Yamada Tomomi, Obata Atsushi, Kashiwagi Yuto, Rokugawa Takemi, Matsushima Shuuichi, Hamada Tadateru, Watabe Hiroshi, Abe Kohji
Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
Department of Drug Safety Evaluation, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
Magn Reson Imaging. 2016 Jul;34(6):724-729. doi: 10.1016/j.mri.2016.03.009. Epub 2016 Mar 12.
The purpose of this study is to investigate the correlation between the liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) and liver histopathology in a mouse model of NASH by using dynamic contrast-enhanced MRI.
Twenty male C57/BL6 mice aged 8weeks were fed a methionine-choline-deficient (MCD) diet for 2, 4 and 6weeks (MCD groups: MCD 2w, 4w, or 6w). Gd-EOB-DTPA-enhanced MR imaging of the liver was performed at 2, 4 and 6weeks after the MCD feeding. The signal intensity of the liver was obtained from dynamic MR images and relative enhancement (RE), and the time to maximum RE (Tmax) and half-life of elimination RE (T1/2) were calculated. After MRI scan, histopathological scores of hepatic steatosis and inflammation and blood biochemistry data, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were obtained.
Plasma AST and ALT levels were significantly increased in mice fed MCD. Histopathological scores indicated that steatohepatitis progressed with the MCD feeding period from 2 to 6weeks, but significant fibrosis was observed only in mice fed MCD for 6weeks. Gd-EOB-DTPA-enhanced MRI showed that Tmax was significantly prolonged in the livers of the 6-week group compared to the control group (control, 4.0±0.7min; MCD 6w, 12.1±1.6min), although there was no alteration in the 2- and 4-week groups. T1/2 was significantly prolonged in mice fed MCD for 4 and 6weeks compared to the control group (control, 19.9±2.0min; MCD 4w, 46.7±8.7min; MCD 6w, 65.4±8.8min). The parameters of Gd-EOB-DTPA kinetics (Tmax and T1/2) in the liver were positively correlated with the liver histopathological score (steatosis vs Tmax, rho=0.69, P=0.0007; inflammation vs Tmax, rho=0.66, P=0.00155; steatosis vs T1/2, rho=0.77, P<0.0001; inflammation vs T1/2, rho=0.73, P=0.0003).
The liver kinetics of Gd-EOB-DTPA correlated well with the inflammation score in the mouse model of NASH, suggesting the possibility of detecting the steatohepatitis stage without fibrosis by Gd-EOB-DTPA-enhanced MR imaging.
本研究旨在通过动态对比增强磁共振成像（MRI），在非酒精性脂肪性肝炎（NASH）小鼠模型中研究钆塞酸二钠（Gd-EOB-DTPA）肝脏动力学与肝脏组织病理学之间的相关性。
将20只8周龄雄性C57/BL6小鼠给予蛋氨酸-胆碱缺乏（MCD）饮食2、4和6周（MCD组：MCD 2周、4周或6周）。在给予MCD饮食后2、4和6周对肝脏进行Gd-EOB-DTPA增强磁共振成像。从动态磁共振图像中获取肝脏的信号强度和相对增强（RE），并计算达到最大RE的时间（Tmax）和消除RE的半衰期（T1/2）。MRI扫描后，获取肝脏脂肪变性和炎症的组织病理学评分以及血液生化数据，如天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平。
给予MCD饮食的小鼠血浆AST和ALT水平显著升高。组织病理学评分表明，脂肪性肝炎随着MCD喂养时间从2周进展到6周，但仅在给予MCD饮食6周的小鼠中观察到明显纤维化。Gd-EOB-DTPA增强MRI显示，与对照组相比，6周组肝脏的Tmax显著延长（对照组，4.0±0.7分钟；MCD 6周，12.1±1.6分钟），而2周和4周组无变化。与对照组相比，给予MCD饮食4周和6周的小鼠T1/2显著延长（对照组，19.9±2.0分钟；MCD 4周，46.7±8.7分钟；MCD 6周，65.4±8.8分钟）。肝脏中Gd-EOB-DTPA动力学参数（Tmax和T1/2）与肝脏组织病理学评分呈正相关（脂肪变性与Tmax，rho = 0.69，P = 0.0007；炎症与Tmax，rho = 0.66，P = 0.00155；脂肪变性与T1/2，rho = 0.77，P < 0.0001；炎症与T1/2，rho = 0.73，P = 0.0003）。
在NASH小鼠模型中，Gd-EOB-DTPA的肝脏动力学与炎症评分密切相关，提示通过Gd-EOB-DTPA增强MR成像检测无纤维化的脂肪性肝炎阶段的可能性。
