Excessive Iron Deposition Research Articles

Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)

Iron is essential for all living organisms. Under normal conditions there is no regulatory and rapid iron excretion in humans and body iron levels are mainly regulated from the absorption of iron from the gut. Regular blood transfusions in thalassaemia and other chronic refractory anaemias can result in excessive iron deposition in tissues and organs. This excess iron is toxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically transfused. Iron removal in transfusional iron overload is achieved using chelation therapy with the chelating drugs deferoxamine (DF) and deferiprone (L1). Effective chelation therapy in chronically transfused patients can only be achieved if iron chelators can remove sufficient amounts of iron, equivalent to those accumulated in the body from transfusions, maintaining body iron load at a non-toxic level. In order to maintain a negative iron balance, both chelating drugs have to be administered almost daily and at high doses. This form of administration also requires that a chelator has low toxicity, good compliance and low cost. DF has been a life-saving drug for thousands of patients in the last 40 years. It is mostly administered by subcutaneous infusion (40–60 mg/kg, 8–12 h, 5 days per week), is effective in iron removal and has low toxicity. However, less than 10% of the patients requiring iron chelation therapy worldwide are able to receive DF because of its high cost, low compliance and in some cases toxicity. In the last 10 years we have witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all transfusional iron-loaded patients. The only clinically available oral iron chelator is L1, which has so far been taken by over 6000 patients worldwide, in some cases daily for over 10 years, with very promising results. L1 was able to bring patients to a negative iron balance at doses of 50–120 mg/kg/day. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in the majority of chronically transfused iron-loaded patients. Despite earlier concerns of possible increased risk of toxicity, all the toxic side effects of L1 are currently considered reversible, controllable and manageable. These include agranulocytosis (0.6%), musculoskeletal and joint pains (15%), gastrointestinal complaints (6%) and zinc deficiency (1%). The incidence of these toxic side effects could in general be reduced by using lower doses of L1 or combination therapy with DF. Combination therapy could also benefit patients experiencing toxicity with DF and those not responding to either chelator alone. The overall efficacy and toxicity of L1 is comparable to that of DF in both animals and humans. Despite the steady progress in iron chelation therapy with DF and L1, further investigations are required for optimising their use in patients by selecting improved dose protocols, by minimising their toxicity and by identifying new applications in other diseases of iron imbalance.

Heme oxygenase-1: role in brain aging and neurodegeneration.

The mechanisms responsible for excessive iron deposition and mitochondrial insufficiency in the aging and degenerating nervous system remain poorly understood. Heme oxygenase-1 (HO-1) is a 32kDa stress protein that degrades heme to biliverdin, free iron and carbon monoxide. Our laboratory has shown that cysteamine, dopamine, beta-amyloid, IL-1beta and TNF-alpha up-regulate HO-1 followed by mitochondrial sequestration of non-transferrin-derived 55Fe in cultured rat astroglia. In these cells and in rat astroglia transfected with the human HO-1 gene, mitochondrial iron trapping is abrogated by the HO-1 inhibitors, tin-mesoporphyrin and dexamethasone. We determined that HO-1 immunoreactivity is enhanced greatly in neurons and astrocytes of the hippocampus and cerebral cortex of Alzheimer subjects and co-localizes to senile plaques and neurofibrillary tangles (NFT). HO-1 staining is also augmented in astrocytes and decorates neuronal Lewy bodies in the Parkinson nigra. Collectively, our findings suggest that HO-1 over-expression contributes to the pathological iron deposition and mitochondrial damage documented in these aging-related neurodegenerative disorders. We recently observed that, paradoxically, HO-1 mRNA levels are markedly suppressed in peripheral lymphocytes of patients with early sporadic Alzheimer disease and may thus provide a useful biological marker of this condition.

Alternative RNA Splicing Generates a Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin in Mammalian Brain

Ceruloplasmin is a copper-containing ferroxidase that is essential for normal iron homeostasis. Whereas ceruloplasmin in plasma is produced and secreted by hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is expressed on the surface of astrocytes. By using a cDNA cloning approach, we have now determined that the GPI-anchored form of ceruloplasmin is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the C-terminal 5 amino acids of the secreted form with an alternative 30 amino acids that signal GPI anchor addition. RNase protection analysis demonstrates that the GPI-anchored form is the major form in the brain, whereas the secreted form predominates in the liver. Individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin, have severe iron deposition in a number of organs, including the brain where it results in neurodegeneration. Therefore, this novel GPI-anchored form of ceruloplasmin is likely to play an important role in iron metabolism in the central nervous system.

