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Magnetic resonance elastography of healthy livers at 3.0 T: Normal liver stiffness measured by SE-EPI and GRE
Accepted Manuscript Title: Magnetic Resonance Elastography of Healthy Livers at 3.0 T: Normal Liver Stiffness Measured by SE-EPI and GRE Authors: Jae Seok Bae, Jeong Min Lee, Sae-Jin Park, Kyung Bun Lee, Joon Koo Han PII: DOI: Reference:
S0720-048X(18)30283-3 https://doi.org/10.1016/j.ejrad.2018.08.015 EURR 8279
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
26-3-2018 10-7-2018 13-8-2018
Please cite this article as: Bae JS, Lee JM, Park S-Jin, Lee KB, Han JK, Magnetic Resonance Elastography of Healthy Livers at 3.0 T: Normal Liver Stiffness Measured by SE-EPI and GRE, European Journal of Radiology (2018), https://doi.org/10.1016/j.ejrad.2018.08.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Magnetic Resonance Elastography of Healthy Livers at 3.0 T: Normal Liver Stiffness Measured by SE-EPI and GRE
Jae Seok Bae, M.D.a,b, Jeong Min Lee, M.D.a,b,c, Sae-Jin Park, M.D.a,b, Kyung Bun Lee,
Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu,
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a
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M.D. d, Joon Koo Han, M.D.a,b,c
Seoul, 03080, Korea b
Department of Radiology, Seoul National University College of Medicine, 103 Daehak-ro,
Institute of Radiation Medicine, Seoul National University Medical Research Center, 103
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c
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Jongno-gu, Seoul, 03080, Korea
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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d
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Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu,
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1Department
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Corresponding Author: Jeong Min Lee 1, M.D.
Seoul, 03080, Korea
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Tel: 82-2-2072-3154 Fax: 82-2-743-6385
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E-mail: [email protected]
ABSTRACT
Purpose: To determine the normal liver stiffness values using magnetic resonance elastography (MRE) at 3.0 T and to compare spin-echo echo planar imaging (SE-EPI) and gradient recalled echo (GRE) MRE. Materials and methods: This retrospective study included 54 living liver donors who had
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normal clinical and pathological results without underlying liver disease and underwent MRE using both SE-EPI and GRE at 3.0 T. Two radiologists placed four or six freehand regions of
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interest (ROI) on the elastograms and measured liver stiffness as well as the area of ROIs.
The mean liver stiffness values and area of ROIs were compared between genders, among age groups, and between groups of different body mass indexes using the t-test and one-way
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analysis of variance, respectively. Interobserver agreement was analyzed using intraclass
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correlation coefficient. The mean liver stiffness values and area of ROIs were compared
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between SE-EPI and GRE using the paired t-test and Bland-Altman analysis.
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Results: The liver stiffness values in living liver donors ranged from 1.52 to 3.12 kilopascal (kPa) on SE-EPI and 1.51 to 2.67 kPa on GRE. The mean liver stiffness values did not differ
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significantly according to the gender, age, and body mass index. Measurement of liver
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stiffness using MRE showed excellent interobserver agreement on both pulse sequences. The mean value of liver stiffness was higher on SE-EPI (2.14 ± 0.33 kPa) than on GRE (2.06 ±
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0.25 kPa), and the difference was statistically significant (P < 0.05). The mean area of ROI was significantly larger with GRE (3387 mm2) than with SE-EPI (2691 mm2) (P < 0.05). Conclusions: The mean liver stiffness values in living donors measured by SE-EPI and GRE
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were not affected by gender, age, or body mass index and showed excellent interobserver agreement. The area of ROI was larger with GRE than with SE-EPI.
Keywords: magnetic resonance elastography; normal liver stiffness; spin echo echoplanar imaging; gradient recalled echo
Introduction
Liver fibrosis is a common pathologic process caused by any type of chronic liver
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disease, and can lead to cirrhosis, portal venous hypertension, and/or development of hepatocellular carcinoma [1]. However, liver fibrosis is reversible in its early stage [2, 3].
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Thus, it is important to detect liver fibrosis early in patients with chronic liver disease.
Although liver biopsy is the state of the art and still superior to imaging biomarkers, and has been performed for the assessment of liver fibrosis, it has limitations including sampling
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error, interobserver variability, and invasiveness. Among the various proposed imaging tools
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for non-invasive diagnosis of liver fibrosis, magnetic resonance elastography (MRE) is a
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well-validated method and has been gaining acceptance for evaluation of patients with
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chronic liver disease [4-6]. Measurement of liver stiffness and staging of hepatic fibrosis using MRE have been reported to be accurate and reliable [7-10].
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However, few studies have reported the liver stiffness values measured by MRE in
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normal liver at 3.0 T, and most of them are limited in the sample size and lack biochemical and pathologic assessment results [11-14]. Instead, most of the studies on MRE have been
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performed in the patients with chronic liver disease and focused on staging of liver fibrosis. Although there have been a few reports on the normal liver-stiffness values in healthy subjects, all the studies were conducted at 1.5 T only [15, 16]. For correct application of
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MRE at 3.0 T, establishment of the normal range of liver stiffness values is an important prerequisite. In addition, there have been efforts to develop new MRE pulse sequences to overcome the drawback of the most commonly used two-dimensional (2D) gradient-recalledecho (GRE) MRE that requires serial breath holds and is sensitive to iron overload [17-20]. The 2D spin-echo echo-planar imaging (SE-EPI) pulse sequence has the fastest imaging
acquisition time and is one of the most promising alternatives to GRE MRE [21, 22]. However, comparison of GRE and SE-EPI MRE in normal subjects has not been performed as well. The aims of this study, therefore, were (i) to define the normal range of liver stiffness
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assessed with SE-EPI and GRE MRE at 3.0 T in healthy living liver donors who showed completely normal range of laboratory results and no fibrosis on pathologic examination, and
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(ii) to compare the liver stiffness values measured by SE-EPI and GRE MRE in healthy
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subjects.
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Materials and methods
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Study Population
This retrospective study was approved by our institutional review board approved
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and the informed consent was waived. From January 2016 to April 2017, a total of 140
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potential living liver donors (M:F = 80:60) underwent evaluation for liver transplantation and gadoxetic acid-enhanced MR at 3.0 T at our hospital. We included subjects in our study
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according to the following criteria: (a) normal results in physical examinations and laboratory tests such as serological tests for hepatitis B surface antigen, hepatitis C virus antibody, coagulation profiles (prothrombin time, activated partial thromboplastin time), aspartate
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aminotransferase, alanine aminotransferase, albumin, total bilirubin, γ-glutamyl transpeptidase, and alkaline phosphatase; (b) absence of any risk factor for chronic liver disease or family history of chronic liver disease; (c) absence of any kind of diagnosed disease and no current intake of any medications; (d) patients underwent MR including elastography at 3.0 T within 2 months of liver donation, with no focal lesion noted in the liver
on MR; and (e) liver donation performed at our hospital. Among these subjects, 86 (M:F = 50:36) were excluded for the following reasons: (a) abnormal laboratory test results (n = 5); (b) liver donation not performed (n = 24); (c) liver donation performed without excisional biopsy of hepatic parenchyma (n = 3); (d) time interval between MR elastography and liver
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donation or percutaneous liver biopsy greater than 60 days (n = 6); (e) identification of any degree of hepatic fibrosis or inflammation on the pathologic specimen (n = 48). Finally, 54
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healthy donor candidates were recruited: 30 males and 24 females, with a mean age of 36.5 ± 11.4 years (range: 18–61 years) and mean body mass index (BMI) of 23.8 ± 3.0 kg/m2
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(range: 18.3–30.9 kg/m2) (Fig. 1).
