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PubMed2006

Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation.

Hepcidin is a negative regulator of iron absorption produced mainly by the liver in response to changes in iron stores and inflammation, and its levels have been shown to regulate the intestinal basolateral iron transporter ferroportin1 (Fp1). Hereditary hemochromatosis patients and Hfe-deficient mice show inappropriate expression of hepcidin but, in apparent contradiction, still retain the ability to regulate iron absorption in response to alterations of iron metabolism. To further understand the molecular relationships among Hfe, hepcidin, and Fp1, we investigated hepcidin and Fp1 regulation in Hfe-deficient mice (Hfe-/- and beta2m-/-) in response to iron deprivation, iron loading, and acute inflammation. We found that whereas basal hepcidin levels were manifestly dependent on the presence of Hfe and on the mouse background, all Hfe-deficient mice were still able to regulate hepcidin in situations of altered iron homeostasis. In the liver, Fp1 was modulated in opposite directions by iron and LPS, and its regulation in Hfe-deficient mice was similar to that observed in wild-type mice. In addition, we found that iron-deprived mice were able to mount a robust response after LPS challenge and that Toll-like receptor 4 (TLR-4)-deficient mice fail to regulate hepcidin expression in response to LPS. In conclusion, these results suggest that although Hfe is necessary for the establishment of hepcidin basal levels, it is dispensable for hepcidin regulation through both the iron-sensing and inflammatory pathways, and hepatic Fp1 regulation is largely independent of hepcidin and Hfe. The inflammatory pathway overrides the iron-sensing pathway and is TLR-4 dependent.

Animals↗
PubMed1983

Enhanced iron removal from liver parenchymal cells in experimental iron overload: liposome encapsulation of HBED and phenobarbital administration.

The effectiveness of N,N'-bis[2-hydroxybenzyl]-ethylene-diamine-N,N'-diacetic acid (HBED) in removing radioiron introduced into the parenchymal cells of mouse liver as 59Fe-ferritin has been investigated. The effectiveness of HBED, an iron chelator of low water solubility, has also been compared with that of desferrioxamine (DF), an iron chelator of high water solubility and currently in clinical use for treatment of transfusional iron overload. Using the 59Fe excretion as the measure of effectiveness of chelation therapy and a standardized single chelator dose of 25 mg/kg, we have found that: (1) a saline suspension of HBED, prepared by sonication and given intraperitoneally to mice, promotes a small but significant increase in excretion of radioiron compared to the untreated controls, whereas DF, in its free form, is ineffective; (2) HBED encapsulated in lipid bilayers of liposomes and given intravenously is superior to nonencapsulated HBED; (3) DF encapsulated in small unilamellar liposomes is ineffective in removing iron given in the form of ferritin; (4) administration of phenobarbital in drinking water, at a concentration of 1 g/liter, induces a 30%-55% increase of iron excretion from untreated control mice and also from mice given HBED either in liposome-encapsulated or nonencapsulated form. We have demonstrated that HBED is superior to DF for removal of storage iron from liver parenchymal cells and that liposomes are useful carriers for iron chelators of low water solubility.

Animals↗
PubMed1986

Association of hereditary spherocytosis and idiopathic hemochromatosis. A synergistic effect in determining iron overload.

Two siblings, both splenectomized at an early age for hereditary spherocytosis, had a severe hemochromatosis develop. The human leukocyte antigen (HLA) system typing showed that they were half HLA identical. All the other members of the family who did not have evidence of hereditary spherocytosis, including those who displayed identical HLA haplotypes with the two patients, did not have any increase in iron stores. These results suggest that the two siblings are heterozygous for idiopathic hemochromatosis and that the coexistence of this condition with hereditary spherocytosis can cause a severe iron overload.

Adult↗
PubMed1987

[Roles of iron overload and chelating treatment in Yersinia infectious complicated by major thalassemia].

A study of 3 personal and 32 published cases showed that Yersinia septicaemia in subjects under 21 presents as digestive disorders with fever and occurs in one half of the cases in thalassaemia patients. Among the factors which may be blamed for this predisposition the most important are excessive tissue iron levels and treatment with chelating agents. Iron overload is present in 70% of patients with Yersinia septicaemia. The risk of infection in such subjects requires appropriate therapeutic measures.

Child↗
PubMed1991

Efficacy and safety of 1-2, dimethyl-3-hydroxypyrid-4-one (L1) as an oral iron chelator in patients of beta thalassaemia major with iron overload.

