|
|
Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-06-1723.
 Previous Article | Table of Contents | Next Article 
Blood, 1 January 2003, Vol. 101, No. 1, pp. 15-19
PERSPECTIVE
Noninvasive measurement of iron: report of an NIDDK
workshop
Gary M. Brittenham and
David G. Badman
From Columbia University College of Physicians and
Surgeons, New York, NY; and the Division of Kidney, Urologic and
Hematologic Diseases/National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, MD.
 |
Abstract |
An international workshop on the noninvasive measurement of iron
was conducted by the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) on April 17, 2001, to assess the current state
of the science and to identify areas needing further investigation. The
workshop concluded that a clear clinical need is evident for quantitative, noninvasive, safe, accurate, and readily available means
of measuring body storage iron to improve the diagnosis and management
of patients with iron overload from such disorders as hereditary
hemochromatosis, thalassemia major, sickle cell disease, aplastic
anemia, and myelodysplasia, among others. Magnetic resonance imaging
(MRI) potentially provides the best available technique for examining
the 3-dimensional distribution of excess iron in the body, but further
research is needed to develop means of making measurements
quantitative. Biomagnetic susceptometry provides the only noninvasive
method to measure tissue iron stores that has been calibrated,
validated, and used in clinical studies, but the complexity, cost, and
technical demands of the liquid-helium-cooled superconducting
instruments required at present have restricted clinical access to the
method. The workshop identified basic and clinical research
opportunities for deepening our understanding of the physical
properties of iron and iron toxicity, for further investigation of MRI
as a method for quantitative determinations of tissue iron, especially
in liver, heart and brain, and for development of improved methods and
more widely available instrumentation for biomagnetic susceptometry.
(Blood. 2003;101:15-19)
| |
Introduction |
Body iron burden is a principal determinant
of clinical outcome in all forms of systemic iron overload, whether
from transfusion (for thalassemia major, sickle cell disease, or
aplastic, myelodysplastic, or other refractory anemias), from increased
dietary iron absorption (hereditary hemochromatosis and other forms of
primary iron overload), or both (refractory anemia with increased
ineffective erythropoiesis). Accurate assessment of the body iron is
essential for managing iron-chelating therapy in patients who are
chronically tranfused 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 patients who would benefit from phlebotomy
therapy from among those at genetic risk for the disease.
On April 17, 2001, an international workshop on the noninvasive
measurement of iron was conducted by the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK) to assess the current state
of the science and to identify areas needing further investigation.
Invited participants included representatives from centers
worldwide that are active in the development of noninvasive measures of
iron, clinicians who care for patients with iron disorders, and experts
in the physics and chemistry of iron and in iron metabolism. The
proceedings of the workshop are summarized below; more detailed information is available at the NIDDK website
(http://www.niddk.nih.gov/fund/other/iron/index.html).
| |
Clinical needs for measurement of iron |
Iron is an essential nutrient required by every human cell. Under
physiologic conditions, the concentration of iron in the human body is
carefully regulated and normally maintained at approximately 40 mg
Fe/kg body weight in women and approximately 50 mg Fe/kg in men,
distributed between functional, transport, and storage compartments.
Iron deficiency designates conditions in which body iron is
decreased and arises from a sustained increase in iron requirements
(usually from blood loss, pregnancy, or growth) over iron
supply.1 Most cases of iron deficiency can now be detected by measurements of serum ferritin, serum transferrin receptor concentration, or both, determined in a sample of peripheral
blood2. Iron overload arises from a sustained increase in
iron supply over iron requirements and develops with conditions in
which the regulation of intestinal iron absorption is altered
(hereditary hemochromatosis, refractory anemia with ineffective
erythropoiesis), bypassed (transfusional iron overload), or
both.1 Iron overload results primarily in an increase in
storage iron held in ferritin and hemosiderin3; functional
iron is little affected. Whether derived from increased absorption of
dietary iron or from transfused red blood cells, progressive iron
accumulation eventually overwhelms the body's capacity for safe
sequestration of the excess. Symptomatic patients may have any of the
characteristic manifestations of systemic iron overload: liver
disease with the eventual development of cirrhosis and, often,
hepatocellular carcinoma, diabetes mellitus, gonadal
insufficiency and other endocrine disorders, arthropathy and increased
skin pigmentation; iron-induced cardiomyopathy may be lethal. The
prognosis in patients with iron overload is influenced by many factors,
including the age at which iron loading begins, the rate and route of
iron loading, the distribution of iron deposition between macrophage
and parenchymal sites,4 the amount and duration of
exposure to circulating nontransferrin-bound iron5;
ascorbate status; and coexisting disorders, especially alcoholism and
viral hepatitis. Although ferritin and hemosiderin iron are almost
surely not the species 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 reference method for evaluating the extent of body iron excess in
systemic iron overload is measurement of the hepatic storage iron
concentration,6 recognizing that the exact relationship between hepatic iron and total body iron burden depends on the underlying disorder. The liver is the only storage compartment whose
iron content is consistently increased with increased body iron stores;
excess storage iron is detectable in reticuloendothelial (Kupffer
cells) and parenchymal (hepatocytes) sites. Total body iron stores can
be measured by quantitative phlebotomy,7 but this approach
cannot be used in transfusion-dependent patients with iron overload and
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
plasma ferritin is not a reliable indicator of body iron.4 Inflammation, infection, liver disease, hemolysis, ineffective erythropoiesis, and ascorbate deficiency common complications of
hereditary hemochromatosis, transfusional iron overload, or bothall
perturb serum ferritin levels independently of changes in total body iron.