A population-based study of the clinical expression of the hemochromatosis gene.

Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. Sixteen of the subjects (0.5 percent) were homozygous for the C282Y mutation, and 424 (14.1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. In a population of white adults of northern European ancestry, 0.5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

Mitochondrial iron sequestration in dopamine-challenged astroglia: role of heme oxygenase-1 and the permeability transition pore.

Little is currently known concerning the mechanisms responsible for the excessive deposition of redox-active iron in the substantia nigra of subjects with Parkinson's disease (PD). In the present study, we demonstrate that dopamine promotes the selective sequestration of non-transferrin-derived iron by the mitochondrial compartment of cultured rat astroglia and that the mechanism underlying this novel dopamine effect is oxidative in nature. We also provide evidence that up-regulation of the stress protein heme oxygenase-1 (HO-1) is both necessary and sufficient for mitochondrial iron trapping in dopamine-challenged astroglia. Finally, we show that opening of the mitochondrial transition pore (MTP) mediates the influx of non-transferrin-derived iron into mitochondria of dopamine-stimulated and HO-1-transfected astroglia. Our findings provide an explanation for the pathological iron sequestration, mitochondrial insufficiency, and amplification of oxidative injury reported in the brains of PD subjects. Pharmacological blockade of transition metal trapping by "stressed" astroglial mitochondria (e.g., using HO-1 inhibitors or modulators of the MTP) may afford effective neuroprotection in patients with PD and other neurological afflictions.

Interrelationships of alcohol and iron in liver disease with particular reference to the iron-binding proteins, ferritin and transferrin.

It is known that the regular consumption of alcohol is responsible for the disruption of normal iron metabolism in humans, resulting in the excess deposition of iron in the liver in approximately one-third of alcoholic subjects. The mechanisms involved are largely unknown; however, it is likely that the two major proteins of iron metabolism, ferritin and transferrin are intimately involved in the process. Tissue damage in alcoholic liver disease and the inherited iron-overload disease, haemochromatosis, are caused by excess alcohol and iron, respectively. The mechanisms of this damage are believed to be similar in both disease conditions and involve free radical-mediated toxicity. A high proportion of haemochromatosis sufferers consume excessive amounts of alcohol and synergistic hepatotoxic events may occur leading to the earlier development of liver cirrhosis. This review describes briefly the role of ferritin and transferrin in normal iron metabolism and in iron overload disease and explores the possible involvement of these proteins in the pathophysiology of excess iron deposition in alcoholic subjects.

Apolipoprotein E ε4 Allele as a Genetic Risk Factor for Left Ventricular Failure in Homozygous β-Thalassemia

AbstractIn homozygous β-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) ε4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in β-thalassemia homozygotes. A total of 251 Greek β-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE ε4 allele frequency (7.9%) not different from population controls (6.5%, P > .05), while patients with LVF had a significantly higher frequency of APOE ε4 (12.8%) than the controls (P < .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE ε4 allele may represent an important genetic risk factor for the development of organ damage in homozygous β-thalassemia.© 1998 by The American Society of Hematology.

Apolipoprotein E 4 Allele as a Genetic Risk Factor for Left Ventricular Failure in Homozygous β-Thalassemia

In homozygous β-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) 4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in β-thalassemia homozygotes. A total of 251 Greek β-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE 4 allele frequency (7.9%) not different from population controls (6.5%, P &gt; .05), while patients with LVF had a significantly higher frequency of APOE 4 (12.8%) than the controls (P &lt; .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk factor for the development of organ damage in homozygous β-thalassemia.© 1998 by The American Society of Hematology.