Twenty-four patients with beta thalassaemia major, aged 8-22 years (mean 15.3 +/- 8.1) were given 1-2, dimethyl-3-hydroxypyrid-4-one (L1) orally for a period of three months. The drug was given in the dose of 25 mg/Kg/day for the first week and gradually increased to 100 mg/Kg/day which was continued until 3 months. The mean urinary iron excretion was 5.73 +/- 3.648 mg/day on 25 mg/Kg/day of L1; 15.2 +/- 11.225 mg/day on 50 mg/Kg/day; 24.2 +/- 12.69 mg/day on 75 mg/Kg/day and 36.3 +/- 19.4 mg/day on 100 mg/Kg/day of L1. Serum ferritin estimated by ELISA before and 3 months after L1 therapy in 21 patients showed significant drop in levels, the mean drop being 964.3 +/- 844.4 (P less than 0.001). The only side-effects noted were transient gastrointestinal symptoms in 5 patients and skeletomuscular pain in 3 patients. Both these groups of symptoms were of transient nature. The efficacy of L1 appears to be excellent and equivalent to the standard iron chelation therapy available at present i.e. desferrioxamine. It appears to be free of major toxicity. L1 is also a specific chelator for iron as it does not deplete trace metals. L1 appears to be a cheap and effective oral alternative to desferrioxamine for treating iron overloading.

Adolescent↗
PubMedDate not supplied

Pathology of lethal fetal growth retardation syndrome with aminoaciduria, iron overload, and lactic acidosis (GRACILE).

Autopsy study of 17 newborn infants with lethal autosomal recessive disease presenting as growth retardation with lactic acidosis, Fanconi aminoaciduria, and hepatic hemosiderosis is reported. The patients succumbed between day 1 and 4 months of life; 9 patients died within the first month. All patients showed severe pathologic changes of liver with cholestasis in all livers. Extensive accumulation of stainable iron of the hepatocytes was present in 9/17 autopsy tissues and in two biopsy specimens. Moderate to abundant iron storage in the Kupffer cells was seen in all liver specimens. The amount of hepatocytic iron was high in livers up to 1 month of age and decreased thereafter. The general features and liver findings of this disorder suggest the name Growth Retardation Aminoaciduria Cholestasis Iron Overload, Lactacidosis and Early Death (GRACILE, OMIM 603358). Calcified concrements were seen in the medulla of 13/16 kidney specimens. Pancreas of 13/14 patients showed interstitial fibrosis and exocrine atrophy. Various pathologic findings such as renal tubular dysgenesis, paucity of hepatic bile ducts and iron storage in the macrophages of spleen and pulmonary alveoli were observed in some cases. Previous extensive clinical genetic and laboratory investigations have revealed that the patients had a previously unrecognized genetic disease. It is inherited as an autosomal recessive trait. The gene locus is 2q33-37. The basic defect of the disease remains unknown.

Acidosis, Lactic↗
PubMed1992

T lymphocytes and iron overload: novel correlations of possible significance to the biology of the immunological system.

This paper is written in the context of our changing perception of the immunological system as a system with possible biological roles exceeding the prevailing view of a system concerned principally with the defense against external pathogens. The view discussed here relates the immunological system inextricably to the metabolism of iron, the circulation of the blood and the resolution of the evolutionary paradox created by oxygen and iron. Indirect evidence for this inextricable relationship between the two systems can be derived from the discrepancy between the theoretical quasi-impossibility of the existence of an iron deficiency state in the adult and the reality of the WHO numbers of people in the world with iron deficiency anemia. With the mounting evidence that TNF, IL-1, and T lymphocyte cytokines affect hemopoiesis and iron metabolism it is possible that the reported discrepancy is a reflection of that inextricable interdependence between the two systems in the face of infection. Further direct evidence for a relationship between T cell subset numbers and iron metabolism is presented from the results of a study of T cell populations in patients with hereditary hemochromatosis. The recent finding of a correlation between low CD8+ lymphocyte numbers, liver damage associated with HCV positivity and severity of iron overload in beta-thalassemia major patients (unpublished data of RW Grady, P. Giardina, M. Hilgartner) concludes this review.

Anemia, Hypochromic↗
PubMed2006

Hemochromatosis and severe iron overload associated with compound heterozygosity for TFR2 R455Q and two novel mutations TFR2 R396X and G792R.

We report three mutations of transferrin receptor 2 (TFR2)--R396X (exon 9; nt 1186C-->T), R455Q (exon 10; nt 1364G-->A) and G792R (exon 18; nt 2374G-->A)--in a man of Scottish descent with hemochromatosis and severe iron overload. He was also heterozygous for the common HFE H63D polymorphism. The patient did not have coding region mutations in HAMP, FPN1, HJV or ALAS2. We conclude that this patient represents another example of hemochromatosis due to mutations of the gene encoding transferrin receptor 2.

Amino Acid Substitution↗
PubMed1994

Bone marrow transplantation in thalassemia: modifications of hepatic iron overload and associated lesions after long-term engrafting.

