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PubMed2006

The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: an update of clinical and immunological data from 70 C282Y homozygous subjects.

Hereditary hemochromatosis (HH) is a clinically heterogeneous disease. Among other factors, the individual immunological profile of CD8+ T-lymphocytes has been described to influence the severity of iron overload, with low numbers being negatively correlated with the total amount of body iron stored. With the objective of testing the modifier effect of the individual CD8+ T-lymphocyte profile on the levels of iron stores with age in HH, we reviewed the clinical and immunological data from a group of well-characterized C282Y homozygous HH subjects, regularly followed-up for a period of 20 years. A total of 70 subjects were analyzed. Sixty-four were adults (> or = 18 years): 42 males (mean age 47 +/- 14; range 22-75 years) and 22 females (mean age 46 +/- 14; range 19-65 years). Six were younger than 18 years, 5 males (mean age 9 +/- 4; range 5-14 years) and 1 female (15 years). The characterization of subjects included measurements, at diagnosis, of the iron parameters, transferrin saturation (TfSat) and serum ferritin, quantification of total body iron stores (TBIS) removed by phlebotomies, presence of associated clinical manifestations, and the T-cell immunophenotype (CD4+ and CD8+ T-lymphocytes) determined by flow cytometry. In general, statistically significant lower values of TfSat (67 +/- 17% vs. 89 +/- 14%, P = 0.0006) and ferritin levels (58 +/- 9 vs. 949 +/- 233 ng/ml, P = 0.02) were found in the young subjects in comparison to adults. After the age of 18, however, no further effect of age was significantly found on the biochemical iron parameters either in males or females. A modifier effect of the individual CD8+ T-lymphocyte profile on the association between iron stores and age was demonstrated by multiple regression analysis, where a significant correlation between TBIS and age was found only in males with low (< or = 0.41 x 10(6)/ml) CD8+ T-cell numbers (R2 = 0.43, P < 0.0001). In conclusion, in the present population of C282Y homozygous subjects, the CD8+ T-lymphocyte profile could be considered a modifier of the iron overload with increasing age in males, with low numbers predicting a severe outcome.

Adult↗
PubMed2001

Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.

OBJECTIVE: The aim of this study was to define in patients with hyperferritinemia and normal transferrin saturation the relationships among hyperferritinemia, iron overload, HFE gene mutations, the presence of metabolic alterations, and nonalcoholic steatohepatitis (NASH). METHODS: Forty patients with increased serum ferritin, resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic evidence of hepatic steatosis, and 60 obligate heterozygotes for hemochromatosis, all negative for alcohol abuse, hepatitis virus infections, and inflammation were studied. Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed. RESULTS: Of the 40 patients with hyperferritinemia, 29 (72%) had biochemical metabolic abnormalities, 18 of the 26 examined (69%) had insulin resistance, 26 (65%) had the presence of one of the two HFE gene mutations (normal controls, 33 of 128 [26%], p < 0.0001), and all had increased liver iron concentration. Thirty-one patients (77%) had histology compatible with NASH. At univariate analysis, NASH was significantly associated with the presence of metabolic alterations, the C282Y mutation, and severity of fibrosis. At multivariate analysis, NASH was associated with the coexistence of multiple metabolic alterations (odds ratio = 5.2, 95% CI = 0.95-28.7). The risk of having NASH augmented in the presence of higher values of ferritin and liver iron concentration. Among the 90 patients with ultrasonographic evidence of hepatic steatosis, 24 (27%) had increased serum ferritin with normal transferrin saturation, but only six remained hyperferritinemic after dietary restriction. CONCLUSION: Increased ferritin with normal transferrin saturation is frequently found in patients with hepatic steatosis, but it reflects iron overload only in those patients in whom it persists despite an appropriate diet. The simultaneous disorder of iron and glucose and/or lipid metabolism, in most of the cases associated with insulin resistance, is responsible for persistent hyperferritinemia and identifies patients at risk for NASH.

Analysis of Variance↗
PubMed1997

Iron overload in light of the identification of a haemochromatosis gene.

This review gives a short summary of the most recent advances in the regulation of iron at the molecular level. The clinical consequences of iron overload are discussed and a critical evaluation of the assays used for the estimation of the body iron status provided. The methodology of the search for a candidate gene for hereditary haemochromatosis is described and the results critically evaluated. The importance of widespread population surveys by PCR-based screening tests for the most likely disease-associated mutation is stressed as a means of early diagnosis of hereditary haemochromatosis, enabling prevention of the development of Life-threatening complications of iron overload.

