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Supersonic Shear Imaging and Transient Elastography With the XL Probe Accurately Detect Fibrosis in Overweight or Obese Patients With Chronic Liver Disease
Clinical Gastroenterology and Hepatology 2015;13:1502–1509
Supersonic Shear Imaging and Transient Elastography With the XL Probe Accurately Detect Fibrosis in Overweight or Obese Patients With Chronic Liver Disease Masato Yoneda, Emmanuel Thomas, Seth N. Sclair, Tiffannia T. Grant, and Eugene R. Schiff Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida BACKGROUND & AIMS:
Assessment of the severity of liver fibrosis is an important step in evaluating patients with chronic liver disease and determining their prognosis. We compared liver stiffness measurements (LSMs) made by supersonic shear imaging (SSI) with those of transient elastography (TE)-XL for their ability to determine the degree of liver fibrosis in overweight or obese patients with chronic liver disease.
METHODS:
We performed a prospective study of 258 patients with chronic hepatitis of different etiologies and a body mass index greater than 25, evaluated at the University of Miami from October 2013 to December 2014. Liver stiffness was measured using the TE-XL probe and SSI of the right and left lobes during the same clinic visit, and comparisons were made for fibrosis stage in 124 biopsy-proven patients. In addition, further analysis was performed on a subgroup of 102 chronic hepatitis C virus (HCV)-positive patients for whom biopsy data were available.
RESULTS:
Reliable LSMs were obtained from 96.1%, 94.6%, and 72.1% of patients using the TE-XL probe, SSI of the right lobe, and SSI of the left lobe, respectively. TE-XL, SSI of the right lobe, and SSI of the left lobe detected severe fibrosis (fibrosis stages 3–4), with area under the receiver operating characteristic curve (AUROC) values of 0.955, 0.954, and 0.910, respectively, compared with results from histologic analysis for the 124 biopsy-proven patients included in the study; these values were 0.952, 0.949, and 0.917, respectively, for the 102 biopsy-proven patients with HCV infection. TE-XL, SSI of the right lobe, and SSI of the left lobe detected fibrosis stage 4 with AUROC values of 0.920, 0.930, and 0.910, respectively, compared with histologic analysis, in all 124-biopsy proven patients, and with AUROC values of 0.907, 0.914, and 0.887, respectively, in the 102 biopsy-proven patients with chronic HCV infection.
CONCLUSIONS:
SSI and the TE-XL probe each accurately quantify liver fibrosis in overweight or obese patients with chronic liver disease, including those with HCV infection, when compared with data obtained from histologic analysis. SSI data obtained from the right lobe and the TE-XL probe can be used to evaluate fibrosis with similar accuracy.
Keywords: Viral Hepatitis; Cirrhosis; Fibrosis Stage; Obesity.
See editorial on page 1510. taging of liver fibrosis is essential in determining the prognosis and optimal treatment for patients with chronic liver disease and also to guide surveillance for the development of hepatocellular carcinoma.1 Liver biopsy is recommended as the reference standard method for the diagnosis and staging of fibrosis in chronic liver disease.2 This procedure, however, is invasive with associated risks of complications, is costly, and is time consuming both for providers and patients.3 In addition, despite being the gold standard test for assessing liver fibrosis, liver biopsy is limited
S
further by sampling error and intra-observer and interobserver variability.4,5 Therefore, there is great need for rapid, quantitative, and noninvasive methods for
Abbreviations used in this paper: AAR, aspartate aminotransferase to alanine aminotransferase ratio; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartate aminotransferase; AUROC, area under the receiver-operating characteristic; BMI, body mass index; F3, fibrosis stage 3; F4, fibrosis stage 4; FIB-4, Fibrosis-4 score; HCV, hepatitis C virus; LSM, liver stiffness measurement; SSI, supersonic shear imaging; SSI-Lt, supersonic shear imaging from the left lobe; SSI-Rt, supersonic shear imaging from the right lobe; TE, transient elastography. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.03.014
August 2015
detecting fibrosis. Several clinical studies have been performed for the assessment of liver fibrosis and, recently, most have validated fibrosis using the ultrasound-based method of transient elastography (TE).6–8 However, in some cases, the standard M probe fails to generate reliable elasticity measurements in overweight patients.9 When using the XL probe, the reliability of TE in overweight or obese patients is improved significantly.10 Recently, a new technology in the field of elastography was developed.11 Supersonic shear imaging (SSI), also named ShearWave (SuperSonic Imagine, Aix-enProvence, France) elastography, is based on the measurement of the velocity of a local shear wave through soft tissue. Several studies have reported on the usefulness of SSI for assessing liver fibrosis in patients with chronic hepatitis.12–17 The purpose of this study was to specifically investigate the diagnostic accuracy and reliability of SSI when compared with assessment of liver fibrosis using TE with the XL probe in overweight or obese patients with chronic liver disease, and additional analyses were performed on a hepatitis C virus (HCV)infected subgroup.
Methods Patients This study was conducted with the approval of the Institutional Review Board at the University of Miami and written informed consent was obtained from each patient. A total of 258 patients (124 with histologic determination of fibrosis stage) with chronic hepatitis, whose body mass index (BMI) was greater than 25 and whose skin capsule distance measurement was greater than 2.5 cm, evaluated at the University of Miami from October 2013 to December 2014, prospectively were included in this study. BMIs higher than 25 and 30 are categorized as overweight and obesity according to the World Health Organization. Liver stiffness measurement (LSM) was assessed using TE with the XL probe (2.5 MHz), and SSI from both the right (SSI-Rt) and left (SSI-Lt) lobes during the same clinic visit. Other methods used in this study are described in the Supplementary Methods section.
Results Patient Characteristics A total of 258 patients prospectively were included in the analysis. The study included patients with the following underlying liver conditions: 168 patients with HCV, 35 patients with nonalcoholic fatty liver disease, 20 patients with chronic hepatitis B virus, 11 patients with primary biliary cirrhosis, 10 patients with primary sclerosing cholangitis, 4 patients with autoimmune hepatitis,
SSI and TE–XL Probe in Overweight Patients 1503
and 10 patients with other liver diseases (alcohol liver disease, a-1 antitrypsin deficiency, and increased liver enzyme levels from unknown origin). The histologic fibrosis stage was available for 124 patients. Among them, the following etiologies were present: 102 patients with HCV, 4 patients with hepatitis B virus, 8 patients with nonalcoholic fatty liver disease, 2 patients with autoimmune hepatitis, 5 patients with primary biliary cirrhosis, 2 patients with primary sclerosing cholangitis, and 1 patient with alcoholic liver disease. The characteristics of the patients were stratified according to BMI and they are summarized in Table 1. The LSM failures (unreliable LSM) occurred in 5.4%, 27.9%, and 3.9% when using SSI-Rt, SSI-Lt, and the TE-XL probe, respectively. The rate of unreliable LSMs by SSI-Lt was significantly higher than those obtained using SSI-Rt and the TE-XL probe. The LSM failure rate tended to increase according to increasing BMI when using SSIRt, SSI-Lt, and the TE-XL probe (Table 1).
Comparison of Liver Stiffness Measurement Using Supersonic Shear Imaging in the Right Lobe, Supersonic Shear Imaging in the Left Lobe, or the Transient Elastography-XL Probe With Other Scoring Systems Used to Evaluate Liver Fibrosis: Fibrosis-4 Score, Aspartate Aminotransferase to Alanine Aminotransferase Ratio and Aspartate Aminotransferase to the Platelet Ratio Index LSMs using SSI-Lt were significantly higher than that obtained from SSI-Rt (12.6 9.2 and 10.6 8.0, respectively; P < .0001). When compared with other fibrosis scoring systems (Fibrosis-4 score [FIB-4], aspartate aminotransferase [AST] to alanine aminotransferase ratio [AAR] and AST to the platelet ratio index [APRI]), there were significant, albeit weak, correlations observed between these scoring systems and LSMs using SSI-Rt, SSI-Lt, and the TE-XL probe (Supplementary Figures 1–3).