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MR Elastography
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All MR examinations including elastography were performed on a 3.0 T MR scanner
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(Magnetom Skyra, Siemens Healthineers, Erlangen, Germany) with a commercially available MRE hardware (Resoundant active and passive drivers, Siemens Healthineers, Erlangen,
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Germany) and a thirty-channel, body array coil. MRE imaging was performed after acquisition of routine liver MR images including injection of contrast medium (Gadoxetic
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acid, Primovist, Bayer Healthcare, Berlin, Germany) at a standard dose (1 mL/10 kg body
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weight, 0.025 mmol/kg). In our hospital, MRE was performed with two acoustic pressureactivated drivers placed on the patient’s right and left upper abdomen adjacent to the liver and spleen, respectively. The passive drivers transmitted low-amplitude longitudinal
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mechanical waves of 60-Hz to the liver and spleen, as synchronized with the imaging sequences. Shear waves were generated in the liver and were imaged by using SE-EPI and GRE. Four contiguous axial slices centered at the hepatic hilum were acquired over four sequential breath holds at the end-expiration for GRE image acquisition, whereas a single breath hold at the end-expiration was required for SE-EPI image acquisition (Fig. 2). For SE-
EPI MRE, six contiguous slices were obtained in the early phase of the study period and liver stiffness was measured in all six slices. After setting up the protocol, four slices were acquired for SE-EPI as same as GRE. The detailed MR parameters are summarized in Table 1. After completion of MRE image acquisition, the wave images were automatically
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processed using the inversion algorithm to generate images depicting tissue stiffness (elastograms) [23]. Areas of liver stiffness were represented in units of kilopascals (kPa) on
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these quantitative images in gray scale or color scale [24]. The time interval between MRE and surgery or percutaneous biopsy was 26 ± 14 days (range: 4–60 days).
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Image Analysis
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Ninety five percent confidence interval maps were automatically generated by an
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intrinsic software as a checkerboard pattern and were superimposed on the elastograms to
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indicate where reliable stiffness values could be measured. In addition, segmentation of liver was automatically performed in some subjects, using commercially available software (Inline
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liver segmentation, Siemens Healthineers, Erlangen, Germany) and the boundary of the liver
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generated by autosegmentation was overlaid on elastograms. To obtain liver stiffness values of the hepatic parenchyma, ROIs were drawn freehand on each of the four or six confidence and
with 6 years and 4 years of
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map-overlaid elastograms by two radiologists (
experience in liver MR, respectively), who were blinded to the clinical and histologic information. The two radiologists reviewed their ROI sets jointly and reached consensus for
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selection of the final ROI sets for analysis. All ROIs (mean area: 2690 ± 983 mm2, range: 1123–5189 mm2 on SE-EPI; mean area: 3387 ± 1424 mm2, range: 727–6411 mm2 on GRE by
; mean area: 3788 ± 1922 mm2, range: 1266–8449 mm2 on SE-EPI; mean area:
4203 ± 2075 mm2, range: 803–8184 mm2 on GRE by
) were drawn to include as much
of the liver parenchyma in the right lobe as possible while avoiding area with low quality data
such as immediate subcapsular area, fissures, or large vessels [25]. The liver stiffness values were obtained in kilopascals (kPa). Thereafter, mean liver stiffness values were calculated by averaging the stiffness values from the four or six elastograms. In addition, two reviewers (
and
) reviewed all MRE images and graded respiratory motion artifacts
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according to the binary scale as follows: no to mild artifact versus moderate to severe artifact.
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All the procedures described above were performed on both SE-EPI and GRE MRE [25].
Histologic Analysis
For acquisition of liver tissue sample, approximately 1 mm3 of hepatic parenchyma
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was excised from the right hemiliver during the liver donation. The specimens underwent
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fixation in formalin and were embedded in paraffin. Thereafter, sections of 4-μm-thickness with 15 years of
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were stained with hematoxylin and eosin (H&E). A pathologist (
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experience) who was blinded to clinical information and MR findings evaluated all the pathologic slides for degree of inflammation, fibrosis, and steatosis. The degree of
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inflammation and fibrosis was graded according to the METAVIR scoring system [26]. The
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degree of macrovesicular steatosis was graded based on the percentage of hepatocytes involved in macrovesicular fat droplets at 4x magnification of H&E sections [27]. In our
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hospital, at least 10% macrovesicular steatosis was considered to be substantial macrovesicular steatosis that was a contraindication to liver donation and warranted further
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evaluations or dietary modifications to improve steatosis prior to liver donation [10].
Statistical Analysis For statistical analysis, other than interobserver agreement, data from the consensus of our two reviewers were used. The liver stiffness value was compared between genders using the independent sample t-test. To assess the liver stiffness value according to age, we
grouped the donors under three age groups of < 30 years (n = 16), 30–40 years (n = 16), and > 40 years (n = 22) and compared the mean liver stiffness values in each age group by using one-way analysis of variance. Correlation of liver stiffness value with macrovesicular fat fraction of the liver was assessed by using Pearson’s correlation test. We also categorized the
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subjects according to the WHO cutoffs for normal BMI for Asians into low BMI group (BMI < 23.5 kg/m2) and high BMI group (BMI ≥ 23.5 kg/m2) and compared the liver stiffness
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values between the two groups [28]. In addition, interobserver agreement of the liver stiffness measurements on SE-EPI and GRE was assessed using the intraclass correlation coefficient (ICC). ICC values were classified by using the following criteria: poor: 0–0.39; fair: 0.40–
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0.59; good: 0.60–0.74; and excellent: 0.75–1.0 [29].
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To compare the mean liver stiffness values and area of ROI measured with SE-EPI
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and GRE, paired t-test was performed. In addition, mean differences between liver stiffness
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values on SE-EPI and GRE were obtained by Bland–Altman analysis and the 95% limits of agreement were determined using the mean and standard deviation (SD) of the differences
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between the two pulse sequences [30]. Lastly, McNemar’s test was performed to compare
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frequencies of moderate or severe respiratory artifacts on each pulse sequence. All statistical analyses were performed by using commercially available software (SPSS, version 22, IBM,
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Armonk, NY; MedCalc, version 14, MedCalc software, Mariakerke, Belgium). A P-value < 0.05 was considered statistically significant.
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Results
Technical failure was observed in one subject on SE-EPI and in another subject on
GRE and liver stiffness could not be measured on the corresponding pulse sequence: the values obtained from those subjects were not included in analysis.
Range of the Normal Liver Stiffness Values and Effect of Age and Gender On SE-EPI, the stiffness values of the liver in the living liver donors ranged from 1.52 to 3.12 kPa with a mean ± SD of 2.14 ± 0.33 kPa (95% confidence interval [CI], 2.062.25 kPa). On GRE, the liver stiffness values ranged from 1.51 to 2.67 kPa with a mean ± SD
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of 2.06 ± 0.25 kPa (95% CI, 1.99-2.12 kPa). The mean liver stiffness values did not differ according to gender. Although male
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subjects showed slightly higher liver stiffness (2.21 ± 0.37 kPa, 95% CI, 2.07-2.35 kPa) compared to female subjects (2.06 ± 0.24 kPa, 95% CI, 1.95-2.16 kPa) on SE-EPI, the
difference was not statistically significant (P = 0.101). Similarly, male subjects also had
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higher liver stiffness values (2.10 ± 0.25 kPa, 95% CI, 2.01-2.19 kPa) compared to female
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not statistically significant (P = 0.164) (Fig. 3).
