1 - Niederau C; Fischer R; Purschel A; Stremmel W; Haussinger D;
Strohmeyer G. Long-term survival in patients
with hereditary hemochromatosis. Gastroenterology 1996
BACKGROUND & AIMS: The course of hereditary hemochromatosis
may depend on the degree of iron overload and the time of therapeutic
intervention. This analysis evaluates the impact of early diagnosis
and iron removal on survival and complications in hereditary hemochromatosis.
METHODS: A Cohort of 251 patients with hemochromatosis was followed
up for 14.1 +/- 6.8 years. RESULTS: Survival was reduced in the
total group of patients when compared with a matched normal population.
Survival in noncirrhotic and nondiabetic patients and in patients
diagnosed between 1982 and 1991 was identical with rates expected.
Survival was reduced in patients with severe iron overload vs. those
with less severe overload. The percentage of early diagnoses increased
threefold between 1947 and 1969 to that between 1970 and 1981; there
was only a further 20%-25% increase in the last decade. Deaths caused
by liver cancer, cardiomyopathy, liver cirrhosis, and diabetes mellitus
were increased as compared with expected rates. Liver cancers were
associated with cirrhosis and amount of mobilizable iron but not
with hepatitis B or C markers. CONCLUSIONS: Prognosis of hemochromatosis
and most of its complications, including liver cancer, depend on
the amount and duration of iron excess. Early diagnosis and therapy
largely prevent the adverse consequences of iron overload.
2 - Brissot P, Bourel M, Herry D, et al. Assessment
of liver iron content in 271 patients: a reevaluation of direct
and indirect methods. Gastroenterology 1981;80: 557-565.
Two direct methods for hepatic iron assessment (liver iron concentration
and stainable liver iron--judged by a new histologic grading) and
three indirect methods (serum iron and transferrin saturation, deferoxamine-chelation
test, and ferritinemia) were reevaluated in 271 patients. These
patients consisted of: 103 with idiopathic hemochromatosis, 39 with
alcoholic cirrhosis, 54 with noncirrhotic alcoholic liver diseases,
13 with nonalcoholic liver diseases, and 62 with miscellaneous disorders.
The results indicate that: (a) liver iron concentration, well correlated
with mobilized excess iron (r = 0.88; p < 0.01), is the method
of reference and validates the proposed histologic grading; (b)
serum ferritin, which is in good correlation with liver iron concentration
(r = 0.80; p < 0.01), is a valuable indirect method for hepatic
iron evaluation; (c) regarding the other indirect methods a "boundary
zone" may be delimited, thus corresponding to liver iron concentration
values of 10.7 mumol/100 mg dry liver weight, beyond which values
of serum iron less than 28.6 micrometer or transferrin saturation
less than 45% or chelatable iron less than 45 mumol/24 h are rare;
and (d) using the various indirect methods, there is a marked risk
in idiopathic hemochromatosis to underestimate and in alcoholic
liver diseases to overestimate hepatic iron content.
3 - Feder JN, Gnirke A, Thomas W, et al. A novel
class I-like gene is mutated in patients with hereditary haemochromatosis.
Nut Genet 1996; 13:399-408.
Hereditary haemochromatosis (HH), which affects some 1 in 400 and
has an estimated carrier frequency of 1 in 10 individuals of Northern
European descent, results in multi-organ dysfunction caused by increased
iron deposition, and is treatable if detected early. Using linkage-disequilibrium
and full haplotype analysis, we have identified a 250-kilobase region
more than 3 megabases telomeric of the major histocompatibility
complex (MHC) that is identical-by-descent in 85% of patient chromosomes.
Within this region, we have identified a gene related to the MHC
class I family, termed HLA-H, containing two missense alterations.
One of these is predicted to inactivate this class of proteins and
was found homozygous in 83% of 178 patients. A role of this gene
in haemochromatosis is supported by the frequency and nature of
the major mutation and prior studies implicating MHC class I-like
proteins in iron metabolism.
4 - Jouanolle AM, Fergelot P, Gandon G, Youanq J, Le Gall JY, David
V. A candidate gene or hemochromatosis: frequence
of the C282y and H63D mutations. Hum Genet 1997; 100:544-547.
The gene whose alteration causes hereditary hemochromatosis (HFE
according to the international nomenclature) was, more than 20 years
ago, shown to map to 6p21.3. It has since escaped all efforts to
identify it by positional cloning strategies. Quite recently, a
gene named HLA-H was reported as being responsible for the disease.
Two missense mutations, Cys282Tyr (C282Y) and His63Asp (H63D), were
observed, but no proof was produced that the gene described is the
hemochromatosis gene. To validate this gene as the actual site of
the alteration causing hemochromatosis, we decided to look for the
two mutations in 132 unrelated patients from Brittany. Our results
indicate that more than 92% of these patients are homozygous for
the C282Y mutation, and that all 264 chromosomes but 5 carry either
mutation. These findings confirm the direct implication of HLA-H
5 - Deugnier Y, Loréal O, Turlin B, et al. Liver
pathology in genetic hemochromatosis: a review of 135 homozygous
cases and their bioclinical correlations. Gastroenterology
6 - Guyader D; Gandon Y; Deugnier Y; Jouanolle H; Loreal O; Simon
M; Bourel M; Carsin M; Brissot P. Evaluation
of computed tomography in the assessment of liver iron overload.
A study of 46 cases of idiopathic hemochromatosis. Gastroenterology
The aim of the present study was to evaluate the effectiveness
of single-energy computed tomography in determining iron overload
in idiopathic hemochromatosis, with special reference to slightly
overloaded cases. Liver attenuation was determined in 100 patients
(46 cases of idiopathic hemochromatosis, 32 cases of chronic liver
disease, and 22 normal controls). The iron load was determined for
the first two groups by biochemical determination of liver iron
concentration (performed in all but 12 subjects in the chronic liver
disease group) and hepatic histologic grading. The main results
for liver attenuation (upper normal limit, 72 Hounsfield units)
showed that despite a high specificity (0.96), this parameter was
of low sensitivity (0.63). Although mean liver attenuation in idiopathic
hemochromatosis (77 +/- 14) was significantly higher than in chronic
liver diseases (53 +/- 17; p less than 10(-4) and normal controls
(66 +/- 3; p less than 10(-3], and despite an overall good correlation
between liver attenuation and liver iron concentration (r = 0.72;
p less than 10(-3], liver attenuation was unable to detect moderate
iron overload. Fourteen of 18 patients with a liver iron concentration
of less than 150 mumol/g dry liver wt had liver attenuation values
of less than 72. Moreover, 3 of 18 subjects with a liver iron concentration
of greater than 150 had a liver attenuation of less than 72. Of
these 17 false-negatives, only 7 could be attributed to associated
steatosis. On the whole, single-energy computed tomography, when
used on a routine basis for diagnosing iron overload, is of limited
clinical value in idiopathic hemochromatosis due to its poor sensitivity.
