tests of the studied groups. Characteristics
Patients (n = 60)
Controls (n = 50)
t-test
P-value
Age (years)
25–69 (48.04 ± 8.54) 18.8–43.2 (31.0 ± 5.66) 35–78.8 (47.1 ± 3.2) 25–68.8 (35.1 ± 3.9) 60.8–98.8 (71.5 ± 8.5) 63.8–207.1 (48.7 ± 15.4) 18.7–33.5 (24.5 ± 6.3) (50.5–109.3) 89.5 ± 12.7 36.7–56.6 (40. 2 ± 5.3)
18–65 (44.72 ± 12.11) 15.8–31.7 (20.0 ± 7.24) 25–37.8 (28.1 ± 2.9) 14–42.7 (20.1 ± 2.9) 46–115.7 (47.1 ± 11.9) 37.5–50 (40.1 ± 6.9) 00.0–17.5 (5.5 ± 8.563) 5.5–85.4 (40.1 ± 7.9) 18.7–34.6 (23. 2 ± 4.3)
1.681
0.095
6.261
0.017⁄
32.347
<0.001⁄
22.497
<0.001⁄
12.512
<0.001⁄
3.653
0.0004⁄
13.385
<0.001⁄
23.909
<0.001⁄
18.223
<0.001⁄
2
BMI (kg/ m ) AST (IU/L) ALT (IU/L) Alkaline phosphatase (IU/L) Serum albumin (g/L) Total bilirubin (lmol/L) GGT (IU/L) Gamma-globulins (g/L)
Results are expressed as range (mean ± standard deviation). n = number, BMI = body mass index, kg = kilogram, m2 = square meters, AST = Aspartate aminotransaminase, ALT = Alanine aminotransaminase, IU/L = international unit/ liter, g/L = gram/liter, lmol/L = micromole/liter, GGT = Gamma-glutamyl transferase.
SWE
16 14
Mean±SD
12 10 8 6 4 2 0
F0
F1
F2
F3
F4
Fig. 2. Demonstrates the mean LS measurements (mean ± SD) in different subgroups of the studied patients obtained in kPa by using ElastPQ SWE technique.
Table 2 Staging of liver fibrosis in the study participants according to the METAVIR score of fibrosis and the hepatic ElastPQSWE measurements. Study participants
Control (n = 50) Patients (n = 60)
n (%)
F0 F1 F2 F3 F4
ElastPQSWE
50 (100%) 5 (8.3%) 10 (16.7%) 23(38.3%) 17 (28.4%) 5 (8.3%)
ANOVA
Range
Mean ± SD
F
0.43–4.5 1.43–5.70 5.77–8.30 7.36–9.08 9.09–11.55 10.56–14.50
3.12 ± 0.40 3.77 ± 1.44 7.50 ± 0.68 8.45 ± 0.62 9.64 ± 1.20 12.61 ± 1.41
147.57 < 0.0001
P-value
Tukey’s test (P-value) F0& F1 0.119
F0& F2 <0.001
F0& F3 <0.001
F0& F4 <0.001
F1& F2 0.01
F1& F3 <0.001
F1& F4 <0.001
F2& F3 0.019
F2& F4 <0.001
F3& F4 <0.001
n = number, (%) = percent, SWE = shear wave elastography, SD = standard deviation, ANOVA = analysis of variants, F = fisher exact test.
Table 3 Accuracy of ElastPQSWE in differentiating the grades of hepatic fibrosis with optimal cut off point of liver stiffness measured in (kPa) in the studied patients (n = 60).
PF1 (F0 vs. F1-2-3-4) PF2 (F0-1 vs. F2-3-4) PF3 (F0-1-2 vs. F3-4) F = 4 (F0-1-2-3 vs. F4)
Cut-off
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
AUC
Accuracy (%)
6.9 7.5 9.1 10.21
93.3 93.3 90.9 100.0
100.0 90.8 97.7 96.2
100.0 87.5 90.5 55.6
98.0 95.2 96.6 100.0
0.998 0.976 0.957 0.992
99 98 96 99
between the METAVIR scores of liver fibrosis and liver stiffness measurements assessed by ElastPQSWE (p > 0.0001). So, the increased METAVIR score of fibrosis was associated with increased means of liver stiffness measurements in kPa (Fig. 2). However, on
comparing the METAVIR stages of fibrosis to each other by the Tukey’s test, all comparisons were found to be significant (p < 0.05) except when F0 was compared to F1; it was nonsignificant (p = 0.119); as shown in Table 2.
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 3. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage PF1 at a cutoff value of 6.9 kPa. The AUC is 0.998 with 93.3% sensitivity, 100% specificity and 99% accuracy.
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Fig. 5. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage PF3 at a cutoff value of 9.1 kPa. The AUC is 0.957 with 90.9% sensitivity, 97.7% specificity and 96% accuracy.
The optimal cut-off values for different levels of fibrosis were determined by analyzing the ROC curves for ElastPQSWE. The cut-off values of ElastPQSWE for each METAVIR stage of fibrosis, along with the area under curves (AUCs), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for optimal cutoff values for each of the ROC curves were summarized in Table 3. The ROC curve (Fig. 3A and B) was drawn to differentiate fibrosis stage of at least F1 or more from other stages of fibrosis by using ElastPQSWE with an AUC of 0.998 at an optimal cut-off value of 6.9 kPa (sensitivity 93.3%, Specificity 100% and accuracy 99%). Moreover, the AUC for differentiating fibrosis stage of at least F2 or more from other stages of fibrosis, was 0.976 with an optimal cut-off value of 7.5 kPa (sensitivity 93.3%, specificity 90.8% and accuracy 98%) (Fig. 4A and B). Additionally, the AUC for differentiating fibrosis stages of F3 or more from other stages of fibrosis, was 0.957 with an optimal cut-off value of 9.1 kPa (sensitivity 90.9%, specificity 97.7% and accuracy 96%) (Fig. 5A and B). On the other hand, the AUC for differentiating stage F4 fibrosis from fibrosis stage less than F4 was 0.992 with an optimal cut-off value of 10.21 kPa (sensitivity 100%, specificity 96.2% and accuracy 99%) (Fig. 6A and B).
4. Discussion
Fig. 4. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage PF2 at a cutoff value of 7.5 kPa. The AUC is 0.976 with 93.3% sensitivity, 90.8% specificity and 98% accuracy.