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subjects (2.00 ± 0.25 kPa, 95% CI, 1.89-2.11 kPa) on GRE; however, this difference was also
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The liver stiffness values among the age groups also demonstrated no statistically significant differences. On SE-EPI, the liver stiffness values of the three age groups (age <
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30, 30 ≤ age ≤ 40, and age > 40) were 2.25 ± 0.31 kPa (95% CI, 2.08-2.42 kPa), 2.07 ± 0.33 kPa (95% CI, 1.90-2.25 kPa), and 2.11 ± 0.33 kPa (95% CI, 1.96-2.27 kPa), respectively (P =
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0.289). On GRE, the liver stiffness values of the three age groups (age < 30, 30 ≤ age ≤ 40,
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and age > 40) were 2.14 ± 0.24 kPa (95% CI, 2.01-2.26 kPa), 2.04 ± 0.22 kPa (95% CI, 1.922.16 kPa), 2.01 ± 0.28 kPa (95% CI, 1.88-2.14 kPa), respectively (P = 0.305) (Fig. 3).
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Influence of Steatosis and BMI on the Liver Stiffness Value Among the 52 liver donors, only one subject showed substantial macrovesicular
steatosis (15%) in the pathologic specimen obtained during the transplantation surgery. In fact, the subject had a fat fraction of 10% on the proton MR spectroscopy included on the initial screening MR and underwent percutaneous liver biopsy. The biopsy results also
demonstrated macrovesicular steatosis of 10%. The subject underwent weight reduction by 10 kg for two months following which liver donation was performed. The macrovesicular fat fraction in the donors ranged from 0% to 15%. On SE-EPI, there was no correlation with the estimated fat content in the liver and mean liver stiffness (r
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= 0.159, 95% CI, −0.119-0.414, P = 0.261), whereas on GRE, liver stiffness value was correlated with degree of fat fraction (r = 0.287, 95% CI, 0.015-0.519, P = 0.039) (Fig. 4).
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The liver stiffness values did not differ significantly between the group with BMI < 23.5 kg/m2 and the group with BMI ≥ 23.5 kg/m2 on both pulse sequences. On SE-EPI, the mean liver stiffness values were 2.16 ± 0.31 kPa (95% CI, 2.03-2.28) in the BMI < 23.5
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kg/m2 group and 2.13 ± 0.35 kPa (95% CI, 1.99-2.27) in the BMI ≥ 23.5 kg/m2 group (P =
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0.787). On GRE, the liver stiffness values were 2.01 ± 0.28 kPa (95% CI, 1.90-2.13) in the
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BMI < 23.5 kg/m2 group and 2.10 ± 0.22 kPa (95% CI, 2.01-2.19) in the BMI ≥ 23.5 kg/m2
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group (P = 0.234) (Fig. 4).
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Interobserver Agreement for Liver stiffness and Area of ROI
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Reliability of the MRE using SE-EPI and GRE was evaluated in 52 patients; two patients in whom technical failure occurred were excluded. ICC values for liver stiffness
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measured on SE-EPI and GRE were 0.89 (95% CI, 0.77-0.94) and 0.84 (95% CI, 0.72-0.91), respectively, which were in excellent agreement. With regard to the area of ROI placed on SE-EPI and GRE, ICC values were 0.55 (95% CI, 0.09-0.77) and 0.77 (95% CI, 0.30-0.90),
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respectively. Only the area of ROI on GRE showed good agreement between the two reviewers.
Comparison of the SE-EPI and GRE
The mean liver stiffness value was slightly higher on SE-EPI than on GRE (P = 0.017). Bland-Altman plot revealed that the mean difference of liver stiffness values between SE-EPI and GRE was 0.09 ± 0.25 kPa (95% CI, 0.016-0.158 kPa; limits of agreement 0.412-0.586 kPa) (Fig. 5). Except for one subject, all the differences fell within the limits of
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agreement. The area of ROI placed on elastograms was 2691 ± 983 mm2 (95% CI, 2417-2965 mm2) and 3387 ± 1424 mm2 (95% CI, 2991-3784 mm2) on SE-EPI and GRE, respectively.
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The difference between the area of ROIs was statistically significant (P < 0.001) (Fig. 2). No
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moderate to severe respiratory motion artifacts were noted either with on SE-EPI or GRE.
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Discussion
To the best of our knowledge, this is the first study to evaluate the normal range of
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liver stiffness values in clinically and pathologically normal subjects with MRE at 3.0 T.
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Although a few previous studies have reported normal liver stiffness in healthy volunteers with GRE at 3.0 T, the sample sizes used in those studies were small (equal to or less than
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22). More importantly, no laboratory tests or pathologic examinations were performed in those studies [11-14]. On the contrary, we included patients with strict normal ranges of laboratory and pathologic results and therefore, the liver stiffness values obtained in our study
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may be regarded as true normal values. To clinicians, the range of normal liver stiffness values is useful because it can be used for screening the general population to identify subjects with suspicious chronic liver disease who require further work up. In addition, we performed MRE with SE-EPI as well as with GRE, and therefore, our results may be useful for interpretation of liver stiffness values obtained with both pulse sequences.
For GRE MRE, the mean and range of liver stiffness values in our study were 2.06 kPa and 1.51 to 2.67 kPa, respectively. This result is slightly lower than those of previous studies performed in healthy subjects with GRE at 3.0T, which yielded mean liver stiffness values of 2.21-2.34 kPa that ranged from 1.67 to 2.92 kPa [11, 13]. This discrepancy could be
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partly caused by differences in ethnicity because the study by Mannelli et al. was conducted in Western countries whereas our study included Asian subjects. It has been reported that
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liver stiffness values are higher in Europeans compared to Asians [31]. Furthermore, while
the small sample size and differences in other clinical characteristics such as BMI could also have influenced the results, detailed information on the population was not available.
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Meanwhile, our results are in concordance with the findings of other studies performed at 1.5
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T that yielded mean liver stiffness values of 2.05-2.12 kPa, ranging from 1.54 to 2.87 kPa
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[15, 16].
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With regards to the MRE values of normal liver measured with SE-EPI at 3.0 T, our result was 2.14 kPa, which was slightly higher than the values of 1.75 kPa and 2.05 kPa from
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two different vendors reported by Trout et al. [32]. However, that study included only
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twenty-four adults and the subjects did not undergo medical examination such as laboratory tests or pathologic confirmation. Moreover, the difference between liver stiffness values
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obtained from the two different vendors in that study was 0.30 kPa, which is approximately three times larger than the difference between our result (2.14 kPa) and the higher value reported by Trout (2.05 kPa). Further studies with larger population and multiple vendors will
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be required to define the correct normal range of liver stiffness values with SE-EPI. Liver stiffness values have been reported to be higher in males than in females [33,
34]. However, liver stiffness was measured using sonographic transient elastography in those studies rather than MRE. According to the studies that assessed liver stiffness in healthy subjects using MRE, there was no significant difference in liver stiffness values between
genders, which is consistent with our results [15, 27]. Therefore, we hypothesize that this discrepancy could be attributed to the difference in modalities. With regard to the effect of age, Poynard et al. reported that aging accelerated progression of fibrosis in patients with chronic liver disease [35]. On the contrary, in subjects without known hepatic pathology, our
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study and other studies using transient elastography as well as MRE have shown that liver stiffness was not significantly affected by age [15, 16, 36].
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Previous studies demonstrated no significant correlation between steatosis and liver stiffness in healthy subjects [15, 16]. Although we had the same result as those studies with
SE-EPI, we had opposite results with GRE. These results may have been caused by the right-
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skewed distribution of the macrovesicular fat fraction in our living liver donors. Of the 54
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donors, 52 (96%) had five percent or less fat fraction and belonged to a population without
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steatosis; only one subject was considered to have significant macrovesicular steatosis.