Hepatic histologic examination together with biochemical determination
remains the most accurate means to assess liver iron.
7 - Stark DD, Bass NM, Moss AA, et al. Nuclear
magnetic resonance imaging of experimentally induced liver disease.
Radiology 1983;148:743-751. .
Experimental animal models of hepatitis, fatty liver, and hepatic
iron overload were evaluated using a 3.5-kGauss nuclear magnetic
resonance (NMR) imaging system. Increases in image intensity measurements
and in T2 relaxation times equalled the sensitivity of histologic
findings for the detection of early stages of hepatitis. A significant
shift in T1 relaxation times characterized the early stages of hepatic
necrosis. Liver triglyceride content correlated significantly with
increases in NMR intensity measurements (p less than 0.01); however,
changes in liver water content had a much greater influence on intensity,
T1, and T2. Thus, it may be possible to distinguish hepatitis from
benign fatty liver. Liver iron content correlated with decreases
in NMR intensity measurements (p less than 0.001), and iron levels
as low as 1.2 mg/g were detected. NMR may more specifically identify
hepatocellular iron overload than do other techniques that do not
distinguish hepatocellular from reticuloendothelial iron.
8 - Brasch RC, Wesbey GE, Gooding CA, Koerper MA. Magnetic
resonance imaging of transfusional hemosiderosis complicating thalassemia
major. Radiology 1984;150:767-771. .
Tissue deposits of hemosiderin, a paramagnetic iron-protein complex,
resulted in marked abnormalities of magnetic resonance (MR) spin-echo
signal intensity within the viscera of three children with transfusional
hemosiderosis and thalassemia major. In all patients the liver and
bone marrow demonstrated abnormally low spin-echo intensities and
the kidneys and muscles had abnormally high intensities. These observations
correlate with in vitro MR observations of ferric (Fe+3) solutions,
in which concentrations of ferric salts greater than 20 mmol yielded
a low MR intensity signal and ferric concentrations less than 15
mmol yielded higher intensities than did water alone. MR imaging
is sensitive to the tissue deposition of hemosiderin, and MR intensity
appears to provide a rough measure of the amount of iron deposited.
9 - Stark DD, Moseley ME, Bacon BR, et al. Magnetic
resonance imaging and spectroscopy of hepatic iron overload.
Experimental animals that had been given excess iron in their diet
were studied by magnetic resonance (MR) imaging in vivo and by magnetic
resonance (MR) spectroscopy in vitro. Hepatic iron overload in patients
with transfusional iron excess was studied by MR imaging, and isolated
iron protein fractions were studied in vitro by MR spectroscopy.
The spin echo image intensity of livers with iron overload was decreased
because of the extreme decreases in T2 compared with normal; T1
was decreased only moderately. The relaxation rates 1/T2 and 1/T1
both showed a linear relationship to hepatic iron levels. Ferritin
solutions showed moderate decreases in T2 and mild decreases in
T1. The T2 relaxivity of ferritin, which is due to the iron core
rather than the apoferritin protein shell, does not appear sufficient
to account for the extreme decrease in T2 observed in hepatic iron
overload. Low molecular weight cytosol iron is present in lower
concentrations than ferritin but potentially has much greater relaxivity
and may contribute to the MR findings. These techniques may be useful
in other studies of iron metabolism.
10 - Hernandez RJ; Sarnaik SA; Lande I; Aisen AM; Glazer GM; Chenevert
T; Martel W. MR evaluation of liver iron
overload. J Comput Assist Tomogr 1988 Jan-Feb;12(1):91-4.
Children and young adults with hemolytic anemias requiring frequent
transfusions develop increased liver iron content. We evaluated
15 chronically transfused children with sickle cell disease to determine
whether spin-echo magnetic resonance (MR) imaging was useful in
assessing the degree of iron overload. Quantitative MR parameters
were correlated with liver biopsy iron determinations and serum
ferritin levels. The best predictor of liver iron was the ratio
of the intensities between the liver and paraspinal musculature
on somewhat T1 weighted sequence (repetition time 0.5 s, echo time
28 ms), R2 = 0.58. Magnetic resonance was able to separate those
patients with liver iron levels greater than 100 micrograms/mg (intensity
ratios approximately 0.4), from those with levels less than 100
micrograms/mg (intensity ratios near 1). However, MR was unable
to quantitate liver iron in patients with values ranging from 100
to 400 micrograms/mg since similar intensity ratios were present
in this range. Thus, MR provides a qualitative rather than quantitative
assessment of liver iron overload.
11 - Johnston DL; Rice L; Vick GW 3d; Hedrick TD; Rokey R.
Assessment of tissue iron overload by nuclear
magnetic resonance imaging. Am J Med 1989 Jul;87(1):40-7.
PURPOSE: The ability of stored intracellular iron to enhance magnetic
susceptibility forms the basis by which tissue iron can be detected
by nuclear magnetic resonance (NMR) imaging. We used this technique
to assess myocardial, spleen, and liver iron content in patients
with known or suspected iron overload disorders. PATIENTS AND METHODS:
Spin echo NMR images were obtained in 30 patients; 20 had chronic
anemias treated by multiple blood transfusions, five had idiopathic
hemochromatosis, and five had non-hemochromatotic liver disease
with elevated serum ferritin levels and no stainable iron on liver
biopsy. The acquisition of oblique images through the short axis
of the left ventricle permitted assessment of left ventricular function,
while demonstrating the liver and spleen on the same image. Iron
content was assessed using a signal intensity ratio of organ (spleen,
liver, or myocardium) to skeletal muscle. RESULTS: In patients with
multiple blood transfusions, iron content was highest in liver,
followed by the spleen. Significant iron overload was detected in
the myocardium of only one patient. Left ventricular systolic wall
thickening was normal in patients receiving multiple blood transfusions.