Without proper and timely interference, progressive hepatic fibrosis will gradually lead to cirrhosis, hepatocellular carcinoma, and finally liver failure [13,14] with increased mortality rates [3]. Therefore, in patients with chronic HCV infection, the accurate diagnosis and assessment of liver fibrosis is essential for the pre-
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 6. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage of F4 at a cutoff value of 10.21 kPa. The AUC is 0.992 with 100% sensitivity, 96.2% specificity and 99% accuracy.
vention, prognosis and optimization of treatment plan [15,16]. Liver biopsy is the gold standard diagnostic modality for liver fibrosis, but because of its associated morbidities, this technique cannot be used as routine [17].
Recently, non-invasive methods for assessing liver fibrosis have been thoroughly studied [8]. As an alternative of a costly and painful biopsy procedure, an easy ultrasound examination becomes the routine method to assess liver disease status [18]. Transient elastography (TE) is the oldest and most applied ultrasound-based elastographic technique. However, results can be difficult to obtain in patients with obesity or narrow intercostals spaces, and ascites [11]. Quantitative SWE is an efficient technique for the noninvasive diagnosis and staging of liver fibrosis [19]. The SWE with ElastPQ feature can be considered as an alternative non-invasive diagnostic modality to liver biopsy [11]. The current prospective study sheds light on the diagnostic utility of SWE with ElastPQ feature for liver fibrosis assessment in patients with chronic HCV infections while using liver biopsy as the standard reference. In previous studies [6,7,9], individuals with body mass index (BMI) higher than 30 kg/m2 were excluded from these studies due to the difficulty of shear wave elastographic imaging of lesions deeper than 5 cm. On contrary, by using the ElastPQ, we did not face such restriction as the maximum penetration depth of ElastPQ technique is 8 cm which allowed measurements in patients with relatively high BMI (31.0 ± 5.66) including patients with ascites providing an accurate method in evaluating liver stiffness. This supports the suggestion of Ferraioli, et al. [10] who recommended the use of ElastPQ technique as an ideal method for the non-invasive assessment of liver stiffness in patients with BMI >30 kg/m2. In the current study, we routinely performed blood tests for all study subjects including AST, ALT, alkaline phosphatase, serum albumin, total bilirubin, GGT and gamma-globulins. As seen in other studies [19–21], all these liver function tests were significantly higher in patients when compared to controls (p < 0.05). Similarly, as concluded by another study done by Ziol et al. [6], we found a highly significant correlation between the METAVIR scores of liver fibrosis and the LS measurements (in kPa) assessed by ElastPQ SWE (p < 0.0001). This is trustworthy because tissue stiffness largely depends on its molecular building blocks (collagen) and on the microscopic structural organization of these blocks (septa) [22].
Fig. 7. Represents a sixty-three year old healthy male volunteer with normal liver function tests, normal B-mode ultrasonographic examination and no fibrosis. The elasticity map obtained by using ElastPQ SWE through the intercostals access with the sample box is placed in the upper part of left hepatic lobe. The elasticity score is 2.17 ± 0.89 kPa.
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 8. Shows a forty-four year old HCV positive male patient with elevated liver enzymes and with no fibrosis (F0). The elasticity map obtained by using ElastPQ SWE through the intercostals access with the sample box is placed in the upper part of the right lobe. The elasticity score is 4.15 ± 1.43 kPa.
Fig. 9. Reveals a forty year old HCV positive female patient with elevated liver enzymes and non significant fibrosis of F1 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the upper part of the right lobe. The elasticity score is 5.69 ± 2.23 kPa.
As the ElastPQ technique is recently introduced in the field of sonoelastographic hepatic imaging modalities, only few studies
have been published so far [3]. The few available data of LS assessment by means of this technique in healthy volunteers revealed
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 10. Demonstrates a forty-eight year old chronic HCV positive male patient with elevated liver enzymes and non significant fibrosis of F1 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 7.0 ± 0.47 kPa.
Fig. 11. Demonstrates a fifty year old chronic HCV positive female patient with elevated liver enzymes and significant fibrosis of F2 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 8.89 ± 2.69 kPa.
values ranging between 3.1 kPa and 4.0 kPa [11,23], which goes in parallel with our observations in normal controls (3.12 ± 0.40 kPa). On the other hand, Ziol et al. [6] who used the TE technique, found the mean LS measurements in patients with chronic HCV infection was 5.5 kPa For F0-1; 6.6 kPa for F2; 10.3 kPa for F3; and 30.8 kPa for F4. These figures were relatively higher than our findings and this can be explained by the difference in the used elastographic technique in assessment of LS. However, Sporea et al. [11] stated that the TE technique for evaluation of LS, has a 3% failure rate and a non-negligible number of cases with unreliable results [11]. But, similar to our findings, Ziol et al. [6] found a highly significant correlation between the METAVIR scores of liver fibrosis and LS measurements in patients with chronic HCV
infection (p < 0.0001). Additionally, we compared the METAVIR stages of fibrosis to each other and all comparisons were found to be significant (p < 0.05) except when F0 was compared to F1; it was non-significant (p = 0.119). Additionally, we observed that, the increase in LS is more significant between stages of F1 versus F3 or F4 than between stages of F1 and F2., However, we noticed that the increased significance of liver stiffness between stages of F1 and F2 (p < 0.01) on one side and stages of F2 and F3 (p < 0.019) on the other side, are parallel. On the other hand, Ziol et al. [6] noted that the increase in LS is more significant between stages of F2 and F3 than between stages F1 and F2. The ElastPQ cut-off values in the current study showed a good accuracy for distinguishing patients with substantial fibrosis
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 12. Reveals a thirty-nine year old chronic HCV positive male patient with elevated liver enzymes and significant fibrosis of F2 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the left lobe. The elasticity score is 8.32 ± 1.82 kPa.
Fig. 13. Demonstrates a fifty-five year old chronic HCV positive male patient with elevated liver enzymes and significant fibrosis of F3 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 9.70 ± 3.27 kPa.
