MR Spectroscopy of the Liver in Correlation with Histology in NASH Patients

描述（由申请方提供）：非酒精性脂肪肝（NAFL）包括广泛的过程，包括肝脂肪变性和非酒精性脂肪性肝炎（NASH），20%-40%的NASH患者可进展为终末期肝病。我们建议将NASH患者的磁共振波谱（MRS）谱模式与肝组织学分期1至4的纤维化程度（Kleiner等人）和单纯脂肪变性对照组进行比较。我们的目标是证明随着纤维化的增加，PME/PDE比率增加。这种差异的证明将导致非侵入性方法的发展，以评估NASH在其自然史中的纵向进展或消退，以及提供一种方法来随访对治疗干预的反应。成功识别独特的MRS谱可能被证明是一种潜在的模式，为未来的调查NASH的病理生理学和MRS的作用，作为一个非侵入性的替代肝脏活检在了解线粒体异常，包括呼吸链缺陷。将通过标准MRS信号定量算法（高级磁共振算法）确定PME、Pi、PDE和NTP的峰面积，分析NASH受试者不同纤维化阶段的MRS谱，并将其分别与单纯性脂肪变性对照组以及每组NASH患者进行比较。将计算峰面积比（PME/NTP、PDE/NTP、PME/PDE和Pi/NTP），并进行统计学分析。研究设计允许对86例患者进行充分的统计学评估。该奖项将为我提供必要的工具，以进一步扩展我在脂肪肝领域的专业知识，重点是NASH/NAFL的研究以及评估疾病严重程度和对不同治疗方式反应性的非侵入性技术。我还预计，NIH和其他资助机构未来将提供资金，用于在NAFL患者中进行MR波谱分析，并将MR波谱与纤维化的生化标志物相关联。我们还能够在接受NAFLD治疗管理的患者中结合肝活检使用该工具，即，胰岛素增敏剂、抗氧化剂和其他研究治疗非酒精性脂肪性肝病的方法。公共卫生相关性：在美国和世界范围内，非酒精摄入导致的脂肪肝是一种日益增长且未满足的需求。目前，研究疾病进展和干预措施有效性的唯一方法是通过侵入性肝活检，这给患者带来不便，并且容易出现并发症和采样错误。我们建议探索是否可以使用非侵入性成像技术（磁共振波谱）来提供更准确和信息量更大的方法来研究这些患者。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver (NAFL) includes a wide spectrum of processes, including hepatic steatosis and nonalcoholic steatohepatitis (NASH), which can progress to end-stage liver disease in 20%-40% of patients with NASH. We are proposing to compare the Magnetic Resonance Spectroscopy (MRS) spectra patterns of patients with NASH to the degree of fibrosis on liver histology stages 1 through 4 (Kleiner, et al), and a control group with simple steatosis. Our goal is to demonstrate increased PME/PDE ratios with increasing fibrosis. Demonstration of such a difference will lead to the development of noninvasive methods of evaluating longitudinal progression, or regression, of NASH in its natural history, as well as providing a means to follow up on the response to therapeutic interventions. Successful identification of unique MRS spectra may prove to be a potential modality for future investigation into the pathophysiology of NASH and the role of MRS as a noninvasive surrogate to liver biopsy in understanding mitochondrial abnormalities, including respiratory chain defects. MRS spectra from different stages of fibrosis in subjects with NASH will be analyzed by determining peak areas from PME, Pi, PDE, and NTP via a standard MRS signal quantitation algorithm (Advanced Magnetic Resonance algorithm) and compare them to the control group of simple steatosis, as well as to each group of NASH patients separately. Peak area ratios (PME/NTP, PDE/NTP, PME/PDE, and Pi/NTP) will be calculated, and statistically analyzed. The study design permits adequate statistical assessment upon examination of eighty-six patients. This award will provide me with the necessary tools to further expand my expertise in the field of fatty liver disease, with an emphasis on research in NASH/NAFL and the noninvasive techniques of assessment of disease severity and responsiveness to different therapeutic modalities. I also anticipate the facilitation of future grant funds from NIH and other funding agencies, to conduct MR Spectroscopy in NAFL patients and correlate the MR spectra to biochemical markers of fibrosis. We would also be able to use this tool in conjunction with liver biopsy in patients undergoing therapeutic management of NAFLD, i.e., Insulin sensitizers, anti-oxidant, and other studied therapies in patients with nonalcoholic fatty liver disease. PUBLIC HEALTH RELEVANCE: Fatty liver disease that is not the result of alcohol intake is an increasing and unmet need in the US and worldwide. Currently, the only method available to study disease progression and the effectiveness of interventions is through invasive liver biopsies, which inconvenience the patient, and are subject to complications and sampling error. We are proposing to explore whether a non-invasive imaging technique (magnetic resonance spectroscopy) can be used to provide a more accurate and informative method to study these patients.