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    Liver and iron. References concerning MR.
    Yves Gandon - Medical Imaging, Rennes, France.



    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 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 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 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. Radiology 1985;154:137-142.

    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 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 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 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 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 iron overload. 

    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 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 hemochromatosis. 

    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 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 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. 

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