Although 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 limit its
acceptability to patients and preclude its frequent use in serial
observations. The workshop concluded that physicians have a pressing
clinical need for quantitative means of measuring body storage iron
that are noninvasive, safe, accurate, and readily available to improve
the diagnosis and management of patients with iron overload, including
those with hereditary hemochromatosis, thalassemia major, sickle cell
disease,4,8 aplastic anemia, myelodysplasia, and other
disorders. Priorities in clinical research in iron overload were
identified as (1) developing, calibrating, and validating new methods
or modifications of current methods for quantitative measurement of
tissue storage iron that are noninvasive, safe, accurate, and readily
available for clinical use; (2) examining the relationship between
total iron burden and manifestations of iron toxicity in different
forms of iron overloadfor example, hereditary hemochromatosis and
transfusional iron overload in thalassemia major, sickle cell disease,
aplastic and myelodysplastic anemias; (3) assessing the value of
noninvasive measurements of hepatic iron in guiding iron-chelating
therapy in transfusional iron overload in patients with thalassemia
major, sickle cell disease, aplastic anemia, and myelodysplastic anemia
and in identifying patients who would benefit from phlebotomy therapy
among those found to be at genetic risk for hereditary hemochromatosis;
and (4) determining the relationships between the iron concentration in
specific tissues and damage to the heart, liver, pancreas, other
endocrine organs, and joints in different forms of iron overloadfor
example, in hereditary hemochromatosis and in transfusional iron
overload with thalassemia major, sickle cell disease, and aplastic and
myelodysplastic anemias.
| |
Physical properties of iron |
Iron in biologic systems is found with a variety of oxidation
states, reduction potentials, magnetic properties, degrees of aggregation, solubilities, mobilities, and kinetic and thermodynamic proclivities toward free-radical generation.3,9 Each of
these variables influences not only biologic activities and toxicities but also the detection and quantification of iron. Reduction-oxidation reactions are involved in the cellular uptake, transmembrane transport, and incorporation of iron into essential heme and nonheme enzymes for
use and into ferritin for storage.10 Iron is likely to be found in the ferric oxidation state when tightly locked in place for
purposes of transport or storage and in the ferrous oxidation state
when a change of chemical environment is necessary. Iron can also be a
detrimental catalyst in biologic free-radical oxidations, although the
exact nature of the reactions involved remain uncertain. Iron-catalyzed
free-radical production may take place through the Fenton and
Haber-Weiss reactions, producing hydroxyl radical,3 or,
perhaps, by reactions of ferrous iron with dioxygen, producing ferryl,
perferryl radicals, or other reactive oxygen species.11,12 The recent extraordinary advances in our understanding of the cellular
and molecular bases of iron uptake, transport, and storage have
revealed new intricacies in the complexities of iron metabolism. Nonetheless, the specific toxic forms of iron have not been identified with certainty, and methods of measurement of the harmful species are
lacking. Priorities in basic research in the physical properties of
iron3 were identified as (1) characterizing the chemical nature of cytoplasmic iron in transit among different sites and routes
of uptake, storage, use, and release by cells, including the redox
reactions of iron storage and intracellular transport, the structure of
iron in ferritin and hemosiderin, and the mechanisms of iron
mobilization from these storage sites; (2) determining the forms and
behavior of iron exported by cells for binding to circulating
transferrin or appearing as nontransferrin-bound plasma iron; and (3)
understanding mitochondrial iron metabolism and homeostasis and their
disorders. Progress in these areas could lead to the identification of
the precise species of iron that are responsible for toxicity and
eventually to the means for their measurement and management.
