Non-invasive Assessment of Liver Disease in Rats Using Multiparametric Magnetic Resonance Imaging: A Feasibility Study

Background & Aims Non-invasive quantitation of chronic liver disease using multiparametric MRI has the potential to refine clinical care pathways, trial design and preclinical drug development. The aim of the study was to evaluate the use of multiparametric liver MRI in experimental rat models of chronic liver disease. Methods : Liver injury was induced in male wild-type Sprague-Dawley rats using 4 or 12 weeks carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters (T1 mapping, T2* mapping and proton density fat fraction (PDFF)) were correlated with gold standard histopathological measures, assessed by a blinded expert adjudicator. One-way analysis of variance with Tukey’s post-hoc test was used to assess differences between groups and Spearman’s rank-order correlation to examine associations. Results Mean hepatic T1 increased significantly in rats treated with CCl4 for 12 weeks compared to controls (1122±78 ms vs. 959±114 ms; d=162.7, 95% CI (11.92, 313.4), P =0.038) and correlated strongly with histological collagen content (rs=0.717, P =0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819, P <0.0001), steatosis grade (rs=0.850, P <0.0001) and steatohepatitis score (rs=0.818, P <0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated liver significantly shortened T2*. Conclusions In preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required. Key points Abbreviations : ALT/AST : Alanine/aspartate aminotransferase ANOVA : One-way analysis of variance CCl4 : Carbon tetrachloride CDAA : Choline-deficient, l-amino acid-defined CLD : Chronic liver disease CPA : Collagen proportionate area CV : Coefficient of variation H&E : Hematoxylin and eosin i.p. : Intraperitoneal MCD : Methionine choline deficient MRE : Magnetic resonance elastography MRI : Magnetic resonance imaging MRS : Magnetic resonance spectroscopy ms : Millisecond N(m)AS : NAFLD (model) Activity Score NAFLD : Non-alcoholic fatty liver disease (NAFLD) NASH : Non-alcoholic steatohepatitis (NASH) OO : Olive oil ORO : Oil Red O PDFF : Proton density fat fraction PRESS : Point RESolved Spectroscopy ROI : Region of interest SD : Standard deviation α-SMA : Alpha-smooth muscle actin