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PubMed2005

Abdominal lymphadenopathy in beta-thalassemia: MRI features and correlation with liver iron overload and posttransfusion chronic hepatitis C.

OBJECTIVE: The objective of our study was to describe the MRI features of abdominal lymphadenopathy in patients with beta-thalassemia major and investigate the relation of abdominal lymphadenopathy with the severity of iron overload and posttransfusion chronic hepatitis C. MATERIALS AND METHODS: Abdominal MRI studies of 60 consecutive patients with beta-thalassemia major, performed for quantification of liver iron overload at a single institution, were retrospectively studied for the presence of lymph nodes and their distribution, size, and number. The signal intensity ratios of liver, spleen, and the largest lymph node to the right paraspinous muscle (L/M, S/M, and LN/M, respectively) were calculated on T1-weighted gradient-echo images. MRI findings for the lymph nodes were compared with the histologically assigned activity level of chronic hepatitis C that was available in 17 patients who had undergone liver biopsy within 1 month of the MRI examination. RESULTS: Hypointense abdominal lymph nodes larger than 7 mm were seen in 19 (32%) of 60 thalassemic patients in perihepatic and paraortic distributions. Lymphadenopathy was related to both the severity of hepatic siderosis, as expressed by the L/M values, and the presence of chronic hepatitis C, given that 18 (95%) of the 19 thalassemic patients with lymphadenopathy had chronic hepatitis C. Moreover, thalassemic patients with a moderate or severe level of hepatic inflammation presented with abdominal lymphadenopathy more frequently than those with mild hepatic inflammation. CONCLUSION: The development of hypointense abdominal lymphadenopathy in patients with beta-thalassemia major who have received multiple transfusions depends both on the severity of liver iron overload and on the presence and the activity level of coexistent chronic hepatitis C.

Abdomen↗
PubMed2006

MRI for the determination of pituitary iron overload in children and young adults with beta-thalassaemia major.

Hypogonadism, resulting from iron-induced pituitary dysfunction, is the most frequently reported complication in patients with beta-thalassaemia major. The aim of this study was to evaluate pituitary Magnetic Resonance Imaging (MRI) signal intensity reduction, on T2*-weighted images, as a marker of pituitary iron overload. Thirty patients (13 females and 17 males, mean age: 16.6+/-4.1) with beta-thalassaemia major on conventional treatment and 13 healthy volunteers (7 females and 6 males, mean age: 11+/-4.51 years) were studied with T2*-weighted images of the anterior pituitary using a 1.5T unit. Four thalassaemic patients (2 females and 2 males) had clinical hypogonadism and required hormonal replacement treatment. Results revealed a statistically significant reduction of pituitary signal intensity in the thalassaemia group compared to controls (p<0.001). Moreover, hypogonadal patients had significantly decreased MRI values compared to thalassaemic patients without hypogonadism (p=0.017). Relatively decreased adeno-hypophyseal MRI signal intensity was recorded in pubertal thalassaemic patients. A significant negative correlation was observed between pituitary MRI values and age (r=-0.67, r(2)=0.443, p=0.001), whereas ferritin levels and pituitary MRI values were moderately correlated (r=-0.56, r(2)=0.32, p=0.08) in adult thalassaemic patients. In conclusion, pituitary MRI indices as measured on T2*-weighted images seem to reflect pituitary iron overload and could, therefore, be used for a preclinical detection of patients who are in greater danger of developing hypogonadism.

Adolescent↗
PubMed1981

Synovial iron deposits in black subjects with iron overload.