(PF2) from those without substantial fibrosis (F0–F1). The AUC was 0.998 for diagnosis of fibrosis stage F1 (or greater) at a cutoff value of 6.9 kPa, with 93.3% sensitivity, 100% specificity and 99% accuracy. Furthermore, we found that the AUC of 0.957 accurately distinguished stage F3 fibrosis (or greater) at a cut-off value of 9.1 with 90.9% sensitivity, 97.7% specificity and 96% accuracy. Additionally, the AUC of 0.992 accurately distinguished stage F4 fibrosis at a cut-off value of 10.21 with 100% sensitivity, 96.2% specificity and 99% accuracy. These results are in conflict with those of the study of Leung et al. [24], who diagnosed PF1 fibrosis
at cut-off value of 6.5 with AUC of 0.86, sensitivity 83.5% and specificity 91.2%. Furthermore, they identified PF2 fibrosis at cut-off value of 7.1 with AUC of 0.88, sensitivity 84.7% and specificity 92.1%. Additionally, they reached the diagnosis of severe fibrosis (PF3 and F4) by using cut-off values for SWE of the liver of 7.9 kPa and 10.1 kPa, respectively. Additionally, our results are in contrary with those obtained by Ziol et al. [6], who used different cut-off values. These differences may be attributed to the use of different techniques as well as the difference in the study designs and inclusion criteria. Moreover, we observed high negative
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 14. Demonstrates a sixty year old chronic HCV positive male patient with elevated liver enzymes and significant fibrosis of F3 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the left lobe. The elasticity score is 9.93 ± 3.53 kPa.
Fig. 15. Demonstrates a sixty year old chronic HCV positive male patient with elevated liver enzymes and significant advanced fibrosis of F4 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 11.48 ± 10.33 kPa.
predictive values of SWE with ElastPQ feature in staging of liver fibrosis in patients with HCV infection. This is in a good agreement with the observations obtained by Bavu et al. [25]. Up to our knowledge, very limited studies illustrated the LS assessment by means of ElastPQ technique. So, we thought that our study might provide an important close idea about the SWE
with ElastPQ feature and its diagnostic utility, as a reliable noninvasive technique, in staging of liver fibrosis in patients with chronic HCV infection. Additionally, we used the ROC curves analysis to estimate the optimal cut-off values of liver stiffness measurements by using ElastPQSWE, which facilitated accurate discrimination between non advanced (F1) and advanced (F2–F4)
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 16. Demonstrates a sixty year old male chronic HCV positive patient with elevated liver enzymes and significant advanced fibrosis of F4 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 17.67 ± 0.00 kPa.
fibrosis. Therefore, these values could be regarded as a reference standard for ultrasound elastographic studies by using ElastPQSWE technique for staging of liver fibrosis. Regrettably, we faced some limitations in this study including the relatively small number of the studied population. Also, we did not study other morbid conditions that might affect the liver visco-elasticity as steatosis, and iron overload. In addition, our study did not include patients with different causes of chronic liver disease. Another limitation was lack of accurate correlation between elasticity measurements in different hepatic segments. So, further extended studies on a larger number of subjects with expanded margins of inclusion criteria and precise hepatic segmental correlations for elastographic measurements should be performed to establish the best possible diagnostic values. In conclusion, the current results suggest that quantitative noninvasive assessment of liver stiffness by ElastPQ SWE technique, which recently enters the market, appears as a reliable tool to detect significant fibrosis in patients with chronic HCV infection. Therefore, it can replace the more costly and invasive procedures including liver biopsy for the purpose of quantifying fibrosis in such patients. Also, our results confirm that ElastPQSWE technique can provide an optimal way to routinely monitor liver tissue stiffness, especially in relatively obese patients. Also, it has high negative predictive values in staging of liver fibrosis and high accuracy (97.6%) in recognition of the earlier fibrosis stage (F2), as well as differentiation between subjects without or with mild fibrosis (F0-F1) and patients with advanced fibrosis (PF2). Conflict of interest The authors have no financial or other competing interests to declare. References [1] Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol 2011;25:291–303. [2] Mohamed YA, Mumtaz GR, Riome S, et al. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect Dis 2013;13:288–308.
[3] Ferraioli G, Parekh P, Levitov AP, Filice C. Shear wave elastography for evaluation of liver fibrosis. J Ultrasound Med 2014;33:197–203. [4] Saldera1 K, Naqvi NF, Mahmood T, Shaikh SS. Shear wave elastography; assessment of liver fibrosis in a patient of chronic liver disease associated infected by hepatitis B and C. Professional Med J 2016;23(1):99–103. [5] Koizumi Y, Hirooka M, Kisaka Y, et al. Liver fibrosis in patients with chronic hepatitis C: non-invasive diagnosis by means of real-time tissue elastographyestablishment of the method for measurement. Radiology 2011;258:610–7. [6] Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41(1):48–55. [7] Arda K, Ciledag N, Arıbas BK, et al. Quantitative assessment of the elasticity values of liver with shear wave ultrasonographic elastography. Indian J Med Res 2013;137:911–5. [8] Cabassa P, Ravanelli M, Rossini A, et al. Acoustic radiation force impulse quantification of spleen elasticity for assessing liver fibrosis. Abdom Imag 2015;40:738–44. [9] Karlas T, Pfrepper C, Wiegand J, et al. Acoustic radiation force impulse imaging (ARFI) for non-invasive detection of liver fibrosis: Acoustic radiation force impulse imaging (ARFI) examination standards and evaluation of inter-lobe differences in healthy subjects and chronic liver disease. Scand J Gastroenterol 2011(46):1458–67. [10] Ferraioli G, Tinelli C, Lissandrin R, et al. Reproducibility and performance of a new point shear wave elastography technique for assessing fibrosis in chronic Hepatitis C. World J Gastroenterol 2014;20(16):4787–96. [11] Sporea I, Bota S, Gra˘dinaru-Tasßca˘u O, Șirli R, Popescu A. Comparative study between two point Shear Wave Elastographic techniques: acoustic radiation force impulse (ARFI) elastography and ElastPQ. Med Ultrason 2014;16 (4):309–14. [12] Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR cooperative study group. Hepatology 1996;24 (2):289–93. [13] Kim S, Han K, Ahn S. Non-invasive assessment of liver fibrosis: time to move from cross sectional studies to longitudinal ones. J Gastroen Hepatol 2010;25:1472. [14] Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209–18. [15] Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013;57:1333–42. [16] Chen S, Sanchez W, Callstrom MR, et al. Assessment of liver visco-elasticity by using shear waves induced by ultrasound radiation force. Radiology 2013;266 (3):964–70. [17] Feng YH, Hu XD, Zhai L, et al. Shear wave elastography results correlate with liver fibrosis histology and liver function reserve. World J Gastroenterol 2016;22(17):4338–44. [18] Ferraioli G, Tinelli C, Lissandrin R, et al. Reproducibility and performance of a new point shear wave elastography technique for assessing fibrosis in chronic Hepatitis C. World J Gastroenterol 2014;20(16):4787–96. [19] Deffieux T, Gennisson JL, Bousquet, et al. Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography. J Hepatol 2015;62(2):317–24.