| |
Detection of iron overload by magnetic resonance imagining |
MRI uses the magnetic properties of the body to provide detailed
3-dimensional images of any structure or tissue. Magnetic resonance
measures the contribution of hydrogen nuclei (protons) to the net
magnetization of the body within defined spatial regions. Hydrogen
nuclei are a principal constituent of body tissues, mostly in water
molecules and lipids. A spinning, charged hydrogen nucleus produces a
dipole moment (magnetic field) that can interact with an external
magnetic field. MRI instruments generate a strong and homogeneous
magnetic field by using a large magnet made by passing an electric
field through superconducting coils of wire. Patients are placed in a
horizontal cylinder and are exposed to the magnetic field. At
equilibrium, hydrogen nuclei in the body, which normally have randomly
oriented spins, align in a direction parallel to the magnetic field.
The MRI machine then applies short electromagnetic pulses through a
coil at a specific radio frequency (RF). The hydrogen nuclei absorb the
RF energy and precess away from equilibrium (ie, alter the orientation
of their spins). When the RF pulse is turned off, the precessing nuclei
release the absorbed energy and return to equilibrium. An external RF
coil detects the electromagnetic signals that are emitted as the nuclei return to equilibrium. The strength of the signals varies, depending on
the applied RF magnetic fields. A sample returns to equilibrium in the
longitudinal plane over a characteristic interval called the T1
relaxation time (the time constant for excited nuclei to dissipate
excess energy to the environment). In the transverse plane, the return
to equilibrium occurs over a characteristic interval called the T2
relaxation time (the time constant for excited nuclei to go out of
phase with each other). Both T1 and T2 depend on the local environment
of the hydrogen nuclei. These values may also be expressed as
relaxation rates, R1 ( = 1/T1) or R2 ( = 1/T2). Rapid progress is
being made in the development of improved MRI instrumentation,
especially in the development of machines with higher magnetic field
strength.13
With MRI, tissue iron is detected indirectly by the effects on
relaxation times of ferritin and hemosiderin iron interacting with
nearby hydrogen nuclei. Paramagnetic ferritin and hemosiderin iron
shorten proton relaxation times, particularly T2, an effect termed
susceptibility-induced relaxation,14 but a detailed, theoretical understanding of these effects is lacking.15
The interactions are complex and involve 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), and,
because ferritin iron and hemosiderin iron have different effects on T1
and T2,16 relative proportion of these 2 iron storage
materials. Loading factors within a tissue are not uniform; they differ
with different types and amounts of iron excess.17 Studies
of ferritin in solution in vitro show a clear effect of loading factor
on relaxation times18; in tissue, clustering of ferritin
within cells further complicates analysis.19 Moreover, conventional MRI measurements are also 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 intermachine variation.20 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
overload20 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,21 at least with current technology.
New methods for using MRI to estimate tissue iron are under
development, based on the inverse relationship between the
susceptibility-induced relaxation, measured as R2, and iron
concentration. One approach, applied in studies of brain iron, involves
measuring the tissue relaxation rate (R2) in subjects in high- and
low-field MRI instruments and then calculating the field-dependent R2
increase (FDRI), the difference between the R2 measured with the 2 MRI
instruments. In tissue, only ferritin iron is known to increase R2 in a
field-dependent manner, suggesting that the FDRI measure may provide a
specific measure of this tissue iron pool.22,23 Another
approach also involves the measurement of R2, but it uses a spin-echo
imaging methodology to produce a series of images at different echo
times. Using these images, a map of the entire liver is generated in which contrast is predominantly dependent on the R2 of the liver at
different echo times.24 The advantage of this approach is that the results are independent of the MRI instrument used. Efforts to
validate these approaches against chemical measurements of tissue iron
are in progress.