Renal Function in Adult Beta-Thalassemia/Hb E Disease

β-Thalassemia hemoglobin E (β-thal/Hb E) is the commonest form of hemoglobinopathy in Thailand. Shortened red cell life span, rapid iron turnover and tissue deposition of excess iron are major factors responsible for functional and physiological abnormalities found in various forms of thalassemia. Increased deposition of iron had been found in renal parenchyma of thalassemic patients, but no systematic study of the effect of the deposits on renal functions has been available. The purpose of this study is to describe the functional abnormalities of the kidney in patients with β-thal/Hb E and provide evidence that increased oxidative stress might be one of the factors responsible for the damage. Urine and serum samples from 95 patients with β-thal/Hb E were studied comparing with 27 age-matched healthy controls. No difference in the creatinine clearance was observed. β-thal/Hb E patients excreted significantly more urinary protein (0.8 ± 0.5 vs. 0.3±0.1 g/day, p < 0.001). Aminoaciduria was found in 16% of the patients. Analysis of urinary protein by SDS-PAGE electrophoresis and silver staining revealed abnormal pattern of protein with increased small molecular weight (<45 kD) bands. Morning urine analysis showed significant lower urine osmolality (578.3 ± 164.6 vs. 762.4 ± 169.9 mosm/kg, p < 0.001) in patients. Patients excreted more NAG (N-acetyl beta-D-glucosaminidase, 26.3 ± 41.3 vs. 8.4 ± 3.9 U/g Cr, p < 0.0001) and β₂-microglobulin, 124.3 ± 167 vs. 71 ± 65.5 µg/g Cr, p = 0.001. Plasma and urine MDA (malonyldialdehyde) levels were both raised (p < 0.0001). Nine patients were selected for renal acidification study. All were found to be normal, but showed poor response to DDAVP challenge (urine osmolality 533 ± 71). This is the first report of renal tubular defects found associated with β-thal/Hb E disease. The mechanism leading to the damage is not known but it might be related to increased oxidative stress secondary to tissue deposition of iron, as indicated by the raised levels of serum and urine MDA. It is not known whether these functional defects would have any long-term effects on the patients. Further studies are warranted and means of prevention of these defects should urgently be sought.

Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of regulation of dietary iron absorption and excessive iron deposition in major organs of the body. Recently, a candidate gene for HH (also called HFE) was identified that encodes a novel MHC class I-like protein. Most patients with HH are homozygous for the same mutation in the HFE gene, resulting in a C282Y change in the HFE protein. Studies in cultured cells show that the C282Y mutation abrogates the binding of the recombinant HFE protein to beta2-microglobulin (beta2M) and disrupts its transport to the cell surface. The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body. In the studies presented here, we demonstrate by immunohistochemistry that the HFE protein is expressed in human placenta in the apical plasma membrane of the syncytiotrophoblasts, where the transferrin-bound iron is normally transported to the fetus via receptor-mediated endocytosis. Western blot analyses show that the HFE protein is associated with beta2M in placental membranes. Unexpectedly, the transferrin receptor was also found to be associated with the HFE protein/beta2M complex. These studies place the normal HFE protein at the site of contact with the maternal circulation where its association with transferrin receptor raises the possibility that the HFE protein plays some role in determining maternal/fetal iron homeostasis. These findings also raise the question of whether mutations in the HFE gene can disrupt this association and thereby contribute to some forms of neonatal iron overload.

Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis.

Genetic hemochromatosis (GH) is associated with excess iron deposition in hepatocytes, which results in progressive hepatic injury. The pathogenesis of hepatic injury in GH is poorly understood. In this study, we found enhanced oxidative stress in patients with GH, as evidenced by hepatic malondialdehyde (MDA)-protein adducts and by increased oxidatively modified serum proteins. MDA-lysine epitopes and oxidatively modified serum proteins, as well as immunoglobulin G autoantibodies against MDA-lysine epitopes, were increased in untreated GH patients and to a lesser extent in GH heterozygotes compared with normal individuals. These markers of ongoing oxidative stress decreased with phlebotomy treatment in GH patients. In addition, TGF-beta1 colocalized with hepatic iron and MDA protein adducts in hepatocytes and sinusoidal cells of hepatic acinar zone 1 and normalized after iron removal. Our data suggest that iron overload increases both lipid peroxidation and TGF-beta1 expression, which together could promote hepatic injury and fibrogenesis.