Correlation Between Liver Stiffness Measurement Obtained Using Supersonic Shear Imaging in the Right Lobe, Supersonic Shear Imaging in the Left Lobe, or the Transient Elastography-XL Probe and Histologic Fibrosis Staging Overall, LSMs using SSI-Rt, SSI-Lt, and TE-XL probes stratified according to histologic fibrosis stage and these data are shown in Table 2 and Figure 1. In the hepatitis C subgroup, LSMs using SSI-Rt, SSI-Lt, and the TE-XL probe stratified by the histologic fibrosis stage and these data are shown in Table 2 and Figure 2. LSMs obtained using SSI-Rt and the TE-XL probe showed a stepwise increase with the corresponding histologic severity of hepatic fibrosis (P < .0001) in both 124 biopsy-proven patients
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Clinical Gastroenterology and Hepatology Vol. 13, No. 8
Table 1. Clinical and Biochemical Characteristics of Patients Stratified According to BMI Characteristics
All patients (N ¼ 258)
BMI category Age, y 57 12 [56–59] Sex, male:female 115:59 BMI, m/kg2 30.1 4.1 [29.6–30.6] AST level, U/mL 62.2 72.6 [53.3–71.1] ALT level, U/mL 75.8 88.9 [64.9–86.6] Platelet count, 109/L 186.4 71.8 [177.6–195.2] Albumin level, g/dL 4.27 0.45 [4.22–4.33] FIB-4 index 2.71 2.63 [2.39–3.03] AST:ALT ratio 0.94 0.40 [0.89–0.99] APRI 1.14 1.86 [0.91–1.34] Liver diseases HCV 168 (65.1%) HBV 20 (7.8%) NAFLD 35 (13.6%) PSC 10 (3.9%) PBC 11 (4.3%) AIH 4 (1.6%) Others 10 (3.9%) SSI-Rt LSM, kPa 10.6 8.0 [9.6–11.6] IQR/M (%) 7.7 5.3 [7.0–8.4] Unreliable LSM 14 (5.4%) SSI-Lt LSM, kPa 12.6 9.2 [11.2–13.9] IQR/M (%) 11.9 6.9 [10.9–12.9] Unreliable LSM 72 (27.9%) TE-XL LSM, kPa 10.9 9.0 [9.8–12.0] IQR/M (%) 16.6 7.0 [15.7–17.5] Unreliable LSM 10 (3.9%)
Group A (n ¼ 90)
Group B (n ¼ 79)
Group C (n ¼ 89)
25 < BMI < 28
28 BMI < 30
BMI > 30
56 12 [53–58] 47:43 26.5 1.0 [26.2–26.7] 75.4 100.8 [54.3–96.5] 91.1 123.0 [65.4–116.9] 185.3 80.6 [168.4–202.2] 4.23 0.55 [4.12–4.35] 2.92 2.52 [2.39–3.44] 0.95 0.32 [0.88–1.01] 1.41 2.37 [0.92–1.90]
59 12 [56–62] 50:29 29.1 0.6 [29.0–29.2]b 50.3 41.3 [41.0–59.5]b 63.8 58.7 [50.7–77.0] 177.5 52.8 [165.6–189.3] 4.34 0.36 [4.26–4.43] 2.37 1.60 [2.01–2.73] 0.93 0.34 [0.86–1.01] 0.83 0.10 [0.63–1.03]b
57 10 [55–59] 40:49a 34.7 3.4 [33.9–35.4]a,c 59.6 57.4 [47.5–71.6] 70.8 65.6 [57.0–84.6] 195.3 76.5 [179.2–211.5] 4.26 0.40 [4.17–4.34] 2.80 3.37 [2.09–3.51] 0.95 0.52 [0.84–1.06] 1.14 1.90 [0.74–1.54]
61 9 7 7 2 1 3
(67.8%) (10%) (7.8%) (7.8%) (2.2%) (1.1%) (3.3%)
56 6 6 2 4 3 2
(70.8%) (7.6%) (7.6%) (2.5%) (5.1%) (3.8%) (2.5%)
51 5 22 1 5 0 5
(57.3) (5.6%) (24.7%) (1.1%) (5.6%) (0%) (5.6%)
11.5 9.3 [9.5–13.5] 7.3 4.9 [6.3–8.3] 2 (2.2%)
9.1 5.8 [7.8–10.5] 8.4 5.4 [7.2–9.6] 4 (5.1%)
11.0 8.2 [9.2–12.8] 7.5 5.7 [6.2–8.8] 8 (9.0%)c
12.5 8.5 [10.4–14.5] 11.6 6.8 [9.9–13.2] 21 (23.3%)
12.3 10.6 [9.5–15.0] 11.7 6.4 [10.0–13.3] 20 (25.3%)
13.0 8.7 [10.7–15.3] 12.6 7.6 [10.6–14.5] 31 (34.8%)
11.7 10.9 [9.4–14.0] 16.1 7.2 [14.5–17.6] 2 (2.2%)
10.3 7.8 [8.6–12.1] 16.4 6.5 [14.9–17.8] 2 (2.5%)
10.7 7.7 [9.0–12.4] 17.5 7.2 [15.9–19.0] 6 (6.7%)
NOTE. Data are expressed as n (%), or mean SD [95% CI]. P values were calculated using the c2 test when comparing sex and unreliable LSM/total numbers between the groups. Other P values were calculated using the Student t test. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; HBV, hepatitis B virus; IQR/M, interquartile range/median; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. a P < .05 for comparisons between groups B and C. b P < .05 for comparisons between groups A and B. c P < .05 for comparisons between groups A and C.
with liver disease from all etiologies and the hepatitis C subgroup analysis.
Receiver-Operating Characteristic Curves for Detecting Severe Fibrosis: Stages 3 to 4 In 124 biopsy-proven patients with liver disease from all etiologies, the area under the receiver-operating characteristic curves (AUROCs) for estimating the diagnostic performance of LSMs using SSI-Rt, SSI-Lt, and the TE-XL probe for detecting severe fibrosis (fibrosis stages 3–4 [F3–F4]) was 0.954, 0.915, and 0.955, respectively (Figure 3A). The optimal cut-off value and diagnostic accuracy (sensitivity, specificity, positive and negative predictive values) are shown in Table 2. The AUROCs for detecting severe fibrosis using FIB-4, AAR, and APRI were 0.767, 0.589, and 0.753, respectively, in our study population (Figure 3A).
In the hepatitis C subgroup, the AUROCs for estimating the diagnostic performance of LSMs using SSIRt, SSI-Lt, and the TE-XL probe for detecting severe fibrosis was 0.949, 0.917, and 0.952, respectively (Figure 4A). The optimal cut-off values and diagnostic accuracy are shown in Table 2. In addition, in this subgroup, the AUROCs for detecting severe fibrosis using FIB-4, AAR, and APRI were 0.792, 0.618, and 0.752, respectively (Figure 4A).
Receiver-Operating Characteristic Curves for Detecting Cirrhosis: Stage 4 In 124 biopsy-proven patients with liver disease from all etiologies, the AUROCs for detecting F4 fibrosis (cirrhosis) using SSI-Rt, SSI-Lt, and the TE-XL was 0.930, 0.910, and 0.920, respectively (Figure 3B). Furthermore, the AUROCs for detecting F4 fibrosis using FIB-4, AAR,
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Table 2. Optimal Cut-Off and Diagnostic Accuracy of SSI-Rt, SSI-Lt, and TE-XL Probe for Detecting Fibrosis Stage Type of elastography
Fibrosis stage
Cut-off value
Patients with liver disease from all etiologies (n ¼ 124) SSI-Rt F1 6.2 F2 7.9 F3 9.3 F¼4 11.4 SSI-Lt F1 7.4 F2 8.6 F3 10.9 F¼4 14.7 TE-XL F1 5.5 F2 7.7 F3 8.8 F¼4 11.3 HCV subgroup (n ¼ 102) SSI-Rt F1 6.2 F2 7.9 F3 9.3 F¼4 11.9 SSI-Lt F1 8.1 F2 9.0 F3 10.3 F¼4 10.9 TE-XL F1 5.5 F2 7.8 F3 10.4 F¼4 11.3
AUROC (95% CI)
Se, %
Sp, %
PPV, %
NPV, %
kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa
0.855 0.903 0.954 0.930 0.784 0.859 0.915 0.910 0.877 0.928 0.955 0.920
(0.712–0.959) (0.839–0.967) (0.913–0.996) (0.880–0.979) (0.595–0.974) (0.780–0.939) (0.856–0.973) (0.852–0.968) (0.762–0.992) (0.876–0.980) (0.916–0.994) (0.865–0.974)
75.9 74.4 90.7 89.5 72.4 79.4 84.8 75.8 84.4 78.0 94.2 88.9
87.5 97.1 90.3 84.6 80.0 79.2 84.8 86.4 70.0 89.2 85.1 85.5
98.8 98.4 89.1 73.9 98.4 91.5 84.8 75.8 96.8 94.1 83.1 72.7
21.2 61.1 91.8 94.3 14.3 57.6 84.8 86.4 29.2 64.7 90.9 94.7
kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa
0.754 0.874 0.949 0.914 0.654 0.831 0.917 0.887 0.838 0.906 0.952 0.907
(0.609–0.898) (0.793–0.954) (0.898–0.999) (0.851–0.977) (0.424–0.885) (0.735–0.928) (0.851–0.982) (0.812–0.961) (0.665–1.000) (0.837–0.974) (0.906–0.998) (0.841–0.974)
75.8 72.5 90.7 83.9 71.8 74.5 86.1 85.2 84.6 77.9 88.1 90.0
83.3 96.4 88.9 83.3 66.7 78.9 78.9 76.6 71.4 90.0 91.1 83.8
98.6 98.0 86.7 70.3 98.1 91.1 79.5 67.7 97.5 94.6 88.1 71.1
18.5 58.7 92.3 91.7 9.1 51.7 85.7 90.0 26.3 64.3 91.1 95.0
NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.
and APRI were 0.817, 0.598, and 0.746, respectively (Figure 3B). In our hepatitis C subgroup, the AUROCs for detecting F4 fibrosis using SSI-Rt, SSI-Lt, and the TE-XL probe was 0.914, 0.887, and 0.907, respectively (Figure 4B). The optimal cut-off values and diagnostic accuracy for this subgroup are shown in Table 2. In addition, in this subpopulation, the AUROCs for detecting F4 fibrosis using FIB-4, AAR, and APRI were 0.831, 0.611, and 0.756, respectively (Figure 4B).
Comparison of the Diagnostic Performance of Supersonic Shear Imaging in the Right Lobe, the Transient Elastography-XL Probe, and Scoring Systems (Fibrosis-4 Score, Alanine Aminotransferase Ratio, Aspartate Aminotransferase Platelet Ratio Index) for Assessing Severe Fibrosis (Stages 3 to 4) and Cirrhosis (Stage 4) Pairwise comparisons of AUROCs values between SSIRt, the TE-XL probe, and the FIB-4, AAR, and APRI were performed on 112 patients with chronic liver disease from all etiologies for whom liver biopsy data were available. Twelve patients were excluded from this analysis because of a failure to obtain LSMs using SSI-Rt or the TE-XL probe. For our subgroup analysis of 102 HCV-positive patients, we used data from 94 individuals because 8 patients were
excluded from the analysis as a result of failure to obtain LSMs using SSI-Rt or the TE-XL probe. Because of this high failure rate, LSM values obtained using the SSI-Lt approach were excluded from this analysis. For the diagnosis of severe fibrosis (F3–F4) and cirrhosis (F4), no significant differences were found between the SSI-Rt and the TE-XL methods in both the patients with chronic liver disease from all etiologies and the HCV subgroup (Supplementary Table 1). Furthermore, measurements obtained by both the SSI-Rt and the TE-XL probe showed significantly better diagnostic performance for detecting advanced fibrosis and cirrhosis when compared with the data obtained from the majority of the biochemical scoring systems evaluated here in both the patients with chronic liver disease from all etiologies and the HCV-positive subgroup (Supplementary Table 1).
The Parameters Contributing to Discordance Between Supersonic Shear Imaging, Transient Elastography, and Histologic Fibrosis Stage Determination Discordance of at least 2 stages between the histologic fibrosis stage and the fibrosis stage estimated using the cut-off values of SSI-Rt and the TE-XL were observed in 16 of 116 (13.8%) and 12 of 119 (10.1%) patients,
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Clinical Gastroenterology and Hepatology Vol. 13, No. 8 Figure 1. Box plots showing the interquartile range (box), median (middle line in the box), range (horizontal lines), and outliers (circles) of the LSM obtained using (A) SSI-Rt, (B) SSI-Lt, and (C) TE-XL in 124 biopsy-proven patients with liver disease from all etiologies.
respectively. The effect of age, sex, BMI, AST, alanine aminotransferase, serum albumin level, platelet count, and interquartile range/median LSMs on this discordance was assessed by comparing these discordant cases with the nondiscordant ones (Supplementary Table 2). In univariate analysis, BMI was associated significantly with the discordance obtained from measurements using SSI-Rt. There was no significant association between any of the aforementioned clinical characteristics and the discordance that was obtained through the use of the TE-XL probe.
