Magnetic resonance imaging (MRI) may eventually provide a noninvasive means of quantitatively measuring the amount of iron deposited in tissues of people who have diseases that cause an excessive amount of iron deposition in the body. In October 2002, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) invited research grant applications (R01 or R21) for projects that have the potential to improve the utility of MRI as a method for quantitative determinations of tissue iron, especially in the liver, heart, and brain.
A quantitative means of measuring body storage of iron that would be non-invasive, safe, accurate, and readily available would improve the diagnosis and management of patients with diseases that cause iron overload, including hereditary hemochromatosis, thalassemia major, sickle cell disease, aplastic anemia, myelodysplasia and other disorders. MRI potentially provides a useful and widely available technique for examining the three-dimensional distribution of excess iron in the body, but further research is needed to develop a way to make measurements quantitative.The body iron burden is a principal determinant of clinical outcome in all forms of systemic iron overload:
- Transfusion-caused iron overload (thalassemia major, sickle cell disease, and aplastic, myelodysplastic, or other refractory anemias)
- Increased dietary iron absorption (hereditary hemochromatosis and other forms of primary iron overload)
- Refractory anemia with increased ineffective erythropoiesis caused by both of the above
Accurate assessment of the body iron is essential for managing iron-chelating therapy in transfused patients to prevent iron toxicity while avoiding the adverse effects of excess chelator administration. In hereditary hemochromatosis, determination of the magnitude of body iron stores permits identification of persons who would benefit from phlebotomy therapy from those who are at genetic risk for the disease.
Under physiologic conditions, the concentration of iron in the human body is carefully regulated and normally maintained at about 40 mg Fe/kg body weight in women and about 50 mg Fe/kg in men, distributed between functional, transport, and storage compartments. Iron overload arises from a sustained increase in iron supply over iron requirements and develops with conditions that alter the regulation of intestinal iron absorption (hereditary hemochromatosis, refractory anemia with ineffective erythropoiesis), bypass it (transfusional iron overload), or both.
Regardless of the cause, progressive iron accumulation eventually overwhelms the body's capacity for safe sequestration of the excess, resulting in a variety of pathologies. The prognosis in patients with iron overload is influenced by many factors. While ferritin and hemosiderin iron almost surely are not directly responsible for the adverse effects of iron, the overall magnitude of storage iron accumulation seems to be a principal determinant of clinical outcome in all forms of systemic iron overload.
The Need for Improved Measuring
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) organized an international workshop on the non-invasive measurement of iron on April 17, 2001, to assess the current state of the science and to identify areas needing further investigation. The workshop participants concluded that additional work was needed to develop better quantitative means of measuring body storage of iron. These measurement methods should be non-invasive, safe, accurate, and readily available to improve the diagnosis and management of patients with iron overload.
Currently, biomagnetic susceptometry (SQUID) provides the only non-invasive method for measurement of tissue iron stores that has been calibrated, validated, and used in clinical studies. However, the complexity, cost, and technical demands of the liquid-helium-cooled, superconducting instruments that are currently required have restricted clinical access to the method.
Participants of the workshop identified magnetic resonance imaging (MRI) as an existing, widely available technology that, with further research, potentially could answer that need. Detailed information on the workshop is available at the NIDDK website: http://www.niddk.nih.gov/fund/other/archived-conferences/2001/iron/meeting-summary.pdf
Current and Potential Methods of Measurement
The reference method for evaluating the extent of body iron excess in systemic iron overload is measurement of the hepatic storage iron concentration. Total body iron stores can be measured by quantitative phlebotomy. However, transfusion-dependent patients with iron overload do not benefit from this approach, and it is generally acceptable only if the procedure provides therapeutic benefit. The measurement of plasma ferritin provides an indirect estimate of body iron stores, but the usefulness of this measure is limited by the many common clinical conditions in which the plasma ferritin is not a reliable indicator of body iron. While liver biopsy with chemical analysis of tissue iron content provides the most quantitative direct measure of iron status generally available, the discomfort and risk of the procedure limits its acceptability to patients and precludes its frequent use in serial observations.
MRI uses the magnetic properties of the body to provide detailed three-dimensional images of any structure or tissue. With MRI, tissue iron is detected indirectly by the effects on relaxation times of ferritin and hemosiderin iron interacting with nearby hydrogen nuclei. The interactions are complex, involving factors such as
- Tissue hydration
- Water diffusion coefficient within the tissue
- Distribution of iron and water within the tissue examined
- Number of iron atoms per molecule of ferritin and hemosiderin (called the loading factor)
- Relative proportion of ferritin iron and hemosiderin iron (these two iron storage materials have different effects on both T1 and T2)
Conventional MRI measurements are affected by the instrument used, the applied field strength, the repetition time used in the imaging sequence, the method used to analyze the relaxation curves, and other technical aspects of the measurement procedure. Comparison of absolute signal intensities from one MRI unit to another is unreliable because of substantial inter-machine variation.
In the absence of a theoretical understanding of the effects of iron on MRI, empirical efforts to estimate hepatic iron concentrations have used a variety of instruments, magnetic field strengths, imaging sequences (spin-echo, gradient recalled-echo), and parameters (T1 and T2 relaxation times and signal intensity ratios as measured in proton, T1-, T2- or T2-weighted images), but no standard or generally accepted method has been adopted for clinical application.
To date, MRI has been more useful as a screening technique for the detection of marked iron overload than as a means for quantitative measurement. In particular, with increasing iron concentrations, the signal intensity of the liver is reduced to such an extent that discrimination between different concentrations becomes impossible, at least with current technology.
Research Goals and TopicsThe following are examples of basic and clinical research that could be addressed in the application of MRI to the measurement of tissue iron:
NIDDK Program Officer: David G. Badman, Ph.D., Hematology Program Director, (301) 594-7717.
- Improve understanding of the contribution of ferritin and hemosiderin iron to magnetic resonance effects to guide development of optimal methods for measuring relaxation times and susceptibility
- Improve techniques for data acquisition, choice of field strength, selection of timing parameters, reduction of noise, identification of region of interest and selection of analytic methods
- Devise phantoms and/or other means for calibrating and validating iron concentration detected by magnetic resonance imaging that could enhance standardization between different laboratories
- Develop new methods for non-invasive measurements of iron deposition in the heart, in endocrine tissue, and in specific areas of the brain to determine the role of abnormalities of brain iron in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases, mitochondrial disorders and Parkinson's disease.
- Determine whether a dual field approach, used by some for MRI measurement of brain iron with promise of greater accuracy than conventional single-field images, can be applied to assessment of liver iron
- Investigate the most appropriate magnetic resonance method for determining relaxation times and susceptibility
- Determine which data acquisition method is best with selected timing parameters
- Develop improved methods of selecting a region-of-interest.
- Examine the mechanistic contribution of iron in iron-containing materials (e.g. ferritin and hemosiderin) to magnetic resonance relaxation, to be able to select the optimum measurement field strength and methods