Two patients with treated idiopathic hemochromatosis had normal
signal intensity ratios, and three untreated patients had evidence
of significant deposits of iron in the liver and spleen as indicated
by a reduction in signal intensity ratios (0.2 +/- 0.01 and 0.9
+/- 0.01, respectively). Five patients with non-hemochromatotic
liver disease and high serum ferritin levels had normal signal intensity
ratios by NMR imaging. CONCLUSION: NMR imaging is a useful method
of detecting tissue iron and distinguishing disease due to iron
overload. Myocardial iron deposition is a late event, occurring
after accumulation of iron in the spleen and liver.
12 - Kaltwasser JP; Gottschalk R; Schalk KP; Hartl W. Non-invasive
quantitation of liver iron-overload by magnetic resonance imaging.
Br J Haematol 1990 Mar;74(3):360-3.
A standard magnetic resonance imaging (MRI) system allowing spin
echo times of 10 ms was used to quantitate liver iron concentration
in nine healthy normal subjects and 13 patients with various grades
of iron overload. Body iron status was estimated by measuring the
serum ferritin concentration. In 11 subjects (two normal healthy
controls, eight patients with HLA-related hereditary haemochromatosis
and one patient with thalassaemia major) non-haem hepatic iron concentration
was determined chemically in biopsy specimens (dry weight), in parallel
to serum ferritin and MRI-T2 relaxation times. A moderate correlation
(r = 0.79) was obtained for the correlation of the T2-relaxation
rate (1/T2) and serum ferritin of the 22 subjects investigated.
A much closer correlation (r = 0.98) was observed for the 1/T2 liver
iron relationship in the 10 subjects analysed by liver biopsy. It
is concluded from these preliminary observations, that MR-imaging
may provide a useful non-invasive tool for the quantitative determination
of liver iron in iron overload-syndromes.
13 - Andersen PB; Birgegard G; Nyman R; Hemmingsson A. Magnetic
resonance imaging in idiopathic hemochromatosis. Eur J
Haematol 1991 Sep;47(3):174-8.
The therapeutic management of patients with idiopathic hemochromatosis
(IH) requires an accurate estimate of hepatic iron overload in order
to prevent tissue fibrosis and organ failure. Magnetic resonance
imaging (MRI) was used to estimate liver iron overload in 5 patients
with IH and in 8 normal controls. Signal intensity ratio between
liver and subcutaneous fat in T1-, proton- and T2-weighted images
was significantly lower in IH when compared with normal controls,
and increased gradually during treatment by phlebotomy. Mean serum
ferritin at diagnosis was 755 micrograms/l (range: 648-900) in IH
and 85 micrograms/l (range: 19-232) in normal controls. A high correlation
(r = -0.93) was present between liver signal intensity ratio and
serum ferritin; both changed in parallel during removal of iron
by phlebotomy. MRI may provide a safe and accurate method of detecting
iron overload in the precirrhotic phase of IH, obviating the need
for liver biopsy. It may also be used to monitor treatment.
14 - Guyader D; Gandon Y; Robert JY; Heautot JF; Jouanolle H; Jacquelinet
C; Messner M; Deugnier Y; Brissot P. Magnetic
resonance imaging and assessment of liver iron content in genetic
hemochromatosis. J Hepatol 1992 Jul;15(3):304-8.
Computed tomography (CT) scanning is not highly sensitive in the
assessment of liver iron content and magnetic resonance imaging
(MRI) appears to be more efficient. The aim of this study was to
determine the effectiveness of MRI in the evaluation of liver iron
content using a standard spin-echo technique. The study included
23 patients with genetic hemochromatosis and 24 non-iron-overloaded
patients as controls. A comparison was made of: (a) MRI signal intensity
of liver, spleen, paravertebral muscles and subcutaneous adipose
tissue using two different spin-echo sequences (SE 500/28; SE 2000/28,56);
(b) liver attenuation determined by a single energy CT scan; and
(c) a biochemical determination of hepatic iron. There was a significant
decrease in liver signal intensity in the genetic hemochromatosis
group (256 +/- 201, mean +/- S.D.) compared with the control group
(801 +/- 413, p less than 0.001), but there was no correlation with
liver iron concentration. However, such a correlation was found
and was even more highly significant than in CT when the ratio between
the liver and another organ was taken into account. For a lower
limit of liver/spleen ratio calculated at 0.46 (mean 2 S.D. in the
control group), the specificity (0.96) of MRI was satisfactory,
but the sensitivity (0.78) remained insufficient (MRI being unable
to detect an iron overload of up to 125 mumol/g). Hopefully, these
results might be improved in the near future by using more sensitive
sequences such as gradient echo sequences.
15 - Kim IY; Mitchell DG; Vinitski S; Consigny PM; Hann HW; Rifkin
MD; Rubin R. MR imaging of hepatic iron
overload in rat. J Magn Reson Imaging 1993 Jan-Feb;3(1):67-70.
To investigate the relationship of hepatic signal intensity and
T2 with histologic grading in an animal model of oral iron overload
and to determine the duration of feeding necessary to produce abnormalities
detectable on magnetic resonance (MR) images, hepatic iron overload
was induced in 12 rats by feeding them a diet supplemented with
4% carbonyl iron for 2-11 weeks. Iron overload seen on MR images
was graded independently and blindly by two radiologists as normal,
mild, moderate, or severe. The rats were killed, and histologic
findings were graded blindly by four pathologists using a similar
subjective scale. Hepatic T2 values were estimated from spin-echo
images. In the rats with iron overload, intracellular iron deposition
was noted on histologic studies. On MR images, hepatic signal intensity
and T2 decreased after only 2 weeks of dietary iron overload, and
both continued to decrease with longer duration of feeding. There
was significant correlation between iron overload duration and changes
on MR images and between MR images and histologic grading (r = .92,
P = .0001 for both). The mean T2 of hepatic iron overload decreased
with longer duration of feeding.
16 - Rocchi E; Cassanelli M; Borghi A; Paolillo F; Pradelli M;
Casalgrandi G; Burani A; Gallo E. Magnetic
resonance imaging and different levels of iron overload in chronic
liver disease. Hepatology 1993 Jun;17(6):997-1002.