Discussion Chronic liver disease progression often is asymptomatic; however, patients usually present with complications at advanced stages of disease. TE, the first developed ultrasound-based elastography method, has been validated for liver fibrosis assessment and it recently was included in the European Association for the Study of the Liver guidelines for fibrosis assessment in patients with chronic B and C hepatitis infection.18 Furthermore, TE received approval from the US Food and Drug Administration on April 5, 2013, and it is expected that its use subsequently will increase not only in Europe, but also in the United States. In a previously published study, the rate of failed and unreliable measurements by TE using the standard M probe was 18.9% to 29.2%.9,19 The most important predictive factor of failed and unreliable measurements was BMI. The XL probe uses a frequency of 2.5 MHz to increase penetrability.20 By using the XL probe, a reliable LSM was obtained in 59% to 93% of those who had an unreliable study using the M probe.21–24 A more recent study reported that 95% (103 of 106) of patients could be evaluated successfully with LSM using the XL probe.17
Figure 2. Box plots showing the interquartile range (box), median (middle line in the box), range (horizontal lines), and outliers (circles) of the LSM obtained using (A) SSI-Rt, (B) SSI-Lt, and (C) TEXL in the HCV-infected subgroup.
Recently, a new elastography system using SSI was developed.11 Only 5 published studies have compared TE with SSI in the evaluation of liver fibrosis,12,13,15–17 and they reported similar performance rates in predicting advanced fibrosis and cirrhosis. Of these, 3 studies used the XL probe in addition to the M probe. Two of these 3 studies did not use histologic fibrosis parameters as a gold standard for comparison.12,13 Therefore, the data showing its effectiveness in patients who have high BMI need further validation. In this study, we evaluated the diagnostic accuracy and reliability of LSMs using SSI and the TE-XL probe for the assessment of liver fibrosis in overweight or obese (BMI, 25) patients with chronic liver disease. We also performed an analysis on an HCV-infected subgroup because the LSM values for determining fibrosis stage vary with etiology. We showed a significant and strong positive correlation between LSMs obtained using the TE-XL probe and SSI even in overweight or obese patients with chronic liver disease. The percentage of unreliable SSI-Rt in our study was 5.4%, and LSM failure increased according to increasing BMI. We found that the optimal cut-off values for LSMs obtained using SSI-Rt for severe fibrosis (F3) and cirrhosis (F4) were 9.3 kPa and 11.4 kPa, respectively, in patients with chronic liver disease from all etiologies, and 9.3 kPa and 11.9 kPa in the HCV subgroup (Table 2). Ferraioli et al13 recently reported these values as 8.7 kPa and 10.4 kPa, respectively, in their study, which included 121 patients with chronic hepatitis of all etiologies, and Cassinotto et al17 reported cut-off values of 8.9 kPa and 10.7 kPa, respectively, in their study composed of 349 patients with similar clinical characteristics. Our study was restricted to overweight or obese patients; however, we obtained results similar to those reported previously.13,17 Likewise, it has been reported that BMI did not increase LSMs using TE.22 Similarly, BMI also may not affect LSMs
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Figure 3. Receiver-operating characteristic curves for detecting (A) severe fibrosis (fibrosis stages 3– 4) and (B) cirrhosis in 124 biopsy-proven patients with liver disease from all etiologies.
obtained using SSI from the data presented here. Furthermore, when compared with the data proposed in the Stebbing et al8 meta-analysis of TE, our cut-off values presented here, obtained using the TE-XL probe, were quite similar for detecting F2 fibrosis (7.7 vs 7.71 kPa), but were lower for detecting F4 fibrosis (11.3 vs 15.1 kPa). We believe our results for detecting F4 differed because the LSMs obtained using the XL probe have been reported to be lower than those obtained by the M probe.24 The rate of failure obtained using SSI on the left lobe was significantly higher than that obtained using SSI on the right lobe, and the actual values of LSMs from the left lobe were significantly higher than with the right lobe as reported previously using virtual touch tissue quantification.25 We previously reported that 33.1% of the study cohort had a difference of at least one stage between the right and left lobes as determined by liver biopsy.26 However, based on the results presented here, higher failure rates and different LSMs suggest there may be some challenges with LSMs obtained from the left lobe.
LSMs obtained from the left lobe may be impacted by effects arising from the surrounding structures, including the diaphragm and stomach. In addition, pulsatile movements from the aorta and heart have been reported also to influence LSMs.25 Furthermore, this study was focused on overweight or obese patients. The BMI and intercostal wall thickness are known to be the main factors associated with failure of LSM with SSI, probably owing to a poorer transmission of the ultrasound shear wave when the thickness of soft tissue/fat increases. Our study compared the diagnostic accuracy of the TE-XL probe and SSI for assessing liver fibrosis in overweight or obese patients. We showed that both SSI and TE-XL are valuable diagnostic tools for the diagnosis of severe fibrosis (F3–F4) and cirrhosis (F4) with AUROCs greater than 0.9 even in overweight or obese patients. Furthermore, both types of elastography showed higher accuracy than several clinical scoring systems in the diagnosis of severe fibrosis and cirrhosis. The major advantages of TE and SSI, compared with liver
Figure 4. Receiver-operating characteristic curves for detecting (A) severe fibrosis (fibrosis stages 3– 4) and (B) cirrhosis in the HCV subgroup.
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biopsy, are that these techniques are painless, rapid, and have no associated complications, and are accepted universally by patients. Moreover, SSI can be integrated into a conventional ultrasound system using conventional probes and therefore can be performed during standard examinations of the liver that are performed routinely in patients with chronic liver diseases such as hepatocellular carcinoma surveillance. Even in cases in which the diagnosis of cirrhosis is obvious, there are 2 additional benefits of measuring liver stiffness in these patients. First, a higher degree of stiffness in patients with cirrhosis could be of diagnostic value for detecting the presence of large varices,27 and it may be predictive of other complications and subsequent liver-related deaths.28 However, based on our data, a higher BMI may cause discordance between the histologic fibrosis stage and the fibrosis stage estimated using the cut-off values of SSI. One limitation of our study was that we calculated our accuracy measures based on the population being studied; therefore, our results are optimized for this specific population and likely may overestimate performance reliability. Another limitation was the relatively small number of patients; particularly with respect to the availability of data from patients with liver biopsy evaluation. Selection bias was another limitation because, in this study, we did not investigate patients who had any clinical evidence of hepatic decompensation. Furthermore, a recent study has shown that the error in liver biopsy results makes it impossible to distinguish it from a perfect noninvasive marker.29 In conclusion, this study investigated the potential clinical usefulness and comparison of SSI and the TE-XL probe for assessing liver fibrosis in overweight or obese patients with chronic liver disease. In addition, this study compared SSI and the TE-XL probe by US investigators in a US population. Furthermore, this study presents data from SSI obtained from the left lobe in addition to data obtained routinely from the right liver lobe. Because SSI requires a well-trained sonographer, these findings could be used to determine if the accuracy of SSI is indeed susceptible to operator variation. Larger prospective multicenter studies may be necessary to further ensure that SSI is indeed a reliable diagnostic tool in overweight patients.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.03.014.
References 1. National Institutes of Health. National Institutes of Health Consensus Development Conference statement: management of hepatitis C 2002 (June 10-12, 2002). Hepatology 2002; 36(Suppl 1):S3–S20.
Clinical Gastroenterology and Hepatology Vol. 13, No. 8 2. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology 2009;49:1017–1044. 3. Cadranel JF. Good clinical practice guidelines for fine needle aspiration biopsy of the liver: past, present and future. Gastroenterol Clin Biol 2002;26:823–824. 4. Bedossa P, Dargere D, Paradise V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–1457. 5. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986;1:523–525. 6. Talwalkar JA, Kurtz DM, Schoenleber SJ, et al. Ultrasoundbased transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2007;5:1214–1220. 7. Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Gastroenterology 2008;134:960–974. 8. Stebbing J, Farouk L, Panos G, et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol 2010;44:214–219. 9. Sirli R, Sporea I, Bota S, et al. Factors influencing reliability of liver stiffness measurements using transient elastography (M-probe)-monocentric experience. Eur J Radiol 2013; 82:e313–e316. 10. Myers RP, Pomier-Layrargues G, Kirsch R, et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 2012;55:199–208. 11. Muller M, Gennisson JL, Deffieux T, et al. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Ultrasound Med Biol 2009;35:219–229. 12. 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;37:1361–1373. 13. Ferraioli G, Tinelli C, Dal Bello B, et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012;56: 2125–2133. 14. Sirli R, Bota S, Sporea I, et al. Liver stiffness measurements by means of supersonic shear imaging in patients without known liver pathology. Ultrasound Med Biol 2013;39:1362–1367. 15. Sporea I, Bota S, Jurchis A, et al. Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013; 39:1933–1941. 16. Poynard T, Munteanu M, Luckina E, et al. Liver fibrosis evaluation using real-time shear wave elastography: applicability and diagnostic performance using methods without a gold standard. J Hepatol 2013;58:928–935. 17. Cassinotto C, Lapuyade B, Mouries A, et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®. J Hepatol 2014;61:550–557. 18. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011;55:245–264. 19. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828–835.
August 2015 20. Bamber J, Cosgrove D, Dietrich CF, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: basic principles and technology. Ultraschall Med 2013;34:169–184. 21. de Lédinghen V, Vergniol J, Foucher J, et al. Feasibility of liver transient elastography with FibroScan using a new probe for obese patients. Liver Int 2010;30:1043–1048. 22. Friedrich-Rust M, Hadji-Hosseini H, Kriener S, et al. Transient elastography with a new probe for obese patients for noninvasive staging of non-alcoholic steatohepatitis. Eur Radiol 2010;20:2390–2396. 23. de Lédinghen V, Wong VW, Vergniol J, et al. Diagnosis of liver fibrosis and cirrhosis using liver stiffness measurement: comparison between M and XL probe of FibroScan®. J Hepatol 2012;56:833–839. 24. S¸irli R, Sporea I, Deleanu A, et al. Comparison between the M and XL probes for liver fibrosis assessment by transient elastography. Med Ultrason 2014;16:119–122. 25. Toshima T, Shirabe K, Takeishi K, et al. New method for assessing liver fibrosis based on acoustic radiation force impulse: a special reference to the difference between right and left liver. J Gastroenterol 2011;46:705–711.
