Farrar Christian T, DePeralta Danielle K, Day Helen, Rietz Tyson A, Wei Lan, Lauwers Gregory Y, Keil Boris, Subramaniam Arun, Sinskey Anthony J, Tanabe Kenneth K, Fuchs Bryan C, Caravan Peter
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St., Suite 2301, Charlestown, MA 02129, United States.
Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, WRN 401, 55 Fruit St., Boston, MA 02114, United States.
J Hepatol. 2015 Sep;63(3):689-96. doi: 10.1016/j.jhep.2015.04.029. Epub 2015 May 25.
BACKGROUND & AIMS: Liver biopsy, the gold standard for assessing liver fibrosis, suffers from limitations due to sampling error and invasiveness. There is therefore a critical need for methods to non-invasively quantify fibrosis throughout the entire liver. The goal of this study was to use molecular Magnetic Resonance Imaging (MRI) of Type I collagen to non-invasively image liver fibrosis and assess response to rapamycin therapy.
Liver fibrosis was induced in rats by bile duct ligation (BDL). MRI was performed 4, 10, or 18 days following BDL. Some BDL rats were treated daily with rapamycin starting on day 4 and imaged on day 18. A three-dimensional (3D) inversion recovery MRI sequence was used to quantify the change in liver longitudinal relaxation rate (ΔR1) induced by the collagen-targeted probe EP-3533. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for Sirius Red staining and hydroxyproline content.
ΔR1 increased significantly with time following BDL compared to controls in agreement with ex vivo measures of increasing fibrosis. Receiver operating characteristic curve analysis demonstrated the ability of ΔR1 to detect liver fibrosis and distinguish intermediate and late stages of fibrosis. EP-3533 MRI correctly characterized the response to rapamycin in 11 out of 12 treated rats compared to the standard of collagen proportional area (CPA). 3D MRI enabled characterization of disease heterogeneity throughout the whole liver.
EP-3533 allowed for staging of liver fibrosis, assessment of response to rapamycin therapy, and demonstrated the ability to detect heterogeneity in liver fibrosis.
肝活检是评估肝纤维化的金标准，但由于抽样误差和侵入性而存在局限性。因此，迫切需要能够对整个肝脏的纤维化进行无创量化的方法。本研究的目的是利用I型胶原的分子磁共振成像（MRI）对肝纤维化进行无创成像，并评估对雷帕霉素治疗的反应。
通过胆管结扎（BDL）在大鼠中诱导肝纤维化。在BDL后4、10或18天进行MRI检查。一些BDL大鼠从第4天开始每天接受雷帕霉素治疗，并在第18天进行成像。使用三维（3D）反转恢复MRI序列来量化由胶原靶向探针EP-3533诱导的肝脏纵向弛豫率（ΔR1）的变化。对肝组织进行纤维化病理评分，并分析天狼星红染色和羟脯氨酸含量。
与对照组相比，BDL后ΔR1随时间显著增加，这与纤维化增加的体外测量结果一致。受试者操作特征曲线分析表明，ΔR1能够检测肝纤维化并区分纤维化的中期和晚期。与胶原比例面积（CPA）标准相比，EP-3533 MRI在12只接受治疗的大鼠中有11只正确地表征了对雷帕霉素的反应。3D MRI能够表征整个肝脏的疾病异质性。
EP-3533可用于肝纤维化分期、评估对雷帕霉素治疗的反应，并证明了检测肝纤维化异质性的能力。
