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PubMed1987

Risk of iron overload and 'hemochromatosis allele(s)' in patients on maintenance hemodialysis.

In the present study, we have evaluated the relationship between serum ferritin (SF) levels, 'hemochromatosis allele(s)', blood transfusions and iron parenteral administration in 69 hemodialysis patients. We demonstrated significantly higher SF levels in patients with hemochromatosis allele(s) (HA+) than in patients without hemochromatosis alleles (HA-). In addition, HA+ patients who had received blood transfusions up to 15 months prior to the study had SF levels even higher than those without blood transfusions. On the other hand, HA- patients had normal levels of SF, independent of blood transfusions. After intravenous administration of 1 g iron saccharate, SF levels were significantly higher only in HA+ transfused patients. In conclusion, our study demonstrated that HA+ patients are at a higher risk of iron overload and therefore the use of transfusional and/or parenteral iron should be strictly limited.

Adolescent↗
PubMed1986

Alcohol consumption among South African blacks and its relationship to iron overload.

The drinking habits of 123 black men (28 from Cape Town and 95 from Pietermaritzburg) were recorded, and their weekly alcoholic iron intakes calculated. Serum ferritin levels and liver function were measured in 57 subjects (Cape Town 12, Pietermaritzburg 45). Sorghum beer, with its high iron content, was considerably more popular in Pietermaritzburg than Cape Town, and the weekly iron consumption in Pietermaritzburg was significantly higher (P less than 0.05) than in Cape Town. The serum ferritin level was significantly higher in Cape Town than in Pietermaritzburg (P less than 0.05), no significant correlation being found between iron intake and serum ferritin. Age was positively correlated with serum ferritin (P less than 0.01). Of the subjects studied, 74% had abnormal lactate dehydrogenase levels. These results are considered in the light of the numerous problems associated with this type of project. The need for prospective studies in order to demonstrate a causal relationship between alcoholic iron intake and iron overload is emphasized.

Adult↗
PubMed2001

Indirect evidence for the potential ability of magnetic resonance imaging to evaluate the myocardial iron content in patients with transfusional iron overload.

The purpose of this study was to evaluate the potential ability of magnetic resonance imaging (MRI) for evaluation of myocardial iron deposits. The applied MRI technique has earlier been validated for quantitative determination of the liver iron concentration. The method involves cardiac gating and may, therefore, also be used for simultaneous evaluation of myocardial iron. The tissue signal intensities were measured from spin echo images and the myocardium/muscle signal intensity ratio was determined. The SI ratio was converted to tissue iron concentration values based on a modified calibration curve from the liver model. The crucial steps of the method were optimized; i.e. recognition and selection of the myocardial slice for analysis and positioning of the regions of interest (ROIs) within the myocardium and the skeletal muscle. This made the myocardial MRI measurements sufficiently reproducible. We applied this method in 41 multiply transfused patients. Our data demonstrate significant positive linear relationships between different iron store parameters and the MRI-derived myocardial iron concentration, which was significantly related to the serum ferritin concentration (rho=0.62, P<0.0001) and to the MRI-determined liver iron concentration (rho=0.36, P=0.02). The myocardial MRI iron concentrations demonstrated also a significant positive correlation with the number of blood units given (rho=0.45, P=0.005) and the aminotransferase serum concentration (rho=0.54, P=0.0008). Our data represents indirect evidence for the ability of MRI techniques based on myocardium/muscle signal intensity ratio measurements to evaluate myocardial iron overload.

Adolescent↗
PubMed2002

Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.

Hereditary hemochromatosis (HH) is classically associated with a Cys282Tyr (C282Y) mutation of the HFE gene. Non-C282Y HH is a heterogeneous group accounting for 15% of HH in Northern Europe. Pathogenic mutations of the transferrin receptor 2 (TfR2) gene have been identified in 4 Italian pedigrees with the latter syndrome. The goal of this study was to perform a mutational analysis of the TfR2 and HFE genes in a cohort of non-C282Y iron overload patients of mixed ethnic backgrounds. Several sequence variants were identified within the TfR2 gene, including a homozygous missense change in exon 17, c2069 A-->C, which changes a glutamine to a proline residue at position 690. This putative mutation was found in a severely affected Portuguese man and 2 family members with the same genotype. In summary, pathologic TfR2 mutations are present outside of Italy, accounting for a small proportion of non-C282Y HH.

Canada↗
PubMedDate not supplied

Exogenous iron overload in perinatal hemochromatosis: a case report.