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[20] Rafie Yakoob R, Al Bozom I, Thandasser RB, et al. Noninvasive biomarkers FibroTest and ActiTest versus liver biopsy in chronic hepatitis C patients: the Middle East experience. Ann Gastroenterol 2015;28(2):265–70. [21] Gabr SA, Alghadir AH. Prediction of fibrosis in hepatitis C patients: assessment using hydroxyproline and oxidative stress biomarkers. Virusdisease 2014;25 (1):91–100. [22] Kirk GD, Astemborski J, Mehta SH, et al. Assessment of liver fibrosis by transient elastography in persons with hepatitis C Virus Infection or HIV– Hepatitis C virus coinfection. Clin Infect Dis 2009;48:963–72.
[23] Ling W, Lu Q, Quan J, Ma L, Luo Y. Assessment of impact factors on shear wave based liver stiffness measurement. Eur J Radiol 2013;82:335–41. [24] Leung VYF, Shen J, Wong VWS, et al. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B Carriers: comparison of shear-wave lastography and transient elastography with liver biopsy correlation. Radiology 2013;269(3):910–8. [25] Bavu E, Gennisson JL, Couade 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(9):1361–73.
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Original Article
Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature Rania E. Mohamed a,⇑, Mohamed A. Amin a, Hazem M. Omar b, Mohamed Y. Rabea c, Mona A. Abd Elazeem d a
Radiodiagnosis and Imaging Department, Tanta University, Tanta, Egypt Diagnostic and Interventional Radiology Department, National Liver Institute, Menoufya University, Menoufya, Egypt Tropical Medicine Department, Tanta University, Tanta, Egypt d Pathology Department, Tanta University, Tanta, Egypt b c
a r t i c l e
i n f o
Article history: Received 21 August 2016 Accepted 16 December 2016 Available online xxxx Keywords: Ultrasound Elastography Shear wave Liver Point quantification
a b s t r a c t Introduction: Hepatic fibrosis is the underlying pathological condition in chronic hepatitis C virus (HCV) infection. Shear wave elastography (SWE) with elastography point quantification (ElastPQ) feature is a recently developed method for measuring tissue elasticity. Aim of this study: To evaluate the diagnostic value of SWE with ElastPQ feature for the quantitative assessment of liver fibrosis in patients with chronic HCV infection. Patients and methods: This prospective study included 60 patients with chronic HCV infection and 50 healthy controls. All participants underwent imaging with ElastPQ technique for evaluation of the liver stiffness (LS). All patients underwent ultrasound guided liver biopsy. The METAVIR scores of fibrosis were illustrated. Results: The study participants included 50 controls (mean LS 3.12 ± 0.40 kPa), 5 patients with F0 score (mean LS 3.77 ± 1.44 kPa); 10 patients with F1 score (mean LS 7.50 ± 0.68 kPa), 23 patients with F2 score (mean LS 8.45 ± 0.62 kPa), 17 patients with F3 score (mean LS 9.64 ± 1.20 kPa) and 5 patients with F4 score (mean LS 12.61 ± 1.41 kPa). There was a highly significant correlation between the METAVIR scores of liver fibrosis and LS measurements assessed by ElastPQ SWE (p > 0.0001). Conclusion: The ElastPQ SWE technique appears as a reliable non-invasive tool that can provide an optimal way to monitor liver tissue stiffness in patients with chronic HCV infection with high accuracy (97.6%) in recognition of the earlier fibrosis stage (F2). Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
1. Introduction Chronic viral hepatitis infections are the most important public health problems leading to a significant rate of morbidity and mortality. Hepatitis C virus (HCV) infection in Egypt carries the highest prevalence worldwide [1], which is estimated to be 14.7% in the 15–59 years age group, reflecting a national level epidemic [2]. A wide variety of liver diseases usually ends in hepatic fibrosis which
Abbreviations: SWE, shear wave elastography; ElastPQ, elastography point quantification; LB, liver biopsy; LS, liver stiffness. Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine. ⇑ Corresponding author. E-mail address: [email protected] (R.E. Mohamed).
is responsible for most of the clinical complications in patients with chronic HCV infection. Fibrosis is a dynamic pathological scarring condition in which chronic inflammation leads to the production and accumulation of collagen and extracellular matrix proteins with potential progression to cirrhosis [3]. Furthermore, the clinical management and prognosis in patients with chronic liver disease depend largely on the degree of fibrosis [4]. Liver biopsy (LB) is still considered as the standard reference for the evaluation of liver fibrosis and degree of histo-pathological damage in patients with chronic liver disease [3]. However, this method is not suitable for frequent monitoring due to its invasive nature which may be associated with some complications, in addition to technical limitations derived from small sampling or intra-observers and inter-observer variability in staging of fibrosis. All these limitations have motivated the efforts to search for new
http://dx.doi.org/10.1016/j.ejrnm.2016.12.010 0378-603X/Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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non-invasive approaches [5,6]. In the last decade, ultrasoundbased techniques have become commercially available to quantify the degree of liver fibrosis [3]. Shear wave ultrasonographic elastography (SWE) with elastography point quantification (ElastPQ) feature is a recently developed, non-invasive method for measuring tissue elasticity, which gives a local assessment and measurement of the shear wave propagation speed at each point of interest of an organ in kilopascals (kPa). This imaging method is operator-independent, reproducible, and quantitative [7–9]. It works by generating electronic voltage pulses, which are transmitted to the transducer. In the transducer, a piezo electric array converts the electronic pulse into an ultrasonic pressure wave [10,11]. The maximum penetration depth of ElastPQ is 8 cm. Therefore, it may offer an ideal way to monitor liver tissue stiffness [10]. The aim of this study is to prospectively evaluate the diagnostic value of SWE with ElastPQ feature as a non-invasive method for the in vivo quantitative assessment of liver fibrosis in patients with chronic hepatitis C virus and compare the results with fibrosis stage assessed by the histological METAVIR scoring system and biopsy samples as the reference methods.
