title: Gd-EOB-DTPA-enhanced-MR imaging in the inflammation stage of nonalcoholic steatohepatitis (NASH) in mice.
abstract: 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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Obata
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Kashiwagi
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Takemi
authors.initials: T
authors.lastname: Rokugawa
authors.affiliation: Department of Drug Safety Evaluation, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Shuuichi
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Department of Obesity and Metabolic Diseases, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Tadateru
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Division of Radiation Protection & Safety Control, Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watabe
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., Osaka 561-0825, Japan. Electronic address: kohji.abe@shionogi.co.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D003287:Contrast Media; D004195:Disease Models, Animal; D019786:Gadolinium DTPA; D007089:Image Enhancement / Q000379:methods*; D007249:Inflammation / Q000000981:diagnostic imaging* / Q000209:etiology; D008099:Liver / Q000000981:diagnostic imaging / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000000981:diagnostic imaging* / Q000473:pathology
chemical_list: D003287:Contrast Media; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA
keywords: Dynamic contrast-enhanced-magnetic resonance imaging; Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; Methionine-choline-deficient (MCD) diet; Mouse; Nonalcoholic steatohepatitis