QSM to Guide Iron Chelating Therapy in Transfusional Iron Overload

QSM 指导铁螯合疗法治疗输血铁过量

• 批准号: 10558645
• 负责人: Gary M Brittenham
• 金额: $ 53.13万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558645
• 关键词: Agranulocytosis; Agreement; Auditory; Binding; Biophysics; Biopsy Specimen; Body measure procedure; Breathing; Cells; Chelating Agents; Chemicals; Cirrhosis; Clinical Research; Concentration measurement; Cooley' s anemia; Data; Deposition; Development; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Edema; Error Sources; Erythrocyte Transfusion; Excretory function; FDA approved; Fatty acid glycerol esters; Fibrosis; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Growth; Heart; Heart failure; Hepatic; Histologic; Histology; Impairment; In Vitro; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; Kidney Failure; Laboratories; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Magnetism; Maps; Measurement; Measures; Methods; Neutropenia; Organ; Pancreas; Patients; Phase; Practice Guidelines; Predisposition; Property; Reference Standards; Refractory anemias; Relaxation; Reporting; Reproducibility; Research; Research Institute; Resources; Safety; Scanning; Sickle Cell Anemia; Signal Transduction; Techniques; Thalassemia; Tissues; Toxic effect; Transfusion; Translating; Variant; Visual impairment; Water; arthropathies; chemical standard; clinical practice; computerized data processing; data acquisition; improved; in vivo; insight; iron chelation therapy; liver biopsy; liver transplantation; programs

The overall objective of this research is to improve the safety of iron-chelating therapy (ICT) in patients with transfusional iron overload by developing accurate non-invasive measurement of the liver iron concentration (LIC), the best measure of the body iron burden in all forms of systemic iron overload. Our scientific premise is that MRI using quantitative susceptibility mapping (QSM) will be free of the inherent interfering factors, particularly fibrosis, that distort current LIC measurements based on R2 (=1/T2) and R2* (=R2+R2') estimates. Transfusional iron overload progressively develops in patients with refractory anemia who undergo regular red blood cell (RBC) transfusion (thalassemia major, sickle-cell disease, and other disorders), because the body lacks any effective means to excrete excess iron. Excess iron from transfused RBCs eventually leads to the formation of circulating non-transferrin-bound iron that is then progressively deposited in the liver, pancreas, heart and other organs, causing cirrhosis, diabetes, heart failure, and other disorders. ICT, which we have developed the practice guideline, can remove excess iron from cells, clear circulating non–transferrin-bound iron, and maintain or return body iron to safe levels. Safe therapy requires careful adjustment of the dose of iron-chelating agents to the body iron burden to optimize iron excretion while avoiding chelator toxicity, including gastrointestinal disorders, auditory and visual impairment, agranulocytosis and neutropenia, arthropathy, growth retardation, and potentially fatal hepatic failure, renal failure, and gastrointestinal hemorrhage. LIC at present is primarily estimated by noninvasive MRI using R2 (=1/T2) and R2* (=R2+R2') techniques that depend upon the contribution of iron to relaxation (R2) and intravoxel dephasing (R2'). A fundamental limitation of the R2 and R2* approaches is that intravoxel contents other than iron, including fibrosis, steatosis and necroinflammation, also alter relaxation. We have the biophysical insight to eliminate the R2 and R2* interfering effects using QSM, which we have developed to measure tissue magnetic properties. QSM is generated from processing the phase, while R2* is determined from the magnitude, of the same gradient echo MRI data without additional scans. Magnetic susceptibility measured by QSM has a simple linear relationship with intravoxel contents in accordance with chemical decomposition, allowing iron quantification without interfering errors from fibrosis, steatosis, necroinflammation and other intravoxel contents. Hence, we conservatively anticipate a >5 fold improvement in the accuracy of LIC measurements using hepatic QSM (hQSM) compared to the current R2 and R2* method. Our research plan has 3 specific aims: Aim 1. Develop hQSM for accurate measurement of LIC without interfering errors. Aim 2. Validate hQSM using histology and chemical measurement of LIC in liver explants. Aim 3. Evaluate hQSM in patients with transfusional iron overload under ICT.

本研究的总体目标是提高铁螯合疗法（ICT）在以下患者中的安全性： 通过开发肝脏铁浓度的准确非侵入性测量， (LIC)是衡量所有形式的全身性铁过载中体内铁负荷的最佳指标。我们的科学前提是 使用定量磁化率绘图（QSM）的MRI将不受固有干扰因素的影响， 特别是纤维化，其使基于R2（=1/T2）和R2*（=R2+ R2 ′）估计的当前LIC测量失真。 接受常规红细胞输注治疗的难治性贫血患者逐渐出现输血铁超负荷 血细胞（RBC）输血（地中海贫血，镰状细胞病和其他疾病），因为身体 缺乏有效的方法来排出多余的铁。来自输注红细胞的过量铁最终导致 形成循环的非转铁蛋白结合的铁，然后逐渐沉积在肝脏，胰腺， 心脏和其他器官，引起肝硬化，糖尿病，心力衰竭和其他疾病。信息和通信技术， 制定了实践指南，可以从细胞中去除多余的铁，清除循环中的非转铁蛋白结合 铁，并保持或返回身体铁到安全水平。安全的治疗需要仔细调整 铁螯合剂可减轻体内铁负荷，以优化铁排泄，同时避免螯合剂毒性， 包括胃肠道疾病、听觉和视觉障碍、粒细胞缺乏症和中性粒细胞减少症， 关节病、生长迟缓和潜在致死性肝衰竭、肾衰竭和胃肠道 出血目前，LIC主要通过无创MRI使用R2（=1/T2）和R2*（=R2+ R2 '）进行估计。 依赖于铁对弛豫（R2）和体素内失相（R2 '）的贡献的技术。一 R2和R2* 方法的基本限制是除了铁以外的体素内含量，包括 纤维化、脂肪变性和坏死性炎症也改变松弛。我们有生物物理学的洞察力来消除 使用QSM的R2和R2* 干扰效应，我们已经开发了QSM来测量组织磁特性。 QSM是通过处理相位而产生的，而R2* 是通过处理相同的相位的幅度而确定的。 梯度回波MRI数据，无需额外扫描。QSM测量的磁化率具有简单的线性关系 与体素内含量的关系符合化学分解，允许铁定量 而没有来自纤维化、脂肪变性、坏死性炎症和其它体素内内容的干扰误差。所以我们 保守地预期使用肝脏QSM的LIC测量准确度提高>5倍 （hQSM）与当前R2和R2* 方法相比。我们的研究计划有三个具体目标：目标1。发展 hQSM用于精确测量LIC，无干扰误差。目标2.使用组织学和 肝外植体中LIC的化学测量。目标3.评价输注铁剂患者的hQSM 信息和通信技术下的过载。