2. Materials and methods 2.1. Study participants and study design The current study is a prospective study, carried out in the period between March 2015 and May 2016. Study participants, recruited from the Hepatology outpatient clinic in our institutions, included sixty consecutive patients with chronic HCV infection, in addition to fifty consecutive healthy volunteers served as a control group. The patients were 38 males and 22 females; their ages ranged between 25 and 69 years, while controls were 32 males and 18 females; their ages ranged between 18 and 65 years. Patients were recognized on the basis of clinical data, and laboratory findings including the liver function tests, and polymerase chain reaction (PCR) for HCV. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) levels were estimated in all subjects. Serum levels of AST and ALT above 37 unit/liter and 40 unit/liter, respectively, were considered abnormal. However, so as to avoid inclusion of transient episodes of acute hepatitis, only patients with stable AST and ALT within the last 6 months and thereafter were included in this study. The patients’ characteristics, epidemiological data and biochemical test results were recorded. Assessment of liver fibrosis with the liver stiffness (LS) measurements was prospectively estimated in all subjects by using ElastPQ SWE. The study criteria excluded patients with history of decompensated liver diseases or co-infection with chronic hepatitis B virus or other liver disease that may have influenced the hepatic parenchyma and the extent of liver stiffness such as; congestive heart disease, liver failure, chronic renal disease, hemchromatosis, hepatolenticular degeneration, biliary obstructive disease and fatty liver. Patients with liver tumor or gross ascites, and patients who received antiviral and/or interferon therapy during the study period were also excluded. The control group consisted of healthy volunteers, who visited the Hepatology outpatient clinic of our institution for medical checkup. They did not receive any medications and did not show history of chronic liver disease. They all had normal B-mode ultrasonographic examination, normal liver function tests, and negative PCR. An official permission to perform this work was achieved from the local medical research ethical committee. A written informed consent was also obtained from all study participants.
2.2. Ultrasound and ElastPQ shear wave elastography technique Initially, all study participants underwent B-mode liver ultrasound scanning with iU22 ultrasound system (iU22, Philips Medical Systems, Bothell, WA, USA), which was adapted to generate shear waves via its ElastPQ feature (Fig. 1A). During ultrasound examination, quantitative evaluation of the LS was performed by ElastPQ using a convex transducer C5-1 (1–5 MHz; C5-1, Philips Healthcare). Sub-costal and intercostals scans were used to reach and visualize the 8 liver segments (I–VIII). The maximum penetration depth of ElastPQ is 8 cm. [10]. Each region of interest (ROI) was simulated by a fixed sample box with predefined size of 15 5 mm, which was placed by moving a trackball, in a hepatic parenchymal area that did not include large vasculature, biliary structures and away from the heart, diaphragm, liver/kidney interface, or liver capsule (at least 1.5–3 cm below the Glisson’s capsule). The study participants were all instructed to suspend their breath during the actual scanning with breathing rehearsals were allowed while measurements were obtained. Furthermore, for all study participants; three 10measurement elastographic cine clips were obtained at each of the following locations in the liver: (a) left lobe, (b) upper right lobe, and (c) lower right lobe. So, to provide a more comprehensive evaluation, total of thirty measurements were obtained across the liver for off line analysis. We considered the median values of LS measurements, which were automatically calculated, were reliable if 10 valid successful measurements (out of the 30 measurements) of both hepatic lobes in each study participant were obtained. These measurements were expressed either in meters/seconds (m/s) or kilopascals (kpa). However, if we could not obtain 10 valid measurements after 20–25 attempts, we considered these cases as invalid failed measurements and they were excluded from the study [3,11]. The means of the median values were then statistically calculated in the group of patients and compared with those of the control group. The median values of LS measurements card (which is displayed to the left of the image; as shown in Fig. 1B) and the bias reference table were automatically calculated and displayed on the screen over a B-mode ultrasound image. The bias reference table is a reference table which describes the potential variation that obtained at different sample depths in m/s and does not vary by patient (Fig. 1C). Finally a sample report was generated at the end of examination (Fig. 1D). The average of these measurements was then used to estimate the degree of liver stiffness, which was correlated with a predicted biopsy METAVIR score. The mean values of each fibrosis stage were statistically calculated and then they were compared with each other. 2.3. Liver biopsy and histopathological evaluation All patients underwent ultrasound guided liver biopsy, which was performed in the same day, immediately after ElastPQSWE. The liver biopsy was carried out through a semi-automatic 18G needle by experienced interventional radiologist. All the biopsy specimens were analyzed by a qualified pathologist using the METAVIR scoring system [12], which evaluates both necro-inflammatory changes as well as degree of fibrosis. The fibrosis score was assessed on a five-point scale (F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = few septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis). 2.3.1. Statistical analysis The SPSS for Windows version 18.0 software package (SPSS Inc, Chicago, IL) was used for statistical data analysis. Data of continuous variables were reported as mean ± standard deviation (SD),
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
R.E. Mohamed et al. / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx
3
Fig. I A
Fig.I C
Fig.I B
Fig. I D
Fig. 1. (A–D): Demonstrates the ElastPQ SWE technique and its machine (1 A). The liver stiffness measurement card (1 B) which is displayed to the left of the obtained image. The bias reference Fig. 1C which is shown as a reference table to describe the potential variation in meters/s obtained at different sample depths and does not vary by patient. Fig. 1D shows the automatically generated sample report of 10 valid successful LS measurements of both hepatic lobes. It is displayed on the screen of the ElastPQ SWE machine.
while categorical variables were reported as number of patients and percentages (%). The Chi-square, t-tests and ANOVA tests (with the Fisher exact and Tukey’s subtests) were used to compare and correlate the given data. The P value below 0.05 was considered statistically significant. The final histopathological diagnosis was considered as the reference standard. Additionally, the areas under the curves (AUCs); the receiver operating characteristic (ROC) curves, were built for ElastPQ to evaluate its diagnostic performance in differentiating different stages of liver fibrosis. The optimal cutoff values were used to evaluate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of ElastPQSWE in all study participants.