Animals↗
PubMed1994

Assessment of hepatic iron overload in thalassemic patients by magnetic resonance spectroscopy.

The transverse relaxation time of water protons is shortened by the presence of iron. This shortening depends on the amount and the environment of iron in the sample. We have developed a method for measuring short transverse relaxation time noninvasively by magnetic resonance spectroscopy. To evaluate magnetic resonance spectroscopy as a means of assessing hepatic iron content in patients with transfusional iron overload, we compared the results obtained with this method with those obtained by other means of assessing total body iron content. The correlation between the liver biopsy iron concentration and 1/transverse relaxation time was highly significant (r = 0.95, p < 0.004, n = 6) for iron loads up to 3% dry weight. The correlation between serum ferritin and 1/transverse relaxation time was also significant, but the correlation coefficient was much lower (r = 0.67, p < 0.002, n = 20). The correlation between 24-hr urinary iron excretion and 1/transverse relaxation time was not significant, nor was that between AST and 1/transverse relaxation time. We conclude that magnetic resonance spectroscopic determination of the transverse relaxation time of hepatic water is an accurate method of measuring liver iron content, especially when the iron content is below 3%. Because it is a noninvasive method that is associated with negligible side effects, it could provide clinicians with an excellent means of assessing the effectiveness of the various therapeutic strategies used in the management of patients with iron overload.

Adolescent↗
PubMedDate not supplied

Yersinia enterocolitis in iron overload.

Yersinia enterocolitis with peritonitis and septicaemia developed in a 4-year-old child with thalassemia intermedia and iron overload. It is likely that the illness was exacerbated by continued administration of desferrioxamine, a bacterial siderophore, which facilitated systemic spread of Yersinia. It is recommended that Yersinia enterocolitis be considered in children with iron overload and that desferrioxamine be discontinued and prophylactic antibiotics be administered while Yersinia is sought.

Child, Preschool↗
PubMed2002

Iron overload and cardiovascular complications in dialysis patients.

Patients with end-stage renal disease (ESRD) are at a markedly increased risk for cardiovascular complications compared with the general population. In addition to traditional cardiovascular risk factors such as diabetes mellitus, hypertension, hyperlipidaemia or cigarette smoking, a number of population-specific factors are implicated, such as anaemia, hyperhomocysteinaemia, hyperphosphataemia and vascular calcification, as well as inflammation and oxidative stress. Iron overload has been suggested to increase the cardiovascular risk in the general population. Iron supplementation is a widespread clinical practice in ESRD, especially in patients on maintenance haemodialysis (HD). Iron may therefore contribute to cardiovascular complications through effects on low-density lipoprotein oxidation and endothelial dysfunction. Although the effects of iron stores and iron therapy on cardiovascular risk are not well defined in HD patients, the 'iron hypothesis' deserves attention: serum ferritin is a marker of morbidity and mortality in HD patients, and the administration of high amounts of intravenous iron increases the risks of hospitalization and death. In contrast to intravenous iron therapy, intestinal iron absorption is regulated by body iron stores and is suppressed in the presence of infection and iron overload. Prospective studies are needed to clarify the influence of iron stores and iron therapy on overall and cardiovascular morbidity and mortality in ESRD patients.

Acute Kidney Injury↗
PubMed1995

[Yersinia enterocolitica septicemia, iron overload and deferoxamine].

Infections due to Yersinia enterocolitica are usually limited to the bowel. When infection is generalized, the role of iron overload and iron chelation has been discussed. We report the case of a 55 year-old patient with sideroblastic anemia who received repetitive transfusions and deferoxamine for 4 years and heme arginate for 2 months, and who was admitted in our institution for Yersinia enterocolitica sepsis. Treatment by third-generation cephalosporins and aminoglycosides has allowed favorable outcome.

Anemia, Sideroblastic↗
PubMed1993

Quantitative ultrasonic analysis of myocardium in patients with thalassemia major and iron overload.