The need for accurate and noninvasive evaluation of liver iron
stores prompted us to evaluate the reliability of high-field magnetic
resonance imaging equipment in liver patients with low or moderate
siderosis, given the poor results obtained using systems operating
at low field strength in such cases. Twenty patients with sporadic
porphyria cutanea tarda and 28 with comparable chronic liver diseases
(chronic hepatitis or cirrhosis) and moderate siderosis were compared
with 10 patients with idiopathic or secondary hemochromatosis and
10 healthy controls. Plasma iron profile, ferritin concentration
and liver iron concentration, determined with atomic absorption
spectroscopy, were matched with the magnetic resonance parameters-namely,
transverse relaxation time and the signal intensity for a given
proton amount, obtained with equipment operating at a field strength
of 1.5 T. Hemochromatosis patients with mean liver iron concentrations
of 550 mumol/gm dry wt (vs. 10 mumol of controls) exhibited an impressive
reduction in the signal intensity with respect to the other three
groups, and this reduction prevented any further comparison with
the same porphyria cutanea tarda and chronic liver disease groups,
whose liver iron level was twice that of the controls. The signal
intensity remained almost unchanged in the latter groups, whereas
the transverse relaxation time was significantly reduced. Moreover,
correlation with liver iron was significantly inverse in the case
of the transverse relaxation time (n = 17, r = 0.62, p = 0.008)
and direct in the case of the transverse relaxation rate. The transverse
relaxation time values returned to normal in five patients who had
completed an iron-depletion program.(ABSTRACT TRUNCATED AT 250 WORDS).
17 - Bondestam S; Lamminen A; Anttila VJ; Ruutu T; Ruutu P.
Magnetic resonance imaging of transfusional hepatic
iron overload. Br J Radiol 1994 Apr;67(796):339-41.
The transfusional iron overload in 11 adult patients suffering
from haematological malignancy was studied in 14 consecutive 1.0
Tesla magnetic resonance imaging (MRI) studies. Routine T1- and
T2-weighted spin echo sequences and a fat suppressed sequence (STIR)
were used. The ratio from a region of interest of the liver parenchyma
and from a manganese chloride reference phantom was measured. There
was a definite difference between the signal ratio from the haematological
patient group and the control group (p = 0.0001). The patients showed
a diminished signal ratio in all pulse sequences used. There was
a statistically significant inverse linear correlation between the
number of transfused red cell units and the signal ratio in the
T1-weighted (p = 0.03) and the T2-weighted (p = 0.03) images. A
definite decrease of the effect is found after 20-30 red cell unit
transfusions in T2-weighted and STIR images.
18 - Dixon RM; Styles P; al-Refaie FN; Kemp GJ; Donohue SM; Wonke
B; Hoffbrand AV; Radda GK; Rajagopalan B. Assessment
of hepatic iron overload in thalassemic patients by magnetic resonance
spectroscopy. Hepatology 1994 Apr;19(4):904-10.
The transverse relaxation time of water protons is shortened by
the presence of iron. This shortening depends on the amount and
the environment of iron in the sample. We have developed a method
for measuring short transverse relaxation time noninvasively by
magnetic resonance spectroscopy. To evaluate magnetic resonance
spectroscopy as a means of assessing hepatic iron content in patients
with transfusional iron overload, we compared the results obtained
with this method with those obtained by other means of assessing
total body iron content. The correlation between the liver biopsy
iron concentration and 1/transverse relaxation time was highly significant
(r = 0.95, p 0.004, n = 6) for iron loads up to 3% dry weight. The
correlation between serum ferritin and 1/transverse relaxation time
was also significant, but the correlation coefficient was much lower
(r = 0.67, p 0.002, n = 20). The correlation between 24-hr urinary
iron excretion and 1/transverse relaxation time was not significant,
nor was that between AST and 1/transverse relaxation time. We conclude
that magnetic resonance spectroscopic determination of the transverse
relaxation time of hepatic water is an accurate method of measuring
liver iron content, especially when the iron content is below 3%.
Because it is a noninvasive method that is associated with negligible
side effects, it could provide clinicians with an excellent means
of assessing the effectiveness of the various therapeutic strategies
used in the management of patients with iron overload.
19 - Jensen PD; Jensen FT; Christensen T; Ellegaard J. Non-invasive
assessment of tissue iron overload in the liver by magnetic resonance
imaging. Br J Haematol 1994 May;87(1):171-84.
We investigated the clinical usefulness of a standard magnetic
resonance imaging (MRI) system for non-invasive determination of
the liver iron concentration in 38 patients with iron overload and
15 normal controls by measurement of the signal intensity ratio
between liver and skeletal muscle (SIR). However, SIR was found
dependent on the applied repetition time (TR) of the MRI system,
which led us to investigate this relationship in autopsy material
of liver and muscle tissue specimens with various iron content.
Based on these results, adjustment of SIR measurements to a constant
value of TR was achieved. By use of this technique we found a close
correlation between MRI and chemically determined liver iron concentration
(r2 = 0.98) as well as the serum ferritin concentration (r2 = 0.86).
The reproducibility was sufficiently good for the use of MRI in
the follow-up of iron reductive treatment. The use of iron store
parameters in serum was found insufficient as indicators of endpoint
for venesection therapy, if 20 mumol Fe/g dry weight was applied
as the upper reference limit of the liver iron concentration. It
is concluded that MRI based on SIR measurements offers a precise
and reproducible non-invasive method for the determination and follow-up
of iron overload within a wide range of liver iron concentrations.
Our findings may increase the clinical use of MRI in haematological
patients with iron overload.
20 - Engelhardt R; Langkowski JH; Fischer R; Nielsen P; Kooijman
H; Heinrich HC; Bucheler E. Liver iron
quantification: studies in aqueous iron solutions, iron overloaded
rats, and patients with hereditary hemochromatosis. Magn
Reson Imaging 1994;12(7):999-1007.