We report an infant with fatal neonatal liver disease in whom efforts to correct an associated unremitting anemia resulted in massive exogenous iron overload that was expressed as perinatal hemochromatosis (PH). Levels of iron and copper were elevated in multiple tissues. Echovirus subtype 9, recovered from the urine at age 3 weeks, may have been etiologic in the liver failure. PH is best viewed as a definable phenotype with an undefined genetic and/or environmental basis that emerges only in the context of severe perinatal liver disease. The absence of hemosiderin in splenic and bone marrow reticuloendothelial (RE) cells of our patient suggests an important role for RE cell dysfunction.

Anemia↗
PubMed1979

Synthesis and evaluation of the thiosemicarbazone, dithiocarbazonate, and 2'-pyrazinylhydrazone of pyrazinecarboxaldehyde as agents for the treatment of iron overload.

Three prototype tridentate ligands (i.e., pyrazinecarboxaldehyde thiosemicarbazone, sodium pyrazinecarboxaldehyde dithiocarbazonate, and pyrazinecarboxaldehyde 2'-pyrazinylhydrazone) were prepared and evaluated for their relative abilities to remove iron from model systems designed to mimic particular aspects of chronic transfusional iron overload. These compounds were synthesized by condensation of pyrazinecarboxaldehyde with the appropriate substituted hydrazide. Iron-binding properties were determined, and the ability to remove iron from the proteins transferrin and ferritin was ascertained. An in vivo model system employing iron-loaded mice was used to demonstrate that all three compounds were effective at reducing tissue iron levels.

Animals↗
PubMed1997

Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload.

OBJECTIVE: To evaluate the frequency of arthropathy and osteoporosis in genetic hemochromatosis (GH) and to quantify potential risk factors for these 2 conditions. METHODS: Radiographic evidence of arthropathy was systematically sought in plain radiographs of 32 patients (28 men) with histologically proven GH (17 with hepatic cirrhosis). Bone mineral density was measured by x-ray absorptiometry of L2-L4 and osteoporosis was defined as a T score > or = 2.5 standard deviation below the mean. Potential risk factors investigated were age, body mass index, cirrhosis, alcohol abuse, hepatitis B and C infections, HLA phenotype, serum free testosterone levels, and the amount of iron removed by phlebotomy to reach depletion. The independent role of risk factors for the presence of osteoporosis was tested by multiple logistic regression analysis. RESULTS: Radiologic signs of arthropathy were observed in 81.3% of cases. Patients with arthropathy were older than patients without (p < 0.001), but did not differ in the frequency of cirrhosis, amount of iron removed, and HLA typing. Osteoporosis was observed in 9 patients and was positively associated with the amount of iron removed and cirrhosis. However, in multivariate analysis, cirrhosis was not independently associated with osteoporosis, but patients with higher iron removed had a greater probability to have osteoporosis [odds ratio (OR) = 3.23 for any increase of 5 g, 95% confidence interval (CI): 1.09-9.58], whereas the presence of HLA-A3 was associated with a reduction of risk (OR 0.013, 95% CI: 0.0015-1.13). CONCLUSION: These findings indicate the high prevalence of osteoarticular involvement in Italian patients with GH. Neither cirrhosis nor the amount of iron removed was associated with arthropathy. In contrast, in univariate analysis the risk of osteoporosis was significantly increased by liver cirrhosis. With multivariate analysis we found that osteoporosis was highly influenced by the degree of iron overload, playing an independent role in accelerating bone loss in patients with GH.

Adult↗
PubMed1990

Coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase activities in iron-overloaded and ethanol-treated rats.

The activities of coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase in liver homogenates of iron-overloaded and acutely or chronically ethanol-treated rats were assayed by high performance liquid chromatographic methods. Decreased coproporphyrinogen oxidase activity was found in chronically carbonyliron-fed rats while the activities of protoporphyrinogen oxidase and ferrochelatase remained unchanged. Coproporphyrinogen oxidase and protoporphyrinogen oxidase activities in both chronically and acutely ethanol-treated animals were not significantly different from controls. In chronically ethanol-fed rats normal ferrochelatase activity was found.

Animals↗
PubMed2001

Suppressive effects of bifidobacteria on lipid peroxidation in the colonic mucosa of iron-overloaded mice.

