1 - Niederau C; Fischer R; Purschel A; Stremmel W; Haussinger
D; Strohmeyer G. Long-term survival in patients with hereditary
hemochromatosis. Gastroenterology 1996 Apr;110(4):1107-19.
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
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 in hemochromatosis.
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 1992; 102:2050-2059.
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 1989 Sep;97(3):737-43.
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
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. Radiology
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
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
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
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
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
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 both regimens.
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 1995 Sep-Oct;80(5):398-404.
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
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
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
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 35%.
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
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 severe cirrhosis.
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
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 Sep;188(3):637-41.
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
40 - Fujisawa I; Morikawa M; Nakano Y; Konishi J.
Hemochromatosis of the pituitary gland: MR imaging. Radiology 1988
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 Jan-Feb;18(1):136-8.
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 iron deposition.
42 - Noma S; Konishi J; Morikawa M; Yoshida Y. MR
imaging of thyroid hemochromatosis. J Comput Assist Tomogr 1988 Jul-Aug;12(4):623-5.
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 iodine concentration.
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.