BACKGROUND: Patients with beta-thalassemia major present with severe anemia and need continuous transfusion therapy. The consequent iron overload leads to hemochromatosis. Initial cardiac dysfunction has been documented even in thalassemics without clinical manifestations of heart failure as well as by conventional echocardiographic-Doppler techniques. The purpose of this study was to assess the acoustic quantitative properties of myocardium in patients with iron overload. METHODS AND RESULTS: Thirty-eight patients with beta-thalassemia major, without clinical signs of cardiac failure, and 20 age- and sex-matched young controls were studied by echocardiography. An on-line analysis of the ultrasonic radiofrequency signal was performed to obtain quantitative operator-independent measurements of the integrated backscatter (IB) signal of the ventricular septum and the posterior wall. The integrated values of the radiofrequency signal were normalized for the pericardial interface and expressed in percent (IB%). Thalassemic patients had been receiving transfusion therapy for 16 +/- 5 years and had received 313 +/- 138 transfusion units; they all had received chelation treatment (desferroxiamine) for 9 +/- 2 years. Patients and controls showed comparable values of echocardiographically assessed percent fractional shortening (32 +/- 3% versus 36 +/- 4%, p = NS), whereas thalassemics showed higher values of left ventricular mass index (118 +/- 30 versus 98 +/- 15 g/m2, p < 0.05). The IB% values were higher in patients with thalassemia major than in controls for both septum (35 +/- 14% versus 21 +/- 6%, p < 0.001) and posterior wall (16 +/- 6% versus 11 +/- 3%, p < 0.001). In thalassemic patients, no significant correlation was found between the septum IB% value and hematological parameters, such as the total number of transfusions (r = 0.2, p = NS) or the mean ferritin value (r = 0.1, p = NS). No significant correlation was also found between the septum IB% value and the echocardiographically assessed left ventricular mass index (r = 0.2, p = NS). CONCLUSIONS: These data demonstrate that myocardial reflectivity is abnormally increased in patients with thalassemia major under transfusion treatment, probably due to myocardial iron deposits and/or secondary structural changes. These quantitatively assessed abnormalities in regional reflectivity can be detected when conventional echocardiographic parameters of systolic left ventricular function are undistinguishable from normal controls.

Adolescent↗
PubMed2005

Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study.

We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Each underwent serum transferrin saturation (TfSat) and ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat more than 50% (men), more than 45% (women); and SF more than 300 ng/ml (men), more than 200 ng/ml (women). Mean TfSat and percentages of participants with elevated TfSat were significantly greater in whites than in blacks. Mean SF and percentages of participants with elevated SF were significantly greater in blacks than in whites. TfSat and SF varied by gender and age in whites and blacks. Prevalences of genotypes that included either C282Y or H63D were significantly greater in whites than in blacks. The prevalence of elevated TfSat and SF plus genotypes C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks. Among whites with HFE C282Y homozygosity, 76.8% of men and 46.9% of women had elevated TfSat and SF values. Three black participants had HFE C282Y homozygosity; one had elevated TfSat and SF values. Possible explanations for differences in TfSat and SF in whites and blacks and pertinence to the detection of hemochromatosis, iron overload, and other disorders with similar phenotypes are discussed.

Adult↗
PubMed2000

A trial of deferiprone in transfusion-dependent iron overloaded children.

OBJECTIVE: To determine the efficacy and safety of deferiprone. DESIGN: Prospective study. SETTING: 5 paediatric medical units at the Lady Ridgeway Hospital for Children (LRHC), Colombo. PATIENTS: Transfusion-dependent iron overloaded children in the age group 2 to 15 years. INTERVENTION: Patients were given a total daily dose of 75 mg/kg of deferiprone orally in divided doses. MEASUREMENTS: Efficacy of deferiprone therapy was assessed by 4-monthly serum ferritin assays using the ELISA technique. Safety of deferiprone therapy was assessed by 4-weekly white cell counts, platelet counts and serum transaminase levels. The Z-test was used to assess the significance of the difference between the mean initial serum ferritin level and the mean subsequent serum ferritin level. RESULTS: 54 patients received deferiprone therapy for a mean duration of 9 +/- 3 months. Initial serum ferritin levels ranged from 1500 to 10,700 ng/ml with a mean of 5743. Subsequent serum ferritin levels, obtained in 48 patients ranged from 740 to 7300 ng/ml with a mean of 3558 (p < 0.001). In 47 of the 48 patients subsequent serum ferritin levels were lower than initial levels. One child developed severe neutropaenia, which reverted to normal on discontinuation of treatment. 11 children developed arthropathy, which responded to ibuprofen therapy combined in some cases with a reduction of the dose of deferiprone to 50 mg/kg/day. Serum transaminase levels were raised in 5 patients but reverted to pretreatment values or lower despite continuation of deferiprone therapy. CONCLUSIONS: Deferiprone is a safe and effective oral iron-chelating agent which can be used, under strict supervision, in transfusion-dependent iron overloaded children.