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Therefore, correlation between liver stiffness on GRE and macrovesicular fat fraction may have limited clinical implications because all but one of the subjects yielding these results
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were normal (51 of 52, 98%). For comprehensive investigation of the relationship between
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steatosis and liver stiffness values with MRE, a larger population with varying degrees of steatosis would be needed. In terms of BMI, our results showed that there was no significant
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difference in the liver stiffness value between the group with BMI < 23.5 kg/m2 and the group with BMI ≥ 23.5 kg/m2. Similar results have been reported in transient elastography and
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MRE, which are well correlated with our results [16, 31]. Reliability for liver stiffness measurements was excellent on both SE-EPI and GRE
in the present study, which is consistent with the results of previous studies [25, 32, 37]. This high value of interobserver agreement of liver stiffness could have been achieved as the reviewers placed the largest possible ROIs on multiple elastograms to represent stiffness of the whole liver. Our study confirmed the strong reliability of the MRE. In contrast, the area
of ROI measured by the two reviewers showed good agreement on GRE and fair agreement on SE-EPI. This result might reflect the subjective nature of free-hand drawing of ROI. However, considering the excellent agreement for liver stiffness, the discrepancy in area of ROI between reviewers may not have any clinical significance. The smaller of the two ROIs
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would still have been large enough to represent global stiffness of the liver. In our study, the difference between the mean liver stiffness measured using SE-EPI
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and GRE was 0.09 kPa (P = 0.017). The difference of 0.09 kPa may not be clinically
important in most cases, and therefore, SE-EPI and GRE may be applied interchangeably in most clinical situations [38]. This finding corroborates the results of the study by Trout et al.,
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which was the only study that compared SE-EPI and GRE in non-patients and showed higher
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liver stiffness values on SE-EPI than on GRE with statistical significance [32]. Conversely,
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other studies that performed comparisons between SE-EPI and GRE in patients with chronic
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liver disease demonstrated controversial results [17, 25, 39]. Further studies will be required to compare normal liver stiffness values measured with SE-EPI and GRE.
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The size of ROIs on GRE was larger than that on SE-EPI in our study, which is in
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contrast to the results of previous studies that reported higher ROI sizes on SE-EPI than on GRE [25, 40]. To be specific, larger areas of the central portion of right lobe of the liver were
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measurable with high confidence on elastograms in most subjects. The reason for this phenomenon could be a propagation error of waves or different levels of elastograms along the z-axis on each pulse sequence due to different timing of breath-holds. However, there
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were no significant abnormality in wave images nor remarkable discrepancy of the level of wave images between SE-EPI and GRE. Further studies would be needed to clarify the relationship of the area of ROI between SE-EPI and GRE. It has been suggested that SE-EPI has an advantage over GRE by virtue of its relative robustness to respiratory motion artifacts in patients with chronic liver disease [25, 40].
However, none of our subjects demonstrated moderate or severe respiratory artifacts. Since healthy volunteers hold their breaths better than patients with chronic liver disease owing to unimpaired respiratory function, GRE in healthy population would be less affected by breathing artifacts [41, 42]. In addition, normal healthy subjects suffer less from iron
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depositions which cause T2* shortening that lowers image quality than patients with chronic liver disease [19, 43]. These two differences in the normal population compared to patients
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with liver disease support the feasibility of GRE MRE in healthy subjects.
There were several limitations in our study. First, only healthy liver donors without any degree of hepatic fibrosis were included in this study. Therefore, cut-off values for
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diagnosis of hepatic fibrosis could not be obtained from our results. Further, there was only
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one subject with substantial steatosis in our population. To investigate the effect of clinically
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significant steatosis on the liver stiffness, further studies with larger populations would be
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required. Secondly, all the MRE images were obtained with the same MR scanner from a single vendor. Thus, generalization of our results would be limited in clinical situations
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where many MR scanners from multiple vendors are used. In addition, calculations of mean
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liver stiffness values were also limited. Since we averaged liver stiffness measured on four or six MRE images without consideration of the area of ROI on each image, the stiffness values
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of small and large ROIs were treated equally. However, larger ROIs would better represent whole liver than small ROIs. Therefore, giving weight to each measured liver stiffness value by the area of the ROI would reflect stiffness of the background liver better than simply
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averaging the liver stiffness values of each elastogram. Lastly, fifty-four subjects may not be a large enough sample size to represent the general population. However, our study population is one of the largest among MRE-based studies. In conclusion, we have reported liver stiffness values in clinically and pathologically normal living liver donors measured with MRE using SE-EPI and GRE at 3.0 T. The liver
stiffness did not show significant differences related to gender, age, or BMI and demonstrated excellent reliability. In addition, SE-EPI and GRE may be used interchangeably in most clinical situations. The results of our study can be used as a reference for normal liver
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stiffness values on SE-EPI and GRE at 3.0 T.
Conflict of interest
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Declarations of interest: none
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syndrome, J Hepatol 48(4) (2008) 606-13. [35] T. Poynard, P. Mathurin, C.L. Lai, D. Guyader, R. Poupon, M.H. Tainturier, R.P. Myers, M. Muntenau, V. Ratziu, M. Manns, A. Vogel, F. Capron, A. Chedid, P. Bedossa, P. Group, A comparison of fibrosis progression in chronic liver diseases, J Hepatol 38(3) (2003) 257-65. [36] R. Sirli, I. Sporea, A. Tudora, A. Deleanu, A. Popescu, Transient elastographic
evaluation of subjects without known hepatic pathology: does age change the liver stiffness?, J Gastrointestin Liver Dis 18(1) (2009) 57-60. [37] H. Morisaka, U. Motosugi, K.J. Glaser, S. Ichikawa, R.L. Ehman, K. Sano, T. Ichikawa, H. Onishi, Comparison of diagnostic accuracies of two- and three-dimensional MR
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the liver, Magn Reson Imaging 32(6) (2014) 679-83. [42] M.B. Fallon, G.A. Abrams, Pulmonary dysfunction in chronic liver disease, Hepatology 32(4 Pt 1) (2000) 859-65.
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Figure 1. Flow diagram of the study population. MRE = magnetic resonance elastography.
Figure 2. Representative MR elastography (MRE) images from SE-EPI (upper row) and
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GRE (lower row) of a 37-year-old healthy male. Axial magnitude (A and D), wave images (B and E), and elastograms with 95% confidence map (C and F) of the second slice from each
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pulse sequence are demonstrated. Boundaries of the liver generated by the autosegmentation
software are indicated in corresponding elastograms (C and F). Note the larger area with high
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confidence on GRE compared with that on SE-EPI. The liver stiffness from this slice was
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1.93 kPa on SE-EPI and 1.81 kPa on GRE. The area of ROI was 4491 mm2 and 5699 mm2 on
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SE-EPI and GRE, respectively.
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SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo, ROI = region of
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interest.
Figure 3. Influence of gender (A, B) and age (C, D) on liver stiffness values. On the upper
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row, box plots show distribution of liver stiffness values according to gender on SE-EPI (A)
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and on GRE (B). On the lower row, box plots demonstrate distribution of liver stiffness values between three different age groups on SE-EPI (C) and on GRE (D).
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SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo.
Figure 4. Scatterplot diagrams presenting correlation between liver stiffness values and macrovesicular fat fraction on SE-EPI (A) and on GRE (B). Box plots comparing liver stiffness values in high BMI group and low BMI group according to the WHO cutoff for normal BMI for Asians (23.5 kg/m2) on SE-EPI (C) and on GRE (D).
SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo.
Figure 5. Bland-Altman plot demonstrates agreement between SE-EPI and GRE. The blue solid line indicates the mean difference in liver stiffness values between the two pulse
the mean.
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A
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SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo.
