Technical Development of Quantitative Biomarkers of Fatty Liver Disease with MRI

描述（由申请人提供）：本提案的总体目标是开发和验证使用磁共振成像（MRI）进行非酒精性脂肪性肝病（NAFLD）早期诊断和定量分级的无创定量方法。NAFLD是一种新出现的疾病，现在被认为是最常见的慢性肝病类型，仅在美国就有9000万至1亿（>30%）人受到影响，其中包括10%的儿童。NAFLD的最早和标志性特征是肝细胞的细胞内脂肪浸润（脂肪变性）。在许多患者中，脂肪变性导致炎症和纤维化。这些患者发展为肝硬化，并可能死于肝衰竭和/或肝细胞癌，需要肝移植。NAFLD的诊断是有限的，因为它依赖于活检，这是昂贵的，有风险的，并且是高度可变的脂肪变性分级。迫切需要准确的定量非侵入性方法来促进NAFLD的早期检测和定量分级。我们试图通过开发MRI方法来解决这一未满足的需求，该方法将肝脏“脂肪分数”量化为脂肪变性的生物标志物。重要的是，许多NAFLD患者同时存在肝脏铁超载。虽然铁在NAFLD中的作用尚不清楚，但由于铁诱导的加速信号衰减（T2* 衰减），其存在混淆了脂肪的MRI估计。因此，这项工作的第二个目标是量化T2* 作为肝铁过载的生物标志物，通过同时估计T2* 和脂肪分数来解耦铁和脂肪的影响的方法。其他重要的混淆因素也必须加以解决。这些包括：T1弛豫、图像噪声、脂肪的多个NMR光谱峰和涡流。我们将使用PI开发的已建立的定性水脂分离方法作为开发新方法的基础。为了实现我们的目标，我们的目标是：1）在单次屏气（20秒）中开发肝脏脂肪变性（脂肪分数）和铁过载（T2*）的新的定量MRI生物标志物，并完全覆盖肝脏。我们将通过并行成像加速这些方法，以实现临床可接受的扫描时间（20秒）。然后，我们将在2a）脂肪变性和铁过载的组合小鼠模型和2b）由于脂肪变性而排斥移植的移植的人类肝脏中验证这些方法，并进行严格的活检成像相关性研究。最后，我们将进行3）一项前瞻性临床试点研究，比较我们的定量MRI方法与疑似NAFLD患者的活检。该提案响应了NIDDK计划公告PA-09-181，用于开发NIDDK感兴趣的疾病（包括NAFLD）的诊断和分级的非侵入性方法。我们的目标是满足对非侵入性量化脂肪变性的生物标志物的迫切需求，其次是铁，而没有活检的不准确性，危险性和成本。这些定量MRI生物标志物的成功开发将为预防性干预治疗肝硬化、肝衰竭和肝细胞癌这一重要且日益普遍的病因提供前所未有的机会。 公共卫生相关性：该提案的目标是开发，实施和验证使用磁共振成像（MRI）测量非酒精性脂肪性肝病（NAFLD）患者肝脏中脂肪和铁含量的方法。NAFLD是肝衰竭和肝癌的一个越来越重要的原因，目前还没有可靠和安全的方法来诊断和评估这种疾病的严重程度，这种疾病影响近三分之一的成年人和十分之一的儿童。我们的目标是开发新的MRI方法，提供NAFLD严重程度的早期检测和评估，以指导停止或逆转肝损伤的治疗。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop and validate non-invasive quantitative methods for early diagnosis and quantitative grading of Non-Alcoholic Fatty Liver Disease (NAFLD), using magnetic resonance imaging (MRI). NAFLD is an emerging condition now recognized as the most common type of chronic liver disease, afflicting an estimated 90-100 million (>30%) people in the United States alone, including 10% of all children. The earliest and hallmark feature of NAFLD is intracellular fatty infiltration of hepatocytes (steatosis). In many patients, steatosis leads to inflammation and fibrosis. These patients develop cirrhosis and may succumb to liver failure and/or hepatocellular carcinoma, necessitating liver transplant. Diagnosis of NAFLD is limited because it relies on biopsy, which is expensive, risky, and is highly variable for grading of steatosis. There is an urgent unmet need for accurate quantitative non-invasive methods to facilitate early detection and quantitative grading of NAFLD. We seek to address this unmet need by developing MRI methods that quantify hepatic "fat-fraction" as a biomarker of steatosis. Importantly, hepatic iron overload coexists in many patients with NAFLD. Although the role of iron in NAFLD is unknown, its presence confounds MRI estimates of fat due to iron-induced accelerated signal decay (T2* decay). Therefore, a secondary goal of this work is to quantify T2* as a biomarker of hepatic iron overload, through methods that decouple the effects of iron and fat by estimating T2* and fat-fraction simultaneously. Other important confounding factors must also be addressed. These include: T1 relaxation, image noise, the multiple NMR spectral peaks of fat, and eddy currents. We will use an established qualitative water-fat separation method developed by the PI as a foundation from which new methods are developed. To achieve our goals, we aim to 1) develop new quantitative MRI biomarkers of hepatic steatosis (fat-fraction) and iron overload (T2*) in a single breath- hold (20s), with complete liver coverage. We will accelerate these methods with parallel imaging to achieve clinically acceptable scan times (20s). We will then validate these methods in 2a) a combined mouse model of steatosis and iron overload, and in 2b) explanted human livers rejected for transplantation due to steatosis, with a rigorous biopsy-imaging correlation study. Finally, we will perform 3) a prospective clinical pilot study that compares our quantitative MRI methods with biopsy in patients with suspected NAFLD. This proposal responds to the NIDDK program announcement PA-09-181 for development of non-invasive methods for diagnosis and grading of diseases of interest to the NIDDK, which includes NAFLD. We aim to meet the urgent unmet need for biomarkers that non-invasively quantify steatosis, and secondarily iron, without the inaccuracy, danger, and cost of biopsy. Successful development of these quantitative MRI biomarkers will provide an unprecedented opportunity for pre-emptive intervention for the treatment of this important and increasingly prevalent cause of cirrhosis, liver failure and hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop, implement and validate methods to measure the amount of fat and iron in the livers of people with Non-Alcoholic Fatty Liver Disease (NAFLD) using magnetic resonance imaging (MRI). NAFLD is an increasingly important cause of liver failure and liver cancer, and currently there are no reliable and safe methods to diagnose and evaluate the severity of this disease, which affects nearly 1 in 3 adults and 1 in 10 children. We aim to develop new MRI methods that will provide early detection and evaluation of the severity of NAFLD in order to guide treatments that halt or reverse liver damage.