Can Gd-EOB-DTPA Affect Proton Density Fat Fraction Using 6-Point DIXON Methods? A Multicenter, Multivendor Phantom Study

Purpose: To evaluate the influence of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) on proton density fat fraction (PDFF) using multiple vendors’ DIXON methods in a multicenter, multivendor phantom study. Materials and Methods: Pairs of phantoms with va-rying fat volume percentages (0, 5, 10, 15, 20, 30, 40, and 50) and Gd-EOB-DTPA concentrations (0 and 0.4 mM) were constructed. The phantom without Gd-EOB-DTPA in each pair was defined as the precontrast phantom, and the corresponding phantom with Gd-EOB-DTPA in each pair was defined as the postcontrast phantom. The phantoms were scanned via three vendors’ DIXON techniques to determine PDFFs. Agreement between PDFFs determined in precontrast and postcontrast phantoms was evaluated via Bland–Altman analysis. Results: Mean differences (precontrast PDFF postcontrast PDFF) and limits of agreement were Philips 5.1% (−0.8% to 11.0%), Siemens 6.1% (−0.9% to 13.1%), and GE 1.3% (−1.2% to 3.9%). Con-clusions: PDFFs measured using the three vendors’ DIXON techniques were smaller in the postcontrast phantoms than in the corresponding precontrast phantoms regardless of different scanning parameters, because T1 bias was improved by Gd-EOB-DTPA.


Introduction
Nonalcoholic fatty liver disease is a common cause of chronic liver disease worldwide [1]. It includes nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Nonalcoholic fatty liver entails a small risk of associated cirrhosis, whereas NASH entails a much greater risk of cirrhosis, which can progress to hepatocellular carcinoma [2] [3]. Although liver management and monitoring treatment responses in patients with NASH require a liver biopsy, it is a potentially invasive procedure that is occasionally associated with complications and mortality [4].
Magnetic resonance imaging (MRI) is a noninvasive, quantitative, and repeatable method for assessing liver fat. Water and fat proton densities are used to quantify liver fat, via a parameter defined as the proton density fat fraction (PDFF). One MRI method called DIXON utilizes chemical shift between water and fat protons. However, several factors can confound the accurate determination of PDFF, including T1 bias (which refers to the longer T1 of water compared to fat), T2* decay, the multipeak spectral complexity of fat, and others [5].
To minimize the influence of these factors, a low flip angle to minimize T1 bias, multi-echo techniques to correct T2* decay, and a multipeak fat model are used in the latest DIXON methods [5] [6] [7] [8]. Many vendors now offer multi-echo DIXON techniques for PDFF, but the scanning parameters used in these techniques are not the same. In a previous study, PDFFs calculated by different vendors' 3T MRI machines were consistent with each other even when the same scanning parameters were not used [9]. Although generally, PDFF is acquired from non-contrast liver, recent reports suggest that PDFFs determined via post-gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast imaging are more accurate because of improvement of T1 bias and a high signal-to-noise ratio [10] [11]. Notably, however, the influence of Gd-EOB-DTPA on PDFF has not been evaluated in a multivendor study in various clinical settings.
The purpose of the current study was to evaluate the influence of Gd-EOB-DTPA on PDFF using multiple vendors' prescribed DIXON methods in a multicenter, multivendor phantom study.

Phantoms
The phantoms used in the current study were the same phantoms used in previously reported studies [9] [11] [12]. Duplicate vegetable oil (mixture of soybean and rapeseed oil) and water phantoms were constructed with fat volume

MRI
The 3T MRI machines and DIXON sequences used were the Ingenia (Philips Healthcare, Best, The Netherlands), mDIXON Quant; the Skyra (Siemens Healthcare, Erlangen, Germany), q-DIXON, and the Discovery MR750w (GE Healthcare, Waukesha, Wis, USA), IDEAL IQ. Scanning parameters are shown in Table 1. All data were acquired when those of a previous research we conducted were obtained; thus, the data derived from precontrast phantoms is consistent with that in a previous report [9]. All DIXON sequences used 6-echo for T2* decay correction, a low flip angle to minimize T1 bias, and a multipeak fat model. The optimum T2* and the signal intensities of water and fat at a TE of 0 ms were calculated from the signal intensities of multiecho images. The PDFF map was generated automatically from the signal intensities of water and fat.
Regions of interest (ROIs) were placed in the center of the phantom, and PDFFs were measured. The average of three scans was used in the analysis.

Statistical Analysis
Bland-Altman analysis was used to evaluate agreement between precontrast and postcontrast PDFF in each machine. In the Bland-Altman analysis, 95% limits of agreement (LOA) were defined as the mean difference ± 1.96 × the standard deviation. All statistical analyses were performed using BellCurve for Excel version 2.11 (Social Survey Research Information Co., Ltd., Tokyo, Japan).

Results
The precontrast and postcontrast PDFFs are summarized in Table 2. Representative PDFF maps are shown in Figure 1. For all DIXON methods, the postcontrast PDFFs were smaller than the corresponding precontrast PDFFs.

Discussion
In this multivendor, multicenter study all PDFFs measured using the different vendors' DIXON techniques were smaller in the postcontrast phantoms than in the corresponding precontrast phantoms. The results are consistent with those of a previous single vendor study [12]. It is important for medical doctors and technicians to know that Gd-EOB-DTPA has similar effects in various DIXON techniques with different clinical MRI parameters.
Previous authors have reported that the respective T1 values of water and fat are 933 ms and 361 ms in precontrast liver [14]. The difference in T1 between water and fat is called "T1 bias". Accurate PDFF measurements require the elimination of this bias; thus, low flip angle sequences are recommended. Notably, however, a low flip angle is associated with noise in PDFF measurements [6]. In contrast, in Gd-EOB-DTPA postcontrast liver, the respective T1 values of water and fat are 358 ms and 359 ms [14]. The administration of Gd-EOB-DTPA decreases water's T1 but not fat's T1, which improves T1 bias [10] [11]. Longitudinal magnetization relaxation of water occurs more rapidly in postcontrast conditions than in precontrast conditions because of a shorter T1, which leads to a comparatively reduced postcontrast PDFF. Furthermore, Gd-EOB-DTPA improves the signal-to-noise ratio. These findings support the validity of the present study and suggest that postcontrast PDFF is theoretically more accurate.
The postcontrast PDFFs were smaller in the postcontrast phantoms than in the corresponding fat volumes. Although, we were unable to measure the T1 of the water and the fat separately, the degree of T1 change of the water in the phantom may have been different to that in the liver. If the T1 of the water is less than that of the fat in the postcontrast phantom, the PDFF can be underestimated, as it was in this study. This subject needs a further investigation.
The current study had some limitations. MRI parameters among vendors are not unified, and this can influence evaluations conducted in actual clinical settings. Acquisition parameters are dependent on institutions; thus, PDFF ranges will differ in each institution. For example, under the current study's settings the precontrast-postcontrast change in PDFF determined using the GE machine was smaller than those determined using the other vendors' machines. Repetition time (TR) is one of the parameters that determine the degree of the T1 weighted image. Under the current study's settings, repetition time using the GE machine was two to three times longer than those of the other machines, and this may have influenced the results. The degree of change in PDFF will vary from institution to institution.

Conclusion
The PDFFs measured using the vendors' DIXON techniques were smaller in the postcontrast phantoms than in the corresponding precontrast phantoms regardless of different scanning parameters, because T1 bias was improved by Gd-EOB-DTPA.