SSI and TE–XL Probe in Overweight Patients 1509 26. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–2618. 27. Berzigotti A, Seijo S, Arena U, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013;144:102–111. 28. Vergniol J, Foucher J, Terrebonne E, et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology 2011;140:1970–1979. 29. Mehta SH, Lau B, Afdhal NH, et al. Exceeding the limits of liver histology markers. J Hepatol 2009;50:36–41.
Reprint requests Address requests for reprints to: Masato Yoneda, MD, PhD, Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, 1500 NW 12th Avenue, Suite 1101, Miami, Florida 33136. e-mail: [email protected]. edu; fax: (305) 243-3877. Conflicts of interest The authors disclose no conflicts. Funding This study was funded through support from the Schiff Center for Liver Diseases at the University of Miami Miller School of Medicine.
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Supplementary Methods Clinical and Laboratory Evaluation The weight and height of each patient was measured using a calibrated scale after the patients had removed their shoes and any heavy items of clothing. Venous blood samples were obtained after the patients had fasted overnight (12 hours) and were used to measure the serum AST level, alanine aminotransferase level, albumin level, and platelet count. All of these parameters were measured using standard techniques. The FIB-4 index was calculated as follows: age AST (IU/L)/ platelet count (109/L)/O alanine aminotransferase (IU/L).1 The AAR was calculated as follows: AST/alanine aminotransferase.2 The APRI was calculated as follows: AST (/ULN)/platelet count (109/L) 100.3
Liver Histology Liver biopsy samples were obtained via a right intercostal space approach from the right liver lobe. First, sonography was performed to determine the safest intercostal space from which to obtain a biopsy sample. After disinfection of the entry point, local anesthesia was applied to the skin, intercostal space, peritoneum, and liver capsule. The liver biopsy then was performed in the left lateral decubitus position. The liver biopsy specimens then were stained with H&E and Masson’s trichrome stains and all of the biopsy specimens subsequently were analyzed independently by an experienced pathologist. Liver fibrosis stages were evaluated semiquantitatively according to the METAVIR scoring system.4 Liver fibrosis was staged according to an F0 to F4 scale: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.4
Transient Elastography LSM was performed using a Fibroscan 502 Touch (EchoSens, Paris, France) with the XL probe. The details of the technique and the examination procedure have been described in previous reports.5,6 A pulse-echo acquisition was performed to follow the propagation of the shear wave and measure its velocity, which is related directly to the tissue stiffness. Measurements of the right lobe of the liver were performed through the intercostal spaces with the patient lying in the dorsal decubitus position with their right arm in maximal abduction. This site also was used for the SSI measurements and the median was calculated and expressed in kilopascals. Reliable LSMs were obtained as the median of 10 valid measurements, with a success rate (the ratio of the number of acquisitions) of 60% or higher and an interquartile range (the range of the middle 50% of the data) of less than 30%. Unreliable LSMs were considered from
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the following scenarios: fewer than 10 valid acquisitions, a success rate of less than 60%, and/or an interquartile range of 30% or greater.
Measurement of Stiffness Using Supersonic Shear Imaging SSI was performed with an Aixplorer ultrasound system (SuperSonic Imagine, Aix-en-Provence, France). The principle underlying SSI involves the combination of a radiation force induced in tissues by focused ultrasonic beams and a very high frame rate ultrasound imaging sequence able to capture the propagation of resulting shear waves in real time. The radial forces that generate the shear waves are focused at increasing depths, causing a shear wave front that propagates in the area scanned. The ultrasound system then captures the generated shear waves. Shear wave speed subsequently is estimated by a Doppler-like acquisition over a region of interest. The shear wave speed then is used to calculate tissue stiffness. Elasticity is displayed using color mapping of the elasticity encoded pixel by pixel in an image superimposed on the standard B-mode image. In this manner, stiffer tissues appear red and softer tissues appear blue.7,8 SSI examinations were conducted in accordance with the manufacturer’s instructions. LSM was performed with the patient lying in a dorsal decubitus position with the right arm in maximal abduction in the right (SSI-Rt) and the left lobe (SSI-Lt). The operator, assisted by a real-time, B-mode ultrasound image, places the designated region of interest, 10 mm in diameter, in the color map. Five measurements were performed on each lobe.9 The median value of the 5 SSI measurements, expressed in kilopascals, were used as the representative measurement. The manufacturer of the SSI device did not recommend any technical parameter for quality assessment of the measurements. We used the interquartile range and success rate to assess the quality of SSI measurements such as that used by Sporea et al,9 and the same criteria for unreliable LSM was used for TE.
Statistical Analysis The statistical analyses were performed using JMP (version 10.0.2; SAS Institute, Cary, NC). For univariate comparisons between the patient groups, the Student t test was used. Because the variables often were not distributed normally, group comparisons of more than 2 independent groups were performed using the Kruskal–Wallis test. The correlation between LSM by the TE-XL probe, SSI-Rt, SSILt, and other scoring systems was tested using the Spearman rank correlation coefficient. The diagnostic performance and SSI was assessed by analyzing the receiver operating characteristic curves. The probability of a true-positive (sensitivity) and true-negative (specificity) assessment was determined for selected cut-off values and
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the AUROC was calculated. Cut-off values were determined for the TE-XL probe, SSI-Rt, and SSI-Lt to predict advanced fibrosis (F 3) and cirrhosis (F4) by using an optimization step that maximized the Youden index. The determination of correlation coefficients and a linear regression analysis were conducted to test for associations between the variables. Finally, the AUROC of the noninvasive tests were compared using the paired method by Zhou et al,10 excluding patients who had incomplete studies. The 95% confidence intervals were calculated using Woolf’s method.11 P values less than .05 were considered significant.
References 1. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–1325. 2. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734–739. 3. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518–526.
SSI and TE–XL Probe in Overweight Patients 1509.e2 4. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24:289–293. 5. Sandrin L, Tanter M, Gennisson JL, et al. Shear elasticity probe for soft tissues with 1-D transient elastography. IEEE Trans Ultrason Ferroelectr Freq Control 2002;49:436–446. 6. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705–1713. 7. Muller M, Gennisson JL, Deffieux T, et al. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Ultrasound Med Biol 2009;35:219–229. 8. Bercoff J, Tanter M, Fink M. Supersonic shear imaging: a new technique for soft tissue elasticity mapping. IEEE Trans Ultrason Ferroelectr Freq Control 2004;51:396–409. 9. Sporea I, Bota S, Jurchis A, et al. Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013; 39:1933–1941. 10. Zhou X, Obuchowski N, McClish D. Statistical methods in diagnostic medicine. 1st ed. New York: John Wiley & Sons, 2002. 11. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955;19:251–253.
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Supplementary Figure 1. Correlation between LSM obtained using SSI-Rt and (A) FIB-4 (r2 ¼ 0.25; P < .0001), (B) AAR (r2 ¼ 0.16; P < .0001), and (C) APRI (r2 ¼ 0.16; P < .0001).
Supplementary Figure 2. Correlation between LSM obtained using SSI-Lt and (A) FIB-4 (r2 ¼ 0.18; P < .0001), (B) AAR (r2 ¼ 0.07; P ¼ .0035), and (C) APRI (r2 ¼ 0.10; P ¼ .0009).
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SSI and TE–XL Probe in Overweight Patients 1509.e4
Supplementary Figure 3. Correlation between LSM obtained using the TE-XL probe and (A) FIB-4 (r2 ¼ 0.21; P < .0001), (B) AAR (r2 ¼ 0.08; P ¼ .0003), and (C) APRI (r2 ¼ 0.14; P ¼ .0009).
Supplementary Table 1. Pairwise Comparisons of AUROC Values for Elastographic and Clinical Scoring Systems SSI-Rt
TE-XL
FIB-4
AAR
In the patients with liver disease from all etiologies (F 3) SSI-Rt TE-XL P ¼ .1274 FIB-4 P ¼ .0201a P ¼ .0161a AAR P ¼ .0002a P ¼ .0001a P ¼ .0175a APRI P ¼ .0009a P ¼ .0006a P ¼ .1261 P ¼ .0161a In the patients with liver disease from all etiologies (F4) SSI-Rt TE-XL P ¼ .4255 FIB-4 P ¼ .0730 P ¼ .1080 AAR P ¼ .0049a P ¼ .0033a P ¼ .0191a APRI P ¼ .0067a P ¼ .0116a P ¼ .0035a P ¼ .1979 In the HCV infected subgroup (F 3) SSI-Rt TE-XL P ¼ .8924 FIB-4 P ¼ .0816 P ¼ .0471a AAR P < .0001a P < .0001a P ¼ .0156a APRI P ¼ .0382a P ¼ .0218a P ¼ .0343a P ¼ .2147 In the HCV-infected subgroup (F4) SSI-Rt TE-XL P ¼ .4245 FIB-4 P ¼ .3239 P ¼ .1776 AAR P < .0020a P ¼ .0010a P ¼ .0005a APRI P ¼ .1118 P ¼ .0700 P ¼ .0349a P ¼ .0496a P < .05 were considered significant.
a
APRI -
-
-
-
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Supplementary Table 2. Clinical Parameters Contributing to Discordance of at Least Two Stages Between SSI-Rt/TE-XL and Histologic Fibrosis Stage SSI-Rt Nondiscordant Patients (N ¼ 100) Age, y Sex, M:F BMI AST level, IU/L ALT level, IU/L Albumin level, g/dL Platelet count, 109/L IQR/M (%)
59 10 56:44 29.7 3.4 69.0 73.3 74.9 76.8 4.17 0.49 165.5 66.2 7.4 5.2
TE-XL
Discordant Patients (N ¼ 16)
P values
Nondiscordant patients (N ¼ 107)
Discordant patients (N ¼ 12)
P values
57 8:8 31.7 51.1 60.2 4.40 185.0 7.1
.6316 .6541 .0377a .3518 .4658 .0678 .2603 .8142
59 10 56:51 29.9 3.6 68.9 76.4 75.1 79.3 4.21 0.45 169.9 65.3 16.7 7.3
59 12 7:5 30.4 4.6 43.2 21.9 54.3 32.0 4.39 0.21 184.5 46.0 18.4 6.5
.7950 .6931 .6546 .2488 .3692 .1718 .4521 .4290
10 4.3 50.9 62.4 0.24 45.7 5.5
NOTE. Data are expressed as means SD. P values were calculated using the c2 test when comparing the gender between nondiscordant patients and discordant patients. The other P values were calculated using the Student t test. ALT, alanine aminotransferase; IQR/M, interquartile range/median liver stiffness measurement. a P < .05 was considered significant.