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sequences, and the dotted red lines indicate 1.96 standard deviations (SD) above and below
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A
M
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N
A
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2D GRE
Matrix
128 × 128
128 × 64
Slice thickness (mm)
6.0
6.0
Number of slices
4 or 6
4
Echo time (msec)
47
22
Repetition time (msec)
1000
50
Bandwidth (Hz/pixel)
2380
EPI factor
100
MEG amplitude (mT/m)
36
MEG frequency (Hz)
60
MEG direction
Slice
Number of breath holds
1
Total acquisition time (sec)
11
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2D SE-EPI
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Table 1. MR Parameters of SE-EPI and GRE
399 0
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36
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Slice 4 68
Note. 2D = two dimensional, SE = spin echo, EPI = echo-planar imaging, GRE = gradient
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recalled echo, MRE = MR elastography, MEG = motion-encoding gradient
S0720-048X(18)30283-3 https://doi.org/10.1016/j.ejrad.2018.08.015 EURR 8279
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
26-3-2018 10-7-2018 13-8-2018
Please cite this article as: Bae JS, Lee JM, Park S-Jin, Lee KB, Han JK, Magnetic Resonance Elastography of Healthy Livers at 3.0 T: Normal Liver Stiffness Measured by SE-EPI and GRE, European Journal of Radiology (2018), https://doi.org/10.1016/j.ejrad.2018.08.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Magnetic Resonance Elastography of Healthy Livers at 3.0 T: Normal Liver Stiffness Measured by SE-EPI and GRE
Jae Seok Bae, M.D.a,b, Jeong Min Lee, M.D.a,b,c, Sae-Jin Park, M.D.a,b, Kyung Bun Lee,
Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu,
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a
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M.D. d, Joon Koo Han, M.D.a,b,c
Seoul, 03080, Korea b
Department of Radiology, Seoul National University College of Medicine, 103 Daehak-ro,
Institute of Radiation Medicine, Seoul National University Medical Research Center, 103
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c
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Jongno-gu, Seoul, 03080, Korea
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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d
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Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu,
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1Department
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Corresponding Author: Jeong Min Lee 1, M.D.
Seoul, 03080, Korea
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Tel: 82-2-2072-3154 Fax: 82-2-743-6385
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E-mail: [email protected]
ABSTRACT
Purpose: To determine the normal liver stiffness values using magnetic resonance elastography (MRE) at 3.0 T and to compare spin-echo echo planar imaging (SE-EPI) and gradient recalled echo (GRE) MRE. Materials and methods: This retrospective study included 54 living liver donors who had
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normal clinical and pathological results without underlying liver disease and underwent MRE using both SE-EPI and GRE at 3.0 T. Two radiologists placed four or six freehand regions of
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interest (ROI) on the elastograms and measured liver stiffness as well as the area of ROIs.
The mean liver stiffness values and area of ROIs were compared between genders, among age groups, and between groups of different body mass indexes using the t-test and one-way
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analysis of variance, respectively. Interobserver agreement was analyzed using intraclass
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correlation coefficient. The mean liver stiffness values and area of ROIs were compared
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between SE-EPI and GRE using the paired t-test and Bland-Altman analysis.
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Results: The liver stiffness values in living liver donors ranged from 1.52 to 3.12 kilopascal (kPa) on SE-EPI and 1.51 to 2.67 kPa on GRE. The mean liver stiffness values did not differ
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significantly according to the gender, age, and body mass index. Measurement of liver
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stiffness using MRE showed excellent interobserver agreement on both pulse sequences. The mean value of liver stiffness was higher on SE-EPI (2.14 ± 0.33 kPa) than on GRE (2.06 ±
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0.25 kPa), and the difference was statistically significant (P < 0.05). The mean area of ROI was significantly larger with GRE (3387 mm2) than with SE-EPI (2691 mm2) (P < 0.05). Conclusions: The mean liver stiffness values in living donors measured by SE-EPI and GRE
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were not affected by gender, age, or body mass index and showed excellent interobserver agreement. The area of ROI was larger with GRE than with SE-EPI.
Keywords: magnetic resonance elastography; normal liver stiffness; spin echo echoplanar imaging; gradient recalled echo
Introduction
Liver fibrosis is a common pathologic process caused by any type of chronic liver
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disease, and can lead to cirrhosis, portal venous hypertension, and/or development of hepatocellular carcinoma [1]. However, liver fibrosis is reversible in its early stage [2, 3].
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Thus, it is important to detect liver fibrosis early in patients with chronic liver disease.
Although liver biopsy is the state of the art and still superior to imaging biomarkers, and has been performed for the assessment of liver fibrosis, it has limitations including sampling
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error, interobserver variability, and invasiveness. Among the various proposed imaging tools
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for non-invasive diagnosis of liver fibrosis, magnetic resonance elastography (MRE) is a
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well-validated method and has been gaining acceptance for evaluation of patients with
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chronic liver disease [4-6]. Measurement of liver stiffness and staging of hepatic fibrosis using MRE have been reported to be accurate and reliable [7-10].
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However, few studies have reported the liver stiffness values measured by MRE in
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normal liver at 3.0 T, and most of them are limited in the sample size and lack biochemical and pathologic assessment results [11-14]. Instead, most of the studies on MRE have been
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performed in the patients with chronic liver disease and focused on staging of liver fibrosis. Although there have been a few reports on the normal liver-stiffness values in healthy subjects, all the studies were conducted at 1.5 T only [15, 16]. For correct application of
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MRE at 3.0 T, establishment of the normal range of liver stiffness values is an important prerequisite. In addition, there have been efforts to develop new MRE pulse sequences to overcome the drawback of the most commonly used two-dimensional (2D) gradient-recalledecho (GRE) MRE that requires serial breath holds and is sensitive to iron overload [17-20]. The 2D spin-echo echo-planar imaging (SE-EPI) pulse sequence has the fastest imaging
acquisition time and is one of the most promising alternatives to GRE MRE [21, 22]. However, comparison of GRE and SE-EPI MRE in normal subjects has not been performed as well. The aims of this study, therefore, were (i) to define the normal range of liver stiffness
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assessed with SE-EPI and GRE MRE at 3.0 T in healthy living liver donors who showed completely normal range of laboratory results and no fibrosis on pathologic examination, and
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(ii) to compare the liver stiffness values measured by SE-EPI and GRE MRE in healthy
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subjects.
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Materials and methods
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Study Population
This retrospective study was approved by our institutional review board approved
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and the informed consent was waived. From January 2016 to April 2017, a total of 140
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potential living liver donors (M:F = 80:60) underwent evaluation for liver transplantation and gadoxetic acid-enhanced MR at 3.0 T at our hospital. We included subjects in our study
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according to the following criteria: (a) normal results in physical examinations and laboratory tests such as serological tests for hepatitis B surface antigen, hepatitis C virus antibody, coagulation profiles (prothrombin time, activated partial thromboplastin time), aspartate
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aminotransferase, alanine aminotransferase, albumin, total bilirubin, γ-glutamyl transpeptidase, and alkaline phosphatase; (b) absence of any risk factor for chronic liver disease or family history of chronic liver disease; (c) absence of any kind of diagnosed disease and no current intake of any medications; (d) patients underwent MR including elastography at 3.0 T within 2 months of liver donation, with no focal lesion noted in the liver
on MR; and (e) liver donation performed at our hospital. Among these subjects, 86 (M:F = 50:36) were excluded for the following reasons: (a) abnormal laboratory test results (n = 5); (b) liver donation not performed (n = 24); (c) liver donation performed without excisional biopsy of hepatic parenchyma (n = 3); (d) time interval between MR elastography and liver
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donation or percutaneous liver biopsy greater than 60 days (n = 6); (e) identification of any degree of hepatic fibrosis or inflammation on the pathologic specimen (n = 48). Finally, 54
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healthy donor candidates were recruited: 30 males and 24 females, with a mean age of 36.5 ± 11.4 years (range: 18–61 years) and mean body mass index (BMI) of 23.8 ± 3.0 kg/m2
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(range: 18.3–30.9 kg/m2) (Fig. 1).