At present, MRI provides a means of probing the 3-dimensional
distribution of excess iron in the body, but further efforts are needed
to make measurements quantitative. Priorities in basic and clinical
research in the application of MRI to the measurement of tissue iron
were identified as (1) acquiring an improved understanding of the
contribution of ferritin and hemosiderin iron to magnetic resonance
effects to guide the development of optimal methods for measuring
relaxation times and susceptibility, including the best 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; (2) devising phantoms and other
means for calibrating and validating iron concentration detected by MRI
that could enhance standardization between different laboratories; and
(3) developing new methods for noninvasive 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
disease, amyotrophic lateral sclerosis, prion diseases, mitochondrial
disorders, and Parkinson disease.
| |
Detection of iron overload by magnetic susceptometry |
The magnetic dipole moment is the central physical concept
underlying MRI and magnetic susceptometry. Elementary particle magnetic
moments are determined by quantum mechanical considerations and do not
vary with time, magnetic field, or any other variable. In an applied
magnetic field, all magnetic dipole moments experience torque, tending
to align their axes. The disruptive effect of thermal fluctuations
prevents all but a minute fraction of the available elementary particle
moments in the human body from aligning in this way. Nonetheless, this
minute field-induced fraction provides the diagnostic signals used by
MRI and magnetic susceptometry. The magnetic susceptibility of
a tissue is determined by the strength of the magnetic response evoked
in the tissue by an applied magnetic field.6,25 This
property is much simpler than the resonance behavior that results from
the application of the oscillating magnetic fields used in MRI. While
in a steady applied magnetic field, all materials respond with an
induced magnetic field of their own. This response may be exploited
diagnostically because the magnitude of the induced magnetic field
varies greatly in different materials. In most human biologic
materials, this induced field is diametrically opposed to the applied
field. This diamagnetic response is so weak (approximately
10 6 of the applied field) that its detection requires
sensitive instrumentation, described below. By contrast,
ferromagnetic materials (such as the common bar magnet) respond
with an induced field as strong as or even stronger than the applied
field and in the same direction. No known human tissues are
ferromagnetic. Intermediate between the diamagnetic and ferromagnetic
extremes is the paramagnetic response of the iron in ferritin
and hemosiderin that is in the same direction as the applied field with
a strength approximately 104 of the applied field. This
paramagnetic response is directly proportional to the number of iron
atoms present in iron storage compounds. In a measurement of hepatic
magnetic susceptibility in vivo, the opposing diamagnetic (tissue) and
augmenting paramagnetic (ferritin and hemosiderin iron) responses are
superimposed. By taking into account the small and nearly constant
diamagnetic effect of the liver tissue, the observed resultant magnetic
susceptibility may be used, in effect, to count the number of storage
iron atoms present. The contributions of other paramagnetic materials
(oxygen, deoxyhemoglobin, some trace metals) to the hepatic magnetic
susceptibility are so small that magnetic measurements are highly
specific for ferritin and hemosiderin iron. Thus, determinations of the
magnetic susceptibility of the liver provide a direct measure
of hepatic iron.
To date, measurements of hepatic magnetic susceptibility have required
the use of superconducting magnetometers to measure the small change in
magnetic field produced by the presence of storage iron in the liver
(approximately 1 part in 1 billion of the applied
field).25 Superconducting materials lose all electrical resistance below a certain temperature, called the transition temperature, or TC. Until 1986, all known superconducting
materials had transition temperatures near absolute zero and required a bath of liquid helium (4.2°K) to keep their temperature below TC. The recently developed "high-TC"
materials have TC values well above that of liquid nitrogen
(77°K). The superconducting quantum interference device
(SQUID) is a superconducting loop incorporating a so-called weak link,
known as a Josephson junction, that can function as the most sensitive
and stable magnetic detector known. Since the development of the first
SQUID susceptometer26 with the support of the NIDDK, the
design of this instrument has been the basis for all commercially
available instruments.27 In effect, the susceptometer
provides an automated magnetic "biopsy" of liver ferritin and
hemosiderin iron. In patients with iron overload, the results of
susceptometric measurements of hepatic nonheme iron are quantitatively
equivalent to those obtained by chemical analysis of tissue obtained by
biopsy.6,26 Despite providing noninvasive, quantitative
measurements of hepatic iron stores, clinical adoption of susceptometry
has been limited, in part because of the cost and complexity of the
instruments. At present, the only susceptometers in clinical use are at
Columbia University,6 the University of Hamburg,
Germany,25 and the University of Turin, Italy; a fourth
instrument is being installed at the Children's Hospital Oakland
