Iron overload, a severe complication of increased gastrointestinal absorption of iron or multiple blood transfusions, affects hundreds of thousands of individuals in the US and significant costs are associated with its screening and treatment. As the body has no physiologic mechanism for clearing iron, repeated transfusions cause iron accumulation in organs and lead to iron toxicity. Accurate assessment of iron overload is paramount to quantify excessive iron accumulation and to monitor response to iron chelation therapy. Magnetic resonance imaging (MRI) methods, which indirectly measure iron via its effect on tissue relaxation properties, have been used to noninvasively measure hepatic iron concentration (HIC). Although MRI-based measurements of transverse relaxation rates (R2 and R2*) accurately predict biopsy-proven HICs below 15 mg Fe/g, previous studies have shown that their precision is limited for HICs above 15mgFe/g and inaccurate above 25mgFe/g. Current R2* gradient-echo (GRE) MR techniques fail occasionally for very high iron overloads (HIC~15-25mgFe/g) and always for massive iron overloads (HIC>25mgFe/g) because R2* is so high that the MR signal decays before it can be measured accurately. The Massive Iron Deposit Assessment (MIDAS) study aims to extend the clinically useful range of R2*-based HIC measurements by employing ultra short echo time (UTE) imaging to improve sampling of the relaxation curve. UTE shortens the earliest sampling time, or echo time (TE), of the R2*-measurement sequence, allowing detection of very fast signal decay and a higher R2* fit precision. UTE sequences achieve minimum TEs of approximately 505s, enabling accurate quantification of very high iron concentrations. Our goals are to (1) develop, test, and implement a multi-echo R2*-UTE breath hold sequence for HIC quantitation, and (2) test the accuracy of R2*-UTE in estimating HIC in massively iron-overloaded patients. A multi-echo breath hold R2*-UTE sequence will be first implemented and integrated into the MR scanner. Then, the R2*-UTE sequence will be tested in phantoms over a wide range of R2* values and in healthy volunteers. Finally, approximately 200 patients will be scanned with R2*-GRE and R2*-UTE MRI. Of these, about 35 massively iron-overloaded patients are expected to fail the R2*-GRE screen and to require a clinically indicated liver biopsy for iron quantification. Study data of this cohort will be used for modeling R2*-UTE using HIC by liver biopsy as the reference method. The proposed biopsy-calibrated R2*-UTE technique, being used for the first time to quantitate iron in tissues, will provide a noninvasive, accurate, and cost-effective alternative to biopsy for HIC quantification in massively iron-overloaded patients and ensure appropriate dosing of intensive iron unloading treatment to this group. This will reduce treatment-related toxicity arising from unnecessary exposure to iron chelation and significantly improve patients'care and quality of life.

Public Health Relevance

The accurate quantification of hepatic iron content (HIC) is clinically important in patients who develop massive iron overload because of multiple blood transfusions, in order to monitor response to iron chelation therapy and prevent clinical toxicity from chelation. Our proposed R2*-UTE technique will allow accurate measurement of very high HIC values and is a noninvasive, cost-effective, and suitable alternative to current MRI procedures and liver biopsies to determine iron overload. This technique will greatly benefit populations frequently requiring transfusions, such as patients with hematologic conditions like sickle cell disease and thalassemia, as well as those requiring long-term monitoring of body iron, such as survivors of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088988-04
Application #
8462599
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Serrano, Jose
Project Start
2010-08-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$314,134
Indirect Cost
$126,973
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Taylor, Brian A; Loeffler, Ralf B; Song, Ruitian et al. (2012) Simultaneous field and R2 mapping to quantify liver iron content using autoregressive moving average modeling. J Magn Reson Imaging 35:1125-32
Hankins, Jane S; Smeltzer, Matthew P; McCarville, M Beth et al. (2010) Patterns of liver iron accumulation in patients with sickle cell disease and thalassemia with iron overload. Eur J Haematol 85:51-7