Supersonic Shear Imaging and Transient Elastography With the XL Probe Accurately Detect Fibrosis in Overweight or Obese Patients With Chronic Liver Disease Masato Yoneda, Emmanuel Thomas, Seth N. Sclair, Tiffannia T. Grant, and Eugene R. Schiff Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida BACKGROUND & AIMS:
Assessment of the severity of liver fibrosis is an important step in evaluating patients with chronic liver disease and determining their prognosis. We compared liver stiffness measurements (LSMs) made by supersonic shear imaging (SSI) with those of transient elastography (TE)-XL for their ability to determine the degree of liver fibrosis in overweight or obese patients with chronic liver disease.
METHODS:
We performed a prospective study of 258 patients with chronic hepatitis of different etiologies and a body mass index greater than 25, evaluated at the University of Miami from October 2013 to December 2014. Liver stiffness was measured using the TE-XL probe and SSI of the right and left lobes during the same clinic visit, and comparisons were made for fibrosis stage in 124 biopsy-proven patients. In addition, further analysis was performed on a subgroup of 102 chronic hepatitis C virus (HCV)-positive patients for whom biopsy data were available.
RESULTS:
Reliable LSMs were obtained from 96.1%, 94.6%, and 72.1% of patients using the TE-XL probe, SSI of the right lobe, and SSI of the left lobe, respectively. TE-XL, SSI of the right lobe, and SSI of the left lobe detected severe fibrosis (fibrosis stages 3–4), with area under the receiver operating characteristic curve (AUROC) values of 0.955, 0.954, and 0.910, respectively, compared with results from histologic analysis for the 124 biopsy-proven patients included in the study; these values were 0.952, 0.949, and 0.917, respectively, for the 102 biopsy-proven patients with HCV infection. TE-XL, SSI of the right lobe, and SSI of the left lobe detected fibrosis stage 4 with AUROC values of 0.920, 0.930, and 0.910, respectively, compared with histologic analysis, in all 124-biopsy proven patients, and with AUROC values of 0.907, 0.914, and 0.887, respectively, in the 102 biopsy-proven patients with chronic HCV infection.
CONCLUSIONS:
SSI and the TE-XL probe each accurately quantify liver fibrosis in overweight or obese patients with chronic liver disease, including those with HCV infection, when compared with data obtained from histologic analysis. SSI data obtained from the right lobe and the TE-XL probe can be used to evaluate fibrosis with similar accuracy.
Keywords: Viral Hepatitis; Cirrhosis; Fibrosis Stage; Obesity.
See editorial on page 1510. taging of liver fibrosis is essential in determining the prognosis and optimal treatment for patients with chronic liver disease and also to guide surveillance for the development of hepatocellular carcinoma.1 Liver biopsy is recommended as the reference standard method for the diagnosis and staging of fibrosis in chronic liver disease.2 This procedure, however, is invasive with associated risks of complications, is costly, and is time consuming both for providers and patients.3 In addition, despite being the gold standard test for assessing liver fibrosis, liver biopsy is limited
S
further by sampling error and intra-observer and interobserver variability.4,5 Therefore, there is great need for rapid, quantitative, and noninvasive methods for
Abbreviations used in this paper: AAR, aspartate aminotransferase to alanine aminotransferase ratio; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartate aminotransferase; AUROC, area under the receiver-operating characteristic; BMI, body mass index; F3, fibrosis stage 3; F4, fibrosis stage 4; FIB-4, Fibrosis-4 score; HCV, hepatitis C virus; LSM, liver stiffness measurement; SSI, supersonic shear imaging; SSI-Lt, supersonic shear imaging from the left lobe; SSI-Rt, supersonic shear imaging from the right lobe; TE, transient elastography. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.03.014
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detecting fibrosis. Several clinical studies have been performed for the assessment of liver fibrosis and, recently, most have validated fibrosis using the ultrasound-based method of transient elastography (TE).6–8 However, in some cases, the standard M probe fails to generate reliable elasticity measurements in overweight patients.9 When using the XL probe, the reliability of TE in overweight or obese patients is improved significantly.10 Recently, a new technology in the field of elastography was developed.11 Supersonic shear imaging (SSI), also named ShearWave (SuperSonic Imagine, Aix-enProvence, France) elastography, is based on the measurement of the velocity of a local shear wave through soft tissue. Several studies have reported on the usefulness of SSI for assessing liver fibrosis in patients with chronic hepatitis.12–17 The purpose of this study was to specifically investigate the diagnostic accuracy and reliability of SSI when compared with assessment of liver fibrosis using TE with the XL probe in overweight or obese patients with chronic liver disease, and additional analyses were performed on a hepatitis C virus (HCV)infected subgroup.
Methods Patients This study was conducted with the approval of the Institutional Review Board at the University of Miami and written informed consent was obtained from each patient. A total of 258 patients (124 with histologic determination of fibrosis stage) with chronic hepatitis, whose body mass index (BMI) was greater than 25 and whose skin capsule distance measurement was greater than 2.5 cm, evaluated at the University of Miami from October 2013 to December 2014, prospectively were included in this study. BMIs higher than 25 and 30 are categorized as overweight and obesity according to the World Health Organization. Liver stiffness measurement (LSM) was assessed using TE with the XL probe (2.5 MHz), and SSI from both the right (SSI-Rt) and left (SSI-Lt) lobes during the same clinic visit. Other methods used in this study are described in the Supplementary Methods section.
Results Patient Characteristics A total of 258 patients prospectively were included in the analysis. The study included patients with the following underlying liver conditions: 168 patients with HCV, 35 patients with nonalcoholic fatty liver disease, 20 patients with chronic hepatitis B virus, 11 patients with primary biliary cirrhosis, 10 patients with primary sclerosing cholangitis, 4 patients with autoimmune hepatitis,
SSI and TE–XL Probe in Overweight Patients 1503
and 10 patients with other liver diseases (alcohol liver disease, a-1 antitrypsin deficiency, and increased liver enzyme levels from unknown origin). The histologic fibrosis stage was available for 124 patients. Among them, the following etiologies were present: 102 patients with HCV, 4 patients with hepatitis B virus, 8 patients with nonalcoholic fatty liver disease, 2 patients with autoimmune hepatitis, 5 patients with primary biliary cirrhosis, 2 patients with primary sclerosing cholangitis, and 1 patient with alcoholic liver disease. The characteristics of the patients were stratified according to BMI and they are summarized in Table 1. The LSM failures (unreliable LSM) occurred in 5.4%, 27.9%, and 3.9% when using SSI-Rt, SSI-Lt, and the TE-XL probe, respectively. The rate of unreliable LSMs by SSI-Lt was significantly higher than those obtained using SSI-Rt and the TE-XL probe. The LSM failure rate tended to increase according to increasing BMI when using SSIRt, SSI-Lt, and the TE-XL probe (Table 1).
Comparison of Liver Stiffness Measurement Using Supersonic Shear Imaging in the Right Lobe, Supersonic Shear Imaging in the Left Lobe, or the Transient Elastography-XL Probe With Other Scoring Systems Used to Evaluate Liver Fibrosis: Fibrosis-4 Score, Aspartate Aminotransferase to Alanine Aminotransferase Ratio and Aspartate Aminotransferase to the Platelet Ratio Index LSMs using SSI-Lt were significantly higher than that obtained from SSI-Rt (12.6 9.2 and 10.6 8.0, respectively; P < .0001). When compared with other fibrosis scoring systems (Fibrosis-4 score [FIB-4], aspartate aminotransferase [AST] to alanine aminotransferase ratio [AAR] and AST to the platelet ratio index [APRI]), there were significant, albeit weak, correlations observed between these scoring systems and LSMs using SSI-Rt, SSI-Lt, and the TE-XL probe (Supplementary Figures 1–3).