Research Institute, California. These instruments have now been used in
studies of thousands of patients with iron
overload.6,26,28-32
At present, biomagnetic susceptometry provides the only noninvasive
method for measurement of tissue iron stores that has been calibrated,
validated, and used in clinical studies, but the complexity, cost and
technical demands of the liquid-helium-cooled superconducting
instruments required at present have restricted clinical access to the
method. New approaches to the measurement of magnetic susceptibility
are under investigation. One method uses magnetic resonance to measure
the magnetic susceptibility difference between 2 homogeneous
macroscopic compartments that are in contact by exploiting a resonant
frequency discontinuity between the 2 materials. One material with a
known susceptibility (eg, blood) may then be considered as a reference
to obtain the susceptibility of the second material (eg, liver or
heart).33 The use of a room-temperature device for
susceptibility measurements has been proposed and is being
studied.34 Still another approach is to retain the
advantages of superconductivity but to use the new high-TC
SQUIDs and materials to develop a device that could operate using
liquid nitrogen as the refrigerant.35 Priorities in basic
and clinical research in the further development of biomagnetic susceptometry for the measurement of tissue iron were identified as (1)
developing innovative instrumentation for biomagnetic susceptometry that is suitable for routine clinical use in studies of iron overload, such as liquid-nitrogen cooled superconducting instruments, devices using nonsuperconducting magnetometers, or means of adapting MRI instruments for measurement of magnetic susceptibility; (2) improving biomagnetic susceptometry by the development of methods to more precisely determine the susceptibility of tissue overlying the organ of
interestfor example, the bone, muscle and subcutaneous tissue
overlying the liver; (3) conducting additional research to develop
biomagnetic susceptometry as a means of measuring tissue iron
concentrations in the heart, endocrine tissue, brain, and other organs
through the use of instrumentation with arrays of magnetic sensors or
by examining the potential use of magnetic susceptibility
tomography.25
| |
Summary and recommendations |
Physicians have a pressing clinical need for quantitative means of
measuring body storage iron that are noninvasive, safe, accurate, and
readily available to improve the diagnosis and management of patients
with iron overload, including those with hereditary hemochromatosis,
thalassemia major, sickle cell disease, aplastic anemia,
myelodysplasia, and other disorders. MRI provides a means of probing
the 3-dimensional distribution of excess iron in the body, but further
research is needed to develop means of making measurements
quantitative. At present, biomagnetic susceptometry provides the only
noninvasive method for measurement of tissue iron stores that has been
calibrated, validated, and used in clinical studies, but the
complexity, cost, and technical demands of the liquid-helium-cooled
superconducting instruments now required have restricted clinical
access to the method. The workshop identified basic and clinical
research opportunities for deepening our understanding of iron
toxicity, for further development of MRI as a method for quantitative
determinations of tissue iron, especially in liver and brain, and for
new approaches to methods for biomagnetic susceptometery.
Note:
Since the workshop was held, additional publications on
theoretical36,37 and practical38-41 efforts
to develop noninvasive methods for measurement of tissue iron have
appeared and are cited here for ready reference.
| |
Footnotes |
Submitted June 12, 2002; accepted July 3, 2002.
Prepublished online as
Blood First Edition Paper, August 29, 2002; DOI
10.1182/blood-2002-06-1723.
Supported by the National Institute of Diabetes and Digestive
and Kidney Diseases and by the Office of Rare Diseases, Office of the
Director, National Institutes of Health.
Reprints: David G. Badman, Division of Kidney,
Urologic and Hematologic Diseases/National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, 2 Democracy Plaza, Room 621 MSC 5458, 6707 Democracy Blvd, Bethesda, MD
20892-5458; e-mail: db70f{at}nih.gov.
| |
References |
1.
Brittenham GM.
Disorders of iron metabolism: iron deficiency and overload. In:
Hoffman RBE,Shattil SJ,Furie B, et al., eds.
Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:397-428.
2.
Cook JD.
The measurement of serum transferrin receptor.
Am J Med Sci.
1999;318:269-276[Medline]
[Order article via Infotrieve].
3.
Aisen P, Enns C, Wessling-Resnick M.
Chemistry and biology of eukaryotic iron metabolism.
Int J Biochem Cell Biol.
2001;33:940-959[CrossRef][Medline]
[Order article via Infotrieve].
4.
Harmatz P, Butensky E, Quirolo K, et al.
Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy.
Blood.
2000;96:76-79[Abstract/Free Full Text].
5.
Cable EE, Connor JR, Isom HC.
Accumulation of iron by primary rat hepatocytes in long-term culture: changes in nuclear shape mediated by non-transferrin-bound forms of iron.
Am J Pathol.
1998;152:781-792[Abstract].
6.
Brittenham GM, Sheth S, Allen CJ, Farrell DE.
Noninvasive methods for quantitative assessment of transfusional iron overload in sickle cell disease.
Semin Hematol.
2001;38:37-56[Medline]
[Order article via Infotrieve].
7.
Angelucci E, Brittenham GM, McLaren C, et al.
Hepatic iron concentration and total body iron stores in thalassemia major.