3. Results Liver stiffness was evaluated by means of ElastPQSWE in sixty consecutive patients with chronic HCV infection; in addition to fifty consecutive healthy volunteers served as a control group. The group of patients consisted of 38 (63.3%) males and 22 (36.7%) females; their ages ranged between 25 and 69 years with a mean age of 48.04 ± 8.54 years. On the other hand, the controls
were 32 (64%) males and 18 (36%) females; their ages ranged between 18 and 65 years with a mean age of 44.72 ± 12.11 years. Table 1 showed a comparison of some patients’ characteristics versus the control. In the current study, the mean age (48.04 vs. 44.72 years) was not significantly higher in patients compared to controls (p > 0.05), while the mean BMI was significantly higher in patients compared to controls (p < 0.05). Additionally, all liver function tests were significantly higher in patients compared to controls (p < 0.05). In all included subjects, technical success was achieved and valid results were obtained. According to the METAVIR score of fibrosis, the patients were categorized as follows: 5 (5/60; 8.3%) patients without liver fibrosis (F0 score), 10 (10/60; 16.7%) patients with mild liver fibrosis (F1 score) and patients with significant fibrosis included 23 (23/60; 38.3%) patients of F2 score, 17 (17/60; 28.4%) patients of F3 score and 5 (5/60; 8.3%) patients of F4 score. Furthermore, the mean liver stiffness measurements of the study participants by ElastPQSWE was 3.12 ± 0.40 kPa for healthy control (Fig. 7), 3.77 ± 1.44 kPa for F0 patients (Fig. 8), 7.50 ± 0.68 kPa for F1 patients (Figs. 9 and 10), 8.45 ± 0.62 kPa for F2 patients (Figs. 11 and 12), 9.64 ± 1.20 kPa for F3 patients (Figs. 13 and 14) and 12.61 ± 1.41 kPa for F4 patients (Figs. 15 and 16). Moreover, we found a highly significant correlation
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Table 1 Demographic data and liver function tests of the studied groups. Characteristics
Patients (n = 60)
Controls (n = 50)
t-test
P-value
Age (years)
25–69 (48.04 ± 8.54) 18.8–43.2 (31.0 ± 5.66) 35–78.8 (47.1 ± 3.2) 25–68.8 (35.1 ± 3.9) 60.8–98.8 (71.5 ± 8.5) 63.8–207.1 (48.7 ± 15.4) 18.7–33.5 (24.5 ± 6.3) (50.5–109.3) 89.5 ± 12.7 36.7–56.6 (40. 2 ± 5.3)
18–65 (44.72 ± 12.11) 15.8–31.7 (20.0 ± 7.24) 25–37.8 (28.1 ± 2.9) 14–42.7 (20.1 ± 2.9) 46–115.7 (47.1 ± 11.9) 37.5–50 (40.1 ± 6.9) 00.0–17.5 (5.5 ± 8.563) 5.5–85.4 (40.1 ± 7.9) 18.7–34.6 (23. 2 ± 4.3)
1.681
0.095
6.261
0.017⁄
32.347
<0.001⁄
22.497
<0.001⁄
12.512
<0.001⁄
3.653
0.0004⁄
13.385
<0.001⁄
23.909
<0.001⁄
18.223
<0.001⁄
2
BMI (kg/ m ) AST (IU/L) ALT (IU/L) Alkaline phosphatase (IU/L) Serum albumin (g/L) Total bilirubin (lmol/L) GGT (IU/L) Gamma-globulins (g/L)
Results are expressed as range (mean ± standard deviation). n = number, BMI = body mass index, kg = kilogram, m2 = square meters, AST = Aspartate aminotransaminase, ALT = Alanine aminotransaminase, IU/L = international unit/ liter, g/L = gram/liter, lmol/L = micromole/liter, GGT = Gamma-glutamyl transferase.
SWE
16 14
Mean±SD
12 10 8 6 4 2 0
F0
F1
F2
F3
F4
Fig. 2. Demonstrates the mean LS measurements (mean ± SD) in different subgroups of the studied patients obtained in kPa by using ElastPQ SWE technique.
Table 2 Staging of liver fibrosis in the study participants according to the METAVIR score of fibrosis and the hepatic ElastPQSWE measurements. Study participants
Control (n = 50) Patients (n = 60)
n (%)
F0 F1 F2 F3 F4
ElastPQSWE
50 (100%) 5 (8.3%) 10 (16.7%) 23(38.3%) 17 (28.4%) 5 (8.3%)
ANOVA
Range
Mean ± SD
F
0.43–4.5 1.43–5.70 5.77–8.30 7.36–9.08 9.09–11.55 10.56–14.50
3.12 ± 0.40 3.77 ± 1.44 7.50 ± 0.68 8.45 ± 0.62 9.64 ± 1.20 12.61 ± 1.41
147.57 < 0.0001
P-value
Tukey’s test (P-value) F0& F1 0.119
F0& F2 <0.001
F0& F3 <0.001
F0& F4 <0.001
F1& F2 0.01
F1& F3 <0.001
F1& F4 <0.001
F2& F3 0.019
F2& F4 <0.001
F3& F4 <0.001
n = number, (%) = percent, SWE = shear wave elastography, SD = standard deviation, ANOVA = analysis of variants, F = fisher exact test.
Table 3 Accuracy of ElastPQSWE in differentiating the grades of hepatic fibrosis with optimal cut off point of liver stiffness measured in (kPa) in the studied patients (n = 60).
PF1 (F0 vs. F1-2-3-4) PF2 (F0-1 vs. F2-3-4) PF3 (F0-1-2 vs. F3-4) F = 4 (F0-1-2-3 vs. F4)
Cut-off
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
AUC
Accuracy (%)
6.9 7.5 9.1 10.21
93.3 93.3 90.9 100.0
100.0 90.8 97.7 96.2
100.0 87.5 90.5 55.6
98.0 95.2 96.6 100.0
0.998 0.976 0.957 0.992
99 98 96 99
between the METAVIR scores of liver fibrosis and liver stiffness measurements assessed by ElastPQSWE (p > 0.0001). So, the increased METAVIR score of fibrosis was associated with increased means of liver stiffness measurements in kPa (Fig. 2). However, on
comparing the METAVIR stages of fibrosis to each other by the Tukey’s test, all comparisons were found to be significant (p < 0.05) except when F0 was compared to F1; it was nonsignificant (p = 0.119); as shown in Table 2.
