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bioRxiv · 10.1101/261032

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

Hoy, A. M.·McDonald, N.·Lennen, R. J.·Milanesi, M.·Herlihy, A. H.·Kendall, T. J.·Mungall, W.·Gyngell, M.·Banerjee, R.·Janiczek, R. L.·Murphy, P. S.·Jansen, M. A.·Fallowfield, J. A.
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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 Tukeys post-hoc test was used to assess differences between groups and Spearmans rank-order correlation to examine associations.\n\nResultsMean 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*.\n\nConclusionsIn preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.\n\nKey pointsO_LINon-invasive quantitative measures of chronic liver injury are needed for stratification and monitoring of disease in clinical practice and in drug development\nC_LIO_LIWe 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 iron\nC_LIO_LIMultiparametric 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 disease\nC_LIO_LIFurther development of multiparametric liver MRI could refine drug development strategies and impact upon trial design and clinical care pathways\nC_LI

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Hoy, A. M., McDonald, N., Lennen, R. J., Milanesi, M., Herlihy, A. H., Kendall, T. J., Mungall, W., Gyngell, M., Banerjee, R., Janiczek, R. L., Murphy, P. S., Jansen, M. A., Fallowfield, J. A.. 2018-02-07. Non-invasive Assessment of Liver Disease in Rats Using Multiparametric Magnetic Resonance Imaging: A Feasibility Study. https://doi.org/10.1101/261032

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