N Engl J Med.
2000;343:327-331[Abstract/Free Full Text].
8.
Cohen AR, Martin MB.
Iron chelation therapy in sickle cell disease.
Semin Hematol.
2001;38:69-72[Medline]
[Order article via Infotrieve].
9.
Ghio AJ, Taylor DE, Stonehuerner JG, Piantadosi CA, Crumbliss AL.
The release of iron from different asbestos structures by hydrogen peroxide with concomitant O2 generation.
Biometals.
1998;11:41-47[CrossRef][Medline]
[Order article via Infotrieve].
10.
Zhao G, Bou-Abdallah F, Yang X, Arosio P, Chasteen ND.
Is hydrogen peroxide produced during iron(II) oxidation in mammalian apoferritins?
Biochemistry.
2001;40:10832-10838[CrossRef][Medline]
[Order article via Infotrieve].
11.
Qian SY, Buettner GR.
Iron and dioxygen chemistry is an important route to initiation of biological free radical oxidations: an electron paramagnetic resonance spin trapping study.
Free Radic Biol Med.
1999;26:1447-1456[CrossRef][Medline]
[Order article via Infotrieve].
12.
Schafer FQ, Qian SY, Buettner GR.
Iron and free radical oxidations in cell membranes.
Cell Mol Biol (Noisy-le-grand).
2000;46:657-662[Medline]
[Order article via Infotrieve].
13.
Beck B, Plant DH, Grant SC, et al.
Progress in high field MRI at the University of Florida.
MAGMA.
2002;13:152-157[Medline]
[Order article via Infotrieve].
14.
Gillis P, Roch A, Brooks RA.
Corrected equations for susceptibility-induced T2-shortening.
J Magn Reson.
1999;137:402-407[Medline]
[Order article via Infotrieve].
15.
Gossuin Y, Roch A, Muller RN, Gillis P.
Relaxation induced by ferritin and ferritin-like magnetic particles: the role of proton exchange.
Magn Reson Med.
2000;43:237-243[CrossRef][Medline]
[Order article via Infotrieve].
16.
Vymazal J, Urgosik D, Bulte JW.
Differentiation between hemosiderin- and ferritin-bound brain iron using nuclear magnetic resonance and magnetic resonance imaging.
Cell Mol Biol (Noisy-le-grand).
2000;46:835-842[Medline]
[Order article via Infotrieve].
17.
Vymazal J, Hajek M, Patronas N, et al.
The quantitative relation between T1-weighted and T2-weighted MRI of normal gray matter and iron concentration.
J Magn Reson Imaging.
1995;5:554-560[Medline]
[Order article via Infotrieve].
18.
Vymazal J, Zak O, Bulte JW, Aisen P, Brooks RA.
T1 and T2 of ferritin solutions: effect of loading factor.
Magn Reson Med.
1996;36:61-65[Medline]
[Order article via Infotrieve].
19.
Brooks RA, Vymazal J, Goldfarb RB, Bulte JW, Aisen P.
Relaxometry and magnetometry of ferritin.
Magn Reson Med.
1998;40:227-235[Medline]
[Order article via Infotrieve].
20.
Bonkovsky HL, Rubin RB, Cable EE, Davidoff A, Rijcken TH, Stark DD.
Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques.
Radiology.
1999;212:227-234[Abstract/Free Full Text].
21.
Angelucci E, Giovagnoni A, Valeri G, et al.
Limitations of magnetic resonance imaging in measurement of hepatic iron.
Blood.
1997;90:4736-4742[Abstract/Free Full Text].
22.
Bartzokis G, Cummings JL, Markham CH, et al.
MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects.
Magn Reson Imaging.
1999;17:213-222[CrossRef][Medline]
[Order article via Infotrieve].
23.
Bartzokis G, Tishler TA.
MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntington's disease.
Cell Mol Biol (Noisy-le-grand).
2000;46:821-833[Medline]
[Order article via Infotrieve].
24.
Clark PR, St Pierre TG.
Quantitative mapping of transverse relaxivity (1/T(2)) in hepatic iron overload: a single spin-echo imaging methodology.
Magn Reson Imaging.
2000;18:431-438[CrossRef][Medline]
[Order article via Infotrieve].
25.
Fischer R.
Liver iron susceptometry. In:
Andra W,Nowak H, eds.
Magnetism in Medicine: a Handbook. Berlin: Wiley-VCH; 1998:286-301.
26.
Brittenham GM, Farrell DE, Harris JW, et al.
Magnetic-susceptibility measurement of human iron stores.
