Technical Validation of MRI Biomarkers of Liver Fat

描述(由申请人提供)：该提案广泛的、长期的目标是改善数百万有非酒精性脂肪性肝病(NAFLD)风险的美国人的健康。近期的目标是从技术上验证磁共振成像(MRI)测定的质子密度脂肪分数(PDFF)作为肝脏脂肪生物标记物的有效性：目的1.对照独立的、明确的参考标准进行准确性验证。我们将以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将准确地预测TG浓度。我们将确定更准确的技术。目的2.精密度，重复性好，重现性好。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跨部位、扫描器和读取器的重复性。我们假设，PDFF将是可重复和可重现的。我们将确定更具可重复性和可重复性的技术。目的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手术的肥胖成年人体重减轻与肝脏脂肪之间的关系，展示其作为重复测量肝脏脂肪含量的客观工具的有效性。我们假设，随着体重的减轻，PDFF将单调下降。调节这种关系的因素将被确定。意义：NAFLD是美国成人和儿童最常见的慢性肝病。它可能会进展为肝硬变，并有助于心血管疾病和2型糖尿病的发展。肝活检是目前评估肝脏脂肪和诊断NAFLD的临床黄金标准，是侵入性的。这一局限性阻碍了NAFLD的诊断、治疗和预防方面的进展。临床护理和研究需要一种有效的、非侵入性的肝脏脂肪含量生物标志物。加州大学圣地亚哥分校和威斯康星大学改进了新的屏气核磁共振方法，解决了传统核磁共振测量肝脏脂肪的误差来源。这些新方法可以快速估计PDFF，即肝脏中可归因于脂肪的可移动质子的比例。初步数据表明，PDFF可以准确预测肝脏甘油三酯浓度，这是衡量肝脏脂肪含量的生化指标；但需要进行严格的验证，才能将MRI确定的PDFF确定为可靠和有用的生物标记物。研究设计和方法：我们计划一项两点前瞻性队列研究。两个站点的设计提供了竞争技术的公正比较、充分的患者登记以及跨站点比较性能特征的能力。我们将招募140名肥胖成年人(每个部位70人)参加手术减肥计划(腹腔镜可调节胃束带)。登记的受试者将有不同的基线肝脏脂肪含量；术中多次活组织检查提供一个明确的参考标准，以比较PDFF测量结果；并以不同的速度减轻体重和肝脏脂肪。在手术前后的多个时间点，使用两种磁共振成像技术测量PDFF。 与公共健康相关：这项提案将表明，磁共振成像是一种安全、快速、相对便宜和准确的替代肝活检的方法，用于测量数千万受脂肪肝影响或有脂肪肝风险的美国人的肝脏脂肪。

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.