Technical Development of Quantitative Biomarkers of Fatty Liver Disease with MRI

描述(由申请人提供)：这项提案的总体目标是开发和验证非侵入性定量方法，利用磁共振成像(MRI)对非酒精性脂肪性肝病(NAFLD)进行早期诊断和定量分级。非酒精性脂肪肝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，仅在美国就估计有9000-1亿人(30%)受到影响，其中包括10%的儿童。NAFLD最早也是最显著的特征是肝细胞内脂肪渗入(脂肪变性)。在许多患者中，脂肪变性会导致炎症和纤维化。这些患者发展为肝硬变，并可能死于肝功能衰竭和/或肝细胞癌，需要进行肝移植。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，并且对脂肪变性的分级具有很高的变异性。目前迫切需要准确的、定量的、非侵入性的方法来促进NAFLD的早期发现和定量分级。我们试图通过开发MRI方法来量化肝脏“脂肪分数”作为脂肪变性的生物标记物来解决这一未得到满足的需求。重要的是，许多NAFLD患者同时存在肝脏铁超载。尽管铁在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)，它的存在混淆了MRI对脂肪的估计。因此，这项工作的第二个目标是通过同时估计T2*和脂肪分数来分离铁和脂肪的影响的方法，量化T2*作为肝脏铁超载的生物标志物。还必须解决其他重要的混杂因素。这些问题包括：T1弛豫、图像噪声、脂肪的多个核磁共振波谱峰和涡流。我们将使用PI开发的已建立的定性水-脂肪分离方法作为基础，以此为基础开发新的方法。为了实现我们的目标，我们的目标是：1)开发新的定量MRI生物标记物，在一次屏气(20s)中检测肝脏脂肪变性(脂肪部分)和铁超载(T2*)，并完全覆盖肝脏。我们将通过并行成像加速这些方法，以达到临床可接受的扫描时间(20秒)。然后，我们将在2a)脂肪变性和铁超载的组合小鼠模型以及2b)因脂肪变性而被拒绝移植的人肝移植模型中验证这些方法，并进行严格的活检-成像相关性研究。最后，我们将进行一项前瞻性的临床先导研究，将我们的定量MRI方法与疑似NAFLD患者的活检进行比较。这项建议响应了NIDDK项目公告PA-09-181，该公告旨在开发非侵入性方法，用于NIDDK感兴趣的疾病的诊断和分级，其中包括NAFLD。我们的目标是满足对生物标志物的迫切需求，这些生物标志物可以非侵入性地量化脂肪变性，其次是铁，而不会出现活检的不准确、危险和成本。这些定量核磁共振生物标记物的成功开发将为预防干预提供前所未有的机会，以治疗这一日益普遍的重要原因，导致肝硬化、肝功能衰竭和肝细胞癌。 公共卫生相关性：这项提案的目标是开发、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是导致肝功能衰竭和肝癌的一个日益重要的原因，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，这种疾病影响到近1/3的成年人和1/10的儿童。我们的目标是开发新的MRI方法，为NAFLD的严重程度提供早期检测和评估，以指导停止或逆转肝脏损害的治疗。

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.