For the noninvasive liver iron quantification by MRI in human iron
overload diseases, fundamental proton relaxation mechanisms were
studied in aqueous solutions with ferritin and other iron compounds,
in experimentally iron overloaded rats, and in patients with iron
overload diseases. MR-relaxation rates as a function of iron concentrations
in the range of 0-7.5 mg Fe/g aqueous iron solutions, 0-5.4 mg Fe/g
rat liver in vivo, and 0.16-4.9 mg Fe/g human liver in vivo were
determined from multi- and sets of single-spin echo sequences (1.5
T imager). As predicted by theory, transverse relaxation rates (1/T2)
in aqueous iron solutions, in liver tissue of rats, and in human
liver tissue increased linearly with the iron concentration. A preliminary
calibration for the liver iron quantification by MRI was performed
from in vivo measurements of liver 1/T2-relaxation rates and liver
iron quantification by atomic absorption spectroscopy in biopsies
from 13 patients. With the single spin-echo method, precise in vivo
liver iron quantification in humans also above 2.0 mg Fe/g liver
tissue (T2 15 ms) should be accomplished on any imager with shortest
spin-echo time available, at least TE 20 ms.
21 - Jensen PD; Jensen FT; Christensen T; Ellegaard J. Evaluation
of transfusional iron overload before and during iron chelation
by magnetic resonance imaging of the liver and determination of
serum ferritin in adult non-thalassaemic patients. Br
J Haematol 1995 Apr;89(4):880-9.
The ability to quantitate transfusional iron overload is crucial
for determining the need for and the efficacy of chelation therapy
in patients with long-standing transfusion-dependent anaemias. We
evaluated the usefulness of some indirect measures of iron overload
in estimating the iron concentration in the liver--the most important
iron storage organ--in 26 non-chelated adult non-thalassaemic patients.
Liver iron concentration was determined non-invasively by magnetic
resonance imaging (MRI). The standard error of the estimated liver
iron concentration was 80 mumol Fe/g dried liver tissue when using
the number of transfused blood units, and 93 mumol Fe/g when using
a serum ferritin assay. Follow-up in 11 patients (12-48 months)
revealed that serum ferritin is a poor measure of the liver iron
concentration during iron chelation. However, this discrepancy was
individually different and seemed to be dependent on the erythropoietic
marrow activity. By monitoring the liver iron concentration by MRI,
we compared the efficacy of chelation with desferrioxamine given
either by subcutaneous continuous infusions or by bolus injections.
Depletion of liver iron stores could be achieved efficiently by
22 - Mazza P; Giua R; De Marco S; Onetti MG; Amurri B; Masi C;
Lazzari G; Rizzo C; Cervellera M; Peluso A; et al. Iron
overload in thalassemia: comparative analysis of magnetic resonance
imaging, serum ferritin and iron content of the liver. Haematologica
BACKGROUND: Iron overload in patients with thalassemia is a common
feature which requires continuous chelation therapy and monitoring.
Serum ferritin determination is widely accepted as a simple method
for following iron load in patients with primary hemochromatosis;
however, several reports on thalassemic patients emphasize that
ferritinemia is not accurate and that other methods such as direct
measurement of iron in the liver (HIC) and magnetic resonance imaging
(MRI) are more precise. MATERIALS AND METHODS: In order to contribute
to the general understanding of iron load in thalassemia we used
liver MRI to study 33 thalassemic patients, most of whom were also
evaluated for iron content by liver biopsy. The data were then compared
with serum ferritin levels. RESULTS: Ferritin levels ranged between
276 and 8031 ng/mL, and liver iron content ranged from 1.6 to 31.0
mg/g dry weight; grade III or IV liver siderosis was recorded in
23/33 patients, just as 23/33 patients were found to have severe
or very severe siderosis at MRI. Significant correlations with ferritin
levels were recorded between grade IV and grades III, II and I (p
0.01, p = 0.02, and p = 0.03, respectively). Ferritinemia also showed
significant linearity with liver iron content (r = 0.603, p = 0.001).
No significant differences of levels were recorded, however, between
patients found to have severe and those with mild iron load at MRI
(p = 0.073). CONCLUSIONS: Our study shows that serum ferritin levels
exhibit a tendency to be significantly correlated with the true
status of hemochromatosis in thalassemic patients; however, the
discrepancies recorded in several patients and the scarce or total
lack of correlation with MRI suggest exploring other approaches
to this problem in order to make proper decisions about therapy.
23 - Onetti MG; Castriota-Scanderbeg A; Criconia GM; Mazza P; Sacco
M; Amurri B; Masi . Hepatic iron overload
in thalassemic patients: proposal and validation of an MRI method
of assessment. Pediatr Radiol 1996 Sep;26(9):650-6.
BACKGROUND: A simple, accurate, reproducible and noninvasive method
of body iron overload assessment would be of great clinical use.
Objective. The purpose of the study was the implementation of a
0. 5-T MRI method for liver iron overload measurement. MATERIALS
AND METHODS: Thirty patients with thalassemia major took part in
the study. Liver and paraspinal muscle signal intensity (SI) measurements
were performed on T1-weighted images and normalized on a standard
phantom, and a subjective hemochromatosis grading scale was made
on both T1- and T2-weighted images. Serum ferritin levels and tissue
iron from liver biopsy specimens were determined for comparison.
RESULTS: A close correlation was found between bioptic liver iron
and both the liver-to-phantom SI ratio (r = -0.88) and the subjective
grading scale (rho = 0.89). Serum ferritin correlated poorly with
liver iron deposition, whether assessed by biopsy (r = 0. 62) or
MRI (r = -0.69). CONCLUSIONS: Both the subjective and the quantitative
MRI methods proposed here are clinically valuable, with the former
being adequate for a gross, the latter for an accurate estimation
of tissue iron overload.
24 - Lawrence SP; Caminer SJ; Yavorski RT; Borosky BD; Rak KM;
Merenich JA; McDermott MT; McNally PR. Correlation
of liver density by magnetic resonance imaging and hepatic iron
levels. A noninvasive means to exclude homozygous hemochromatosis.
J Clin Gastroenterol 1996 Sep;23(2):113-7.
The diagnosis of hemochromatosis requires liver biopsy and the
quantification of hepatic iron. Magnetic resonance imaging (MRI)
of the liver shows a characteristic decrease in tissue signal intensity
in iron overload states, but its role in the diagnosis of hemochromatosis
has not been fully delineated. Forty-three patients (31 men and
12 women) were referred for the evaluation of hemochromatosis based
upon a fasting transferrin saturation 55% and/or a serum ferritin
400 ng/ml in males or 300 ng/ml in females. Each patient prospectively
underwent MRI of the liver prior to percutaneous liver biopsy and
quantitative hepatic iron determination. Homozygous hemochromatosis
was diagnosed in 10 patients based upon an hepatic iron/age index
or = 2. MRI was performed with a 1.5 Tesla system using standard
spin-echo sequences (T1; TR = 300-500 ms, TE = 13-17 ms, PD; TR
= 2,000-2,600 ms, TE = 30 ms). Signal intensity values were blindly
determined for regions of interest in liver and skeletal muscle
at T1 and proton density. Ratios of liver to muscle (LM) for T1
and proton density (PD) calculated from these values showed a significant
correlation with quantitative iron by multiple regression analysis.
The LMPD ratio provided the best correlation with hepatic iron (r
= -0.6946; p 0.001). Linear regression analysis also provides an
equation that can be used to predict hepatic iron based upon the
LMPD ratio; micrograms/g of hepatic iron = (-5,174 x LMPD) + 9,932.
All patients with LMPD ratios of 0.5 had hepatic iron/age indices
of 2.0, thereby excluding homozygous hemochromatosis. These results
suggest that LMPD ratios derived from MRI of the liver can accurately
predict hepatic iron content. These ratios can be clinically useful
in the evaluation of hemochromatosis among patients who either refuse
or have contraindications to liver biopsy.
25 - Macfarlane JD; Vreugdenhil GR; Doornbos J; van der Voet GB.
Idiopathic haemochromatosis: magnetic resonance signal intensity
ratios permit non-invasive diagnosis of low levels of iron overload.
Neth J Med 1995 Aug;47(2):49-53.
OBJECTIVE: The detection of low levels of iron overload by magnetic
resonance imaging. METHODS: Eight consecutive patients suspected
of having idiopathic haemochromatosis. Comparison of signal intensity
ratios and absolute iron content of liver. RESULTS: There was a
good correlation between the signal intensity ratios and iron content
in the range 2-30 micrograms Fe/mg dry weight. CONCLUSIONS: The
ability of a non-invasive technique to detect low levels of iron
overload could be useful in the assessment of therapy and in the
screening of relatives of probands with idiopathic haemochromatosis.
26 - Thomsen C; Wiggers P; Ring-Larsen H; Christiansen E; Dalhoj
J; Henriksen O; Christoffersen P. Identification
of patients with hereditary haemochromatosis by magnetic resonance
imaging and spectroscopic relaxation time measurements. Magn
Reson Imaging 1992;10(6):867-79.
A total of 4302 healthy blood donors were screened for elevated
serum ferritin and transferrin saturation. Fifteen had increased
serum ferritin at a follow-up examination. Five relatives of these
donors also entered the study. Eleven patients had elevated liver
iron concentrations, while five had normal liver iron concentrations.
The R2 relaxation rate in the liver was first measured with a conventional
multi-spin-echo imaging sequence, and then by a volume-selective
spectroscopic multi-spin-echo sequence, in order to achieve a minimum
echo time of 4 msec. No correlation was found between the relaxation
rate R2 and the liver iron concentration, when R2 was calculated
from the imaging data. Multi-exponential transverse relaxation could
be resolved when the spectroscopic sequence was used. A strong correlation
between the initial slope of the relaxation curve and the liver
iron concentration was found (r = 0.90, p 0.001). Signal intensity
ratios between liver and muscle were calculated from the first three
echoes in the multi-echo imaging sequence, and from a gradient echo
sequence. A strong correlation between the logarithm of the signal
intensity ratios and the liver iron concentration was found. Although
both spectroscopic T2 relaxation time measurements and signal intensity
ratios could be used to quantify liver iron concentration, the gradient
echo imaging seemed to be the best choice. Gradient echo imaging
could be performed during a single breath hold, so motion artifacts
could be avoided. The accuracy of liver iron concentration estimates
from signal intensity ratios in the gradient echo images was about
27 - Gandon Y; Guyader D; Heautot JF; Reda MI; Yaouanq J; Buhe
T; Brissot P; Carsin M; Deugnier Y. Hemochromatosis:
diagnosis and quantification of liver iron with gradient-echo MR
imaging. Radiology 1994 Nov;193(2):533-8.
PURPOSE: To assess the role of magnetic resonance (MR) imaging
in detection and quantification of liver iron overload. MATERIALS
AND METHODS: MR imaging at 0.5 T was prospectively performed on
77 patients (67 with liver iron overload and 10 without) who underwent
a liver biopsy with biochemical determination of the liver iron
concentration (LIC) (normal, 36 mumol per gram of liver tissue [dry
weight]). Ratios of signal intensities and liver T2 relaxation time
were calculated from images obtained with spin-echo and breath-hold
gradient-echo (GRE) sequences. RESULTS: Liver-to-tissue signal intensity
ratios were better correlated with LIC than T2 relaxation time.
Long-echo-time GRE sequences were the most sensitive for detection
of slight overload. Thus, high sensitivity (94%) and specificity
(90%) were obtained with a liver-to-fat ratio threshold of 1. The
quantification of iron with MR imaging was accurate when the LIC
was 80-300 mumol/g. For heavy overload, above 300 mumol/g, quantification
was impossible owing to complete signal loss. Pancreatic and splenic
signal intensity were unchanged in most cases. CONCLUSION: This
method, which can be improved by using more sensitive sequences
with a high-field-strength system, should be competitive with biopsy
for the diagnosis of substantial liver iron overload.
28 - Ernst O; Sergent G; Bonvarlet P; Canva-Delcambre V; Paris
JC; L'Hermine . Hepatic iron overload:
diagnosis and quantification with MR imaging. AJR Am J
Roentgenol 1997 May;168(5):1205-8.
OBJECTIVE: The aim of this study was to assess the sensitivity
of MR imaging in the diagnosis of liver hemochromatosis and its
ability to quantify hepatic iron concentration (HIC). SUBJECTS AND
METHODS: MR images were prospectively obtained in 58 patients suspected
to have hemochromatosis. We used a scanner with a 0.5-T magnet and
two sequences: gradient-echo T1-weighted (400/12 [TR/TE], 90 degrees
flip angle) and gradient-echo T2*-weighted (700/30, 30 degrees flip
angle) sequences. Measurement of the liver-to-muscle signal-intensity
ratio was compared with the HIC value measured at biopsy for each
patient. RESULTS: Both MR sequences showed significant correlation
between decreased signal-intensity ratios and increased HIC (r =
-.87 for T1-weighted sequences and r = -.74 for T2*-weighted sequences).