The traditional alcoholic beverages drunk by many South African blacks are prepared in iron drums, and, as a result, iron overload is common in this population. The typical pattern of iron distribution in such persons with severe iron overload is one in which the major deposits are in hepatocytes and the reticuloendothelial system. However, when cirrhosis is present, significant epithelial deposits are found in a number of organs. In the present study, the synovium of the knee joint was examined in 41 black subjects and synovial iron deposits, when present, were correlated with those in other organs. Significant amounts of iron in the synovial-lining cells were not found in any subject in whom the hepatic iron concentration was less than 1% dry weight. Heavy deposits, which were found in six of 19 subjects with concentrations above this figure, only occurred in those exhibiting cirrhosis and significant levels of histological iron in a number of epithelial tissues. Insofar as iron uptake is concerned, these findings suggest that there are cells within the synovium that have the functional characteristics of epithelial cells.

Adult↗
PubMed1984

Functional efficiency of mitochondrial membrane of rats with hepatic chronic iron overload.

The effect of in vivo hepatic iron overload, induced by two different amounts of iron, on the energy-transducing efficiency of the mitochondrial membrane has been examined. It has been found that when the epatic iron concentration is up to a threshold value mitochondria present an anomalous membrane potential. Addition of oligomycin fully restitutes it. A low content of intramitochondrial K+ is connected with this pathological condition. A relative lack of antioxidant capability is parallely exhibited by these mitochondria. A possible involvement of lipid peroxidation process in vivo in causing the membrane potential drop and the net efflux of intramitochondrial K+ is suggested.

Animals↗
PubMed1995

Pharmacokinetics of the oral iron chelator deferiprone (L1) in patients with iron overload.

Single oral dose pharmacokinetics of the iron chelator deferiprone (L1) were studied in 24 patients with chronic iron overload and correlated with 24 h urinary iron excretion (UIE) and creatinine clearance. Absorption of L1 was rapid with a t1/2 of 22.2 +/- 17.7 (mean +/- SD) min. The elimination half-life (elt1/2) of the drug was 91.1 +/- 33.1 min and of its metabolite, L1-glucuronide (L1G) 147.7 +/- 52.0 min. Creatinine clearance of the patients correlated significantly with the elimination t1/2 of L1G (r = -0.79, P = 0.002). There was also a significant correlation between 24 h UIE in the 14 patients studied and L1 versus time area under the curve (AUC) (P = 0.007). The total amount of L1 recovered in urine in 24 h comprised 77.9 +/- 13.3% of the L1 dose. L1 efficiency (the 24 h UIE divided by the amount of iron the oral dose of L1 is capable of binding) in the 14 patients was 3.8 +/- 1.9%. These data show for the first time that the urinary elimination of L1G is influenced by the renal function of the patient. Although no significant accumulation of L1 and L1G will occur in most of the patients if L1 is given more than once daily, in some patients with impaired renal function, L1G may accumulate.

Administration, Oral↗
PubMed2001

Iron overload diminishes atherosclerosis in apoE-deficient mice.

It has been proposed that elevated levels of tissue iron increase the risk for atherosclerosis, perhaps by favoring the formation of pro-atherogenic oxidized LDL. Working with apoE-deficient (apoE(-/-)) mice, which do not require a high-fat diet to develop atherosclerosis, we compared the effects of standard diet (0.02% iron) or a 2% carbonyl iron diet. After 24 weeks, mice fed the 2% carbonyl iron diet had twice as much iron in their plasma, a ninefold increase in bleomycin-detectable free iron in their plasma, and ten times as much iron in their livers as control mice. Dietary iron overload caused a modest (30%) rise in plasma triglyceride and cholesterol. Nevertheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, two markers of metal-catalyzed oxidative damage in vitro, failed to rise in iron-overloaded animals. Our observations suggest that elevated serum and tissue levels of iron are not atherogenic in apoE(-/-) mice. Moreover, they call into question the hypothesis that elevated levels of tissue iron promote LDL oxidation and oxidative stress in vivo.

Animals↗
PubMed2000

[Iron overload and public health].