Excess iron induces hepatic oxidative stress and transforming growth factor β1 in genetic hemochromatosis

Genetic hemochromatosis (GH) is associated with excess iron deposition in hepatocytes, which results in progressive hepatic injury. The pathogenesis of hepatic injury in GH is poorly understood. In this study, we found enhanced oxidative stress in patients with GH, as evidenced by hepatic malondialdehyde (MDA)-protein adducts and by increased oxidatively modified serum proteins. MDA-lysine epitopes and oxidatively modified serum proteins, as well as immunoglobulin G autoantibodies against MDA-lysine epitopes, were increased in untreated GH patients and to a lesser extent in GH heterozygotes compared with normal individuals. These markers of ongoing oxidative stress decreased with phlebotomy treatment in GH patients. In addition, TGF-β1 colocalized with hepatic iron and MDA protein adducts in hepatocytes and sinusoidal cells of hepatic acinar zone 1 and normalized after iron removal. Our data suggest that iron overload increases both lipid peroxidation and TGF-β1 expression, which together could promote hepatic injury and fibrogenesis. (Hepatology 1997 Sep;26(3):605-10)

Effect of saturated versus unsaturated fat on the pathogenesis of copper deficiency in rats

The type of dietary fat, saturated versus unsaturated, may be an important factor in modifying the pathogenesis of copper deficiency in rats fed fructose. We investigated if saturated fat such as beef tallow as compared with unsaturated fat such as corn oil will prevent abnormalities related to the combination of fructose feeding and copper deficiency. Rats were fed copper-deficient (0.6 μg Cu/g diet) or adequate (6.0 μg Cu/g) diets containing fructose or starch as the sole dietary carbohydrate and beef tallow or corn oil as their fat source. The “typical” pathologies associated with copper deficiency in rats fed fructose such as anemia, pancreatic atrophy, heart hypertrophy, and liver enlargements were not prevented by the consumption of saturated fat (beef tallow). Not only did it not prevent pathologies, but beef tallow raised hepatic iron and increased plasma cholesterol and triglycerides, however, only in rats fed fructose. Plasma triglycerides and cholesterol were also elevated by copper deficiency and fructose feeding. The effect of the interaction among dietary carbohydrate, level of copper, and degree of saturation of fat on excess hepatic iron deposition and on metabolic and biochemical indices associated with heart-related abnormalities needs further investigation.

Signal intensity on MRI of basal ganglia in multiple sclerosis.

It has been reported that a relative reduction in signal intensity on T2 weighted MRI may be seen in the basal ganglia of patients with multiple sclerosis and furthermore that this is due to excessive iron deposition. The basal ganglia are, however, rarely involved clinically or pathologically in multiple sclerosis, casting some doubt on this finding. Therefore MRI was carried out in 46 patients with definite multiple sclerosis and 42 age matched controls. Contiguous, 5 mm thick axial dual echo spin-echo images of the brain were obtained on a 1.5T imager. Visual rating scales were used to measure the lesion load as well as the signal intensity of the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and thalamus. There was a mild degree of low signal intensity in the patient group in the thalamus only. The signal intensity of the thalamus and putamen was never lower than that of the globus pallidus. Low signal in the basal ganglia is rarely, if ever, found in multiple sclerosis and is not a useful radiological sign.

A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.

We identified a mutation in the ceruloplasmin (Cp) gene in a Japanese family with aceruloplasminemia, some of whose members showed extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus. A post-mortem study of the proband revealed excessive iron deposition mainly in the brain, liver and pancreas. The G to A transition at the splice acceptor site introduces a premature termination codon at the amino acid position 991 by defective splicing, thereby truncating the carboxyl terminus of Cp in affected individuals. We conclude that the mutation in the Cp gene is associated with systemic hemosiderosis in humans.

Histological study of iron deposits in selenium-deficient rats.