N Engl J Med.
1982;307:1671-1675[Abstract].
27.
Paulson DN, Fagaly RL, Toussaint RM, Fischer R.
Biomagnetic susceptometer with SQUID Instrumentation.
IEEE Trans Magnetics.
1991;27:3249-3252[CrossRef].
28.
Brittenham GM, Griffith PM, Nienhuis A, et al.
Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.
N Engl J Med.
1994;331:567-573[Abstract/Free Full Text].
29.
Nielsen P, Fischer R, Engelhardt R, Tondury P, Gabbe EE, Janka GE.
Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone.
Br J Haematol.
1995;91:827-833[Medline]
[Order article via Infotrieve].
30.
Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G.
Long-term survival in patients with hereditary hemochromatosis.
Gastroenterology.
1996;110:1107-1119[CrossRef][Medline]
[Order article via Infotrieve].
31.
Fischer R, Tiemann CD, Engelhardt R, et al.
Assessment of iron stores in children with transfusion siderosis by biomagnetic liver susceptometry.
Am J Hematol.
1999;60:289-299[CrossRef][Medline]
[Order article via Infotrieve].
32.
Nielsen P, Engelhardt R, Duerken M, Janka GE, Fischer R.
Using SQUID biomagnetic liver susceptometry in the treatment of thalassemia and other iron loading diseases.
Transfus Sci.
2000;23:257-258[CrossRef][Medline]
[Order article via Infotrieve].
33.
Wang ZJ, Li S, Haselgrove JC.
Magnetic resonance imaging measurement of volume magnetic susceptibility using a boundary condition.
J Magn Reson.
1999;140:477-481[CrossRef][Medline]
[Order article via Infotrieve].
34.
Kumar S, Avrin WF.
A low-cost biomagnetic susceptometer based on room-temperature sensors. In:
Yoshimoto T,Kotani M,Kuriki S,Karibe H,Nakasato N, eds.
Recent Advances in Biomagnetism. Proceedings of the 11th International Conference on Biomagnetism. Sendai, Japan: Tohoku University Press; 1999:1160-1109.
35. Farrell DE, Allen CJ, Arendt PN, et al. A liquid nitrogen cooled device
for making magnetic susceptibility measurements. Am Physical Soc
Abstracts. 1999; VC07.03.
36.
Gossuin Y, Roch A, Lo Bue F, Muller RN, Gillis P.
Nuclear magnetic relaxation dispersion of ferritin and ferritin-like magnetic particle solutions: a pH-effect study.
Magn Reson Med.
2001;46:476-481[Medline]
[Order article via Infotrieve].
37.
Gossuin Y, Gillis P, Lo Bue F.
Susceptibility-induced T(2)-shortening and unrestricted diffusion.
Magn Reson Med.
2002;47:194-195[CrossRef][Medline]
[Order article via Infotrieve].
38.
Jensen PD, Jensen FT, Christensen T, et al.
Indirect evidence for the potential ability of magnetic resonance imaging to evaluate the myocardial iron content in patients with transfusional iron overload.
MAGMA.
2001;12:153-166[Medline]
[Order article via Infotrieve].
39.
Anderson LJ, Holden S, Davis B, et al.
Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload.
Eur Heart J.
2001;22:2171-2179[Abstract/Free Full Text].
40.
Wang ZJ, Haselgrove JC, Martin MB, et al.
Evaluation of iron overload by single voxel MRS measurement of liver T2.
J Magn Reson Imaging.
2002;15:395-400[CrossRef][Medline]
[Order article via Infotrieve].
41.
Salo S, Alanen A, Leino R, Bondestam S, Komu M.
The effect of haemosiderosis and blood transfusions on the T2 relaxation time and 1/T2 relaxation rate of liver tissue.
Br J Radiol.
2002;75:24-27[Abstract/Free Full Text].
| |
Appendix: Invited workshop participants |
Introductory Remarks: David Badman, DKUHD, NIDDK, National
Institutes of Health, Bethesda, MD; Allen Spiegel, Director, NIDDK, National Institutes of Health, Bethesda, MD; Frank Somma, National President, Cooley's Anemia Foundation, Inc.
Session I. Clinical Needs for Measurement of Iron: Gary Brittenham,
Columbia University, New York, NY (Chair); Alan R. Cohen, Children's
Hospital of Philadelphia, PA; Roland Fischer, Universitatskrankenhaus Eppendorf, Hamburg, Germany; Harriet C. Isom, Pennsylvania
State College of Medicine, Hershey; Elliott P. Vichinsky,
Children's Hospital of Oakland Research Institute, CA.
