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Short- and midterm repeatability of magnetic resonance elastography in healthy volunteers at 3.0 T
Magnetic Resonance Imaging 32 (2014) 665–670
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Short- and midterm repeatability of magnetic resonance elastography in healthy volunteers at 3.0 T☆ Yu Shi a, Qiyong Guo a,⁎, Fei Xia b, Jiaxing Sun c, Yuying Gao a a b c
Department of Radiology, Shengjing Hospital, China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, P.R. China Department of Infectious Disease, Shengjing Hospital, China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, P.R. China Department of Ultrasound, Shengjing Hospital, China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, P.R. China
a r t i c l e
i n f o
Article history: Received 18 September 2013 Revised 10 February 2014 Accepted 11 February 2014 Keywords: MR elastography Stiffness Repeatability Liver Healthy volunteers
a b s t r a c t The purpose of this study was to evaluate the short- and midterm repeatability of liver stiffness measurements with magnetic resonance elastography (MRE) in healthy subjects at 3.0 T. Twenty-two healthy volunteers were enrolled in this prospective study. The stiffness measurements were obtained from three slices with three repeated acquisitions for each slice (session 1) by two independent raters. After a mean period of 7 ± 2 days (session 2) and 195 ± 15 days (session 3), each subject was scanned again using the same protocol and MR system. The liver stiffness differences were calculated between sessions or raters. The intraclass correlation coefficient (ICC) was calculated to assess interrater agreement and intersession agreement. The stiffness differences over the short- and midterm intervals was (−0.004 ± 0.086) kPa for sessions 1–2, lower than (−0.055 ± 0.150) kPa for sessions 1–3 and (−0.051 ± 0.173) kPa for sessions 2–3. The liver stiffness was more repeatable for the short-term interval with the mean overall ICC of 0.96 (sessions 1–2) (95% confidence interval [CI]: 0.90–0.98) compared with 0.91 (sessions 1–3) (95% CI: 0.78–0.96) and 0.87 (sessions 2–3) (95% CI: 0.69–0.95) for the midterm intervals. The overall ICC of interrater agreement was excellent at 0.987 (95% CI: 0.983 to 0.990). These results confirm that MRE is a reproducible technique for liver stiffness quantification over short- and midterm intervals up to 6 months in a healthy population at 3.0 T. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Chronic liver disease has emerged as a significant global health issue which leads to liver fibrosis and liver cirrhosis. Advanced liver fibrosis and cirrhosis can ultimately lead to end-stage liver disease or hepatocellular carcinoma, which partially accounts for the increasing rates of liver disease morbidity and mortality over the last decade [1]. Liver fibrosis is a reversible process with a long-term evolution that differs among individuals and can take years or even decades to develop. The evaluation of liver fibrosis is of vital importance for diagnosing and monitoring disease progression [2]. Liver biopsy is currently used as the gold standard in the assessment of hepatic fibrosis. However, many problems with liver biopsy, such as its invasiveness, high cost, sampling errors and inaccuracy due to inter- and intraobserver variability of pathological interpretations, have been reported in peer-reviewed literature [3,4].
☆ This study is supported by grants from the Natural Science Foundation of China (No. 81271566, 81071123). ⁎ Corresponding author. Tel.: +86 24 96615 73211; fax: +86 24 23929902. E-mail address: [email protected] (Q. Guo). http://dx.doi.org/10.1016/j.mri.2014.02.018 0730-725X/© 2014 Elsevier Inc. All rights reserved.
Noninvasive methods for liver fibrosis assessment have received more and more attention over the last decade. MR elastography (MRE), as an emerging technology, is increasingly being used clinically as a noninvasive method to stage liver fibrosis because the mechanical properties of liver tissue (e.g., the tissue stiffness) have been shown to strongly correlate with liver fibrosis [5,6]. MRE takes advantage of the differences in the propagation of shear acoustic waves in normal and diseased tissue to quantify liver stiffness. MRE does not require the use of a contrast agent. Instead, mechanical waves are introduced into the liver by an external acoustic driver placed on the abdomen. The induced microscopic shear wave motion in the liver is imaged using phase-contrast MRI techniques, and the resulting phase images showing the shear wave propagation are processed to calculate images of the stiffness distribution in the liver (elastograms). It has been reported in the literature that MRE shows a greater predictive ability for quantifying liver fibrosis than diffusion-weighted imaging (DWI), contrastenhanced MR imaging and perfusion-weighted imaging [5–8]. If the stiffness is to be used clinically for predicting and monitoring therapeutic effects, the results must be repeatable. Although some studies have demonstrated the short-term repeatability of MRE in exams performed less than a month apart [9–11], little is
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known about the midterm (greater than 6 months) variability of MRE stiffness measurements and the ability of MRE to assess treatment response. In order to determine any disease-based variations in liver stiffness, the repeatability of MRE needs to be established first in a cohort of healthy individuals. Therefore, the purpose of this study was to test whether or not there is any significant variability in the shortand midterm repeatability of hepatic MRE stiffness measurements in healthy individuals. In addition, correlation analyses were conducted between liver stiffness and gender, age, body mass index (BMI), and portal vein bulk flow. 2. Materials and methods 2.1. Subjects This prospective study was approved by the local institutional review board, and written informed consent was obtained from all the participants enrolled. The BMI value was calculated as follows: BMI = weight (kg)/height 2 (m 2). The measurements of portal vein bulk flow were performed using a Philips IU22 color Doppler ultrasound imaging system before MRE. A broad-bandwidth (2–5 MHz extended operating frequency range) transducer was used with the insonation angle set to 60 degrees [12]. 2.2. MR examination The studies were performed in the morning, and the participants were asked to fast for at least 8 h prior to the examination. Each subject prospectively underwent MRE at 3.0 T (GE, SIGNA EXCITE HD), equipped with an 8-element torso phased-array coil. As described in [13,14], for the MRE measurements, axial slices were acquired using a 2D gradient-echo MRE technique. A cylindrical passive drum driver 19 cm in diameter was used to apply acoustic vibrations to the right surface of the abdomen. An active acoustic generator placed outside of the MR examination room produced 60-Hz pneumatic vibrations that were delivered to the passive driver via a long plastic tube. The MRE components were developed by Mayo Clinic (Rochester, MN, USA) and were given to our institute along with a service agreement. An MRI marker was attached to the center of the passive driver for slice localization during imaging. In session 1, the relative position between the passive driver and the liver was examined using the position of the marker obtained from localizer images, and the passive driver was adjusted to align the center of the marker with the hilum where the imaging slices were located. The distance from the marker to the patient's navel was recorded and used during session 2 (S2) and 3 (S3) for consistency of passive driver positioning and localization of the imaging slices.
The imaging parameters for MRE were as follows: repetition time/echo time (TR/TE) = 50/24 ms; continuous 60-Hz vibration; field of view = 34–40 cm; matrix size = 256 × 192; flip angle = 30°; slice thickness = 10 mm; phase offsets = 4; fractional phaseencoding direction (anterior–posterior) field of view = 0.7; the ASSET parallel imaging factor = 2. Two spatial presaturation bands were applied on each side of the selected slice to reduce motion artifacts caused by blood flow. The total acquisition time was 27 sec for one breath-hold to complete each one-slice acquisition. MRE measurements were performed in three consecutive slices with the middle one aligned with the marker on the passive driver. The other two slices were located above and below the central slice with a 10-mm gap in between. This 3-slice MRE acquisition was repeated 2 more times with the subject remaining on the scanner table with the MRE driver left in place between the acquisitions with a 1–2 minute pause between acquisitions. Through November and December of 2011, 22 subjects (13 females, 9 males) with no history or findings of abdominal disease during the period of the study were included (session 1; S1). All volunteers had blood tests performed prior to the MRE measurements to assure that there were no existent hepatic diseases (HD) or any abnormalities caused by preexisting HD in any subject. For each subject, the MRE acquisitions were repeated in two more sessions [S2: 7 ± 2 days later (“short term”); S3: 195 ± 15 days later (“midterm”)] using timeframe definitions similar to that used by Braithwaite et al. to test the reproducibility of abdominal DWI [15]. The locations of the images obtained were matched to those obtained previously using markers as well as visual anatomical landmarks. The same operator performed the MRE procedures on all participants. 2.3. Measurement of liver stiffness MR elastograms were obtained by processing the acquired shear wave images using the multimodel direct inversion (MMDI) algorithm developed by Mayo Clinic, integrated in a commercial workstation (Advantage Windows 4.4, GE Healthcare, Buc, France). A description of the processing can be found in the article described by Dzyubak et al. [16]. Two raters (two radiologists with 7 years and 11 years of experience in abdominal diagnostic radiology and both with one year of experience with MRE measurements) measured the liver stiffness values independently by placing the regions of interest (ROI) manually using the ROI placement considerations discussed by Shire et al. and Dzyubak et al. [9,16]. One flexible ROI encompassing the outer liver area, where the wave amplitude was highest, was defined for each slice. The areas automatically identified by the inversion algorithm as invalid were excluded from the elastogram analysis. Portions of the liver with vessels and the liver edge in the
Fig. 1. The outlined area represents the region of interest for the stiffness measurement defined to exclude areas of wave interference, portal areas and blood vessels, and areas automatically identified by the inversion algorithm as invalid.
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magnitude images and wave multipath interferences on the wave images were also excluded. The hepatic shear stiffness for each slice (in kPa) was reported as the mean value in the ROI, as shown in Fig. 1. After the imaging for each session was performed, the two raters measured the liver stiffness blinded to the other rater's results. For sessions S2 and S3, the same raters redrew the ROIs in a blinded fashion by not comparing the ROIs to the ROIs obtained in S1. The time interval for redrawing the ROIs between sessions or between repetitions in one session for the same slices was at least one week to avoid memory bias. 2.4. Statistical analysis The liver stiffness measurements were organized according to subjects (each volunteer), slices (three slices with different ROIs), repetitions (three repeated MRE acquisitions), sessions (1 or 2 or 3) and raters (1 or 2). Therefore, a total number of 54 measurements (three repetitions per slice, three slices per session, three sessions, two raters) were collected for each subject. The data were analyzed with repeated-measures analysis of variance (ANOVA) to test the null hypothesis that slice, repetition, session and rater had no significant influence on stiffness measurements. If the Mauchly's test of sphericity was significant indicating violations of sphericity (P b 0.05), the Greenhouse–Geisser correction was applied when epsilon was b 0.75, or the Huynh–Feldt correction was applied when epsilon was N 0.75 [17]. The intrasubject coefficient of variation (CV) for each visit was calculated
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from the pooled data across the three repeated acquisitions and the three slices for each imaging session and each rater. The intrasubject CVs were also analyzed with repeated-measures ANOVA to test the null hypothesis that neither rater nor session had a significant effect on the measured stiffness. As long as the test does not show a significant difference, the intrasubject CVs can be averaged over the sessions and raters, and the 95% confidence interval (CI) for the stiffness measurements can be calculated as 1.96 standard deviations from the mean (i.e., 1.96 × CV), suggesting that treatment effects causing a stiffness change of less than 1.96 × CV will not be meaningfully detectable as they would be within the typical variance of the stiffness measurements [18]. The absolute stiffness differences for raters and sessions were calculated as follows: stiffness differences (kPa) = (stiffness measured by rater 1) − (stiffness measured by rater 2) for each of the 3 sessions, or = (stiffness measured in session x1) − (stiffness measured in session x2) for each rater (x1 = session 1 or 2, x2 = session 2, 3). The intraclass correlation coefficient (ICC) was applied to assess interrater agreement and intersession agreement in the stiffness measurements [19]. The intersession CV was also used to examine the repeatability of these short- and midterm measurements: the smaller the CV, the better the repeatability. Gender differences in liver stiffness measurements were tested using a nonparametric Mann–Whitney U test. The correlation between liver stiffness and the physiologic parameters (age, BMI, and portal vein bulk flow) was tested using the nonparametric Spearman correlation test. A P value less than 0.05 was defined as
Fig. 2. Axial magnitude, wave, and elastogram images from each of the 3 sessions of a healthy 29-year-old male. Stiffness values and standard deviations are: session 1: 2.15 ± 0.28 kPa; session 2: 2.31 ± 0.30 kPa; session 3: 2.49 ± 0.43 kPa for rater 1; session 1: 2.21 ± 0.31 kPa; session 2: 2.34 ± 0.25 kPa; session 3: 2.44 ± 0.42 kPa for rater 2.