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MR Elastography
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All MR examinations including elastography were performed on a 3.0 T MR scanner
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(Magnetom Skyra, Siemens Healthineers, Erlangen, Germany) with a commercially available MRE hardware (Resoundant active and passive drivers, Siemens Healthineers, Erlangen,
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Germany) and a thirty-channel, body array coil. MRE imaging was performed after acquisition of routine liver MR images including injection of contrast medium (Gadoxetic
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acid, Primovist, Bayer Healthcare, Berlin, Germany) at a standard dose (1 mL/10 kg body
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weight, 0.025 mmol/kg). In our hospital, MRE was performed with two acoustic pressureactivated drivers placed on the patient’s right and left upper abdomen adjacent to the liver and spleen, respectively. The passive drivers transmitted low-amplitude longitudinal
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mechanical waves of 60-Hz to the liver and spleen, as synchronized with the imaging sequences. Shear waves were generated in the liver and were imaged by using SE-EPI and GRE. Four contiguous axial slices centered at the hepatic hilum were acquired over four sequential breath holds at the end-expiration for GRE image acquisition, whereas a single breath hold at the end-expiration was required for SE-EPI image acquisition (Fig. 2). For SE-
EPI MRE, six contiguous slices were obtained in the early phase of the study period and liver stiffness was measured in all six slices. After setting up the protocol, four slices were acquired for SE-EPI as same as GRE. The detailed MR parameters are summarized in Table 1. After completion of MRE image acquisition, the wave images were automatically
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processed using the inversion algorithm to generate images depicting tissue stiffness (elastograms) [23]. Areas of liver stiffness were represented in units of kilopascals (kPa) on
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these quantitative images in gray scale or color scale [24]. The time interval between MRE and surgery or percutaneous biopsy was 26 ± 14 days (range: 4–60 days).
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Image Analysis
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Ninety five percent confidence interval maps were automatically generated by an
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intrinsic software as a checkerboard pattern and were superimposed on the elastograms to
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indicate where reliable stiffness values could be measured. In addition, segmentation of liver was automatically performed in some subjects, using commercially available software (Inline
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liver segmentation, Siemens Healthineers, Erlangen, Germany) and the boundary of the liver
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generated by autosegmentation was overlaid on elastograms. To obtain liver stiffness values of the hepatic parenchyma, ROIs were drawn freehand on each of the four or six confidence and
with 6 years and 4 years of
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map-overlaid elastograms by two radiologists (
experience in liver MR, respectively), who were blinded to the clinical and histologic information. The two radiologists reviewed their ROI sets jointly and reached consensus for
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selection of the final ROI sets for analysis. All ROIs (mean area: 2690 ± 983 mm2, range: 1123–5189 mm2 on SE-EPI; mean area: 3387 ± 1424 mm2, range: 727–6411 mm2 on GRE by
; mean area: 3788 ± 1922 mm2, range: 1266–8449 mm2 on SE-EPI; mean area:
4203 ± 2075 mm2, range: 803–8184 mm2 on GRE by
) were drawn to include as much
of the liver parenchyma in the right lobe as possible while avoiding area with low quality data
such as immediate subcapsular area, fissures, or large vessels [25]. The liver stiffness values were obtained in kilopascals (kPa). Thereafter, mean liver stiffness values were calculated by averaging the stiffness values from the four or six elastograms. In addition, two reviewers (
and
) reviewed all MRE images and graded respiratory motion artifacts
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according to the binary scale as follows: no to mild artifact versus moderate to severe artifact.
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All the procedures described above were performed on both SE-EPI and GRE MRE [25].
Histologic Analysis
For acquisition of liver tissue sample, approximately 1 mm3 of hepatic parenchyma
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was excised from the right hemiliver during the liver donation. The specimens underwent
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fixation in formalin and were embedded in paraffin. Thereafter, sections of 4-μm-thickness with 15 years of
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were stained with hematoxylin and eosin (H&E). A pathologist (
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experience) who was blinded to clinical information and MR findings evaluated all the pathologic slides for degree of inflammation, fibrosis, and steatosis. The degree of
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inflammation and fibrosis was graded according to the METAVIR scoring system [26]. The
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degree of macrovesicular steatosis was graded based on the percentage of hepatocytes involved in macrovesicular fat droplets at 4x magnification of H&E sections [27]. In our
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hospital, at least 10% macrovesicular steatosis was considered to be substantial macrovesicular steatosis that was a contraindication to liver donation and warranted further
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evaluations or dietary modifications to improve steatosis prior to liver donation [10].
Statistical Analysis For statistical analysis, other than interobserver agreement, data from the consensus of our two reviewers were used. The liver stiffness value was compared between genders using the independent sample t-test. To assess the liver stiffness value according to age, we
grouped the donors under three age groups of < 30 years (n = 16), 30–40 years (n = 16), and > 40 years (n = 22) and compared the mean liver stiffness values in each age group by using one-way analysis of variance. Correlation of liver stiffness value with macrovesicular fat fraction of the liver was assessed by using Pearson’s correlation test. We also categorized the
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subjects according to the WHO cutoffs for normal BMI for Asians into low BMI group (BMI < 23.5 kg/m2) and high BMI group (BMI ≥ 23.5 kg/m2) and compared the liver stiffness
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values between the two groups [28]. In addition, interobserver agreement of the liver stiffness measurements on SE-EPI and GRE was assessed using the intraclass correlation coefficient (ICC). ICC values were classified by using the following criteria: poor: 0–0.39; fair: 0.40–
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0.59; good: 0.60–0.74; and excellent: 0.75–1.0 [29].
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To compare the mean liver stiffness values and area of ROI measured with SE-EPI
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and GRE, paired t-test was performed. In addition, mean differences between liver stiffness
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values on SE-EPI and GRE were obtained by Bland–Altman analysis and the 95% limits of agreement were determined using the mean and standard deviation (SD) of the differences
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between the two pulse sequences [30]. Lastly, McNemar’s test was performed to compare
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frequencies of moderate or severe respiratory artifacts on each pulse sequence. All statistical analyses were performed by using commercially available software (SPSS, version 22, IBM,
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Armonk, NY; MedCalc, version 14, MedCalc software, Mariakerke, Belgium). A P-value < 0.05 was considered statistically significant.
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Results
Technical failure was observed in one subject on SE-EPI and in another subject on
GRE and liver stiffness could not be measured on the corresponding pulse sequence: the values obtained from those subjects were not included in analysis.
Range of the Normal Liver Stiffness Values and Effect of Age and Gender On SE-EPI, the stiffness values of the liver in the living liver donors ranged from 1.52 to 3.12 kPa with a mean ± SD of 2.14 ± 0.33 kPa (95% confidence interval [CI], 2.062.25 kPa). On GRE, the liver stiffness values ranged from 1.51 to 2.67 kPa with a mean ± SD
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of 2.06 ± 0.25 kPa (95% CI, 1.99-2.12 kPa). The mean liver stiffness values did not differ according to gender. Although male
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subjects showed slightly higher liver stiffness (2.21 ± 0.37 kPa, 95% CI, 2.07-2.35 kPa) compared to female subjects (2.06 ± 0.24 kPa, 95% CI, 1.95-2.16 kPa) on SE-EPI, the
difference was not statistically significant (P = 0.101). Similarly, male subjects also had
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higher liver stiffness values (2.10 ± 0.25 kPa, 95% CI, 2.01-2.19 kPa) compared to female
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not statistically significant (P = 0.164) (Fig. 3).