The antioxidative effects of live bifidobacteria on lipid peroxidation in the colonic mucosa were investigated. Bifidobacterium bifidum strain Yakult, which has been used for production of fermented milk, most effectively inhibited lipid peroxidation catalyzed by ferrous iron in liposomes among 10 species of bifidobacteria from human intestinal flora. Oral administration of B. bifidum strain Yakult for 2 wk significantly decreased the level of lipid peroxide (thiobarbituric acid reactive substance) in the colonic mucosa of iron-overload mice (Fe 0.07% in diet). The iron concentrations in plasma and cecum contents were not affected by administration of B. bifidum strain Yakult. Bifidobacterium bifidum strain Yakult had no chelating or incorporating activity for ferrous iron in vitro. Therefore, the antioxidative effect of B. bifidum strain Yakult in the colonic mucosa was not thought to be based on the removal of ferrous iron from the reaction system of lipid peroxidation. These results suggested that B. bifidum strain Yakult protected the colonic mucosa from oxidative injury without inhibiting iron absorption.

Animals↗
PubMed1986

Increased resistance of peroxisome proliferator-induced hepatic lesions to iron overload in rats.

Altered areas (AA), neoplastic nodules (NN) and hepatocellular carcinomas (HCC) induced by chronic administration of ciprofibrate and Wy-14,643 were examined for iron accumulation after systemic iron overload. Eighty percent of AA, 90% NN and 100% HCC showed increased resistance to iron accumulation. However, marked heterogeneity was observed in the amount of iron from area to area within the same lesion with some cells containing no iron, while others showing blue reaction to iron. These findings indicate, that putative preneoplastic and neoplastic hepatic lesions induced by peroxisome proliferators exclude iron in a fashion similar to that of hepatic nodules and carcinomas induced by DNA damaging carcinogens.

Animals↗
PubMed1998

Pyridoxal isonicotinoyl hydrazone and its analogs: potential orally effective iron-chelating agents for the treatment of iron overload disease.

At present, the only iron (Fe) chelator in clinical use for the treatment of Fe overload disease is the tris-hydroxamate deferoxamine (DFO). However, DFO suffers from a number of disadvantages, including the need for subcutaneous infusion (12 to 24 hours a day, 5 or 6 times per week), its poor intestinal absorption, and high cost. Therefore, there is an urgent need for an efficient, economical, and orally effective Fe chelator. Pyridoxal isonicotinoyl hydrazone (PIH) is a tridentate Fe-chelating agent that shows high Fe chelation efficacy both in vitro in cell culture models and also in vivo in rats and mice. In addition, this chelator is relatively nontoxic, economical to synthesize, and orally effective, and it shows high selectivity and affinity for Fe. However, over the last 10 years the development of PIH and its analogs has largely been ignored because of justifiable interest in other ligands such as 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Unfortunately, recent clinical trials have shown that significant complications occur with L1 therapy, and it is controversial whether this chelator is effective at reducing hepatic Fe levels in patients. Because of the current lack of a clinically useful Fe chelator to replace DFO, PIH and its analogs appear to be potential candidate compounds that warrant further investigation. In this review we will discuss the studies that have been performed to characterize these chelators at the chemical and biologic levels as effective agents for treating Fe overload. The evidence from the literature suggests that these ligands deserve further careful investigation as potential orally effective Fe chelators.

Animals↗
PubMed1989

Hepatic mitochondrial oxidative metabolism and lipid peroxidation in experimental hexachlorobenzene-induced porphyria with dietary carbonyl iron overload.

Both human porphyria cutanea tarda and experimental hexachlorobenzene-induced porphyria are associated with hepatic injury and are potentiated by excess hepatic iron. The mechanisms whereby cellular injury occurs and the synergistic role of iron overload are unknown. In the present experiments, we studied hepatic mitochondrial function and lipid peroxidation in rats with hexachlorobenzene-induced porphyria in which iron loading was achieved by dietary carbonyl iron supplementation. Female rats were treated for 8 weeks, receiving a chow diet supplemented with hexachlorobenzene (0.2%, w/w), carbonyl iron (1.0%, w/w) or hexachlorobenzene + iron. Hepatic total porphyrins were increased 100-fold in rats receiving hexachlorobenzene (hexachlorobenzene alone and hexachlorobenzene + Fe), and total hepatic iron was increased approximately 10-fold in rats receiving iron supplementation (Fe alone and hexachlorobenzene + Fe). There was a significant increase in mitochondrial lipid peroxidation in rats treated with hexachlorobenzene alone and hexachlorobenzene + Fe. A significant reduction in mitochondrial respiratory control ratios and in oxidative phosphorylation (ADP/O ratios) using glutamate and succinate as substrates was demonstrated when rats were treated with hexachlorobenzene + iron. The reductions in respiratory control ratios were due to a combination of an inhibitory defect in electron transport as evidenced by an irreversible decrease in State 3 respiration and an uncoupling effect as evidenced by an increase in State 4 respiration. These findings suggest that lipid peroxidation and mitochondrial dysfunction may contribute to the hepatotoxicity seen in hexachlorobenzene-induced porphyria.

Animals↗
PubMedDate not supplied

Quantification of liver iron overload by T2 quantitative magnetic resonance imaging in thalassemia: impact of chronic hepatitis C on measurements.

PURPOSE: Measurement of liver T2 values seems to be an accurate and sensitive magnetic resonance imaging (MRI) method for the quantification of liver hemosiderosis in multiple transfused patients with thalassemia. Because many of these patients have coexistent chronic hepatitis C virus (HCV) infection, the effect of inflammatory changes on liver T2 values was assessed. MATERIALS AND METHODS: Liver MRI studies of 35 HCV+ and 17 HCV- patients with beta-thalassemia, 9 HCV+ patients without thalassemia, and 10 healthy controls of the same age range (13 to 32 years) were reviewed. Iron status was assessed by serum ferritin in all patients, and determination of liver iron concentration (LIC) was available in 16 HCV+ patients with thalassemia. Histologic activity index (HAI) and grades of siderosis were evaluated in all HCV+ patients with thalassemia. RESULTS: Patients with thalassemia had significantly lower T2 values (P < 0.0001) than subjects without thalassemia, whereas no difference existed between HCV+ patients without thalassemia and healthy controls. In HCV+ patients, LIC correlated more nearly with T2 values (r = 0.93) than with serum ferritin (r = 0.73). T2 values were not influenced by HAI score or fibrosis. CONCLUSION: Liver T2 values were found to be more accurate than serum ferritin in predicting liver iron overload and were not influenced by the presence of chronic hepatitis C. Therefore, MRI could serve as a noninvasive alternative to liver biopsy for the quantification of hemosiderosis in HCV+ patients with thalassemia.

Adolescent↗
PubMed1999

Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis.

In a 10-year consecutive series of 263 allogeneic bone marrow transplant recipients, we identified five cases (1.9%) of invasive mucormycosis. Only one infection occurred within the first 100 days after transplantation, while the remainder complicated the late post-transplant course (median day of diagnosis: 343). Sites of infection were considered 'non-classical' and included pulmonary, cutaneous and gastric involvement. No case of fungal dissemination was observed. Mucormycosis was the primary cause of death in three of the five patients. Corticosteroid-treated graft-versus-host disease, either acute or chronic, or severe neutropenia were present in all cases. However, compared with a matched control population, the most striking finding was the demonstration of severe iron overload in each of the mucormycosis patients. The mean level of serum ferritin, transferrin saturation and number of transfused units of red cells (2029 microg/l, 92% and 52 units, respectively) in the study group is significantly higher compared with the control group (P < 0.05). The difference with other risk groups for mucormycosis, including deferoxamine-treated dialysis patients and acidotic diabetics, was analyzed in view of the possible pathogenic role of iron. Although these infections are often fatal, limited disease may have a better prognosis if diagnosed early and treated aggressively.

Adult↗
PubMed2006

Hepatic oxidative DNA damage correlates with iron overload in chronic hepatitis C patients.

Hepatic oxidative stress occurs in chronic hepatitis C (CH-C), but little is known about its producing mechanisms and precise role in the pathogenesis of the disease. To determine the relevance of hepatic oxidatively generated DNA damage in CH-C, 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts were quantified in liver biopsy specimens by immunohistochemical staining, and its relationship with clinical, biochemical, and histological parameters, and treatment response was assessed in 40 CH-C patients. Hepatic 8-OHdG counts were significantly correlated with serum transaminase levels (r=0.560, p=0.0005) and histological grading activity (p=0.0013). Remarkably, 8-OHdG levels were also significantly related to body and hepatic iron storage markers (vs serum ferritin, r=0.565, p=0.0004; vs hepatic total iron score, r=0.403, p=0.0119; vs hepatic hepcidin messenger RNA, r=0.516, p=0.0013). Baseline hepatic oxidative stress was more prominent in nonsustained virological responder (non-SVR) than in SVR to interferon (IFN)/ribavirin treatment (50.8 vs 32.7 cells/10(5) microm2, p=0.0086). After phlebotomy, hepatic 8-OHdG levels were significantly reduced from 53.4 to 21.1 cells/10(5) microm2 (p=0.0125) with concomitant reductions of serum transaminase and iron-related markers in CH-C patients. In conclusion, this study showed that hepatic oxidatively generated DNA damage frequently occurs and is strongly associated with increased iron deposition and hepatic inflammation in CH-C patients, suggesting that iron overload is an important mediator of hepatic oxidative stress and disease progression in chronic HCV infection.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1989

Red cell ferritin and iron overload in heterozygous beta-thalassemia.