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Fig. 3. The graph shows the mean liver stiffness at each of the three imaging sessions for the individual volunteers as determined by each rater. The data for each individual subject were fairly stable over the studied time period.
statistically significant. When the Bonferroni correction was used to adjust for multiple comparisons, the P value was divided by the number of comparisons. All statistical analysis was performed using Medcalc Version 7.4.2.0 (Medcalc Software, Mariakerke, Belgium) and SPSS Version 16.0 J (SPSS Inc, Chicago, IL, USA). 3. Results 3.1. Repeated-measures analysis of variance Fig. 2 shows representative axial magnitude images, stiffness maps, and wave images from all three sessions for one subject. A fair match of the slice locations in the three sessions was achieved. There was no significant difference in the stiffness measurements between the repeated acquisitions (P = 0.984), the three slices (P = 0.279), the raters (P = 0.383), or the three sessions (Greenhouse–Geisser correction, P = 0.163). The data from all subjects were shown in Fig. 3. The overall mean intrasubject CV (Table 1) for the repeatability of the liver stiffness measurements over the short- and midterm intervals was 12.44% (95% CI: 8.97%, 15.91%, 1.96 × CV = 24.39%). 3.2. Liver stiffness measurement and the difference in the absolute stiffness between groups The overall mean stiffness was 2.21 ± 0.26 kPa (ranging from 1.67 to 2.92 kPa) for all the healthy subjects calculated across the 54 data points in this study. The mean and standard deviation of stiffness differences between sessions or raters, with maximum and minimum 95% CIs are shown in Table 2. The stiffness difference over the short-term interval was (− 0.004 ± 0.086) kPa. The difference over the midterm intervals was (− 0.055 ± 0.150) kPa for session 1–3 and (− 0.051 ± 0.173) kPa for session 2–3. The stiffness difference between the two raters was (0.003 ± 0.026) kPa, (0.005 ± 0.037) kPa and (0.005 ± 0.037) kPa for sessions 1, 2, and 3, respectively.
Table 1 Mean intrasubject coefficients of variation (CV) for differences in the stiffness measurements across three acquisition repetitions and three slices for each imaging session and each rater. CV
Session1
Session 2
Session 3
Overall
Rater 1 Rater 2 Overall
12.83% 13.91% 13.37%
12.95% 9.20% 11.08%
11.80% 13.90% 12.85%
12.53% 12.34% 12.44%
3.3. ICC and intersession CVs for the repeatability of raters and sessions The ICC testing interrater agreement was greater than 0.9 for every session, and the overall ICC was excellent at 0.987 (95% CI: 0.983 to 0.990). Evaluating the ICC for intersession agreement (Table 3), the liver stiffness (kPa) was more repeatable in the shortterm interval with a mean overall ICC value of 0.96, compared with 0.91 and 0.87 for the midterm intervals. For both raters, the intersession CV (Table 4) was lower when the scanning was repeated within a short-term interval (between S1 and S2: 2.73%), contrary to when the scanning was performed over a midterm interval (between S1 and S3: 5.10%; between S2 and S3: 5.75%). 3.4. The correlation between liver stiffness and physiologic parameters In this study, the 54 liver stiffness measurements collected from each subject, including measurements from repeated acquisitions, multiple slices, different raters and at different time points, were averaged together and tested for correlation with various physiologic parameters. The physiologic parameters measured in this study included BMI, portal vein bulk flow and age. BMI ranged from 18.2 to 28.2 kg/m 2 (mean ± SD, 22.9 ± 2.6 kg/m 2), and portal vein bulk flow ranged from 706 to 1612 ml/min (mean ± SD, 1178.8 ± 274.6 ml/min). Age ranged from 18 to 56 years (mean ± SD, 33.1 ± 9.6 years). There was no significant correlation between the liver stiffness and the volunteer's age, portal vein bulk flow or BMI (r = 0.33, 0.17, 0.21 respectively, all P N 0.05). A difference in liver stiffness was observed between the genders. The mean liver stiffness in males was higher than in females (male, 2.30 ± 0.18 kPa; female, 2.13 ± 0.25 kPa, Mann–Whitney U test: P = 0.042). 4. Discussion The results from this study showed no significant variation in liver stiffness over the short-term interval (one week between sessions) or the midterm interval (over 6 months between sessions). This indicates that these MRE-based liver stiffness measurements are robust and are capable of serving as a reproducible, quantitative tool over these time frames in healthy volunteers. Likewise, repeated acquisitions and measurements made in different slices within a single session did not cause significant differences in the stiffness measurements. The mean CV of short- and midterm repeatability of the measurements was 12.44%. The stiffness difference in absolute stiffness of short-term interval (S1-2) was lower than that of midterm interval (S1-3 and S2-3). The short-term interval showed better
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Table 2 Differences (D, kPa) in the absolute stiffness measured by the two raters in each session or the differences between two sessions (short-term and midterm) for each rater. Short-term (sessions 1–2) 95% CIa (test value = 0) Midterm (sessions 1–3) 95% CIa (test value = 0) Midterm (sessions 2–3) 95% CIa (test value = 0) Rater 1 −0.005 ± 0.093 Rater 2 −0.004 ± 0.084 Overall −0.004 ± 0.086 Raters 1–2⁎ 0.003 ± 0.026b
−0.046,0.036 −0.041,0.034 −0.031,0.022 −0.009,0.015
−0.056 −0.054 −0.055 0.005
± ± ± ±
−0.127,0.015 −0.119,0.011 −0.101,−0.009 −0.012,0.021
0.160 0.147 0.150 0.037c
−0.051 −0.051 −0.051 0.005
± ± ± ±
0.187 0.167 0.173 0.037d
−0.134,0.032 −0.125,0.024 −0.104,0.003 −0.009,0.019
a Coefficient interval; ⁎ D measured by the two raters in each session: b for session 1; c for session 2; d for session 3.
repeatability with higher ICC and lower intersession CV compared to the midterm interval. An excellent interrater agreement was also achieved with very high ICC values. Moreover, subject variations due to age, BMI and portal vein bulk flow had no significant influence on the stiffness measurements. However, there was a gender difference, with males having higher liver stiffness than females. The stability and reproducibility of the MRE measurements in this study suggest that MRE may be a viable clinical tool for monitoring hepatic changes within an individual over at least a 6-month interval. This finding is of particular significance for the monitoring of the progression of liver fibrosis and the response to antiviral therapy [2,4,20]. The reported average duration of antiviral therapy needed to retard the progression of or cause regression of fibrosis is about 16 weeks. Liver biopsies are sometimes repeated after the completion of therapy to show histological response to treatment [20]. However, the repeated biopsy tests are not acceptable to many of the patients because of their invasiveness. The latest metaanalysis reported by Wang et al. [7] showed that MRE can be used in clinical practice as an excellent tool for the staging of fibrosis, even showing an opportunity to replace liver biopsy. The results of our study further validate the repeatability of MRE over a 6-month time frame and suggest that MRE may be a viable tool for monitoring antiviral response. Hines et al. [11] previously examined sources of variability in MRE readings and determined that scans on different days contributed the most variability to liver stiffness measurements, whereas different scans on the same day and analyzed by different readers contributed relatively less variability. Their reported interval was 2–4 weeks. The results from a study by Shire et al. [9] suggested that the CV of hepatic stiffness measurements performed with MRE on the same day were similar to, but lower than, the CV of values obtained 7–14 days apart. No literature has reported the midterm repeatability of MRE yet. Our study proved that not only short-term interval (7-day) measurements of stiffness, but also midterm interval measurements are reproducible within a given individual. The liver stiffness (kPa) was more repeatable in the short-term interval with a mean overall ICC value of 0.96, compared with 0.91 and 0.87 for the midterm intervals. The intersession CV also tended to be larger for the midterm measurements than for the short-term measurements. In this study, nearly iden-
Table 3 Intersession intraclass correlation coefficient (ICC) results between two raters.