Session II. Physical Properties of Iron: Philip Aisen, Albert Einstein
College of Medicine, Bronx, NY (Chair); Garry Buettner, University of
Iowa, Iowa City; Dennis N. Chasteen, University of New
Hampshire, Durham; Alvin L. Crumbliss, Duke University, Durham, NC;
Roland Frankel, California Polytechnic State University, San Luis Obispo.
Session III. Detection of Iron Overload by MRI: Thomas Mareci,
University of Florida, Gainesville (Chair); George Bartzokis, University of Arkansas, Little Rock; Herbert Bonkovsky, University of
Massachusetts, Worcester; Jeff Bulte, National Institutes of Health,
Bethesda, MD; Peter Van Gelderen, National Institutes of Health,
Bethesda, MD; Pierre Gillis, Université de Mons-Hainaut, Mons,
Belgium; Tim St. Pierre, University of Western Australia, Nedlands,
Australia; Evan S. Siegelman, University of Pennsylvania; Zhiyue J. Wang, Children's Hospital of Philadelphia, PA.
Session IV. Detection of Iron Overload by Magnetic Susceptometry: David
E. Farrell, Case Western Reserve University, Cleveland, OH (Chair);
Paul N. Arendt, Los Alamos National Laboratory, NM; William Avrin,
Quantum Magnetics, Inc., San Diego, CA; Gary M. Brittenham, Columbia
University, New York, NY; Roland Fischer, Universitatskrankenhaus
Eppendorf, Hamburg, Germany; Ronald B. Goldfarb, National Institute of
Standards and Technology, Boulder, CO; Joseph L. Kirschvink, California
Institute Of Technology, Pasadena; Sankaran Kumar, Quantum Magnetics,
Inc., San Diego, CA; Douglas Paulson, Tristan Technologies, Inc., San
Diego, CA.
Session V. Discussion and Recommendations: Robert Balaban, National
Institutes of Health, Bethesda, MD (Chair).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. C. Maradei, A. Maiolino, A. M. de Azevedo, M. Colares, L. F. Bouzas, and M. Nucci
Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation
Blood,
August 6, 2009;
114(6):
1270 - 1275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Jabbour, G. Garcia-Manero, A. Taher, and H. M. Kantarjian
Managing Iron Overload in Patients with Myelodysplastic Syndromes with Oral Deferasirox Therapy
Oncologist,
May 1, 2009;
14(5):
489 - 496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. V. Raman, M. W. Winner III, T. Tran, M. Velayutham, O. P. Simonetti, P. B. Baker, J. Olesik, B. McCarthy, A. K. Ferketich, and J. L. Zweier
In vivo atherosclerotic plaque characterization using magnetic susceptibility distinguishes symptom-producing plaques.
J. Am. Coll. Cardiol. Img.,
January 1, 2008;
1(1):
49 - 57.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Ma and M. M. Udden
Iron metabolism, iron overload, and the porphyrias
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
61 - 77.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.J. House, T.G. St. Pierre, J.K. Foster, R.N. Martins, and R. Clarnette
Quantitative MR Imaging R2 Relaxometry in Elderly Participants Reporting Memory Loss.
AJNR Am. J. Neuroradiol.,
February 1, 2006;
27(2):
430 - 439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Wood, C. Enriquez, N. Ghugre, J. M. Tyzka, S. Carson, M. D. Nelson, and T. D. Coates
MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients
Blood,
August 15, 2005;
106(4):
1460 - 1465.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Papakonstantinou, T. G. Maris, S. Kostaridou, V. Ladis, A. Vasiliadou, and N. C. Gourtsoyiannis
Abdominal Lymphadenopathy in {beta}-Thalassemia: MRI Features and Correlation with Liver Iron Overload and Posttransfusion Chronic Hepatitis C
Am. J. Roentgenol.,
July 1, 2005;
185(1):
219 - 224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. J. Wang, L. Lian, Q. Chen, H. Zhao, T. Asakura, and A. R. Cohen
1/T2 and Magnetic Susceptibility Measurements in a Gerbil Cardiac Iron Overload Model
Radiology,
March 1, 2005;
234(3):
749 - 755.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. G. St. Pierre, P. R. Clark, W. Chua-anusorn, A. J. Fleming, G. P. Jeffrey, J. K. Olynyk, P. Pootrakul, E. Robins, and R. Lindeman
Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance
Blood,
January 15, 2005;
105(2):
855 - 861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction