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

Abstract

Background & AimsNon-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.ResultsMean 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*.ConclusionsIn preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.Key pointsNon-invasive quantitative measures of chronic liver injury are needed for stratification and monitoring of disease in clinical practice and in drug developmentWe adapted and applied a clinically-relevant non-contrast multiparametric MRI protocol in well-established preclinical liver disease models, for simultaneous quantitation of hepatic fat, fibro-inflammatory injury and ironMultiparametric liver MRI was feasible at 7.0 Tesla in experimental rat models and imaging parameters correlated with gold standard histopathological assessments, especially characteristics of fatty liver diseaseFurther development of multiparametric liver MRI could refine drug development strategies and impact upon trial design and clinical care pathways

In vivo magnetic resonance spectroscopy of hyperpolarized [1-13C] pyruvate in a male guinea pig model of life-long Western diet consumption and non-alcoholic fatty liver disease development

“…High fat and high fat/high sugar diets have typically been found to induce obesity in animal models (18); although lean phenotypes of NAFLD are also reported (12). PDFF values of guinea pig (19) and rat (20) livers previously reported in the literature are similar to PDFFs reported in this study for both WD and CD groups. Also of note, the liver PDFF values observed in WD animals were within the range of PDFF values (10-20%) previously reported in human patients with grade 1 and 2 steatosis (21).…”

In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1‐13C]Pyruvate and Proton Density Fat Fraction in a Guinea Pig Model of Non‐Alcoholic Fatty Liver Disease Development After Life‐Long Western Diet Consumption

“…High fat and high fat/high sugar diets have typically been found to induce obesity in animal models, 21 although lean phenotypes of NAFLD are also reported 14 . PDFF values of guinea pig 12 and rat 22 livers previously reported in the literature are similar to PDFFs reported in this study for both WD and CD groups. Also of note, the liver PDFF values observed in WD‐fed animals were within the range of PDFF values (10%–20%) previously reported in human patients with grade 1 and 2 steatosis 23 .…”

Non-invasive assessment of liver fibrosis in autoimmune hepatitis: Diagnostic value of liver magnetic resonance parametric mapping including extracellular volume fraction

“…Moreover, recently published studies have already shown positive correlations between hepatic T1, T2, and ECV with liver fibrosis in both animal and human models [15,[18][19][20]36]. There are also studies showing positive correlations between T1, T2 mapping parameters and MRE with liver fibrosis, however, without focusing on AIH patients [21,37].…”

“…Prolonged T2 relaxation times in regions of fibrosis are potentially attributable to the coexistent inflammation and high water content of the advanced fibrosis. There have been several studies showing correlations between hepatic T1, T2, and ECV with liver fibrosis in both animal and human models [15][16][17][18][19][20][21].…”