Correlation Between Liver Stiffness Measurement Obtained Using Supersonic Shear Imaging in the Right Lobe, Supersonic Shear Imaging in the Left Lobe, or the Transient Elastography-XL Probe and Histologic Fibrosis Staging Overall, LSMs using SSI-Rt, SSI-Lt, and TE-XL probes stratified according to histologic fibrosis stage and these data are shown in Table 2 and Figure 1. In the hepatitis C subgroup, LSMs using SSI-Rt, SSI-Lt, and the TE-XL probe stratified by the histologic fibrosis stage and these data are shown in Table 2 and Figure 2. LSMs obtained using SSI-Rt and the TE-XL probe showed a stepwise increase with the corresponding histologic severity of hepatic fibrosis (P < .0001) in both 124 biopsy-proven patients
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Table 1. Clinical and Biochemical Characteristics of Patients Stratified According to BMI Characteristics
All patients (N ¼ 258)
BMI category Age, y 57 12 [56–59] Sex, male:female 115:59 BMI, m/kg2 30.1 4.1 [29.6–30.6] AST level, U/mL 62.2 72.6 [53.3–71.1] ALT level, U/mL 75.8 88.9 [64.9–86.6] Platelet count, 109/L 186.4 71.8 [177.6–195.2] Albumin level, g/dL 4.27 0.45 [4.22–4.33] FIB-4 index 2.71 2.63 [2.39–3.03] AST:ALT ratio 0.94 0.40 [0.89–0.99] APRI 1.14 1.86 [0.91–1.34] Liver diseases HCV 168 (65.1%) HBV 20 (7.8%) NAFLD 35 (13.6%) PSC 10 (3.9%) PBC 11 (4.3%) AIH 4 (1.6%) Others 10 (3.9%) SSI-Rt LSM, kPa 10.6 8.0 [9.6–11.6] IQR/M (%) 7.7 5.3 [7.0–8.4] Unreliable LSM 14 (5.4%) SSI-Lt LSM, kPa 12.6 9.2 [11.2–13.9] IQR/M (%) 11.9 6.9 [10.9–12.9] Unreliable LSM 72 (27.9%) TE-XL LSM, kPa 10.9 9.0 [9.8–12.0] IQR/M (%) 16.6 7.0 [15.7–17.5] Unreliable LSM 10 (3.9%)
Group A (n ¼ 90)
Group B (n ¼ 79)
Group C (n ¼ 89)
25 < BMI < 28
28 BMI < 30
BMI > 30
56 12 [53–58] 47:43 26.5 1.0 [26.2–26.7] 75.4 100.8 [54.3–96.5] 91.1 123.0 [65.4–116.9] 185.3 80.6 [168.4–202.2] 4.23 0.55 [4.12–4.35] 2.92 2.52 [2.39–3.44] 0.95 0.32 [0.88–1.01] 1.41 2.37 [0.92–1.90]
59 12 [56–62] 50:29 29.1 0.6 [29.0–29.2]b 50.3 41.3 [41.0–59.5]b 63.8 58.7 [50.7–77.0] 177.5 52.8 [165.6–189.3] 4.34 0.36 [4.26–4.43] 2.37 1.60 [2.01–2.73] 0.93 0.34 [0.86–1.01] 0.83 0.10 [0.63–1.03]b
57 10 [55–59] 40:49a 34.7 3.4 [33.9–35.4]a,c 59.6 57.4 [47.5–71.6] 70.8 65.6 [57.0–84.6] 195.3 76.5 [179.2–211.5] 4.26 0.40 [4.17–4.34] 2.80 3.37 [2.09–3.51] 0.95 0.52 [0.84–1.06] 1.14 1.90 [0.74–1.54]
61 9 7 7 2 1 3
(67.8%) (10%) (7.8%) (7.8%) (2.2%) (1.1%) (3.3%)
56 6 6 2 4 3 2
(70.8%) (7.6%) (7.6%) (2.5%) (5.1%) (3.8%) (2.5%)
51 5 22 1 5 0 5
(57.3) (5.6%) (24.7%) (1.1%) (5.6%) (0%) (5.6%)
11.5 9.3 [9.5–13.5] 7.3 4.9 [6.3–8.3] 2 (2.2%)
9.1 5.8 [7.8–10.5] 8.4 5.4 [7.2–9.6] 4 (5.1%)
11.0 8.2 [9.2–12.8] 7.5 5.7 [6.2–8.8] 8 (9.0%)c
12.5 8.5 [10.4–14.5] 11.6 6.8 [9.9–13.2] 21 (23.3%)
12.3 10.6 [9.5–15.0] 11.7 6.4 [10.0–13.3] 20 (25.3%)
13.0 8.7 [10.7–15.3] 12.6 7.6 [10.6–14.5] 31 (34.8%)
11.7 10.9 [9.4–14.0] 16.1 7.2 [14.5–17.6] 2 (2.2%)
10.3 7.8 [8.6–12.1] 16.4 6.5 [14.9–17.8] 2 (2.5%)
10.7 7.7 [9.0–12.4] 17.5 7.2 [15.9–19.0] 6 (6.7%)
NOTE. Data are expressed as n (%), or mean SD [95% CI]. P values were calculated using the c2 test when comparing sex and unreliable LSM/total numbers between the groups. Other P values were calculated using the Student t test. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; HBV, hepatitis B virus; IQR/M, interquartile range/median; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. a P < .05 for comparisons between groups B and C. b P < .05 for comparisons between groups A and B. c P < .05 for comparisons between groups A and C.
with liver disease from all etiologies and the hepatitis C subgroup analysis.
Receiver-Operating Characteristic Curves for Detecting Severe Fibrosis: Stages 3 to 4 In 124 biopsy-proven patients with liver disease from all etiologies, the area under the receiver-operating characteristic curves (AUROCs) for estimating the diagnostic performance of LSMs using SSI-Rt, SSI-Lt, and the TE-XL probe for detecting severe fibrosis (fibrosis stages 3–4 [F3–F4]) was 0.954, 0.915, and 0.955, respectively (Figure 3A). The optimal cut-off value and diagnostic accuracy (sensitivity, specificity, positive and negative predictive values) are shown in Table 2. The AUROCs for detecting severe fibrosis using FIB-4, AAR, and APRI were 0.767, 0.589, and 0.753, respectively, in our study population (Figure 3A).
In the hepatitis C subgroup, the AUROCs for estimating the diagnostic performance of LSMs using SSIRt, SSI-Lt, and the TE-XL probe for detecting severe fibrosis was 0.949, 0.917, and 0.952, respectively (Figure 4A). The optimal cut-off values and diagnostic accuracy are shown in Table 2. In addition, in this subgroup, the AUROCs for detecting severe fibrosis using FIB-4, AAR, and APRI were 0.792, 0.618, and 0.752, respectively (Figure 4A).
Receiver-Operating Characteristic Curves for Detecting Cirrhosis: Stage 4 In 124 biopsy-proven patients with liver disease from all etiologies, the AUROCs for detecting F4 fibrosis (cirrhosis) using SSI-Rt, SSI-Lt, and the TE-XL was 0.930, 0.910, and 0.920, respectively (Figure 3B). Furthermore, the AUROCs for detecting F4 fibrosis using FIB-4, AAR,
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SSI and TE–XL Probe in Overweight Patients 1505
Table 2. Optimal Cut-Off and Diagnostic Accuracy of SSI-Rt, SSI-Lt, and TE-XL Probe for Detecting Fibrosis Stage Type of elastography
Fibrosis stage
Cut-off value
Patients with liver disease from all etiologies (n ¼ 124) SSI-Rt F1 6.2 F2 7.9 F3 9.3 F¼4 11.4 SSI-Lt F1 7.4 F2 8.6 F3 10.9 F¼4 14.7 TE-XL F1 5.5 F2 7.7 F3 8.8 F¼4 11.3 HCV subgroup (n ¼ 102) SSI-Rt F1 6.2 F2 7.9 F3 9.3 F¼4 11.9 SSI-Lt F1 8.1 F2 9.0 F3 10.3 F¼4 10.9 TE-XL F1 5.5 F2 7.8 F3 10.4 F¼4 11.3
AUROC (95% CI)
Se, %
Sp, %
PPV, %
NPV, %
kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa
0.855 0.903 0.954 0.930 0.784 0.859 0.915 0.910 0.877 0.928 0.955 0.920
(0.712–0.959) (0.839–0.967) (0.913–0.996) (0.880–0.979) (0.595–0.974) (0.780–0.939) (0.856–0.973) (0.852–0.968) (0.762–0.992) (0.876–0.980) (0.916–0.994) (0.865–0.974)
75.9 74.4 90.7 89.5 72.4 79.4 84.8 75.8 84.4 78.0 94.2 88.9
87.5 97.1 90.3 84.6 80.0 79.2 84.8 86.4 70.0 89.2 85.1 85.5
98.8 98.4 89.1 73.9 98.4 91.5 84.8 75.8 96.8 94.1 83.1 72.7
21.2 61.1 91.8 94.3 14.3 57.6 84.8 86.4 29.2 64.7 90.9 94.7
kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa kPa
0.754 0.874 0.949 0.914 0.654 0.831 0.917 0.887 0.838 0.906 0.952 0.907
(0.609–0.898) (0.793–0.954) (0.898–0.999) (0.851–0.977) (0.424–0.885) (0.735–0.928) (0.851–0.982) (0.812–0.961) (0.665–1.000) (0.837–0.974) (0.906–0.998) (0.841–0.974)
75.8 72.5 90.7 83.9 71.8 74.5 86.1 85.2 84.6 77.9 88.1 90.0
83.3 96.4 88.9 83.3 66.7 78.9 78.9 76.6 71.4 90.0 91.1 83.8
98.6 98.0 86.7 70.3 98.1 91.1 79.5 67.7 97.5 94.6 88.1 71.1
18.5 58.7 92.3 91.7 9.1 51.7 85.7 90.0 26.3 64.3 91.1 95.0
NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.
and APRI were 0.817, 0.598, and 0.746, respectively (Figure 3B). In our hepatitis C subgroup, the AUROCs for detecting F4 fibrosis using SSI-Rt, SSI-Lt, and the TE-XL probe was 0.914, 0.887, and 0.907, respectively (Figure 4B). The optimal cut-off values and diagnostic accuracy for this subgroup are shown in Table 2. In addition, in this subpopulation, the AUROCs for detecting F4 fibrosis using FIB-4, AAR, and APRI were 0.831, 0.611, and 0.756, respectively (Figure 4B).
Comparison of the Diagnostic Performance of Supersonic Shear Imaging in the Right Lobe, the Transient Elastography-XL Probe, and Scoring Systems (Fibrosis-4 Score, Alanine Aminotransferase Ratio, Aspartate Aminotransferase Platelet Ratio Index) for Assessing Severe Fibrosis (Stages 3 to 4) and Cirrhosis (Stage 4) Pairwise comparisons of AUROCs values between SSIRt, the TE-XL probe, and the FIB-4, AAR, and APRI were performed on 112 patients with chronic liver disease from all etiologies for whom liver biopsy data were available. Twelve patients were excluded from this analysis because of a failure to obtain LSMs using SSI-Rt or the TE-XL probe. For our subgroup analysis of 102 HCV-positive patients, we used data from 94 individuals because 8 patients were
excluded from the analysis as a result of failure to obtain LSMs using SSI-Rt or the TE-XL probe. Because of this high failure rate, LSM values obtained using the SSI-Lt approach were excluded from this analysis. For the diagnosis of severe fibrosis (F3–F4) and cirrhosis (F4), no significant differences were found between the SSI-Rt and the TE-XL methods in both the patients with chronic liver disease from all etiologies and the HCV subgroup (Supplementary Table 1). Furthermore, measurements obtained by both the SSI-Rt and the TE-XL probe showed significantly better diagnostic performance for detecting advanced fibrosis and cirrhosis when compared with the data obtained from the majority of the biochemical scoring systems evaluated here in both the patients with chronic liver disease from all etiologies and the HCV-positive subgroup (Supplementary Table 1).
The Parameters Contributing to Discordance Between Supersonic Shear Imaging, Transient Elastography, and Histologic Fibrosis Stage Determination Discordance of at least 2 stages between the histologic fibrosis stage and the fibrosis stage estimated using the cut-off values of SSI-Rt and the TE-XL were observed in 16 of 116 (13.8%) and 12 of 119 (10.1%) patients,
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Clinical Gastroenterology and Hepatology Vol. 13, No. 8 Figure 1. Box plots showing the interquartile range (box), median (middle line in the box), range (horizontal lines), and outliers (circles) of the LSM obtained using (A) SSI-Rt, (B) SSI-Lt, and (C) TE-XL in 124 biopsy-proven patients with liver disease from all etiologies.
respectively. The effect of age, sex, BMI, AST, alanine aminotransferase, serum albumin level, platelet count, and interquartile range/median LSMs on this discordance was assessed by comparing these discordant cases with the nondiscordant ones (Supplementary Table 2). In univariate analysis, BMI was associated significantly with the discordance obtained from measurements using SSI-Rt. There was no significant association between any of the aforementioned clinical characteristics and the discordance that was obtained through the use of the TE-XL probe.
Discussion Chronic liver disease progression often is asymptomatic; however, patients usually present with complications at advanced stages of disease. TE, the first developed ultrasound-based elastography method, has been validated for liver fibrosis assessment and it recently was included in the European Association for the Study of the Liver guidelines for fibrosis assessment in patients with chronic B and C hepatitis infection.18 Furthermore, TE received approval from the US Food and Drug Administration on April 5, 2013, and it is expected that its use subsequently will increase not only in Europe, but also in the United States. In a previously published study, the rate of failed and unreliable measurements by TE using the standard M probe was 18.9% to 29.2%.9,19 The most important predictive factor of failed and unreliable measurements was BMI. The XL probe uses a frequency of 2.5 MHz to increase penetrability.20 By using the XL probe, a reliable LSM was obtained in 59% to 93% of those who had an unreliable study using the M probe.21–24 A more recent study reported that 95% (103 of 106) of patients could be evaluated successfully with LSM using the XL probe.17
Figure 2. Box plots showing the interquartile range (box), median (middle line in the box), range (horizontal lines), and outliers (circles) of the LSM obtained using (A) SSI-Rt, (B) SSI-Lt, and (C) TEXL in the HCV-infected subgroup.
Recently, a new elastography system using SSI was developed.11 Only 5 published studies have compared TE with SSI in the evaluation of liver fibrosis,12,13,15–17 and they reported similar performance rates in predicting advanced fibrosis and cirrhosis. Of these, 3 studies used the XL probe in addition to the M probe. Two of these 3 studies did not use histologic fibrosis parameters as a gold standard for comparison.12,13 Therefore, the data showing its effectiveness in patients who have high BMI need further validation. In this study, we evaluated the diagnostic accuracy and reliability of LSMs using SSI and the TE-XL probe for the assessment of liver fibrosis in overweight or obese (BMI, 25) patients with chronic liver disease. We also performed an analysis on an HCV-infected subgroup because the LSM values for determining fibrosis stage vary with etiology. We showed a significant and strong positive correlation between LSMs obtained using the TE-XL probe and SSI even in overweight or obese patients with chronic liver disease. The percentage of unreliable SSI-Rt in our study was 5.4%, and LSM failure increased according to increasing BMI. We found that the optimal cut-off values for LSMs obtained using SSI-Rt for severe fibrosis (F3) and cirrhosis (F4) were 9.3 kPa and 11.4 kPa, respectively, in patients with chronic liver disease from all etiologies, and 9.3 kPa and 11.9 kPa in the HCV subgroup (Table 2). Ferraioli et al13 recently reported these values as 8.7 kPa and 10.4 kPa, respectively, in their study, which included 121 patients with chronic hepatitis of all etiologies, and Cassinotto et al17 reported cut-off values of 8.9 kPa and 10.7 kPa, respectively, in their study composed of 349 patients with similar clinical characteristics. Our study was restricted to overweight or obese patients; however, we obtained results similar to those reported previously.13,17 Likewise, it has been reported that BMI did not increase LSMs using TE.22 Similarly, BMI also may not affect LSMs
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Figure 3. Receiver-operating characteristic curves for detecting (A) severe fibrosis (fibrosis stages 3– 4) and (B) cirrhosis in 124 biopsy-proven patients with liver disease from all etiologies.
obtained using SSI from the data presented here. Furthermore, when compared with the data proposed in the Stebbing et al8 meta-analysis of TE, our cut-off values presented here, obtained using the TE-XL probe, were quite similar for detecting F2 fibrosis (7.7 vs 7.71 kPa), but were lower for detecting F4 fibrosis (11.3 vs 15.1 kPa). We believe our results for detecting F4 differed because the LSMs obtained using the XL probe have been reported to be lower than those obtained by the M probe.24 The rate of failure obtained using SSI on the left lobe was significantly higher than that obtained using SSI on the right lobe, and the actual values of LSMs from the left lobe were significantly higher than with the right lobe as reported previously using virtual touch tissue quantification.25 We previously reported that 33.1% of the study cohort had a difference of at least one stage between the right and left lobes as determined by liver biopsy.26 However, based on the results presented here, higher failure rates and different LSMs suggest there may be some challenges with LSMs obtained from the left lobe.
LSMs obtained from the left lobe may be impacted by effects arising from the surrounding structures, including the diaphragm and stomach. In addition, pulsatile movements from the aorta and heart have been reported also to influence LSMs.25 Furthermore, this study was focused on overweight or obese patients. The BMI and intercostal wall thickness are known to be the main factors associated with failure of LSM with SSI, probably owing to a poorer transmission of the ultrasound shear wave when the thickness of soft tissue/fat increases. Our study compared the diagnostic accuracy of the TE-XL probe and SSI for assessing liver fibrosis in overweight or obese patients. We showed that both SSI and TE-XL are valuable diagnostic tools for the diagnosis of severe fibrosis (F3–F4) and cirrhosis (F4) with AUROCs greater than 0.9 even in overweight or obese patients. Furthermore, both types of elastography showed higher accuracy than several clinical scoring systems in the diagnosis of severe fibrosis and cirrhosis. The major advantages of TE and SSI, compared with liver
Figure 4. Receiver-operating characteristic curves for detecting (A) severe fibrosis (fibrosis stages 3– 4) and (B) cirrhosis in the HCV subgroup.
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biopsy, are that these techniques are painless, rapid, and have no associated complications, and are accepted universally by patients. Moreover, SSI can be integrated into a conventional ultrasound system using conventional probes and therefore can be performed during standard examinations of the liver that are performed routinely in patients with chronic liver diseases such as hepatocellular carcinoma surveillance. Even in cases in which the diagnosis of cirrhosis is obvious, there are 2 additional benefits of measuring liver stiffness in these patients. First, a higher degree of stiffness in patients with cirrhosis could be of diagnostic value for detecting the presence of large varices,27 and it may be predictive of other complications and subsequent liver-related deaths.28 However, based on our data, a higher BMI may cause discordance between the histologic fibrosis stage and the fibrosis stage estimated using the cut-off values of SSI. One limitation of our study was that we calculated our accuracy measures based on the population being studied; therefore, our results are optimized for this specific population and likely may overestimate performance reliability. Another limitation was the relatively small number of patients; particularly with respect to the availability of data from patients with liver biopsy evaluation. Selection bias was another limitation because, in this study, we did not investigate patients who had any clinical evidence of hepatic decompensation. Furthermore, a recent study has shown that the error in liver biopsy results makes it impossible to distinguish it from a perfect noninvasive marker.29 In conclusion, this study investigated the potential clinical usefulness and comparison of SSI and the TE-XL probe for assessing liver fibrosis in overweight or obese patients with chronic liver disease. In addition, this study compared SSI and the TE-XL probe by US investigators in a US population. Furthermore, this study presents data from SSI obtained from the left lobe in addition to data obtained routinely from the right liver lobe. Because SSI requires a well-trained sonographer, these findings could be used to determine if the accuracy of SSI is indeed susceptible to operator variation. Larger prospective multicenter studies may be necessary to further ensure that SSI is indeed a reliable diagnostic tool in overweight patients.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.03.014.
References 1. National Institutes of Health. National Institutes of Health Consensus Development Conference statement: management of hepatitis C 2002 (June 10-12, 2002). Hepatology 2002; 36(Suppl 1):S3–S20.
Clinical Gastroenterology and Hepatology Vol. 13, No. 8 2. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology 2009;49:1017–1044. 3. Cadranel JF. Good clinical practice guidelines for fine needle aspiration biopsy of the liver: past, present and future. Gastroenterol Clin Biol 2002;26:823–824. 4. Bedossa P, Dargere D, Paradise V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–1457. 5. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986;1:523–525. 6. Talwalkar JA, Kurtz DM, Schoenleber SJ, et al. Ultrasoundbased transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2007;5:1214–1220. 7. Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Gastroenterology 2008;134:960–974. 8. Stebbing J, Farouk L, Panos G, et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol 2010;44:214–219. 9. Sirli R, Sporea I, Bota S, et al. Factors influencing reliability of liver stiffness measurements using transient elastography (M-probe)-monocentric experience. Eur J Radiol 2013; 82:e313–e316. 10. Myers RP, Pomier-Layrargues G, Kirsch R, et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 2012;55:199–208. 11. Muller M, Gennisson JL, Deffieux T, et al. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Ultrasound Med Biol 2009;35:219–229. 12. 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;37:1361–1373. 13. Ferraioli G, Tinelli C, Dal Bello B, et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012;56: 2125–2133. 14. Sirli R, Bota S, Sporea I, et al. Liver stiffness measurements by means of supersonic shear imaging in patients without known liver pathology. Ultrasound Med Biol 2013;39:1362–1367. 15. Sporea I, Bota S, Jurchis A, et al. Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013; 39:1933–1941. 16. Poynard T, Munteanu M, Luckina E, et al. Liver fibrosis evaluation using real-time shear wave elastography: applicability and diagnostic performance using methods without a gold standard. J Hepatol 2013;58:928–935. 17. Cassinotto C, Lapuyade B, Mouries A, et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®. J Hepatol 2014;61:550–557. 18. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011;55:245–264. 19. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828–835.
August 2015 20. Bamber J, Cosgrove D, Dietrich CF, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: basic principles and technology. Ultraschall Med 2013;34:169–184. 21. de Lédinghen V, Vergniol J, Foucher J, et al. Feasibility of liver transient elastography with FibroScan using a new probe for obese patients. Liver Int 2010;30:1043–1048. 22. Friedrich-Rust M, Hadji-Hosseini H, Kriener S, et al. Transient elastography with a new probe for obese patients for noninvasive staging of non-alcoholic steatohepatitis. Eur Radiol 2010;20:2390–2396. 23. de Lédinghen V, Wong VW, Vergniol J, et al. Diagnosis of liver fibrosis and cirrhosis using liver stiffness measurement: comparison between M and XL probe of FibroScan®. J Hepatol 2012;56:833–839. 24. S¸irli R, Sporea I, Deleanu A, et al. Comparison between the M and XL probes for liver fibrosis assessment by transient elastography. Med Ultrason 2014;16:119–122. 25. Toshima T, Shirabe K, Takeishi K, et al. New method for assessing liver fibrosis based on acoustic radiation force impulse: a special reference to the difference between right and left liver. J Gastroenterol 2011;46:705–711.
SSI and TE–XL Probe in Overweight Patients 1509 26. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–2618. 27. Berzigotti A, Seijo S, Arena U, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013;144:102–111. 28. Vergniol J, Foucher J, Terrebonne E, et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology 2011;140:1970–1979. 29. Mehta SH, Lau B, Afdhal NH, et al. Exceeding the limits of liver histology markers. J Hepatol 2009;50:36–41.
Reprint requests Address requests for reprints to: Masato Yoneda, MD, PhD, Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, 1500 NW 12th Avenue, Suite 1101, Miami, Florida 33136. e-mail: [email protected]. edu; fax: (305) 243-3877. Conflicts of interest The authors disclose no conflicts. Funding This study was funded through support from the Schiff Center for Liver Diseases at the University of Miami Miller School of Medicine.
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Supplementary Methods Clinical and Laboratory Evaluation The weight and height of each patient was measured using a calibrated scale after the patients had removed their shoes and any heavy items of clothing. Venous blood samples were obtained after the patients had fasted overnight (12 hours) and were used to measure the serum AST level, alanine aminotransferase level, albumin level, and platelet count. All of these parameters were measured using standard techniques. The FIB-4 index was calculated as follows: age AST (IU/L)/ platelet count (109/L)/O alanine aminotransferase (IU/L).1 The AAR was calculated as follows: AST/alanine aminotransferase.2 The APRI was calculated as follows: AST (/ULN)/platelet count (109/L) 100.3
Liver Histology Liver biopsy samples were obtained via a right intercostal space approach from the right liver lobe. First, sonography was performed to determine the safest intercostal space from which to obtain a biopsy sample. After disinfection of the entry point, local anesthesia was applied to the skin, intercostal space, peritoneum, and liver capsule. The liver biopsy then was performed in the left lateral decubitus position. The liver biopsy specimens then were stained with H&E and Masson’s trichrome stains and all of the biopsy specimens subsequently were analyzed independently by an experienced pathologist. Liver fibrosis stages were evaluated semiquantitatively according to the METAVIR scoring system.4 Liver fibrosis was staged according to an F0 to F4 scale: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.4
Transient Elastography LSM was performed using a Fibroscan 502 Touch (EchoSens, Paris, France) with the XL probe. The details of the technique and the examination procedure have been described in previous reports.5,6 A pulse-echo acquisition was performed to follow the propagation of the shear wave and measure its velocity, which is related directly to the tissue stiffness. Measurements of the right lobe of the liver were performed through the intercostal spaces with the patient lying in the dorsal decubitus position with their right arm in maximal abduction. This site also was used for the SSI measurements and the median was calculated and expressed in kilopascals. Reliable LSMs were obtained as the median of 10 valid measurements, with a success rate (the ratio of the number of acquisitions) of 60% or higher and an interquartile range (the range of the middle 50% of the data) of less than 30%. Unreliable LSMs were considered from
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the following scenarios: fewer than 10 valid acquisitions, a success rate of less than 60%, and/or an interquartile range of 30% or greater.
Measurement of Stiffness Using Supersonic Shear Imaging SSI was performed with an Aixplorer ultrasound system (SuperSonic Imagine, Aix-en-Provence, France). The principle underlying SSI involves the combination of a radiation force induced in tissues by focused ultrasonic beams and a very high frame rate ultrasound imaging sequence able to capture the propagation of resulting shear waves in real time. The radial forces that generate the shear waves are focused at increasing depths, causing a shear wave front that propagates in the area scanned. The ultrasound system then captures the generated shear waves. Shear wave speed subsequently is estimated by a Doppler-like acquisition over a region of interest. The shear wave speed then is used to calculate tissue stiffness. Elasticity is displayed using color mapping of the elasticity encoded pixel by pixel in an image superimposed on the standard B-mode image. In this manner, stiffer tissues appear red and softer tissues appear blue.7,8 SSI examinations were conducted in accordance with the manufacturer’s instructions. LSM was performed with the patient lying in a dorsal decubitus position with the right arm in maximal abduction in the right (SSI-Rt) and the left lobe (SSI-Lt). The operator, assisted by a real-time, B-mode ultrasound image, places the designated region of interest, 10 mm in diameter, in the color map. Five measurements were performed on each lobe.9 The median value of the 5 SSI measurements, expressed in kilopascals, were used as the representative measurement. The manufacturer of the SSI device did not recommend any technical parameter for quality assessment of the measurements. We used the interquartile range and success rate to assess the quality of SSI measurements such as that used by Sporea et al,9 and the same criteria for unreliable LSM was used for TE.
Statistical Analysis The statistical analyses were performed using JMP (version 10.0.2; SAS Institute, Cary, NC). For univariate comparisons between the patient groups, the Student t test was used. Because the variables often were not distributed normally, group comparisons of more than 2 independent groups were performed using the Kruskal–Wallis test. The correlation between LSM by the TE-XL probe, SSI-Rt, SSILt, and other scoring systems was tested using the Spearman rank correlation coefficient. The diagnostic performance and SSI was assessed by analyzing the receiver operating characteristic curves. The probability of a true-positive (sensitivity) and true-negative (specificity) assessment was determined for selected cut-off values and
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the AUROC was calculated. Cut-off values were determined for the TE-XL probe, SSI-Rt, and SSI-Lt to predict advanced fibrosis (F 3) and cirrhosis (F4) by using an optimization step that maximized the Youden index. The determination of correlation coefficients and a linear regression analysis were conducted to test for associations between the variables. Finally, the AUROC of the noninvasive tests were compared using the paired method by Zhou et al,10 excluding patients who had incomplete studies. The 95% confidence intervals were calculated using Woolf’s method.11 P values less than .05 were considered significant.
References 1. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–1325. 2. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734–739. 3. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518–526.
SSI and TE–XL Probe in Overweight Patients 1509.e2 4. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24:289–293. 5. Sandrin L, Tanter M, Gennisson JL, et al. Shear elasticity probe for soft tissues with 1-D transient elastography. IEEE Trans Ultrason Ferroelectr Freq Control 2002;49:436–446. 6. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705–1713. 7. Muller M, Gennisson JL, Deffieux T, et al. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Ultrasound Med Biol 2009;35:219–229. 8. Bercoff J, Tanter M, Fink M. Supersonic shear imaging: a new technique for soft tissue elasticity mapping. IEEE Trans Ultrason Ferroelectr Freq Control 2004;51:396–409. 9. Sporea I, Bota S, Jurchis A, et al. Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013; 39:1933–1941. 10. Zhou X, Obuchowski N, McClish D. Statistical methods in diagnostic medicine. 1st ed. New York: John Wiley & Sons, 2002. 11. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955;19:251–253.
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Supplementary Figure 1. Correlation between LSM obtained using SSI-Rt and (A) FIB-4 (r2 ¼ 0.25; P < .0001), (B) AAR (r2 ¼ 0.16; P < .0001), and (C) APRI (r2 ¼ 0.16; P < .0001).
Supplementary Figure 2. Correlation between LSM obtained using SSI-Lt and (A) FIB-4 (r2 ¼ 0.18; P < .0001), (B) AAR (r2 ¼ 0.07; P ¼ .0035), and (C) APRI (r2 ¼ 0.10; P ¼ .0009).
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Supplementary Figure 3. Correlation between LSM obtained using the TE-XL probe and (A) FIB-4 (r2 ¼ 0.21; P < .0001), (B) AAR (r2 ¼ 0.08; P ¼ .0003), and (C) APRI (r2 ¼ 0.14; P ¼ .0009).
Supplementary Table 1. Pairwise Comparisons of AUROC Values for Elastographic and Clinical Scoring Systems SSI-Rt
TE-XL
FIB-4
AAR
In the patients with liver disease from all etiologies (F 3) SSI-Rt TE-XL P ¼ .1274 FIB-4 P ¼ .0201a P ¼ .0161a AAR P ¼ .0002a P ¼ .0001a P ¼ .0175a APRI P ¼ .0009a P ¼ .0006a P ¼ .1261 P ¼ .0161a In the patients with liver disease from all etiologies (F4) SSI-Rt TE-XL P ¼ .4255 FIB-4 P ¼ .0730 P ¼ .1080 AAR P ¼ .0049a P ¼ .0033a P ¼ .0191a APRI P ¼ .0067a P ¼ .0116a P ¼ .0035a P ¼ .1979 In the HCV infected subgroup (F 3) SSI-Rt TE-XL P ¼ .8924 FIB-4 P ¼ .0816 P ¼ .0471a AAR P < .0001a P < .0001a P ¼ .0156a APRI P ¼ .0382a P ¼ .0218a P ¼ .0343a P ¼ .2147 In the HCV-infected subgroup (F4) SSI-Rt TE-XL P ¼ .4245 FIB-4 P ¼ .3239 P ¼ .1776 AAR P < .0020a P ¼ .0010a P ¼ .0005a APRI P ¼ .1118 P ¼ .0700 P ¼ .0349a P ¼ .0496a P < .05 were considered significant.
a
APRI -
-
-
-
1509.e5 Yoneda et al
Clinical Gastroenterology and Hepatology Vol. 13, No. 8
Supplementary Table 2. Clinical Parameters Contributing to Discordance of at Least Two Stages Between SSI-Rt/TE-XL and Histologic Fibrosis Stage SSI-Rt Nondiscordant Patients (N ¼ 100) Age, y Sex, M:F BMI AST level, IU/L ALT level, IU/L Albumin level, g/dL Platelet count, 109/L IQR/M (%)
59 10 56:44 29.7 3.4 69.0 73.3 74.9 76.8 4.17 0.49 165.5 66.2 7.4 5.2
TE-XL
Discordant Patients (N ¼ 16)
P values
Nondiscordant patients (N ¼ 107)
Discordant patients (N ¼ 12)
P values
57 8:8 31.7 51.1 60.2 4.40 185.0 7.1
.6316 .6541 .0377a .3518 .4658 .0678 .2603 .8142
59 10 56:51 29.9 3.6 68.9 76.4 75.1 79.3 4.21 0.45 169.9 65.3 16.7 7.3
59 12 7:5 30.4 4.6 43.2 21.9 54.3 32.0 4.39 0.21 184.5 46.0 18.4 6.5
.7950 .6931 .6546 .2488 .3692 .1718 .4521 .4290
10 4.3 50.9 62.4 0.24 45.7 5.5
NOTE. Data are expressed as means SD. P values were calculated using the c2 test when comparing the gender between nondiscordant patients and discordant patients. The other P values were calculated using the Student t test. ALT, alanine aminotransferase; IQR/M, interquartile range/median liver stiffness measurement. a P < .05 was considered significant.