Quantitative Susceptibility Mapping (QSM) to Guide Iron Chelating Therapy

The overall objective of this research is to improve the safety of iron-chelating therapy (ICT) in patients with transfusional iron overload by developing an 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. The scientific premise is that quantitative susceptibility mapping (QSM) provides a quantitative biophysical connection to LIC. Safe ICT requires careful adjustment of the iron chelator dose to the body iron burden to optimize iron excretion while avoiding chelator toxicity, including gastrointestinal disorders, audiovisual impairment, neutropenia, arthropathy, growth retardation, and hepatic and renal failure. QSM enables accurate measurement of LIC by overcoming the inherent cellular interference in current R2 (=1/T2) and R2\* (=R2+R2') estimates that lack a well-defined biophysical connection to the LIC. A fundamental biophysical limitation of the R2 and R2\* approaches is that intravoxel contents other than iron, including fibrosis, steatosis and necroinflammation, also alter relaxation. In the liver, paramagnetic iron stored in ferritin and hemosiderin is the dominant susceptibility source for QSM. Consequently, magnetic susceptibility measured by QSM has a simple linear relationship with the concentration of iron in the liver and is little affected by fibrosis, steatosis and necroinflammation. The investigator's research plan has 3 specific aims: Aim 1. Develop hQSM for accurate measurement of LIC without interfering errors. Investigators will optimize data acquisition and processing for free-breathing navigator acquisition with robust fat-water separation. Aim 2. Validate hQSM using histology and chemical measurement of LIC in liver explants. Investigators will assess the accuracies of LICs measured by hQSM and R2\* in patients before liver transplant with histologic examination using the reference standard of chemical measurement of LIC in liver explants. Aim 3. Evaluate hQSM in patients with transfusional iron overload under ICT. In patients regularly transfused for thalassemia major, investigators will conduct a double-blind clinical study comparing the accuracy of hQSM and R2\* in measuring annual changes in LIC, using regression against the year-long amount of iron administered in red blood cell transfusions and the year-long cumulative dose of iron chelator.