Mean (rater 1) 95% CIa Mean (rater 2) 95% CIa Mean over all 95% CIa a
Short-term (sessions 1–2)
Midterm (sessions 1–3)
Midterm (sessions 2–3)
Overall
0.95 0.89–0.98 0.96 0.91–0.98 0.96 0.90–0.98
0.90 0.76–0.96 0.91 0.78–0.96 0.91 0.78–0.96
0.85 0.66–0.94 0.88 0.71–0.95 0.87 0.69–0.95
0.93 0.86–0.97 0.94 0.88–0.94 0.94 0.87–0.97
CI: confidence interval.
tical slices with similar ROI selections, a standard preprandial state and identical imaging parameters were repeated over the multiple sessions, which contributed to the repeatable stiffness measurements. As proposed by Shire et al. [9], when defining the ROI, the raters should be careful to consider the magnitude, wave, and elastogram images simultaneously to obtain a homogenous region of liver tissue free of wave reflections and interference patterns. Westrictly followed the selection criteria. It is also important to try to ensure that the waves produced in the liver travel along the imaging plane (rather than through the plane) to avoid overestimation of the wavelength [21,22]. As described by Yin et al. [22], the MRE vibration technique used in this study can produce a conelike hemispherical distribution of shear waves whose propagation is governed by diffraction. In order to control for this possible confounding factor, all the slices were prescribed near the center of the driver and were matched across sessions. An alternative approach to solve this issue would be the use of 3D MRE, which is currently only available for neuroimaging. The mean intrasubject CV within a single session for an individual was 12.44%. This single-session variation may be due to a number of factors, including variations in the size and location of ROIs drawn on different slices, variations in the wave field propagation at different slice locations, and physiologic variations between slices and repetitions (e.g., breath-hold variations and blood flow artifacts). The prandial state is known to increase portal vein bulk flow and hepatic sinusoidal perfusion strongly, and our data for portal flow were within the normal range when compared to earlier published results [23–25]. In a study by Mederacke et al. using transient elastography [26], an increase in liver stiffness after eating was observed in patients with chronic or resolved HCV infection as well as in healthy controls, which the authors speculate could be a consequence of increased liver blood flow after food intake, though they did not measure liver blood flow in their study. However, Hines et al. observed no significant changes in the MRE stiffness measurements in healthy subjects after meals, despite large increases in portal blood flow [27]. They claimed that the healthy liver might have an autoregulation mechanism to maintain the portal venous pressure, resulting in stable liver stiffness after meals. Yin et al. [28] further showed that in 13 of 20 healthy volunteers, no substantial stiffness augmentation was observed (defined as a change of more than 10%, or 0.2 kPa), while another 7 healthy volunteers had a slight increase in postprandial liver stiffness, with a mean value of 17.8% (0.35 kPa). All measurements were still within the normal range.
Table 4 Intersession coefficients of variation (CV) for differences in stiffness measurements. CV
Short-term (sessions 1–2)
Midterm (sessions 1–3)
Midterm (sessions 2–3)
Rater 1 Rater 2 Overall
2.92% 2.66% 2.73%
5.29% 4.95% 5.10%
6.04% 5.53% 5.75%
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However, the hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17–4.15 kPa) or 21.24 ± 14.98% (range, 7.69%–63.3%). They speculated that the healthy liver can have better autoregulation to maintain a constant portal pressure gradient in the liver, resulting in a more stable stiffness after an increase in portal vein flow. In our study, in order to control this potential effect of food ingestion as well as to reduce gastrointestinal motion and potential discomfort caused by the driver, we standardized the time of fasting before each scan. Furthermore, no significant correlation was found between liver stiffness and portal vein bulk flow, which was consistent with the results of Hines and Yin [27,28]. Our study showed that liver stiffness was significantly influenced by gender, with higher values found in males than females, which was also shown in several previous studies through the use of both transient US [29] and MRE [30]. Our study has several limitations. First, this work was based on normal volunteer data. Unlike healthy volunteers, patients may be under different kinds of treatment and hepatic disease stages. As such, there may be additional sources of measurement variability for patients that will confound attempts to determine the true repeatability of MRE. For example, patients may be more likely to have regional variations of hepatic stiffness due to variable degrees of fibrosis or inflammation. Physiologic variations in patients, such as body habitus, ascites, bowel location, and breath-hold variability, may introduce more variation in the stiffness measurements in patients compared to healthy volunteers. Patients are also not always able to return for a repeated exam punctually, even over a short-term interval (one week), thus interfering with the ability to assess the repeatability of stiffness measurements in patients. Finally, the healthy volunteers were documented through questioning and liver blood function tests. Therefore, it is possible that some of the volunteers in this study had cryptogenic liver diseases. In conclusion, no significant variability in MRE liver stiffness measurements was found when assessing the short- and midterm (more than 6 months) repeatability of these measurements in healthy volunteers at 3.0 T. The mean intrasubject CV for the repeatability of stiffness over the short- and midterm intervals was 12.44%.
Conflict of interest None.
Acknowledgments This study is supported by grants from the Natural Science Foundation of China (No. 81071123, 81271566). The authors thank Dr. Zhenyu Zhou of the GE Healthcare China Research Team for their support and assistance. We also thank Dr. Richard L Ehman and colleagues at the Mayo Clinic for the MRE technology used in this study.