Red cell ferritin was evaluated in 101 individuals with heterozygous beta-thalassemia to determine its clinical utility as an index for iron deficiency or overload in these subjects. The mean red cell ferritin for the total population was elevated threefold and showed a significant correlation with transferrin saturation, plasma ferritin, and HbA2 levels. Five of six subjects with reduced red cell ferritin had associated iron deficiency; a further five had iron deficiency and normal red cell ferritin. Normal red cell ferritin occurred in 51 subjects, and 44 had increased values. In the elevated red cell ferritin group, 21 individuals had associated normal plasma ferritin, and 23 had increased plasma ferritin. Only in the latter group was red cell ferritin significantly correlated with transferrin saturation and plasma ferritin. Ten individuals had a red cell ferritin greater than or equal to 150 attogram/cell, and liver biopsy performed in four showed grades II to IV iron overload. A clinical feature of subjects with both increased red cell and plasma ferritin levels was a high incidence of inappropriate iron administration. These findings suggest that red cell ferritin, particularly when combined with plasma ferritin, is a useful parameter for determining potential iron overload in individuals with heterozygous beta-thalassemia.

Adolescent↗
PubMed2005

Dose-response effects of ectopic agouti protein on iron overload and age-associated aspects of the Avy/a obese mouse phenome.

Isogenic and congenic offspring from matings of inbred black a/a dams by sibling (or non-sibling from another inbred strain) yellow agouti Avy/a sires provide an animal model of obese yellow agouti Avy/a and isogenic lean pseudoagouti Avy/a mice exhibiting two different in vivo concentrations (high, very low) of ectopic agouti protein (ASP) with congenic lean black a/a mice as null controls. This makes it possible to differentiate between the high and very low dose levels of ectopic ASP with respect to interactions with diverse physiological and molecular pathways. Assay of differential responses to 12 or 24 months of carbonyl iron overload assessed the possible suitability of this animal model for the study of hemochromatosis. Agouti A/a B6C3F1 mice were used as non-congenic null controls. The age-related waxing and waning of body weight, food consumption, and caloric efficiency, as well as associated changes in pancreatic islets and islet cells, and formation of liver tumors were assayed. While the hypothesis that these mice might serve as a tool for investigating hemochromatosis was not confirmed, the data did provide evidence that even the very low levels of ASP in pseudoagouti Avy/a mice affect the network of molecular/metabolic/physiological response pathways that comprises the yellow agouti obese phenome. We suggest that the combination of yellow agouti Avy/a, pseudoagouti Avy/a, and black a/a congenic mice provides a practical tool for applying a dose-response systems biology approach to understanding the dysregulatory influence of ectopic ASP on the molecular-physiological matrix of the organism.

Aging↗
PubMed1996

[Detection of early cardiac dysfunction in patients with transfusion-dependent aplastic anemia and chronic iron overload in childhood. Stress-velocity relation as a sensitive index by echocardiography].

In order to detect early-stage left ventricular dysfunction, we examined a load-independent index, that is, the stress-velocity relation, by echocardiography in 13 patients with aplastic anemia including pure red cell anemia. Even when left ventricular contractility and pump function were within the normal range, its afterload had a tendency to increase in transfusion-dependent patients. The patients who had impairment of cardiac pump function died of congestive heart failure within one year after abnormal findings in stress-velocity relation were detected. Therefore, the stress-velocity relation is a sensitive, useful and noninvasive index for detecting asymptomatic myocardial dysfunction in patients with transfusion-dependency and chronic iron overload. It is necessary for these patients to undergo examinations of echocardiography at regular intervals. In case of abnormally in the stress-velocity relation, treatment for afterload mismatch and more effective chelation should be recommended to reduce the burden on the heart. Thereby, the heart is kept in better condition and the prognosis of these patients will be improved.

Adolescent↗