The sensitivity and specificity of the T2*-weighted sequence (signal-intensity
ratio 0.8) to detect iron overload (HIC 36 mumol/g) were 91% and
88%, respectively. The best correlation was obtained with T2*-weighted
sequences, when patients had an HIC less than 100 mumol/g (r = -.71);
with T1-weighted sequences, the best correlation was obtained when
patients had an HIC of 100-324 mumol/g (r = -.67). We found a significant
correlation between the HIC revealed on MR images, calculated from
both sequences, and that measured at biopsy when patients had an
HIC of less than 300 mumol/g (r = -.93, p .01). CONCLUSION: MR imaging
shows promise in differentiating normal from abnormal hepatic iron
concentration and in grossly quantifying moderate degrees of hepatic
29 - Siegelman ES; Mitchell DG; Semelka R. Abdominal
iron deposition: metabolism, MR findings, and clinical importance.
Radiology 1996 Apr;199(1):13-22.
30 - Art in phase.
31 - Siegelman ES. MR imaging of diffuse
liver disease. Hepatic fat and iron. Magn Reson Imaging
Clin N Am 1997 May;5(2):347-65.
This article reviews the various disorders that result in abnormal
iron and fat within the liver. MR techniques that detect and characterize
fat and iron are discussed. Chemical shift images are useful in
detecting intracellular lipid and can characterize diffuse hepatic
steatosis as well as focal areas of fatty sparing and fatty infiltration.
T2*-weighted gradient-echo sequences are useful in detecting hepatic
iron. Typical imaging features of genetic hemochromatosis and hepatic
iron from blood transfusions are described.
32 - Villeneuve JP; Bilodeau M; Lepage R; Cote J; Lefebvre M.
Variability in hepatic iron concentration measurement
from needle-biopsy specimens. J Hepatol 1996 Aug;25(2):172-7.
BACKGROUND/AIM: Quantitative measurement of hepatic iron by biochemical
analysis of liver biopsy samples is required to assess hepatic iron
stores accurately. Cirrhotic livers, however, contain variable amounts
of fibrous tissue and the distribution of iron within the hepatic
parenchyma is not always uniform. The aim of this study was to assess
the variability in hepatic iron concentration measurement from needle-biopsy
specimens. METHODS: The livers from eight patients with cirrhosis
selected because of elevated serum ferritin were obtained at the
time of liver transplantation (n = 6) or at autopsy (n = 2). Multiple
needle biopsies were done, and hepatic iron concentration was measured
by atomic absorption spectroscopy. The hepatic iron index was calculated
as iron concentration divided by age. RESULTS: Four cases had a
mean hepatic iron index above 2.0, in the range of that reported
in patients with homozygous genetic hemochromatosis, whereas the
other four had an hepatic iron index of less than 2.0. The intra-individual
coefficient of variation for hepatic iron concentration ranged from
11.3 to 43.7%, averaging 24.9%. The coefficient of variation was
smaller in biopsy samples 4 mg dry weight than in samples 4 mg (19.8%
vs 28.6%, p 0.05). Histological examination of surgical biopsies
from these livers showed large amounts of fibrous tissue, and inhomogeneous
distribution or iron in the hepatic parenchyma. CONCLUSIONS: This
study demonstrates an important variability in the measurement of
hepatic iron content from needle biopsy specimens in patients with
33 - Ludwig J; Hashimoto E; Porayko MK; Moyer TP; Baldus WP.
Hemosiderosis in cirrhosis: a study of 447 native
livers. Gastroenterology 1997 Mar;112(3):882-8.
BACKGROUND & AIMS: Hemosiderosis may have a detrimental effect
on some chronic liver diseases. The aim of this study was to determine
the prevalence and diagnostic implications of hemosiderosis in cirrhosis.
METHODS: Tissue iron in 447 cirrhotic livers was studied histologically
and chemically. RESULTS: Positive iron staining was found in 145
cases (32.4%), and increased chemical hepatic iron concentration
was found in 91 cases (20.3%), including 38 cases (8.5%) with hepatic
iron overload in the hemochromatosis range, defined by an iron index
of or = 1.9 (iron index equals hepatic iron concentration in micromoles
per gram divided by age). However, homozygous hemochromatosis seemed
to have caused the cirrhosis in only 5 instances. Stainable iron
was found in 22%-67% of the cases with nonbiliary cirrhosis but
in only 7%-20% of cases with biliary cirrhosis. Most available pretransplant
biopsy specimens failed to show evidence of homozygous hemochromatosis.
CONCLUSIONS: Iron overload is very common in many types of nonbiliary
cirrhosis but rare in biliary cirrhosis. The hemosiderosis of affected
livers seems to be acquired and to occur rapidly once cirrhosis
has developed; cirrhosis alone may cause iron accumulation. In the
presence of cirrhosis, hepatic iron indices of 1.9 should not be
interpreted as proof of homozygous hemochromatosis.
34 - Marti-Bonmati L; Baamonde A; Poyatos CR; Monteagudo E.
Prenatal diagnosis of idiopathic neonatal hemochromatosis
with MRI. Abdom Imaging 1994 Jan-Feb;19(1):55-6.
Intrauterine diagnosis of perinatal hemochromatosis is difficult.
Noninvasive detection of hepatic iron deposition is crucial. We
report the first case diagnosed intrauterine with magnetic resonance
imaging (MRI). By visual analysis, if the fetal liver is less intense
than maternal or fetal fat signal for T2* gradient echo image, hemochromatosis
should be suggested.
35 - Kadoya M; Matsui O; Kitagawa K; Kawamori Y; Yoshikawa J; Gabata
T; Miyayama S; Takashima T. Segmental iron
deposition in the liver due to decreased intrahepatic portal perfusion:
findings at MR imaging. Radiology 1994 Dec;193(3):671-6.