Among 450 thalassemic patients treated in the Hematologic Department, 50 patients who were disease-free 4-6 years after allogeneic bone marrow transplantation were sequentially studied by liver biopsy. The patients received marrow from siblings who were genotypically HLA identical at A, B, C and DR loci. For evaluation of siderosis and associated lesions, each patient underwent liver biopsy before, and again 6 months and yearly for 4 to 6 years after bone marrow transplant. Spontaneous reversibility of liver iron overload, once the need for transfusions ceased when a functioning graft had been established, was observed in the youngest patients, aged 1-8 years, whereas iron excess remained at the end of follow-up in many patients aged 9-15 years. Hypotheses about the mechanism of the iron decrease are discussed. Several cases also obtained improvement of associated pathologies such as hepatitis, probably through modifications in the mechanisms controlling their immunological status.

Adolescent↗
PubMed1995

Assessment of liver iron overload by T2-quantitative magnetic resonance imaging: correlation of T2-QMRI measurements with serum ferritin concentration and histologic grading of siderosis.

PURPOSE: To correlate hepatic 1/T2 values obtained by means of a T2-Quantitative MRI (T2-QMRI) technique with three widely applied methods for the evaluation of hemosiderosis, i.e., (a) liver iron concentrations (LFeC) (b) serum ferritin (SF), and (c) histologic grading of siderosis. The impact of coexisting hepatitis was also considered. T2-QMRI measurements were compared with signal intensity (SI) ratio measurements on conventional SE images. MATERIALS AND METHODS: Liver T2 relaxation times were calculated in 40 thalassemic patients, on a 0.5 T magnetic resonance imaging system using a multiple spin-echo sequence with parameters: TR = 2500 ms, TE = 12 ms in 20 symmetrically repeatable echoes. RESULTS: (a) 1/T2 values were well correlated (r = 0.97) with liver iron concentrations, which ranged from 2.32 to 18.0 mg/g dry weight (normal < 1.6 mg/g). (b) 1/T2 values were also correlated with serum ferritin levels (r = 0.84). At various 1/T2 values, serum ferritin levels were higher for the anti-HCV(+) patients than the anti-HCV(-) ones. (c) T2 values corresponding to successive grades of siderosis presented statistically significant differences. (d) SI ratio measurement assigned less statistically significant results, as compared to T2 values. CONCLUSION: T2-QMRI measurement of T2 relaxation time is more accurate than SI ratios in evaluating liver iron overload. It is particularly useful for hemosiderotic patients with coexisting hepatitis since, in this case, serum ferritin is not considered a reliable index of hemosiderosis.

Adult↗
PubMed1996

Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation.

Patients who require a bone marrow transplant (BMT) for leukaemia, lymphoma or other haematological disorders receive large quantities of blood products, including red cell concentrates, during the transplant period. Many receive red cell transfusions as part of treatment prior to BMT, adding to the potential iron load. However, organ dysfunction as a consequence of the transfused iron load would be surprising given the amounts of iron transfused. We studied 76 survivors of allogeneic and autologous BMT who were at least 1 year post-transplant and found that the majority (88%) had raised ferritins. Impaired liver function was common in these patients and in half was unexplained by viral hepatitis, veno-occlusive disease or graft-versus-host disease (GVHD), suggesting that iron overload may be an important contributing factor to liver disease in the stable post-transplant setting. This view is supported by the observation of improving liver function tests in 10 patients after a trial of venesection therapy.

Adolescent↗
PubMed1987

Neutrophil dysfunctions in thalassaemia major: the role of cell iron overload.

The susceptibility to infections was recorded in 13 patients with beta thalassaemia major (T.P.). The following parameters were also investigated in their polymorphonuclear neutrophils (PMN): nitro blue tetrazolium (NBT) reduction, heated yeast and Escherichia coli phagocytosis, Escherichia coli killing and myeloperoxydase activity. These results were compared to those obtained in healthy controls (H.C.). The Perls's reaction was performed on PMN and graded according to a scoring system with the aim of quantifying the iron intoxication of PMN. Phagocytosis and Perls's reaction of PMN from H.C. were also studied after 20 h of incubation with thalassaemic serum. 6 T.P. out of 13 developed septicaemia during their lifetime and in all 9 septicaemic episodes were noted. Phagocytosis was greatly impaired, disclosing both cellular and serum abnormalities. The mean percentage of Perls's positive PMN was 13% in T.P., contrasting with the constant negative reaction in H.C. The incubation of PMN from H.C. with serum from T.P. induced the simultaneous appearance of a phagocytosis defect and of a positive Perl's reaction. It was concluded that in beta thalassaemia major the phagocytosis of PMN was altered due to a combination of serum and cellular abnormalities and that both may be related to the iron overload.

Adolescent↗
PubMed1980

Binding of serum ferritin to concanavalin A: patients with homozygous beta thalassaemia and transfusional iron overload.

