High-Tc Susceptometer to Monitor Transfusional Iron Overload
Condition: Transfusional Iron Overload; Thalassemia Major; Sickle Cell Disease; Myelodysplastic Syndromes; Aplastic Anemia
MeSH terms: Myelodysplastic Syndromes; Anemia, Sickle Cell; Thalassemia; Anemia, Aplastic; beta-Thalassemia; Iron Overload
Study type: Observational

Summary: 
      The proposed research project will continue the application and development of a new method
      (biomagnetic susceptometry) that measures magnetic fields to determine how much iron is in
      the liver. The amount of iron in the liver is the best indicator of the amount of iron in the
      whole body. Measuring the amount of iron in the body is important because either too much
      (iron overload) or too little iron (iron deficiency) can be harmful. At present, the most
      reliable way to measure the amount of iron in the liver is to remove a sample of the liver by
      biopsy, either by surgery or by using a needle which pierces the skin and liver. Iron stored
      in the liver can be magnetized to a small degree when placed in a magnetic field. In patients
      with iron overload, the investigators previous studies have shown that magnetic measurements
      of liver iron in patients with iron overload are quantitatively equivalent to biochemical
      determinations on tissue obtained by biopsy. In the past the investigators have developed a
      device to measure the amount of magnetization, which was called a SQUID (Superconducting
      QUantum Interference Device) susceptometer. This device was validated and in use for over 20
      years. The safety, ease, rapidity and comfort of magnetic measurements make frequent, serial
      studies technically feasible and practically acceptable to patients. The investigators have
      now developed a new susceptometer, which uses very similar technology to the SQUID, but the
      investigators believe is more accurate and precise. This study aims to validate this new
      instrument. The investigators will do prospective, serial studies of the diagnosis and
      management of patients with iron overload, including thalassemia major (Cooley's anemia),
      sickle cell disease, aplastic anemia, myelodysplasia, hereditary hemochromatosis, and other
      disorders. Funding Source - FDA OOPD.
    

Detailed description: 
      This project will validate our new high-transition-temperature (high-Tc; operating at 77°K,
      cooled by liquid nitrogen) superconducting magnetic susceptometer as the most clinically
      effective means for monitoring iron overload in patients who require chronic red blood cell
      transfusion. Transfusional iron overload is an orphan disease that develops in patients who
      require regular blood transfusions for treatment of a variety of refractory anemias that are
      themselves orphan disorders, including sickle-cell disease, thalassemia major (Cooley's
      anemia), Diamond-Blackfan anemia, aplastic anemia, pure red cell aplasia, hypoplastic and
      myelodysplastic disorders. In the United States, the number of anemic patients with
      transfusional iron overload is estimated to be less than 50,000. Without iron-chelating
      therapy, potentially lethal amounts of iron accumulate in these patients. Because the body
      lacks an effective means to eliminate excess iron, the iron contained in transfused red cells
      is progressively deposited in the liver, heart, pancreas and other organs. Cirrhosis, heart
      failure, diabetes and other disorders develop. Treatment with a chelating agent capable of
      sequestering iron and permitting its excretion from the body provides a means of managing
      transfusional iron overload that can prolong survival and avert or ameliorate iron-induced
      organ damage. Two iron-chelating agents are now approved for use in the U.S. for the
      treatment of transfusional iron overload: (1) deferoxamine B (Desferal®), a parenteral agent
      in use for almost four decades, and (ii) deferasirox (Exjade®), an orally administered agent
      introduced in 2005. With both chelators, optimal management of patients requires careful
      monitoring of body iron to prevent iron-induced toxicity while avoiding adverse effects of
      excessive chelator administration. Our laboratories originally proposed that storage iron
      (ferritin and hemosiderin) could be non-invasively assessed in vivo by measurement of
      magnetic susceptibility. We subsequently developed low-transition-temperature (low-Tc;
      operating at 4°K, cooled by liquid helium) superconducting quantum interference device
      (SQUID) susceptometry as a clinical method for quantitation of hepatic iron stores. The
      transition temperature is the temperature at which the electrical resistance of a
      superconducting material drops to zero. The safety, ease, rapidity and comfort of magnetic
      measurements have made frequent, serial investigations technically feasible and practically
      acceptable to patients. Susceptometry permits accurate, direct, reliable, and repeated
      measurements of hepatic iron stores. Despite these advantages, the cost (about $1,000,000 per
      device), instrumental complexity and need for liquid-helium cooling of the low-Tc
      susceptometers restricted clinical adoption of the method. Worldwide, only four low-Tc
      susceptometers have been used clinically (in New York, Oakland, Hamburg and Turin). Recently,
      with the support of a Bioengineering Research Partnership Grant (R01 DK057209), we have made
      a series of technological breakthroughs and instrumental innovations that have made possible
      replacement, redesign and refinement of the elements of the low-Tc susceptometer, operating
      at 4°K in liquid helium, with components able to function at 77°K in liquid nitrogen. This
      new high-Tc susceptometer, the first medical device utilizing the phenomenon of
      high-temperature superconductivity, is an inexpensive instrument that can easily be used in a
      hospital environment. These Phase 2 clinical studies are designed to test the hypothesis that
      measurements of hepatic iron stores with our new high-Tc susceptometer are clinically
      superior to all other available methods and to supply essential data needed for FDA approval
      of the medical device. The proposed project has three specific aims:

        1. to calibrate the high-Tc susceptometer with the results of biochemical analysis of
           tissue from liver explants from adult and pediatric patients undergoing liver
           transplantation and from clinically indicated liver biopsy; and

        2. to prospectively validate the high-Tc susceptometer using the results of biochemical
           analysis of tissue from liver explants from adult and pediatric patients undergoing
           liver transplantation and from clinically indicated liver biopsy; and

        3. to prospectively compare measurements of hepatic iron concentration by the high-Tc
           susceptometer with (i) estimates derived from liver magnetic resonance imaging (MRI)
           relaxation rates (R2, R2*, signal intensity ratios), (ii) with determinations of serum
           ferritin, and (iii) with histopathological examination, using biochemical analysis of
           liver storage iron concentrations as the reference standard.

      FDA approval of an affordable, readily usable instrument for the non-invasive measurement of
      hepatic iron stores would lead to major advances in the management of patients with
      transfusional iron overload that would find immediate and widespread clinical use both in the
      U.S. and worldwide.
    

Intervention name(s): Hepatic biomagnetic susceptibility measurement
Intervention type(s): Device
Intervention description(s): Subjects will first have an ultrasound study to determine the location of the liver and measure the distance from skin surface to the liver. Subjects will then be examined with the high Tc susceptometer to determine the amount of iron in the liver. The entire procedure will usually take one-half hour or less.
Other intervention name(s): Hepatic magnetic susceptibility measurement; Superconducting biosusceptometry
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Potential participants who are eligible for this study include: (i) patients scheduled for
        clinically indicated liver transplantation or liver biopsy, (ii) patients with
        transfusional iron overload followed in adult and pediatric hematology, and (iii) healthy
        individuals participating as control subjects.
      
Keywords: Iron; Iron overload; Hepatic iron concentration; High-temperature superconductivity; Magnetic susceptibility; Susceptometer