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
R.E. Mohamed et al. / The Egyptian Journal of Radiology and Nuclear Medicine xxx (2016) xxx–xxx
Fig. 3. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage PF1 at a cutoff value of 6.9 kPa. The AUC is 0.998 with 93.3% sensitivity, 100% specificity and 99% accuracy.
5
Fig. 5. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage PF3 at a cutoff value of 9.1 kPa. The AUC is 0.957 with 90.9% sensitivity, 97.7% specificity and 96% accuracy.
The optimal cut-off values for different levels of fibrosis were determined by analyzing the ROC curves for ElastPQSWE. The cut-off values of ElastPQSWE for each METAVIR stage of fibrosis, along with the area under curves (AUCs), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for optimal cutoff values for each of the ROC curves were summarized in Table 3. The ROC curve (Fig. 3A and B) was drawn to differentiate fibrosis stage of at least F1 or more from other stages of fibrosis by using ElastPQSWE with an AUC of 0.998 at an optimal cut-off value of 6.9 kPa (sensitivity 93.3%, Specificity 100% and accuracy 99%). Moreover, the AUC for differentiating fibrosis stage of at least F2 or more from other stages of fibrosis, was 0.976 with an optimal cut-off value of 7.5 kPa (sensitivity 93.3%, specificity 90.8% and accuracy 98%) (Fig. 4A and B). Additionally, the AUC for differentiating fibrosis stages of F3 or more from other stages of fibrosis, was 0.957 with an optimal cut-off value of 9.1 kPa (sensitivity 90.9%, specificity 97.7% and accuracy 96%) (Fig. 5A and B). On the other hand, the AUC for differentiating stage F4 fibrosis from fibrosis stage less than F4 was 0.992 with an optimal cut-off value of 10.21 kPa (sensitivity 100%, specificity 96.2% and accuracy 99%) (Fig. 6A and B).
4. Discussion
Fig. 4. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage PF2 at a cutoff value of 7.5 kPa. The AUC is 0.976 with 93.3% sensitivity, 90.8% specificity and 98% accuracy.
Without proper and timely interference, progressive hepatic fibrosis will gradually lead to cirrhosis, hepatocellular carcinoma, and finally liver failure [13,14] with increased mortality rates [3]. Therefore, in patients with chronic HCV infection, the accurate diagnosis and assessment of liver fibrosis is essential for the pre-
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 6. (A and B): Demonstrates the ROC curves analysis, which illustrates the performance of ElastPQ SWE technique in diagnosis of fibrosis stage of F4 at a cutoff value of 10.21 kPa. The AUC is 0.992 with 100% sensitivity, 96.2% specificity and 99% accuracy.
vention, prognosis and optimization of treatment plan [15,16]. Liver biopsy is the gold standard diagnostic modality for liver fibrosis, but because of its associated morbidities, this technique cannot be used as routine [17].
Recently, non-invasive methods for assessing liver fibrosis have been thoroughly studied [8]. As an alternative of a costly and painful biopsy procedure, an easy ultrasound examination becomes the routine method to assess liver disease status [18]. Transient elastography (TE) is the oldest and most applied ultrasound-based elastographic technique. However, results can be difficult to obtain in patients with obesity or narrow intercostals spaces, and ascites [11]. Quantitative SWE is an efficient technique for the noninvasive diagnosis and staging of liver fibrosis [19]. The SWE with ElastPQ feature can be considered as an alternative non-invasive diagnostic modality to liver biopsy [11]. The current prospective study sheds light on the diagnostic utility of SWE with ElastPQ feature for liver fibrosis assessment in patients with chronic HCV infections while using liver biopsy as the standard reference. In previous studies [6,7,9], individuals with body mass index (BMI) higher than 30 kg/m2 were excluded from these studies due to the difficulty of shear wave elastographic imaging of lesions deeper than 5 cm. On contrary, by using the ElastPQ, we did not face such restriction as the maximum penetration depth of ElastPQ technique is 8 cm which allowed measurements in patients with relatively high BMI (31.0 ± 5.66) including patients with ascites providing an accurate method in evaluating liver stiffness. This supports the suggestion of Ferraioli, et al. [10] who recommended the use of ElastPQ technique as an ideal method for the non-invasive assessment of liver stiffness in patients with BMI >30 kg/m2. In the current study, we routinely performed blood tests for all study subjects including AST, ALT, alkaline phosphatase, serum albumin, total bilirubin, GGT and gamma-globulins. As seen in other studies [19–21], all these liver function tests were significantly higher in patients when compared to controls (p < 0.05). Similarly, as concluded by another study done by Ziol et al. [6], we found a highly significant correlation between the METAVIR scores of liver fibrosis and the LS measurements (in kPa) assessed by ElastPQ SWE (p < 0.0001). This is trustworthy because tissue stiffness largely depends on its molecular building blocks (collagen) and on the microscopic structural organization of these blocks (septa) [22].
Fig. 7. Represents a sixty-three year old healthy male volunteer with normal liver function tests, normal B-mode ultrasonographic examination and no fibrosis. The elasticity map obtained by using ElastPQ SWE through the intercostals access with the sample box is placed in the upper part of left hepatic lobe. The elasticity score is 2.17 ± 0.89 kPa.
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 8. Shows a forty-four year old HCV positive male patient with elevated liver enzymes and with no fibrosis (F0). The elasticity map obtained by using ElastPQ SWE through the intercostals access with the sample box is placed in the upper part of the right lobe. The elasticity score is 4.15 ± 1.43 kPa.
Fig. 9. Reveals a forty year old HCV positive female patient with elevated liver enzymes and non significant fibrosis of F1 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the upper part of the right lobe. The elasticity score is 5.69 ± 2.23 kPa.
As the ElastPQ technique is recently introduced in the field of sonoelastographic hepatic imaging modalities, only few studies
have been published so far [3]. The few available data of LS assessment by means of this technique in healthy volunteers revealed
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 10. Demonstrates a forty-eight year old chronic HCV positive male patient with elevated liver enzymes and non significant fibrosis of F1 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 7.0 ± 0.47 kPa.