PURPOSE: To evaluate the causes of intrahepatic segmental areas
of signal hypointensity [corrected] on T1- and T2-weighted spin-echo
(SE) and gradient-echo (GRE) magnetic resonance (MR) images. MATERIALS
AND METHODS: Six patients in whom wedge-shaped hypointense areas
were seen on hepatic MR images underwent examination with ultrasound
(US), computed tomography (CT), angiography, and CT during arterial
portography (CTAP). Histologic examination was performed in three
patients. RESULTS: The affected liver parenchymas were best depicted
as segmental or lobar hypointense areas on GRE images. Angiography
and CTAP revealed that portal blood supply to the hypointense areas
was absent or decreased due to portal vein tumor thrombus and arterioportal
shunt (n = 1), compression of a portal branch by tumor (n = 2),
portal vein thrombosis (n = 1), or arterioportal shunt (n = 2).
Iron deposition in the hepatocytes was evident in all three patients
with histologic correlation. CONCLUSION: Segmental signal hypocoagulability
was generally due to hepatocyte iron deposition and was accompanied
and possibly caused by a disturbance in portal flow.
36 - Guyader Gandon 98.
37 - Yoon DY; Choi BI; Han JK; Han MC; Park MO; Suh SJ. MR
findings of secondary hemochromatosis: transfusional vs erythropoietic.
J Comput Assist Tomogr 1994 May-Jun;18(3):416-9.
OBJECTIVE: The aim of this study was to demonstrate the MR characteristics
of secondary hemochromatosis (transfusional versus erythropoietic).
MATERIALS AND METHODS: Magnetic resonance images of five patients
with transfusional (n = 3) or erythropoietic (n = 2) hemochromatosis
were reviewed. RESULTS: The liver of all patients had low signal
intensity in all pulse sequences. The spleen had low signal intensity
in all patients with transfusional iron overload, but normal signal
intensity in erythropoietic hemochromatosis, which had similar MR
findings to idiopathic hemochromatosis. However, the pancreas had
variable signal intensity. CONCLUSION: On MRI the signal intensity
of the spleen may allow distinction between transfusional and erythropoietic
38 - Siegelman ES; Mitchell DG; Rubin R; Hann HW; Kaplan KR; Steiner
RM; Rao VM; Schuster SJ; Burk DL Jr; Rifkin MD. Parenchymal
versus reticuloendothelial iron overload in the liver: distinction
with MR imaging. Radiology 1991 May;179(2):361-6.
Parenchymal iron deposition occurs in hemochromatosis, while iron
is deposited in reticuloendothelial (RE) cells after blood transfusions
or rhabdomyolysis. Magnetic resonance images of patients with decreased
liver signal intensity on T2-weighted images at 1.5 T were blindly
compared in an effort to distinguish these conditions. In each of
five patients with hemochromatosis, the pancreas had low signal
intensity, but splenic signal intensity was decreased in only one.
In contrast, only three of the 16 patients with RE iron overload
had low pancreatic signal intensity, while all of these patients
either had low splenic signal intensity (n = 14) or previously underwent
splenectomy (n = 2). Distinction among these causes of iron deposition
is clinically important because parenchymal iron overload from hemochromatosis
may produce significant tissue damage, while the RE iron of transfusions
and rhabdomyolysis is of little clinical consequence.
39 - Siegelman ES; Mitchell DG; Outwater E; Munoz SJ; Rubin R.
Idiopathic hemochromatosis: MR imaging findings
in cirrhotic and precirrhotic patients. Radiology 1993
The authors reviewed T2-weighted and T2*-weighted abdominal magnetic
resonance (MR) images in 19 pathology-proved cases of hepatic iron
overload to compare patterns of iron distribution among cirrhotic
and precirrhotic patients with idiopathic hemochromatosis (IH),
as well as nontransfusional hepatic siderosis of other causes. Fifteen
patients had clinical and laboratory evidence of IH. Four patients
without IH had cirrhosis with moderate siderosis. In the MR images
of all 19 patients, the liver had low signal intensity. The pancreas
of 10 of 11 cirrhotic patients with IH had low signal intensity.
All four precirrhotic patients with IH and all four cirrhotic patients
without IH had pancreas with normal signal intensity at MR. Thus,
pancreatic signal intensity was decreased only in cirrhotic patients
with IH in this limited series. Conversely, pancreatic signal intensity
is often normal in precirrhotic patients with IH prior to the development
of cirrhosis, a stage at which definitive diagnosis by means of
quantitative liver biopsy is important because early phlebotomy
may prevent morbidity and mortality from IH. In cirrhotic patients
with MR evidence of increased hepatic iron, the cause of cirrhosis
is less likely to be IH if pancreatic signal intensity is normal.
40 - Fujisawa I; Morikawa M; Nakano Y; Konishi J. Hemochromatosis
of the pituitary gland: MR imaging. Radiology 1988 Jul;168(1):213-4.
Magnetic resonance imaging of the pituitary gland in a patient
with secondary hemochromatosis is described. On T1-weighted images,
the anterior lobe had almost no signal intensity, and only the high-signal
posterior lobe was seen. These findings are compatible with the
distribution of iron deposition and clinical symptoms in hemochromatosis.
41 - Blankenberg F; Eisenberg S; Scheinman MN; Higgins CB.
Use of cine gradient echo (GRE) MR in the imaging
of cardiac hemochromatosis. J Comput Assist Tomogr 1994
This case report describes the MR appearance of cardiac iron deposition
using spin echo and cine gradient echo imaging (GRE) in a young
man with secondary hemochromatosis. The ratio of the signal intensity
of left ventricular myocardium to skeletal muscle was abnormally
low on both spin echo and GRE compared with normal. The abnormally
low myocardial signal was most severe on the cine gradient echo
sequence. Cine GRE can be used to establish the diagnosis of cardiac
42 - Noma S; Konishi J; Morikawa M; Yoshida Y. MR
imaging of thyroid hemochromatosis. J Comput Assist Tomogr
We present the magnetic resonance (MR) images of exogenous hemochromatosis
in the thyroid gland. On both T1-weighted images and T2-weighted
images the thyroid showed low intensity similar to that of the background.
Magnetic resonance is of value in imaging the tissue deposition
of iron. In assessing thyroid iron accumulation, MR is superior
to CT because CT can not differentiate iron deposition from normal
43 - Housman JF; Chezmar JL; Nelson R. Magnetic
resonance imaging in hemochromatosis: extrahepatic iron deposition.
Gastrointest Radiol 1989 Winter;14(1):59-60.
The magnetic resonance (MR) appearance of the liver in hemochromatosis
has been previously described. We report a case in which iron deposition
in the pancreas, spleen, and lymph nodes is demonstrated by MR.