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Diffraction-biased shear wave fields generated with longitudinal magnetic resonance elastography drivers. Magn Reson Imaging 2008;26:770–80. [23] Thomsen C, Stahlberg F, Henriksen O. Effect of food intake on portal vein volume flow. Proc SMRM 1991;10:809. [24] Lycklama GJ, Burggraaf K, Wasser MN, Schultze LJ, Schoemaker RC, Cohen AF, et al. Variability of splanchnic blood flow measurements using MR velocity mapping under fasting and post-prandial conditions-comparison with echoDoppler. J Hepatol 1997;26:298–304. [25] Burggraaf J, Schoemaker HC, Cohen AF. Assessment of changes in liver blood flow after food intake-comparison of ICG clearance and echo-Doppler. Br J Clin Pharmacol 1996;42:499–502. [26] Mederacke I, Wursthorn K, Kirschner J, Rifai K, Manns MP, Wedemeyer H, et al. Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection. Liver Int 2009;29:1500–6. [27] Hines CD, Lindstrom MJ, Varma AK, Reeder SB. 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Short- and midterm repeatability of magnetic resonance elastography in healthy volunteers at 3.0 T☆ Yu Shi a, Qiyong Guo a,⁎, Fei Xia b, Jiaxing Sun c, Yuying Gao a a b c
Department of Radiology, Shengjing Hospital, China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, P.R. China Department of Infectious Disease, Shengjing Hospital, China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, P.R. China Department of Ultrasound, Shengjing Hospital, China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, P.R. China
a r t i c l e
i n f o
Article history: Received 18 September 2013 Revised 10 February 2014 Accepted 11 February 2014 Keywords: MR elastography Stiffness Repeatability Liver Healthy volunteers
a b s t r a c t The purpose of this study was to evaluate the short- and midterm repeatability of liver stiffness measurements with magnetic resonance elastography (MRE) in healthy subjects at 3.0 T. Twenty-two healthy volunteers were enrolled in this prospective study. The stiffness measurements were obtained from three slices with three repeated acquisitions for each slice (session 1) by two independent raters. After a mean period of 7 ± 2 days (session 2) and 195 ± 15 days (session 3), each subject was scanned again using the same protocol and MR system. The liver stiffness differences were calculated between sessions or raters. The intraclass correlation coefficient (ICC) was calculated to assess interrater agreement and intersession agreement. The stiffness differences over the short- and midterm intervals was (−0.004 ± 0.086) kPa for sessions 1–2, lower than (−0.055 ± 0.150) kPa for sessions 1–3 and (−0.051 ± 0.173) kPa for sessions 2–3. The liver stiffness was more repeatable for the short-term interval with the mean overall ICC of 0.96 (sessions 1–2) (95% confidence interval [CI]: 0.90–0.98) compared with 0.91 (sessions 1–3) (95% CI: 0.78–0.96) and 0.87 (sessions 2–3) (95% CI: 0.69–0.95) for the midterm intervals. The overall ICC of interrater agreement was excellent at 0.987 (95% CI: 0.983 to 0.990). These results confirm that MRE is a reproducible technique for liver stiffness quantification over short- and midterm intervals up to 6 months in a healthy population at 3.0 T. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Chronic liver disease has emerged as a significant global health issue which leads to liver fibrosis and liver cirrhosis. Advanced liver fibrosis and cirrhosis can ultimately lead to end-stage liver disease or hepatocellular carcinoma, which partially accounts for the increasing rates of liver disease morbidity and mortality over the last decade [1]. Liver fibrosis is a reversible process with a long-term evolution that differs among individuals and can take years or even decades to develop. The evaluation of liver fibrosis is of vital importance for diagnosing and monitoring disease progression [2]. Liver biopsy is currently used as the gold standard in the assessment of hepatic fibrosis. However, many problems with liver biopsy, such as its invasiveness, high cost, sampling errors and inaccuracy due to inter- and intraobserver variability of pathological interpretations, have been reported in peer-reviewed literature [3,4].
☆ This study is supported by grants from the Natural Science Foundation of China (No. 81271566, 81071123). ⁎ Corresponding author. Tel.: +86 24 96615 73211; fax: +86 24 23929902. E-mail address: [email protected] (Q. Guo). http://dx.doi.org/10.1016/j.mri.2014.02.018 0730-725X/© 2014 Elsevier Inc. All rights reserved.
Noninvasive methods for liver fibrosis assessment have received more and more attention over the last decade. MR elastography (MRE), as an emerging technology, is increasingly being used clinically as a noninvasive method to stage liver fibrosis because the mechanical properties of liver tissue (e.g., the tissue stiffness) have been shown to strongly correlate with liver fibrosis [5,6]. MRE takes advantage of the differences in the propagation of shear acoustic waves in normal and diseased tissue to quantify liver stiffness. MRE does not require the use of a contrast agent. Instead, mechanical waves are introduced into the liver by an external acoustic driver placed on the abdomen. The induced microscopic shear wave motion in the liver is imaged using phase-contrast MRI techniques, and the resulting phase images showing the shear wave propagation are processed to calculate images of the stiffness distribution in the liver (elastograms). It has been reported in the literature that MRE shows a greater predictive ability for quantifying liver fibrosis than diffusion-weighted imaging (DWI), contrastenhanced MR imaging and perfusion-weighted imaging [5–8]. If the stiffness is to be used clinically for predicting and monitoring therapeutic effects, the results must be repeatable. Although some studies have demonstrated the short-term repeatability of MRE in exams performed less than a month apart [9–11], little is
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known about the midterm (greater than 6 months) variability of MRE stiffness measurements and the ability of MRE to assess treatment response. In order to determine any disease-based variations in liver stiffness, the repeatability of MRE needs to be established first in a cohort of healthy individuals. Therefore, the purpose of this study was to test whether or not there is any significant variability in the shortand midterm repeatability of hepatic MRE stiffness measurements in healthy individuals. In addition, correlation analyses were conducted between liver stiffness and gender, age, body mass index (BMI), and portal vein bulk flow. 2. Materials and methods 2.1. Subjects This prospective study was approved by the local institutional review board, and written informed consent was obtained from all the participants enrolled. The BMI value was calculated as follows: BMI = weight (kg)/height 2 (m 2). The measurements of portal vein bulk flow were performed using a Philips IU22 color Doppler ultrasound imaging system before MRE. A broad-bandwidth (2–5 MHz extended operating frequency range) transducer was used with the insonation angle set to 60 degrees [12]. 2.2. MR examination The studies were performed in the morning, and the participants were asked to fast for at least 8 h prior to the examination. Each subject prospectively underwent MRE at 3.0 T (GE, SIGNA EXCITE HD), equipped with an 8-element torso phased-array coil. As described in [13,14], for the MRE measurements, axial slices were acquired using a 2D gradient-echo MRE technique. A cylindrical passive drum driver 19 cm in diameter was used to apply acoustic vibrations to the right surface of the abdomen. An active acoustic generator placed outside of the MR examination room produced 60-Hz pneumatic vibrations that were delivered to the passive driver via a long plastic tube. The MRE components were developed by Mayo Clinic (Rochester, MN, USA) and were given to our institute along with a service agreement. An MRI marker was attached to the center of the passive driver for slice localization during imaging. In session 1, the relative position between the passive driver and the liver was examined using the position of the marker obtained from localizer images, and the passive driver was adjusted to align the center of the marker with the hilum where the imaging slices were located. The distance from the marker to the patient's navel was recorded and used during session 2 (S2) and 3 (S3) for consistency of passive driver positioning and localization of the imaging slices.
The imaging parameters for MRE were as follows: repetition time/echo time (TR/TE) = 50/24 ms; continuous 60-Hz vibration; field of view = 34–40 cm; matrix size = 256 × 192; flip angle = 30°; slice thickness = 10 mm; phase offsets = 4; fractional phaseencoding direction (anterior–posterior) field of view = 0.7; the ASSET parallel imaging factor = 2. Two spatial presaturation bands were applied on each side of the selected slice to reduce motion artifacts caused by blood flow. The total acquisition time was 27 sec for one breath-hold to complete each one-slice acquisition. MRE measurements were performed in three consecutive slices with the middle one aligned with the marker on the passive driver. The other two slices were located above and below the central slice with a 10-mm gap in between. This 3-slice MRE acquisition was repeated 2 more times with the subject remaining on the scanner table with the MRE driver left in place between the acquisitions with a 1–2 minute pause between acquisitions. Through November and December of 2011, 22 subjects (13 females, 9 males) with no history or findings of abdominal disease during the period of the study were included (session 1; S1). All volunteers had blood tests performed prior to the MRE measurements to assure that there were no existent hepatic diseases (HD) or any abnormalities caused by preexisting HD in any subject. For each subject, the MRE acquisitions were repeated in two more sessions [S2: 7 ± 2 days later (“short term”); S3: 195 ± 15 days later (“midterm”)] using timeframe definitions similar to that used by Braithwaite et al. to test the reproducibility of abdominal DWI [15]. The locations of the images obtained were matched to those obtained previously using markers as well as visual anatomical landmarks. The same operator performed the MRE procedures on all participants. 2.3. Measurement of liver stiffness MR elastograms were obtained by processing the acquired shear wave images using the multimodel direct inversion (MMDI) algorithm developed by Mayo Clinic, integrated in a commercial workstation (Advantage Windows 4.4, GE Healthcare, Buc, France). A description of the processing can be found in the article described by Dzyubak et al. [16]. Two raters (two radiologists with 7 years and 11 years of experience in abdominal diagnostic radiology and both with one year of experience with MRE measurements) measured the liver stiffness values independently by placing the regions of interest (ROI) manually using the ROI placement considerations discussed by Shire et al. and Dzyubak et al. [9,16]. One flexible ROI encompassing the outer liver area, where the wave amplitude was highest, was defined for each slice. The areas automatically identified by the inversion algorithm as invalid were excluded from the elastogram analysis. Portions of the liver with vessels and the liver edge in the
Fig. 1. The outlined area represents the region of interest for the stiffness measurement defined to exclude areas of wave interference, portal areas and blood vessels, and areas automatically identified by the inversion algorithm as invalid.
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magnitude images and wave multipath interferences on the wave images were also excluded. The hepatic shear stiffness for each slice (in kPa) was reported as the mean value in the ROI, as shown in Fig. 1. After the imaging for each session was performed, the two raters measured the liver stiffness blinded to the other rater's results. For sessions S2 and S3, the same raters redrew the ROIs in a blinded fashion by not comparing the ROIs to the ROIs obtained in S1. The time interval for redrawing the ROIs between sessions or between repetitions in one session for the same slices was at least one week to avoid memory bias. 2.4. Statistical analysis The liver stiffness measurements were organized according to subjects (each volunteer), slices (three slices with different ROIs), repetitions (three repeated MRE acquisitions), sessions (1 or 2 or 3) and raters (1 or 2). Therefore, a total number of 54 measurements (three repetitions per slice, three slices per session, three sessions, two raters) were collected for each subject. The data were analyzed with repeated-measures analysis of variance (ANOVA) to test the null hypothesis that slice, repetition, session and rater had no significant influence on stiffness measurements. If the Mauchly's test of sphericity was significant indicating violations of sphericity (P b 0.05), the Greenhouse–Geisser correction was applied when epsilon was b 0.75, or the Huynh–Feldt correction was applied when epsilon was N 0.75 [17]. The intrasubject coefficient of variation (CV) for each visit was calculated
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from the pooled data across the three repeated acquisitions and the three slices for each imaging session and each rater. The intrasubject CVs were also analyzed with repeated-measures ANOVA to test the null hypothesis that neither rater nor session had a significant effect on the measured stiffness. As long as the test does not show a significant difference, the intrasubject CVs can be averaged over the sessions and raters, and the 95% confidence interval (CI) for the stiffness measurements can be calculated as 1.96 standard deviations from the mean (i.e., 1.96 × CV), suggesting that treatment effects causing a stiffness change of less than 1.96 × CV will not be meaningfully detectable as they would be within the typical variance of the stiffness measurements [18]. The absolute stiffness differences for raters and sessions were calculated as follows: stiffness differences (kPa) = (stiffness measured by rater 1) − (stiffness measured by rater 2) for each of the 3 sessions, or = (stiffness measured in session x1) − (stiffness measured in session x2) for each rater (x1 = session 1 or 2, x2 = session 2, 3). The intraclass correlation coefficient (ICC) was applied to assess interrater agreement and intersession agreement in the stiffness measurements [19]. The intersession CV was also used to examine the repeatability of these short- and midterm measurements: the smaller the CV, the better the repeatability. Gender differences in liver stiffness measurements were tested using a nonparametric Mann–Whitney U test. The correlation between liver stiffness and the physiologic parameters (age, BMI, and portal vein bulk flow) was tested using the nonparametric Spearman correlation test. A P value less than 0.05 was defined as
Fig. 2. Axial magnitude, wave, and elastogram images from each of the 3 sessions of a healthy 29-year-old male. Stiffness values and standard deviations are: session 1: 2.15 ± 0.28 kPa; session 2: 2.31 ± 0.30 kPa; session 3: 2.49 ± 0.43 kPa for rater 1; session 1: 2.21 ± 0.31 kPa; session 2: 2.34 ± 0.25 kPa; session 3: 2.44 ± 0.42 kPa for rater 2.
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Fig. 3. The graph shows the mean liver stiffness at each of the three imaging sessions for the individual volunteers as determined by each rater. The data for each individual subject were fairly stable over the studied time period.
statistically significant. When the Bonferroni correction was used to adjust for multiple comparisons, the P value was divided by the number of comparisons. All statistical analysis was performed using Medcalc Version 7.4.2.0 (Medcalc Software, Mariakerke, Belgium) and SPSS Version 16.0 J (SPSS Inc, Chicago, IL, USA). 3. Results 3.1. Repeated-measures analysis of variance Fig. 2 shows representative axial magnitude images, stiffness maps, and wave images from all three sessions for one subject. A fair match of the slice locations in the three sessions was achieved. There was no significant difference in the stiffness measurements between the repeated acquisitions (P = 0.984), the three slices (P = 0.279), the raters (P = 0.383), or the three sessions (Greenhouse–Geisser correction, P = 0.163). The data from all subjects were shown in Fig. 3. The overall mean intrasubject CV (Table 1) for the repeatability of the liver stiffness measurements over the short- and midterm intervals was 12.44% (95% CI: 8.97%, 15.91%, 1.96 × CV = 24.39%). 3.2. Liver stiffness measurement and the difference in the absolute stiffness between groups The overall mean stiffness was 2.21 ± 0.26 kPa (ranging from 1.67 to 2.92 kPa) for all the healthy subjects calculated across the 54 data points in this study. The mean and standard deviation of stiffness differences between sessions or raters, with maximum and minimum 95% CIs are shown in Table 2. The stiffness difference over the short-term interval was (− 0.004 ± 0.086) kPa. The difference over the midterm intervals was (− 0.055 ± 0.150) kPa for session 1–3 and (− 0.051 ± 0.173) kPa for session 2–3. The stiffness difference between the two raters was (0.003 ± 0.026) kPa, (0.005 ± 0.037) kPa and (0.005 ± 0.037) kPa for sessions 1, 2, and 3, respectively.
Table 1 Mean intrasubject coefficients of variation (CV) for differences in the stiffness measurements across three acquisition repetitions and three slices for each imaging session and each rater. CV
Session1
Session 2
Session 3
Overall
Rater 1 Rater 2 Overall
12.83% 13.91% 13.37%
12.95% 9.20% 11.08%
11.80% 13.90% 12.85%
12.53% 12.34% 12.44%
3.3. ICC and intersession CVs for the repeatability of raters and sessions The ICC testing interrater agreement was greater than 0.9 for every session, and the overall ICC was excellent at 0.987 (95% CI: 0.983 to 0.990). Evaluating the ICC for intersession agreement (Table 3), the liver stiffness (kPa) was more repeatable in the shortterm interval with a mean overall ICC value of 0.96, compared with 0.91 and 0.87 for the midterm intervals. For both raters, the intersession CV (Table 4) was lower when the scanning was repeated within a short-term interval (between S1 and S2: 2.73%), contrary to when the scanning was performed over a midterm interval (between S1 and S3: 5.10%; between S2 and S3: 5.75%). 3.4. The correlation between liver stiffness and physiologic parameters In this study, the 54 liver stiffness measurements collected from each subject, including measurements from repeated acquisitions, multiple slices, different raters and at different time points, were averaged together and tested for correlation with various physiologic parameters. The physiologic parameters measured in this study included BMI, portal vein bulk flow and age. BMI ranged from 18.2 to 28.2 kg/m 2 (mean ± SD, 22.9 ± 2.6 kg/m 2), and portal vein bulk flow ranged from 706 to 1612 ml/min (mean ± SD, 1178.8 ± 274.6 ml/min). Age ranged from 18 to 56 years (mean ± SD, 33.1 ± 9.6 years). There was no significant correlation between the liver stiffness and the volunteer's age, portal vein bulk flow or BMI (r = 0.33, 0.17, 0.21 respectively, all P N 0.05). A difference in liver stiffness was observed between the genders. The mean liver stiffness in males was higher than in females (male, 2.30 ± 0.18 kPa; female, 2.13 ± 0.25 kPa, Mann–Whitney U test: P = 0.042). 4. Discussion The results from this study showed no significant variation in liver stiffness over the short-term interval (one week between sessions) or the midterm interval (over 6 months between sessions). This indicates that these MRE-based liver stiffness measurements are robust and are capable of serving as a reproducible, quantitative tool over these time frames in healthy volunteers. Likewise, repeated acquisitions and measurements made in different slices within a single session did not cause significant differences in the stiffness measurements. The mean CV of short- and midterm repeatability of the measurements was 12.44%. The stiffness difference in absolute stiffness of short-term interval (S1-2) was lower than that of midterm interval (S1-3 and S2-3). The short-term interval showed better
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Table 2 Differences (D, kPa) in the absolute stiffness measured by the two raters in each session or the differences between two sessions (short-term and midterm) for each rater. Short-term (sessions 1–2) 95% CIa (test value = 0) Midterm (sessions 1–3) 95% CIa (test value = 0) Midterm (sessions 2–3) 95% CIa (test value = 0) Rater 1 −0.005 ± 0.093 Rater 2 −0.004 ± 0.084 Overall −0.004 ± 0.086 Raters 1–2⁎ 0.003 ± 0.026b
−0.046,0.036 −0.041,0.034 −0.031,0.022 −0.009,0.015
−0.056 −0.054 −0.055 0.005
± ± ± ±
−0.127,0.015 −0.119,0.011 −0.101,−0.009 −0.012,0.021
0.160 0.147 0.150 0.037c
−0.051 −0.051 −0.051 0.005
± ± ± ±
0.187 0.167 0.173 0.037d
−0.134,0.032 −0.125,0.024 −0.104,0.003 −0.009,0.019
a Coefficient interval; ⁎ D measured by the two raters in each session: b for session 1; c for session 2; d for session 3.