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subjects (2.00 ± 0.25 kPa, 95% CI, 1.89-2.11 kPa) on GRE; however, this difference was also
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The liver stiffness values among the age groups also demonstrated no statistically significant differences. On SE-EPI, the liver stiffness values of the three age groups (age <
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30, 30 ≤ age ≤ 40, and age > 40) were 2.25 ± 0.31 kPa (95% CI, 2.08-2.42 kPa), 2.07 ± 0.33 kPa (95% CI, 1.90-2.25 kPa), and 2.11 ± 0.33 kPa (95% CI, 1.96-2.27 kPa), respectively (P =
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0.289). On GRE, the liver stiffness values of the three age groups (age < 30, 30 ≤ age ≤ 40,
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and age > 40) were 2.14 ± 0.24 kPa (95% CI, 2.01-2.26 kPa), 2.04 ± 0.22 kPa (95% CI, 1.922.16 kPa), 2.01 ± 0.28 kPa (95% CI, 1.88-2.14 kPa), respectively (P = 0.305) (Fig. 3).
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Influence of Steatosis and BMI on the Liver Stiffness Value Among the 52 liver donors, only one subject showed substantial macrovesicular
steatosis (15%) in the pathologic specimen obtained during the transplantation surgery. In fact, the subject had a fat fraction of 10% on the proton MR spectroscopy included on the initial screening MR and underwent percutaneous liver biopsy. The biopsy results also
demonstrated macrovesicular steatosis of 10%. The subject underwent weight reduction by 10 kg for two months following which liver donation was performed. The macrovesicular fat fraction in the donors ranged from 0% to 15%. On SE-EPI, there was no correlation with the estimated fat content in the liver and mean liver stiffness (r
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= 0.159, 95% CI, −0.119-0.414, P = 0.261), whereas on GRE, liver stiffness value was correlated with degree of fat fraction (r = 0.287, 95% CI, 0.015-0.519, P = 0.039) (Fig. 4).
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The liver stiffness values did not differ significantly between the group with BMI < 23.5 kg/m2 and the group with BMI ≥ 23.5 kg/m2 on both pulse sequences. On SE-EPI, the mean liver stiffness values were 2.16 ± 0.31 kPa (95% CI, 2.03-2.28) in the BMI < 23.5
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kg/m2 group and 2.13 ± 0.35 kPa (95% CI, 1.99-2.27) in the BMI ≥ 23.5 kg/m2 group (P =
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0.787). On GRE, the liver stiffness values were 2.01 ± 0.28 kPa (95% CI, 1.90-2.13) in the
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BMI < 23.5 kg/m2 group and 2.10 ± 0.22 kPa (95% CI, 2.01-2.19) in the BMI ≥ 23.5 kg/m2
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group (P = 0.234) (Fig. 4).
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Interobserver Agreement for Liver stiffness and Area of ROI
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Reliability of the MRE using SE-EPI and GRE was evaluated in 52 patients; two patients in whom technical failure occurred were excluded. ICC values for liver stiffness
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measured on SE-EPI and GRE were 0.89 (95% CI, 0.77-0.94) and 0.84 (95% CI, 0.72-0.91), respectively, which were in excellent agreement. With regard to the area of ROI placed on SE-EPI and GRE, ICC values were 0.55 (95% CI, 0.09-0.77) and 0.77 (95% CI, 0.30-0.90),
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respectively. Only the area of ROI on GRE showed good agreement between the two reviewers.
Comparison of the SE-EPI and GRE
The mean liver stiffness value was slightly higher on SE-EPI than on GRE (P = 0.017). Bland-Altman plot revealed that the mean difference of liver stiffness values between SE-EPI and GRE was 0.09 ± 0.25 kPa (95% CI, 0.016-0.158 kPa; limits of agreement 0.412-0.586 kPa) (Fig. 5). Except for one subject, all the differences fell within the limits of
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agreement. The area of ROI placed on elastograms was 2691 ± 983 mm2 (95% CI, 2417-2965 mm2) and 3387 ± 1424 mm2 (95% CI, 2991-3784 mm2) on SE-EPI and GRE, respectively.
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The difference between the area of ROIs was statistically significant (P < 0.001) (Fig. 2). No
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moderate to severe respiratory motion artifacts were noted either with on SE-EPI or GRE.
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Discussion
To the best of our knowledge, this is the first study to evaluate the normal range of
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liver stiffness values in clinically and pathologically normal subjects with MRE at 3.0 T.
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Although a few previous studies have reported normal liver stiffness in healthy volunteers with GRE at 3.0 T, the sample sizes used in those studies were small (equal to or less than
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22). More importantly, no laboratory tests or pathologic examinations were performed in those studies [11-14]. On the contrary, we included patients with strict normal ranges of laboratory and pathologic results and therefore, the liver stiffness values obtained in our study
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may be regarded as true normal values. To clinicians, the range of normal liver stiffness values is useful because it can be used for screening the general population to identify subjects with suspicious chronic liver disease who require further work up. In addition, we performed MRE with SE-EPI as well as with GRE, and therefore, our results may be useful for interpretation of liver stiffness values obtained with both pulse sequences.
For GRE MRE, the mean and range of liver stiffness values in our study were 2.06 kPa and 1.51 to 2.67 kPa, respectively. This result is slightly lower than those of previous studies performed in healthy subjects with GRE at 3.0T, which yielded mean liver stiffness values of 2.21-2.34 kPa that ranged from 1.67 to 2.92 kPa [11, 13]. This discrepancy could be
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partly caused by differences in ethnicity because the study by Mannelli et al. was conducted in Western countries whereas our study included Asian subjects. It has been reported that
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liver stiffness values are higher in Europeans compared to Asians [31]. Furthermore, while
the small sample size and differences in other clinical characteristics such as BMI could also have influenced the results, detailed information on the population was not available.
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Meanwhile, our results are in concordance with the findings of other studies performed at 1.5
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T that yielded mean liver stiffness values of 2.05-2.12 kPa, ranging from 1.54 to 2.87 kPa
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[15, 16].
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With regards to the MRE values of normal liver measured with SE-EPI at 3.0 T, our result was 2.14 kPa, which was slightly higher than the values of 1.75 kPa and 2.05 kPa from
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two different vendors reported by Trout et al. [32]. However, that study included only
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twenty-four adults and the subjects did not undergo medical examination such as laboratory tests or pathologic confirmation. Moreover, the difference between liver stiffness values
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obtained from the two different vendors in that study was 0.30 kPa, which is approximately three times larger than the difference between our result (2.14 kPa) and the higher value reported by Trout (2.05 kPa). Further studies with larger population and multiple vendors will
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be required to define the correct normal range of liver stiffness values with SE-EPI. Liver stiffness values have been reported to be higher in males than in females [33,
34]. However, liver stiffness was measured using sonographic transient elastography in those studies rather than MRE. According to the studies that assessed liver stiffness in healthy subjects using MRE, there was no significant difference in liver stiffness values between
genders, which is consistent with our results [15, 27]. Therefore, we hypothesize that this discrepancy could be attributed to the difference in modalities. With regard to the effect of age, Poynard et al. reported that aging accelerated progression of fibrosis in patients with chronic liver disease [35]. On the contrary, in subjects without known hepatic pathology, our
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study and other studies using transient elastography as well as MRE have shown that liver stiffness was not significantly affected by age [15, 16, 36].
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Previous studies demonstrated no significant correlation between steatosis and liver stiffness in healthy subjects [15, 16]. Although we had the same result as those studies with
SE-EPI, we had opposite results with GRE. These results may have been caused by the right-
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skewed distribution of the macrovesicular fat fraction in our living liver donors. Of the 54
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donors, 52 (96%) had five percent or less fat fraction and belonged to a population without
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steatosis; only one subject was considered to have significant macrovesicular steatosis.