Fig. 11. Demonstrates a fifty year old chronic HCV positive female patient with elevated liver enzymes and significant fibrosis of F2 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 8.89 ± 2.69 kPa.
values ranging between 3.1 kPa and 4.0 kPa [11,23], which goes in parallel with our observations in normal controls (3.12 ± 0.40 kPa). On the other hand, Ziol et al. [6] who used the TE technique, found the mean LS measurements in patients with chronic HCV infection was 5.5 kPa For F0-1; 6.6 kPa for F2; 10.3 kPa for F3; and 30.8 kPa for F4. These figures were relatively higher than our findings and this can be explained by the difference in the used elastographic technique in assessment of LS. However, Sporea et al. [11] stated that the TE technique for evaluation of LS, has a 3% failure rate and a non-negligible number of cases with unreliable results [11]. But, similar to our findings, Ziol et al. [6] found a highly significant correlation between the METAVIR scores of liver fibrosis and LS measurements in patients with chronic HCV
infection (p < 0.0001). Additionally, we compared the METAVIR stages of fibrosis to each other and all comparisons were found to be significant (p < 0.05) except when F0 was compared to F1; it was non-significant (p = 0.119). Additionally, we observed that, the increase in LS is more significant between stages of F1 versus F3 or F4 than between stages of F1 and F2., However, we noticed that the increased significance of liver stiffness between stages of F1 and F2 (p < 0.01) on one side and stages of F2 and F3 (p < 0.019) on the other side, are parallel. On the other hand, Ziol et al. [6] noted that the increase in LS is more significant between stages of F2 and F3 than between stages F1 and F2. The ElastPQ cut-off values in the current study showed a good accuracy for distinguishing patients with substantial fibrosis
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 12. Reveals a thirty-nine year old chronic HCV positive male patient with elevated liver enzymes and significant fibrosis of F2 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the left lobe. The elasticity score is 8.32 ± 1.82 kPa.
Fig. 13. Demonstrates a fifty-five year old chronic HCV positive male patient with elevated liver enzymes and significant fibrosis of F3 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 9.70 ± 3.27 kPa.
(PF2) from those without substantial fibrosis (F0–F1). The AUC was 0.998 for diagnosis of fibrosis stage F1 (or greater) at a cutoff value of 6.9 kPa, with 93.3% sensitivity, 100% specificity and 99% accuracy. Furthermore, we found that the AUC of 0.957 accurately distinguished stage F3 fibrosis (or greater) at a cut-off value of 9.1 with 90.9% sensitivity, 97.7% specificity and 96% accuracy. Additionally, the AUC of 0.992 accurately distinguished stage F4 fibrosis at a cut-off value of 10.21 with 100% sensitivity, 96.2% specificity and 99% accuracy. These results are in conflict with those of the study of Leung et al. [24], who diagnosed PF1 fibrosis
at cut-off value of 6.5 with AUC of 0.86, sensitivity 83.5% and specificity 91.2%. Furthermore, they identified PF2 fibrosis at cut-off value of 7.1 with AUC of 0.88, sensitivity 84.7% and specificity 92.1%. Additionally, they reached the diagnosis of severe fibrosis (PF3 and F4) by using cut-off values for SWE of the liver of 7.9 kPa and 10.1 kPa, respectively. Additionally, our results are in contrary with those obtained by Ziol et al. [6], who used different cut-off values. These differences may be attributed to the use of different techniques as well as the difference in the study designs and inclusion criteria. Moreover, we observed high negative
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 14. Demonstrates a sixty year old chronic HCV positive male patient with elevated liver enzymes and significant fibrosis of F3 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the left lobe. The elasticity score is 9.93 ± 3.53 kPa.
Fig. 15. Demonstrates a sixty year old chronic HCV positive male patient with elevated liver enzymes and significant advanced fibrosis of F4 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 11.48 ± 10.33 kPa.
predictive values of SWE with ElastPQ feature in staging of liver fibrosis in patients with HCV infection. This is in a good agreement with the observations obtained by Bavu et al. [25]. Up to our knowledge, very limited studies illustrated the LS assessment by means of ElastPQ technique. So, we thought that our study might provide an important close idea about the SWE
with ElastPQ feature and its diagnostic utility, as a reliable noninvasive technique, in staging of liver fibrosis in patients with chronic HCV infection. Additionally, we used the ROC curves analysis to estimate the optimal cut-off values of liver stiffness measurements by using ElastPQSWE, which facilitated accurate discrimination between non advanced (F1) and advanced (F2–F4)
Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010
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Fig. 16. Demonstrates a sixty year old male chronic HCV positive patient with elevated liver enzymes and significant advanced fibrosis of F4 METAVIR score. The LS is assessed by ElastPQ SWE with the sample box is placed in the right lobe. The elasticity score is 17.67 ± 0.00 kPa.
fibrosis. Therefore, these values could be regarded as a reference standard for ultrasound elastographic studies by using ElastPQSWE technique for staging of liver fibrosis. Regrettably, we faced some limitations in this study including the relatively small number of the studied population. Also, we did not study other morbid conditions that might affect the liver visco-elasticity as steatosis, and iron overload. In addition, our study did not include patients with different causes of chronic liver disease. Another limitation was lack of accurate correlation between elasticity measurements in different hepatic segments. So, further extended studies on a larger number of subjects with expanded margins of inclusion criteria and precise hepatic segmental correlations for elastographic measurements should be performed to establish the best possible diagnostic values. In conclusion, the current results suggest that quantitative noninvasive assessment of liver stiffness by ElastPQ SWE technique, which recently enters the market, appears as a reliable tool to detect significant fibrosis in patients with chronic HCV infection. Therefore, it can replace the more costly and invasive procedures including liver biopsy for the purpose of quantifying fibrosis in such patients. Also, our results confirm that ElastPQSWE technique can provide an optimal way to routinely monitor liver tissue stiffness, especially in relatively obese patients. Also, it has high negative predictive values in staging of liver fibrosis and high accuracy (97.6%) in recognition of the earlier fibrosis stage (F2), as well as differentiation between subjects without or with mild fibrosis (F0-F1) and patients with advanced fibrosis (PF2). Conflict of interest The authors have no financial or other competing interests to declare. References [1] Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol 2011;25:291–303. [2] Mohamed YA, Mumtaz GR, Riome S, et al. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect Dis 2013;13:288–308.
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Please cite this article in press as: Mohamed RE et al. Quantitative assessment of liver fibrosis in chronic viral hepatitis C patients using shear wave elastography with elastography point quantification feature. Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.12.010