Genetic hemochromatosis, due to its frequency (about 300,000 cases in France) and to its severity, must be considered as a public health burden. Its curability--insofar as its diagnosis has been made early--and the disposal of non invasive and reliable phenotypic (transferrin saturation) and genotypic (HFE C282Y mutation) tests make its diagnosis easy. Thus, diagnosis faced with early clinical and biological symptoms must be promulgated as screening in probant families. General screening is still hampered by ethical and socio-economic obstacles, but should be evaluated in large prospective studies. Otherwise, the recently described insulin resistance-associated liver iron overload syndrome might account for epidemiological associations that have been reported between increased body iron stores and cancerous, cardio-vascular and hepatic disorders. This might extend markedly the impact of iron overload in public health and lead to broaden screening and prevention to all iron overload conditions.

Hemochromatosis↗
PubMed1991

[Treatment of iron overload with combination of recombinant human erythropoietin and phlebotomy].

A patient of Coombs negative autoimmune hemolytic anemia was massively transfused of 162 units concentrated red blood cells in 3 months and developed iron overload disease which was confirmed by liver biopsy. Hemolysis was successfully treated with high-dose methyl-prednisolone therapy and splenectomy. To treat iron overload, we administered recombinant human erythropoietin (Epo) in combination with phlebotomy. Total iron removed for 5 months was about 4 g. Thus, combination of Epo and phlebotomy was effective for the treatment of iron overload disease. Furthermore, we compared a degree of clinical effect of subcutaneous administration of Epo with that of intravenous administration in the clinical course and found the former more effective.

Adult↗
PubMed2000

Vitamin C suppresses oxidative lipid damage in vivo, even in the presence of iron overload.

Ascorbate is a strong antioxidant; however, it can also act as a prooxidant in vitro by reducing transition metals. To investigate the in vivo relevance of this prooxidant activity, we performed a study using guinea pigs fed high or low ascorbate doses with or without prior loading with iron dextran. Iron-loaded animals gained less weight and exhibited increased plasma beta-N-acetyl-D-glucosaminidase activity, a marker of tissue lysosomal membrane damage, compared with control animals. The iron-loaded animals fed the low ascorbate dose had decreased plasma alpha-tocopherol levels and increased plasma levels of triglycerides and F(2)-isoprostanes, specific and sensitive markers of in vivo lipid peroxidation. In contrast, the two groups of animals fed the high ascorbate dose had significantly lower hepatic F(2)-isoprostane levels than the groups fed the low ascorbate dose, irrespective of iron load. These data indicate that 1) ascorbate acts as an antioxidant toward lipids in vivo, even in the presence of iron overload; 2) iron loading per se does not cause oxidative lipid damage but is associated with growth retardation and tissue damage, both of which are not affected by vitamin C; and 3) the combination of iron loading with a low ascorbate status causes additional pathophysiological changes, in particular, increased plasma triglycerides.

Animals↗
PubMed2005

[Iron overload and insulin resistance].

There is increasing evidence that moderately elevated body iron stores, below levels commonly found in genetic hemochromatosis, may be associated with adverse health outcomes. Genetic hemochromatosis, characterized by transferrin saturation (TS) greater than 45%, is most often linked to homozygosity of the HFE C282Y allele. The phenotype is also modulated by mutations of more recently discovered genes (including ferroportin, hemojuvelin, hepcidin, and transferrin receptor) and environmental factors (including alcohol, viruses, diet, blood loss). Iron overload without hemochromatosis is characterized by high levels of serum ferritin and normal TS, as seen in dysmetabolic hepatosiderosis. Elevated serum ferritin levels predict incident type 2 diabetes in prospective studies and have been associated with hypertension, dyslipidemia, glucose tolerance disturbances, central adiposity, and metabolic syndrome. High ferritin levels are not synonymous with iron overload and may in some cases be a simple marker of insulin resistance.

Hemochromatosis↗
PubMed2000

Evidences that zidovudine (AZT) could not be directly responsible for iron overload in AZT-treated patients: an in vitro study.

Zidovudine (3'-azido-3'-deoxythymidine or azidothymidine, AZT) has been the first antiretroviral agent approved for clinical use, and it is still currently used in combination therapy of human immunodeficency virus (HIV) infection. On the basis of increasing clinical reports and in vitro studies, a strict correlation between AZT treatment of HIV positive patients and both the development of anemia and iron overload have been in evidence over the last few years. In this report, we have examined some features of zidovudine to better assess a likely implication of this drug in iron overload. For this purpose, we first determinated the iron chelating ability of both AZT and some of its phosphorylated derivatives in solution. The iron chelating ability of AZT toward the intracellular 'chelatable' iron pool was also evaluated. Finally, we investigated the effect of AZT on both iron and transferrin uptake. Our findings indicate that AZT per se cannot be directly responsible for the development of the iron overload found in human or animal models, for which other possible mechanisms are claimed to be involved.

Anti-HIV Agents↗
PubMed2003

Patient compliance with phlebotomy therapy for iron overload associated with hemochromatosis.

OBJECTIVE: The aim of this study was to evaluate patient compliance with phlebotomy therapy of hemochromatosis-associated iron overload. METHODS: We reviewed medical records of white adults with hemochromatosis and iron overload diagnosed during medical care. We defined three elements of compliance: 1) achieving iron depletion (serum ferritin </= 20 ng/ml); 2) timeliness of phlebotomies on a weekly or biweekly schedule to achieve iron depletion; and 3) participation in therapy to maintain serum ferritin </= 50 ng/ml. We evaluated associations of timeliness of phlebotomy and participation in maintenance therapy with these variables: age at diagnosis, sex, pretreatment serum ferritin concentration, HFE genotype, units of blood removed to achieve iron depletion, and presence or absence of cirrhosis at diagnosis. RESULTS: A total of 118 patients were evaluable for iron depletion and 142 for maintenance therapy; 96.6% achieved iron depletion, and 33.1% and 43.2% followed weekly and biweekly schedules, respectively. Timeliness was not significantly associated with the variables we evaluated. In the first year of maintenance therapy, 84.0% of patients complied; the percentage of C282Y homozygotes complying was significantly greater than that of other patients. Average compliance with maintenance therapy decreased 6.8% annually; the mean follow-up after achieving iron depletion was 4.1 +/- 2.8 yr (range 0.6-9.7 yr). CONCLUSIONS: Most patients with hemochromatosis diagnosed in medical care achieve iron depletion with phlebotomy; one-third tolerate and adhere to weekly phlebotomy. There is a constant rate of decline in the percentage of patients who comply with maintenance therapy.

Adolescent↗
PubMed1998

Non-C282Y familial iron overload: evidence for locus heterogeneity in haemochromatosis.

Haemochromatosis (HC) is an autosomal recessive disease with progressive iron overload leading to midlife onset of clinical complications. The causal gene (HFE) maps to 6p, in close linkage with the HLA class I genes. An HFE candidate gene recently identified has two missense mutations (C282Y and H63D) associated with the disease. Here we document the phenotypic and genetic analysis of a nuclear family comprising two sibs with symptomatic and massive iron overload before the age of 25. The disease seemed to be recessively transmitted and fitted the agreed criteria for haemochromatosis, but was neither associated with the C282Y and H63D mutations nor linked with HLA markers. Our data strongly support locus heterogeneity in haemochromatosis by showing evidence that the gene responsible for juvenile haemochromatosis (JH) does not map to 6p. In the absence of clear cut phenotypic distinction from typical haemochromatosis, patients below 30 years of age and C282Y negative should be considered as putative juvenile cases. This has practical implications in genetic counselling and family management.

Adult↗
PubMed1996

Chronic iron overload in rats induces oval cells in the liver.

