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: 10337227
• 负责人: Gary M Brittenham
• 金额: $ 54.03万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337227
• 关键词: Agranulocytosis; Agreement; Auditory; 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; Erythrocytes; Excretory function; FDA approved; Fatty acid glycerol esters; Fibrosis; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Gold; Growth; Heart; Heart failure; Hepatic; Histologic; Histology; Impairment; In Vitro; Iron; Iron Chelating Agents; Iron Overload; Kidney Failure; Laboratories; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Magnetism; 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; base; chemical standard; clinical practice; computerized data processing; data acquisition; improved; in vivo; insight; 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）对患有以下疾病的患者的安全性： 通过开发准确的非侵入性肝脏铁浓度测量来治疗输血铁过载 (LIC)，是所有形式的全身性铁超负荷中身体铁负荷的最佳衡量标准。我们的科学前提是 使用定量磁化率图 (QSM) 的 MRI 将不受固有的干扰因素的影响， 特别是纤维化，会扭曲基于 R2 (=1/T2) 和 R2* (=R2+R2') 估计的当前 LIC 测量结果。 接受定期红细胞治疗的难治性贫血患者会逐渐出现输血铁超负荷。 血细胞（RBC）输注（重型地中海贫血、镰状细胞病和其他疾病），因为身体 缺乏任何有效的方法来排出多余的铁。输注红细胞中过量的铁最终会导致 形成循环的非转铁蛋白结合铁，然后逐渐沉积在肝脏、胰腺、 心脏和其他器官，导致肝硬化、糖尿病、心力衰竭和其他疾病。 ICT，我们拥有 制定了实践指南，可以去除细胞中多余的铁，清除循环中的非转铁蛋白结合 铁，并将体内铁维持或恢复到安全水平。安全治疗需要仔细调整剂量 铁螯合剂可减轻体内铁负荷，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、生长迟缓以及潜在致命的肝衰竭、肾衰竭和胃肠道疾病 出血。目前LIC主要通过无创MRI使用R2(=1/T2)和R2*(=R2+R2')来估计 依赖于铁对弛豫（R2）和体素内移相（R2'）的贡献的技术。一个 R2 和 R2* 方法的基本限制是除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会改变放松。我们拥有生物物理学的洞察力来消除 使用 QSM 测量 R2 和 R2* 干扰效应，我们开发 QSM 是为了测量组织磁特性。 QSM 是通过处理相位生成的，而 R2* 是根据相同的幅度确定的 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 根据化学分解与体素内含量的关系，允许铁定量 不受纤维化、脂肪变性、坏死性炎症和其他体素内容物的干扰。因此，我们 保守地预计使用肝脏 QSM 进行 LIC 测量的准确性将提高 >5 倍 (hQSM) 与当前的 R2 和 R2* 方法相比。我们的研究计划有 3 个具体目标： 目标 1. 开发 hQSM 可准确测量 LIC，无干扰误差。目标 2. 使用组织学和验证 hQSM 肝脏外植体中 LIC 的化学测量。目标 3. 评估输铁患者的 hQSM ICT 下的超载。