非酒精性脂肪性肝炎大鼠模型中肝纤维化的高级 MRI 及治疗反应。
Advanced MRI of Liver Fibrosis and Treatment Response in a Rat Model of Nonalcoholic Steatohepatitis.
机构信息
From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.).
出版信息
Radiology. 2020 Jul;296(1):67-75. doi: 10.1148/radiol.2020192118. Epub 2020 Apr 28.
Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats age- and weight-matched animals received standard chow ( = 12 per group); received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or 9 weeks ( = 8 per group); were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks ( = 12); were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 ( = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020
背景 肝活检是诊断非酒精性脂肪性肝炎（NASH）的参考标准，但具有侵袭性，且存在潜在并发症。 目的 评估 1 型胶原蛋白特异性探针 EP-3533、赖氨酸靶向纤维化探针 Gd-Hyd、MR 弹性成像和固有 T1 在大鼠 NASH 模型中对纤维化的特征和评估治疗反应的作用。 材料与方法 前瞻性 MRI 检查（2018 年 6 月至 11 月），6 组雄性 Wistar 大鼠：年龄和体重匹配的动物接受标准饲料（每组 12 只）；接受胆碱缺乏、L-氨基酸定义的高脂肪饮食（CDAHFD）6 周或 9 周（每组 8 只）；接受 6 周的 CDAHFD，然后在 3 周内切换到标准饲料（每组 12 只）；接受 9 周的 CDAHFD，并在第 6 周开始每天用 Elafibranor 治疗（每组 14 只）。用单因素方差分析检验各组之间的成像测量和组织分析的差异。使用接受者操作特征曲线（AUC）下的面积（定量数字病理学（胶原比例面积 [CPA]）作为参考标准）来量化每个成像测量区分纤维化的能力。使用最佳截断值来评估治疗反应。 结果 区分纤维化（CPA >4.8%）和非纤维化（CPA ≤4.8%）肝脏的 EP-3533 的 AUC 为 0.95（95%置信区间：0.91，1.00），其次是固有 T1、Gd-Hyd 和 MR 弹性成像，其 AUC 分别为 0.90（95%置信区间：0.83，0.98）、0.84（95%置信区间：0.74，0.95）和 0.65（95%置信区间：0.51，0.79）。区分晚期纤维化（CPA >10.3%）的 AUC 分别为 0.86（95%置信区间：0.76，0.97）、0.96（95%置信区间：0.90，1.01）、0.84（95%置信区间：0.70，0.98）和 0.74（95%置信区间：0.63，0.86）。Gd-Hyd MRI 在识别治疗组中的应答者和无应答者方面的准确性最高（26 例中的 24 例，92%；95%置信区间：75%，99%），高于 MR 弹性成像（26 例中的 23 例，88%；95%置信区间：70%，98%）、EP-3533（26 例中的 20 例，77%；95%置信区间：56%，91%）和固有 T1（26 例中的 14 例，54%；95%置信区间：33%，73%）。 结论 胶原靶向分子 MRI 最能早期检测到纤维化的发生，而纤维化探针 Gd-Hyd 最能准确检测治疗反应。
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