Serum ferritin concentrations have been measured in 124 patients with homozygous beta thalassaemia who were between 2 and 21 years old, had received 11--504 units of blood but had not undergone splenectomy. There were highly significant correlations between serum ferritin concentration and both the amount of blood transfused and alanine amino-transferase (ALT) activity. However, multivariate analysis showed that units of blood and ALT activity together only accounted for about 30% of the variation in serum ferritin concentration. Little of the remaining variation could be explained by other variables related to iron metabolism or liver damage. The concentration of concanavalin A binding ferritin increased rapidly with the number of units of blood up to 100 units but thereafter showed no further increase with number of transfusions. The concentration of non-binding ferritin was more closely related to transfusion load. These results suggest that the secretion of glycosylated ferritin from reticuloendothelial cells reaches a maximum with increasing iron accumulation, perhaps reflecting a maximum rate of synthesis. Ferritinaemia in patients with transfusional iron overload therefore seems to be the result of the combined effects of increased ferritin synthesis and the release of intracellular ferritin from damaged cells. A simple relationship between serum ferritin and iron stores cannot be assumed when ferritin concentrations exceed 4000 microgram/l or in patients who have received more than 100 units of transfused blood.

Adolescent↗
PubMed1983

[Anomalies of human gonadal function in periodic hemodialysis: role of the etiology of kidney failure and the role of iron overload].

Levels of testosterone, free testosterone, oestrogen, LH, FSH, prolactin were measured in 39 dialysed men. A LHRH stimulation test was performed. This study was analysed in function of the underlying renal disease, the duration of hemodialysis, and serum ferritin levels. In chronic glomerulonephritis serum gonadotrophins concentrations were significantly higher than in chronic interstitial nephritis or polycystic disease. A correlation between prolactin and ferritin was found, which may reflect the pituitary iron overload. Free testosterone levels were significantly lower in patients with gynecomastia (23-29 patients). In fact, the most direct relationship that we found with gynecomastia in dialysed men was with the free testosterone/oestrogen ratio.

Adult↗
PubMed1994

The effect of iron overload on rat plasma and liver oxidant status in vivo.

There is ample evidence implicating reactive oxygen species in a number of human degenerative diseases such as atherosclerosis and haemochromatosis. Although lipid peroxidation underlies many of the toxic effects of oxidative stress, there is a lack of a sensitive and reliable method for its assessment in vivo. To understand the implications of oxidative stress in vivo, we have used dietary iron overload (IO) in the rat. Oxidant status in these animals was determined by assessing depletion of endogenous antioxidants and formation of various lipid peroxidation products, including acylated F2-isoprostanes, a novel class of free-radical-derived prostaglandin-F2-like compounds. IO led to a significant decrease in the concentration of the antioxidants alpha-tocopherol and ascorbic acid in plasma, and alpha-tocopherol, beta-carotene and ubiquinol-10 in liver. Whereas there was no significant lipid peroxidation in plasma, hepatic F2-isoprostane levels were moderately but significantly increased in IO. In addition, IO caused a significant increase in plasma total and high-density lipoprotein cholesterol levels, an effect that was correlated with depletion of plasma ascorbic acid but not alpha-tocopherol. The data demonstrate that IO causes lipid metabolism disturbances and oxidative stress which is associated with substantial depletion of endogenous antioxidants and moderate lipid peroxidative damage.

Animals↗
PubMed1995

MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease.

Magnetic resonance (MR) marrow signal in the axial and appendicular skeleton of 13 transfusion-dependent and chelated pediatric patients with sickle cell anemia (SSD) was compared with marrow signal in six non-transfusion-dependent patients with SSD. Hepatic, pancreatic, and renal MR signal were also evaluated. Indication for hypertransfusion therapy was primarily prior history of stroke. Transfusion-dependent patients had evidence of iron deposition throughout the imaged marrow and the liver, despite deferoxamine chelation therapy. Non-transfusion-dependent patients did not demonstrate grossly apparent signs of iron overload. Red marrow restoration was present in the spine, pelvis, and long bones and, in some patients, within the epiphyses. Marrow edema secondary to vaso-occlusive crises was evident in the metaphyses and diaphyses of long bones in areas of both red and fatty marrow and was best seen using fat-saturated T2-weighted imaging techniques.

Adolescent↗
PubMed1987

[Iron overload of the liver and protein synthesis. Progress made through experimental models].

To understand the disturbances in protein synthesis observed during idiopathic hemochromatosis, various experimental models may be used. The aim of this research was to review the principal models employed and to demonstrate the value of hepatic tissue culture techniques in each. This method has already made it possible to explain several mechanisms involving the control of proteins in iron metabolism such as transferrin and ferritin. Tissue culture techniques of human hepatocytes should make it possible to elucidate the nature of the basic metabolic disorder in this disease responsible for the iron overload in the near future.

Animals↗