repeatability with higher ICC and lower intersession CV compared to the midterm interval. An excellent interrater agreement was also achieved with very high ICC values. Moreover, subject variations due to age, BMI and portal vein bulk flow had no significant influence on the stiffness measurements. However, there was a gender difference, with males having higher liver stiffness than females. The stability and reproducibility of the MRE measurements in this study suggest that MRE may be a viable clinical tool for monitoring hepatic changes within an individual over at least a 6-month interval. This finding is of particular significance for the monitoring of the progression of liver fibrosis and the response to antiviral therapy [2,4,20]. The reported average duration of antiviral therapy needed to retard the progression of or cause regression of fibrosis is about 16 weeks. Liver biopsies are sometimes repeated after the completion of therapy to show histological response to treatment [20]. However, the repeated biopsy tests are not acceptable to many of the patients because of their invasiveness. The latest metaanalysis reported by Wang et al. [7] showed that MRE can be used in clinical practice as an excellent tool for the staging of fibrosis, even showing an opportunity to replace liver biopsy. The results of our study further validate the repeatability of MRE over a 6-month time frame and suggest that MRE may be a viable tool for monitoring antiviral response. Hines et al. [11] previously examined sources of variability in MRE readings and determined that scans on different days contributed the most variability to liver stiffness measurements, whereas different scans on the same day and analyzed by different readers contributed relatively less variability. Their reported interval was 2–4 weeks. The results from a study by Shire et al. [9] suggested that the CV of hepatic stiffness measurements performed with MRE on the same day were similar to, but lower than, the CV of values obtained 7–14 days apart. No literature has reported the midterm repeatability of MRE yet. Our study proved that not only short-term interval (7-day) measurements of stiffness, but also midterm interval measurements are reproducible within a given individual. The liver stiffness (kPa) was more repeatable in the short-term interval with a mean overall ICC value of 0.96, compared with 0.91 and 0.87 for the midterm intervals. The intersession CV also tended to be larger for the midterm measurements than for the short-term measurements. In this study, nearly iden-
Table 3 Intersession intraclass correlation coefficient (ICC) results between two raters.
Mean (rater 1) 95% CIa Mean (rater 2) 95% CIa Mean over all 95% CIa a
Short-term (sessions 1–2)
Midterm (sessions 1–3)
Midterm (sessions 2–3)
Overall
0.95 0.89–0.98 0.96 0.91–0.98 0.96 0.90–0.98
0.90 0.76–0.96 0.91 0.78–0.96 0.91 0.78–0.96
0.85 0.66–0.94 0.88 0.71–0.95 0.87 0.69–0.95
0.93 0.86–0.97 0.94 0.88–0.94 0.94 0.87–0.97
CI: confidence interval.
tical slices with similar ROI selections, a standard preprandial state and identical imaging parameters were repeated over the multiple sessions, which contributed to the repeatable stiffness measurements. As proposed by Shire et al. [9], when defining the ROI, the raters should be careful to consider the magnitude, wave, and elastogram images simultaneously to obtain a homogenous region of liver tissue free of wave reflections and interference patterns. Westrictly followed the selection criteria. It is also important to try to ensure that the waves produced in the liver travel along the imaging plane (rather than through the plane) to avoid overestimation of the wavelength [21,22]. As described by Yin et al. [22], the MRE vibration technique used in this study can produce a conelike hemispherical distribution of shear waves whose propagation is governed by diffraction. In order to control for this possible confounding factor, all the slices were prescribed near the center of the driver and were matched across sessions. An alternative approach to solve this issue would be the use of 3D MRE, which is currently only available for neuroimaging. The mean intrasubject CV within a single session for an individual was 12.44%. This single-session variation may be due to a number of factors, including variations in the size and location of ROIs drawn on different slices, variations in the wave field propagation at different slice locations, and physiologic variations between slices and repetitions (e.g., breath-hold variations and blood flow artifacts). The prandial state is known to increase portal vein bulk flow and hepatic sinusoidal perfusion strongly, and our data for portal flow were within the normal range when compared to earlier published results [23–25]. In a study by Mederacke et al. using transient elastography [26], an increase in liver stiffness after eating was observed in patients with chronic or resolved HCV infection as well as in healthy controls, which the authors speculate could be a consequence of increased liver blood flow after food intake, though they did not measure liver blood flow in their study. However, Hines et al. observed no significant changes in the MRE stiffness measurements in healthy subjects after meals, despite large increases in portal blood flow [27]. They claimed that the healthy liver might have an autoregulation mechanism to maintain the portal venous pressure, resulting in stable liver stiffness after meals. Yin et al. [28] further showed that in 13 of 20 healthy volunteers, no substantial stiffness augmentation was observed (defined as a change of more than 10%, or 0.2 kPa), while another 7 healthy volunteers had a slight increase in postprandial liver stiffness, with a mean value of 17.8% (0.35 kPa). All measurements were still within the normal range.
Table 4 Intersession coefficients of variation (CV) for differences in stiffness measurements. CV
Short-term (sessions 1–2)
Midterm (sessions 1–3)
Midterm (sessions 2–3)
Rater 1 Rater 2 Overall
2.92% 2.66% 2.73%
5.29% 4.95% 5.10%
6.04% 5.53% 5.75%
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However, the hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17–4.15 kPa) or 21.24 ± 14.98% (range, 7.69%–63.3%). They speculated that the healthy liver can have better autoregulation to maintain a constant portal pressure gradient in the liver, resulting in a more stable stiffness after an increase in portal vein flow. In our study, in order to control this potential effect of food ingestion as well as to reduce gastrointestinal motion and potential discomfort caused by the driver, we standardized the time of fasting before each scan. Furthermore, no significant correlation was found between liver stiffness and portal vein bulk flow, which was consistent with the results of Hines and Yin [27,28]. Our study showed that liver stiffness was significantly influenced by gender, with higher values found in males than females, which was also shown in several previous studies through the use of both transient US [29] and MRE [30]. Our study has several limitations. First, this work was based on normal volunteer data. Unlike healthy volunteers, patients may be under different kinds of treatment and hepatic disease stages. As such, there may be additional sources of measurement variability for patients that will confound attempts to determine the true repeatability of MRE. For example, patients may be more likely to have regional variations of hepatic stiffness due to variable degrees of fibrosis or inflammation. Physiologic variations in patients, such as body habitus, ascites, bowel location, and breath-hold variability, may introduce more variation in the stiffness measurements in patients compared to healthy volunteers. Patients are also not always able to return for a repeated exam punctually, even over a short-term interval (one week), thus interfering with the ability to assess the repeatability of stiffness measurements in patients. Finally, the healthy volunteers were documented through questioning and liver blood function tests. Therefore, it is possible that some of the volunteers in this study had cryptogenic liver diseases. In conclusion, no significant variability in MRE liver stiffness measurements was found when assessing the short- and midterm (more than 6 months) repeatability of these measurements in healthy volunteers at 3.0 T. The mean intrasubject CV for the repeatability of stiffness over the short- and midterm intervals was 12.44%.
Conflict of interest None.
Acknowledgments This study is supported by grants from the Natural Science Foundation of China (No. 81071123, 81271566). The authors thank Dr. Zhenyu Zhou of the GE Healthcare China Research Team for their support and assistance. We also thank Dr. Richard L Ehman and colleagues at the Mayo Clinic for the MRE technology used in this study.
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