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Therefore, correlation between liver stiffness on GRE and macrovesicular fat fraction may have limited clinical implications because all but one of the subjects yielding these results
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were normal (51 of 52, 98%). For comprehensive investigation of the relationship between
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steatosis and liver stiffness values with MRE, a larger population with varying degrees of steatosis would be needed. In terms of BMI, our results showed that there was no significant
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difference in the liver stiffness value between the group with BMI < 23.5 kg/m2 and the group with BMI ≥ 23.5 kg/m2. Similar results have been reported in transient elastography and
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MRE, which are well correlated with our results [16, 31]. Reliability for liver stiffness measurements was excellent on both SE-EPI and GRE
in the present study, which is consistent with the results of previous studies [25, 32, 37]. This high value of interobserver agreement of liver stiffness could have been achieved as the reviewers placed the largest possible ROIs on multiple elastograms to represent stiffness of the whole liver. Our study confirmed the strong reliability of the MRE. In contrast, the area
of ROI measured by the two reviewers showed good agreement on GRE and fair agreement on SE-EPI. This result might reflect the subjective nature of free-hand drawing of ROI. However, considering the excellent agreement for liver stiffness, the discrepancy in area of ROI between reviewers may not have any clinical significance. The smaller of the two ROIs
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would still have been large enough to represent global stiffness of the liver. In our study, the difference between the mean liver stiffness measured using SE-EPI
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and GRE was 0.09 kPa (P = 0.017). The difference of 0.09 kPa may not be clinically
important in most cases, and therefore, SE-EPI and GRE may be applied interchangeably in most clinical situations [38]. This finding corroborates the results of the study by Trout et al.,
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which was the only study that compared SE-EPI and GRE in non-patients and showed higher
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liver stiffness values on SE-EPI than on GRE with statistical significance [32]. Conversely,
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other studies that performed comparisons between SE-EPI and GRE in patients with chronic
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liver disease demonstrated controversial results [17, 25, 39]. Further studies will be required to compare normal liver stiffness values measured with SE-EPI and GRE.
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The size of ROIs on GRE was larger than that on SE-EPI in our study, which is in
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contrast to the results of previous studies that reported higher ROI sizes on SE-EPI than on GRE [25, 40]. To be specific, larger areas of the central portion of right lobe of the liver were
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measurable with high confidence on elastograms in most subjects. The reason for this phenomenon could be a propagation error of waves or different levels of elastograms along the z-axis on each pulse sequence due to different timing of breath-holds. However, there
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were no significant abnormality in wave images nor remarkable discrepancy of the level of wave images between SE-EPI and GRE. Further studies would be needed to clarify the relationship of the area of ROI between SE-EPI and GRE. It has been suggested that SE-EPI has an advantage over GRE by virtue of its relative robustness to respiratory motion artifacts in patients with chronic liver disease [25, 40].
However, none of our subjects demonstrated moderate or severe respiratory artifacts. Since healthy volunteers hold their breaths better than patients with chronic liver disease owing to unimpaired respiratory function, GRE in healthy population would be less affected by breathing artifacts [41, 42]. In addition, normal healthy subjects suffer less from iron
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depositions which cause T2* shortening that lowers image quality than patients with chronic liver disease [19, 43]. These two differences in the normal population compared to patients
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with liver disease support the feasibility of GRE MRE in healthy subjects.
There were several limitations in our study. First, only healthy liver donors without any degree of hepatic fibrosis were included in this study. Therefore, cut-off values for
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diagnosis of hepatic fibrosis could not be obtained from our results. Further, there was only
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one subject with substantial steatosis in our population. To investigate the effect of clinically
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significant steatosis on the liver stiffness, further studies with larger populations would be
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required. Secondly, all the MRE images were obtained with the same MR scanner from a single vendor. Thus, generalization of our results would be limited in clinical situations
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where many MR scanners from multiple vendors are used. In addition, calculations of mean
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liver stiffness values were also limited. Since we averaged liver stiffness measured on four or six MRE images without consideration of the area of ROI on each image, the stiffness values
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of small and large ROIs were treated equally. However, larger ROIs would better represent whole liver than small ROIs. Therefore, giving weight to each measured liver stiffness value by the area of the ROI would reflect stiffness of the background liver better than simply
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averaging the liver stiffness values of each elastogram. Lastly, fifty-four subjects may not be a large enough sample size to represent the general population. However, our study population is one of the largest among MRE-based studies. In conclusion, we have reported liver stiffness values in clinically and pathologically normal living liver donors measured with MRE using SE-EPI and GRE at 3.0 T. The liver
stiffness did not show significant differences related to gender, age, or BMI and demonstrated excellent reliability. In addition, SE-EPI and GRE may be used interchangeably in most clinical situations. The results of our study can be used as a reference for normal liver
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stiffness values on SE-EPI and GRE at 3.0 T.
Conflict of interest
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Declarations of interest: none
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Figure 1. Flow diagram of the study population. MRE = magnetic resonance elastography.
Figure 2. Representative MR elastography (MRE) images from SE-EPI (upper row) and
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GRE (lower row) of a 37-year-old healthy male. Axial magnitude (A and D), wave images (B and E), and elastograms with 95% confidence map (C and F) of the second slice from each
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pulse sequence are demonstrated. Boundaries of the liver generated by the autosegmentation
software are indicated in corresponding elastograms (C and F). Note the larger area with high
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confidence on GRE compared with that on SE-EPI. The liver stiffness from this slice was
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1.93 kPa on SE-EPI and 1.81 kPa on GRE. The area of ROI was 4491 mm2 and 5699 mm2 on
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SE-EPI and GRE, respectively.
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SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo, ROI = region of
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interest.
Figure 3. Influence of gender (A, B) and age (C, D) on liver stiffness values. On the upper
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row, box plots show distribution of liver stiffness values according to gender on SE-EPI (A)
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and on GRE (B). On the lower row, box plots demonstrate distribution of liver stiffness values between three different age groups on SE-EPI (C) and on GRE (D).
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SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo.
Figure 4. Scatterplot diagrams presenting correlation between liver stiffness values and macrovesicular fat fraction on SE-EPI (A) and on GRE (B). Box plots comparing liver stiffness values in high BMI group and low BMI group according to the WHO cutoff for normal BMI for Asians (23.5 kg/m2) on SE-EPI (C) and on GRE (D).
SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo.
Figure 5. Bland-Altman plot demonstrates agreement between SE-EPI and GRE. The blue solid line indicates the mean difference in liver stiffness values between the two pulse
the mean.
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SE-EPI = spin echo echo-planar imaging, GRE = gradient recalled echo.
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sequences, and the dotted red lines indicate 1.96 standard deviations (SD) above and below
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2D GRE
Matrix
128 × 128
128 × 64
Slice thickness (mm)
6.0
6.0
Number of slices
4 or 6
4
Echo time (msec)
47
22
Repetition time (msec)
1000
50
Bandwidth (Hz/pixel)
2380
EPI factor
100
MEG amplitude (mT/m)
36
MEG frequency (Hz)
60
MEG direction
Slice
Number of breath holds
1
Total acquisition time (sec)
11
SC R
2D SE-EPI
IP T
Table 1. MR Parameters of SE-EPI and GRE
399 0
U
36
ED
M
A
N
60
Slice 4 68
Note. 2D = two dimensional, SE = spin echo, EPI = echo-planar imaging, GRE = gradient
A
CC E
PT
recalled echo, MRE = MR elastography, MEG = motion-encoding gradient