To facilitate translational drug development for liver fibrosis, preclinical trials need to be run in parallel with clinical research. Liver function estimation by gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI) is being established in clinical research, but still rarely used in preclinical trials. We aimed to evaluate feasibility of DCE-MRI indices as translatable biomarkers in a liver fibrosis animal model. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (200 mg, 150 mg, and saline for the high-dose, low-dose, and control groups, respectively). Subsequently, DCE-MRI was performed to measure: relative liver enhancement at 3-min (RLE-3), RLE-15, initial area-under-the-curve until 3-min (iAUC-3), iAUC-15, and maximum-enhancement (Emax). The correlation coefficients between these MRI indices and the histologic collagen area, indocyanine green retention at 15-min (ICG-R15), and shear wave elastography (SWE) were calculated. Diagnostic performance to diagnose liver fibrosis was also evaluated by receiver-operating-characteristic (ROC) analysis. Animal model was successful in that the collagen area of the liver was the largest in the high-dose group, followed by the low-dose group and control group. The correlation between the DCE-MRI indices and collagen area was high for iAUC-15, Emax, iAUC-3, and RLE-3 but moderate for RLE-15 (r, − 0.81, − 0.81, − 0.78, − 0.80, and − 0.51, respectively). The DCE-MRI indices showed moderate correlation with ICG-R15: the highest for iAUC-15, followed by iAUC-3, RLE-3, Emax, and RLE-15 (r, − 0.65, − 0.63, − 0.62, − 0.58, and − 0.56, respectively). The correlation coefficients between DCE-MRI indices and SWE ranged from − 0.59 to − 0.28. The diagnostic accuracy of RLE-3, iAUC-3, iAUC-15, and Emax was 100% (AUROC 1.000), whereas those of RLE-15 and SWE were relatively low (AUROC 0.777, 0.848, respectively). Among the gadoxetate-enhanced DCE-MRI indices, iAUC-15 and iAUC-3 might be bidirectional translatable biomarkers between preclinical and clinical research for evaluating histopathologic liver fibrosis and physiologic liver functions in a non-invasive manner.

中文翻译：

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加多西酯增强的动态对比增强MRI在临床前试验中评估肝功能和肝纤维化

为了促进肝纤维化转化药物的开发，需要与临床研究同时进行临床前试验。在临床研究中已经建立了通过使用度加西汀增强动态对比增强MRI（DCE-MRI）进行肝功能评估的方法，但在临床前试验中仍然很少使用。我们旨在评估DCE-MRI指标作为肝纤维化动物模型中可翻译生物标志物的可行性。在Sprague-Dawley大鼠中，硫代乙酰胺（分别为高剂量，低剂量和对照组分别为200 mg，150 mg和盐水）诱导肝纤维化。随后，进行DCE-MRI测量：3分钟时的相对肝脏增强（RLE-3），RLE-15，直到3分钟时的曲线下初始面积（iAUC-3），iAUC-15和最大增强（Emax）。计算这些MRI指数与组织胶原面积，15分钟吲哚菁绿保留（ICG-R15）和剪切波弹性成像（SWE）之间的相关系数。还通过接受者操作特征（ROC）分析评估了诊断肝纤维化的诊断性能。动物模型的成功之处在于高剂量组的肝脏胶原蛋白面积最大，其次是低剂量组和对照组。对于iAUC-15，Emax，iAUC-3和RLE-3，DCE-MRI指数与胶原蛋白面积之间的相关性较高，而对于RLE-15，其DCE-MRI指数与胶原面积之间的相关性较高（r，-0.81，-0.81，-0.78，-0.80和-分别为0.51）。DCE-MRI指数与ICG-R15呈中等相关性：iAUC-15最高，其次是iAUC-3，RLE-3，Emax和RLE-15（r，-0.65，-0.63，-0.62，-0.58 ，和-0.56）。DCE-MRI指数与SWE之间的相关系数介于-0.59至-0.28之间。RLE-3，iAUC-3，iAUC-15和Emax的诊断准确性为100％（AUROC 1.000），而RLE-15和SWE的诊断准确性相对较低（AUROC为0.777、0.848）。在加多西酯增强的DCE-MRI指标中，iAUC-15和iAUC-3可能是临床前和临床研究之间的双向可翻译生物标记，用于以无创方式评估组织病理性肝纤维化和生理性肝功能。