Liver damage induced by a variety of agents including hepatocarcinogens, alcohol, and virus induces proliferation of oval cells. In this study, iron overloading of the liver is used as a means of inducing liver damage over an extended period to ascertain whether it promotes the appearance of oval cells. Rats were fed a 2% carbonyl-iron-supplemented diet for 3 or 6 months. Extensive iron deposits appeared periportally in hepatocytes and some Kupffer cells. Iron deposition was less pronounced pericentrally. Small oval-like cells, morphologically and immunocytochemically similar to CDE-derived oval cells, were identified and quantified. They first emerged periportally and subsequently in small tracts or foci nearer central regions and stained positively for alpha-fetoprotein, pi-class glutathione S-transferase, and the embryonic form of pyruvate kinase. They contained very few iron deposits and were classified as iron free. The major difference between CDE- and iron-overload-derived oval cells was that the latter were negative for transferrin. This study shows that cellular changes occurring in iron-overloaded rat liver are similar to those observed in rats placed on a hepatocarcinogenic diet and in rats chronically exposed to alcohol.

Administration, Oral↗
PubMed1985

Alpha and beta cell evaluation in patients with thalassaemia intermedia and iron overload.

Insulin and glucagon secretion were studied during an oral glucose tolerance test and arginine infusion in 11 patients with thalassaemia intermedia, who showed laboratory evidence of iron overload. Mean blood glucose concentrations in patients with thalassaemia intermedia were significantly higher than normal and 3 of 11 patients had impaired glucose tolerance. The principal abnormality appears to be a deficiency in insulin and glucagon from the pancreas in response to oral glucose tolerance and arginine stimulation tests. Several factors, such as iron overload, chronic hypoxia, zinc deficiency and increased catecholamine production secondary to anaemia, might play a part in the pathogenesis of these abnormalities. Each of these factors affect individual cases to a varied degree. Our data emphasize the mildness of carbohydrate defect as compared to the degree of insulinopenia and indicate the necessity for prescribing measures which prevent excessive iron deposition and improve iron excretion in thalassaemic patients with iron overload.

Adult↗
PubMed1984

Iron overload associated with congenital pyruvate kinase deficiency and high dose ascorbic acid ingestion.

Iron overload is an uncommon complication of untransfused chronic hemolytic anemias. This paper describes only the fourth reported case of erythrocyte pyruvate kinase deficiency and iron overload. Important aspects of this case are the presence of the HLA genotype commonly associated with genetic (idiopathic) hemochromatosis and a history of ingestion of large doses of ascorbic acid. Their roles in the development of iron loading and toxicity are discussed. A beneficial response to treatment with desferrioxamine was observed before significant iron removal. A mechanism for this action of desferrioxamine is proposed.

Ascorbic Acid↗
PubMed1987

The effect of experimental iron-overload on splenic T cell function: analysis using cloning techniques.

The effect of iron-overload on cell-mediated immunity was examined in C57 mice. Two methods of iron-loading were used: (i) dietary carbonyl iron which produced iron-loading primarily of parenchymal cells or (ii) intraperitoneal administration of iron-dextran which produced iron-loading predominantly of Kupffer cells. Both methods of iron-loading resulted in a diminished capacity of spleen cells to generate an allo-specific cytotoxic response in the absence of exogenous interleukin 2 (IL-2). Exogenous IL-2, however, restored the ability of spleen cells from iron-loaded mice to generate allo-specific cytotoxicity in bulk culture. Clonal assays for the precursor cells of cytotoxic T lymphocytes (CTL-P), performed in the presence of added IL-2, demonstrated that iron-loaded mice contained normal numbers of CTL-P. However, cultures of spleen cells from carbonyl iron-loaded mice generated less IL-2 following Concanavalin A stimulation, apparently as a result of a reduction in the number of IL-2-secreting cells amongst the spleen cell population. This work presents further evidence that iron-overload is associated with defective immunoregulatory control.

Animals↗
PubMed1995

Iron overload: prevalence and impact on health.

Clinical manifestations attributable to the damaging effects of iron occur when the total body iron is 5-10 times higher than normal. In adults this degree of iron overload occurs in hereditary hemochromatosis, a human leukocyte antigen (HLA)-linked autosomal recessive disorder, as well as in secondary iron-overload conditions.

Adult↗