Technical Validation of MRI Biomarkers of Liver Fat

描述（由申请人提供）：该提案的广泛，长期目标是改善数百万患有非酒精性脂肪肝（NAFLD）或有风险的美国人的健康。近期目标是通过以下方式在技术上验证磁共振成像（MRI）确定的质子密度脂肪分数（PDFF）作为肝脏脂肪的生物标志物：目的1。相对于独立、确定的参比标准品的准确度。我们将使用组织甘油三酯浓度作为参考标准，确定并比较两种MRI技术测量PDFF的准确性。我们假设PDFF将准确预测TG浓度。我们会找出更准确的技术。目标2.具有高重复性和再现性的精密度。我们将评估通过两种MRI技术测量的PDFF值在受试者内的重复性和在研究中心、扫描仪和阅片仪之间的再现性。我们假设PDFF将是可重复和可再现的。我们将确定更具可重复性和可再现性的技术。目标3。临床和研究价值。我们将使用PDFF作为生物标志物来定义接受胃束带术的肥胖成年人体重减轻与肝脏脂肪之间的关系，证明其作为重复测量肝脏脂肪含量的客观工具的实用性。我们假设PDFF会随着体重减轻而单调下降。将确定调节这种关系的因素。NAFLD是美国成人和儿童最常见的慢性肝病。它可能会发展为肝硬化，并导致心血管疾病和2型糖尿病的发展。肝活检是目前评估肝脏脂肪和诊断NAFLD的临床金标准，具有侵入性。这种局限性阻碍了NAFLD诊断、治疗和预防的进展。临床护理和研究需要肝脏脂肪含量的有效非侵入性生物标志物。加州大学圣地亚哥分校和威斯康星州大学改进的新屏气MRI方法解决了传统MRI测量肝脏脂肪的误差来源。这些新方法允许快速估计PDFF，肝脏中归因于脂肪的移动的质子的分数。初步数据表明，PDFF准确预测肝脏TG浓度，肝脏脂肪含量的生化指标，但需要严格的验证，建立MRI确定的PDFF作为一个可靠和有用的生物标志物。研究设计和方法：我们计划进行一项双中心前瞻性队列研究。双中心设计提供了竞争技术的无偏倚比较、充分的患者入组以及比较各中心性能特征的能力。我们将招募140名肥胖成人（每个研究中心70名）参加手术减肥计划（腹腔镜可调节胃束带术）。入组的受试者将具有可变的基线肝脏脂肪含量;具有多个术中活检，其提供了比较PDFF测量结果的明确参考标准;并且以可变速率减轻体重和肝脏脂肪。将在手术前后的多个时间点使用两种MRI技术测量PDFF。 公共卫生相关性：这项提案将表明，磁共振成像是一种安全，快速，相对便宜，准确的替代肝活检测量肝脏脂肪在数以千万计的美国人受脂肪肝疾病或风险。

DESCRIPTION (provided by applicant): The proposal's broad, long-term objective is to improve the health of millions of Americans with or at risk for non-alcoholic fatty liver disease (NAFLD). The immediate goal is to technically validate magnetic resonance imaging (MRI) determined proton density fat fraction (PDFF) as a biomarker of liver fat by demonstrating: Aim 1. Accuracy against an independent, definitive reference standard. We will determine and compare the accuracy of PDFF as measured by two MRI techniques, using tissue triglyceride concentration as the reference standard. We hypothesize that PDFF will accurately predict TG concentration. We will identify the more accurate technique. Aim 2. Precision with high repeatability and reproducibility. We will assess the repeatability within subjects and reproducibility across sites, scanners and readers of PDFF values as measured by two MRI techniques. We hypothesize that PDFF will be repeatable and reproducible. We will identify the more repeatable and reproducible technique. Aim 3. Clinical and research value. We will use PDFF as a biomarker to define the relationship between weight loss and liver fat in obese adults undergoing gastric banding, demonstrating its utility as an objective tool for repeated measures of liver fat content. We hypothesize that PDFF will decrease monotonically in response to weight loss. Factors that modulate this relationship will be identified. Significance: NAFLD is the most common chronic liver disease of adults and children in the United States. It may progress to cirrhosis and contribute to the development of cardiovascular disease and type 2 diabetes. Liver biopsy, the current clinical gold standard to assess liver fat and diagnose NAFLD, is invasive. This limitation has hindered progress in the diagnosis, treatment, and prevention of NAFLD. A valid non-invasive biomarker of liver fat content is needed for clinical care and research. New breath-hold MRI methods refined at the University of California, San Diego and the University of Wisconsin address the sources of errors in conventional MRI for measuring liver fat. These new methods permit rapid estimation of PDFF, the fraction of mobile protons in liver attributable to fat. Preliminary data suggests that PDFF accurately predicts liver TG concentration, the biochemical measure of liver fat content; but rigorous validation is required to establish MRI-determined PDFF as a reliable and useful biomarker. Research design and methods: We plan a two-site prospective cohort study. The two-site design provides unbiased comparison of competing techniques, adequate patient enrollment, and the ability to compare performance characteristics across sites. We will enroll 140 obese adults (70 per site) participating in a surgical weight loss program (laparoscopic adjustable gastric banding). Enrolled subjects will have variable baseline liver fat content; have multiple intra-operative biopsies providing a definitive reference standard with which to compare PDFF measurements; and lose weight and liver fat at variable rates. PDFF will be measured using two MRI techniques at multiple time points before and after surgery. PUBLIC HEALTH RELEVANCE: This proposal will show that magnetic resonance imaging is a safe, rapid, relatively inexpensive, and accurate alternative to liver biopsy for measuring liver fat in the tens of millions of Americans affected by or at risk for fatty liver disease.