Previous studies have shown that selenium (Se) deficiency is associated with hematological abnormalities, which may result in an increased distribution of iron in various tissues. This report describes histological studies of the location of excess iron deposits in tissues. Male Wistar rats were fed a Torula yeast-based Se-deficient [Se(-)] or Se-adequate [Se(+); containing 0.1 mg Se/kg as sodium selenite] diet for 8 or 82 weeks. Excised tissues were embedded in either paraffin or epoxy resin. A dramatic increase was observed in iron deposition in the liver and kidneys of rats on the Se(-) diet. Prussian blue-stained sections under the light microscope showed iron deposits in the parenchymal cells and Kupffer cells of liver and in the proximal tubules of kidneys. The liver and kidneys of Se(-) rats had considerably altered morphology: lysosomes were enlarged and contained electron-dense areas. X-Ray microanalysis showed that the areas that corresponded to the lysosomes contained iron. No iron deposits were observed in sections of kidney and liver from rats fed the Se(+) diet. Thus, these studies identified subcellular sites of iron deposition in the liver and kidneys of Se(-) rats. These iron deposits may be an important factor in the pathogenesis of Se deficiency.

Serum increase and liver overexpression of carbohydrate 19.9 antigen in patients with genetic haemochromatosis.

CA 19.9 antigen is mainly secreted by biliary and pancreatic duct cells. Its metabolism could be modified in genetic haemochromatosis by iron accumulation within these cells. Therefore, CA 19.9 was assayed in the serum samples of 84 patients with genetic haemochromatosis before and after iron depletion and immunolocalised in the liver of 24 untreated genetic haemochromatosis cases. The study showed that serum CA 19.9 (N < 37 IU/l) was increased (SD) before treatment (41.2 (34)) when compared with after the venesection period (16 (12)), and correlated, before treatment, with the amount of iron excess, transaminases, fibrosis, and biliary iron deposits. Hepatic CA 19.9 was located within the cytoplasm of bile duct and cholangiolar cells. In conclusion, this study shows that a mild, reversible, and non-specific increase in serum CA 19.9 is common in genetic haemochromatosis patients and shows that this increase is related to iron excess, directly or through associated liver damage. The unexplained finding of a mild increase in serum CA 19.9 should lead, in a patient with no diagnosis, to the search for liver iron overload, and, in a patient with untreated genetic haemochromatosis, not to further diagnostic procedures unless this finding persists after completion of the venesection treatment.

Signal intensity of brain metastases on T2-weighted images: specificity for metastases from colonic cancers

In this report, we present and discuss the signal intensity of brain metastases from colon cancer on both T1- and T2-weighted images. In five of 6 cases, metastases were seen as markedly hypointense areas on T2-weighted images. This finding should alert one to the possibility of a primary cancer of the colon. Some haemorrhagic metastases from other malignancies also showed marked hypointensity. They usually exhibited hyperintensity on T1-weighted images. A case of colon metastasis was also haemorrhagic, and in this case a hyperintense area was observed on T1-weighted images. The marked hypointense area corresponded to peripheral necrosis and probably some viable tumour. Aetiologically, such hypointensity was not induced by severe fibrosis, calcification or excessive iron deposition.

Site of principal metabolic defect in idiopathic haemochromatosis: insights from transplantation of an affected organ.

Idiopathic haemochromatosis is an inherited defect of iron metabolism characterised by excessive iron absorption and deposition in the tissues leading to damage in the liver and other organs.' The nature of the fundamental metabolic abnormality remains unknown, but the liver and the gut have both been proposed as the principal site of expression of the metabolic defect.' We recently had the opportunity to study this question when a liver was transplanted from a donor who subsequently proved to have had presymptomatic idiopathic haemochromatosis into a young woman with normal iron metabolism. We describe here the changes in iron status observed in our patient in the first 29 months after liver transplantation.

MRI of hepatic iron deposition in patients with renal transplant

Excess hepatic iron deposition was found in five of 15 (33%) renal transplant patients undergoing magnetic resonance (MR) screening for avascular necrosis of the femoral heads. Only one of these patients had overt liver disease. The number of prior blood transfusions was a significant factor for this deposition, whereas the age and sex of the patients, number and type of transplants, histocompatibility alleles (HLA), and years of hemodialysis and of chronic renal failure were not significant etiological factors. Liver/fat intensity ratios of less than 0.29 on T1-weighted images and ratios of less than 0.21 on T2-weighted images and a calculated T2 value of less than 35 ms were the best indicators of iron overload. Renal transplant patients are at great risk for excess hepatic iron deposition and MR imaging is a promising tool for the diagnosis of iron overload in this patient population.