Adolescent↗
PubMed1981

[Iron-overload in patients on maintenance hemodialysis: diagnostic criteria, indications and treatment by desferrioxamine (author's transl)].

33 patients with chronic renal failure were divided into two groups. Group I consisted of 8 non-dialysed patients without any clinical or biochemical sign of liver disturbance nor any iron supplementation. Group II consisted of 25 maintenance hemodialysis (MHD) patients treated from 2 to 13 years. 19 subjects had chronic B hepatitis. Total exogenous iron load parenteral iron and/or blood transfusions) was calculated. Body iron overload (hemosiderosis) was assessed by liver iron concentration (LIC) in needle biopsy specimens according to Barry's method (less than 200 microgram/100 mg dry weight) and serum ferritin levels (less than 360 ng/ml). 4 patients whose serum ferritin was increased with or without hepatic fibrosis and with or without any organ dysfunction due to hemochromatosis received i.v. infusions of desferrioxamine in doses of 2 g at each dialysis. Serum ferritin levels were correlated with LIC (p less than 0.001) and iron load (p less than 0.001). Hemosiderosis was noted in 16 MHD patients (group II) and correlated with iron load. Hemochromatosis was noted in 4 patients (group II). 4 hemodialysed patients with iron overload were treated by desferrioxamine from 6 to 18 months. During this therapy, body iron stores fell and organ dysfunction (heart failure, hepatic cytolysis, anaemia, diabetes mellitus improved. Long-term chelation therapy by desferrioxamine was effective and the chelated iron was readily removed by dialysis. These data show the importance of precise evaluation of iron stores in MHD patients.

Adult↗
PubMed2000

Abnormal regulation of HFE mRNA expression does not contribute to primary iron overload.

BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis (HHC) is a common, recessively inherited, genetic disorder associated with an abnormality of the HFE gene. Subjects homozygous for a point mutation in the gene coding sequence, leading to the amino acid substitution C282Y, are usually affected by the disease. A second point mutation, causing the amino acid substitution H63D, has been described, and compound heterozygotes for the two mutations or homozygotes for the H63D mutation are at risk of developing a milder form of HHC. In populations of northern European origin the C282Y substitution accounts for more than 90% of cases of HHC. In Italy, however, fewer than 70% of patients with HHC are homozygous or compound heterozygous for HFE mutations. Even in the absence of mutations in its coding region, the HFE gene might be involved in the pathogenesis of HHC through inhibition of transcription of the gene or reduced stability of its mRNA. DESIGN AND METHODS: Since little is known about the regulation of HFE expression, we investigated 17 subjects heterozygous for one of the HFE mutations and with biochemical evidence of iron overload and compared the levels of wild type and mutated mRNAs in their peripheral blood cells. c-DNA regions flanking the mutated codons were amplified by reverse transcriptase polymerase chain reaction (PCR). PCR products derived from the two alleles were differentiated and quantified by digestion with restriction enzymes, electrophoresis in an agarose gel stained with ethidium bromide and densitometric scanning of the gel. RESULTS: In all cases wild type and mutated mRNAs were expressed at similar levels, suggesting that reduced expression of an HFE allele coding a normal protein is not involved in the pathogenesis of iron overload. However, we can not rule out that a tissue specific regulation of HFE expression in the cells directly involved in iron absorption is altered and contributes to the pathogenesis of the disease. E INTERPRETATION AND CONCLUSIONS: Our results suggest that primary iron overload is a multigenic syndrome; this hypothesis is strongly supported by the recent demonstration that the juvenile hemochromatosis locus maps to human chromosome 1q.

Adolescent↗
PubMed1979

[Demonstration by iron overloading study and HLA genotyping of recessive transmission of idiopathic haemochromatosis in two pseudodominant pedigrees (author's transl)].

We studied iron overloading and HLA genotype in two families with overt forms of idiopathic haemochromatosis in two successive generations. In each family the spouse of the patient with overt haemochromatosis in the first generation had clinical and laboratory signs of moderate iron overload and a HLA haplotype A3, B14 and A3, B7 respectively--which is frequently associated with the haemochromatosis gene. This specific HLA haplotype had been transmitted to the second generation patient with overt disease, which thus could be considered as having received a haemochromatosis gene from each parent. Although the finding of cases of overt disease in successive generation firstly suggests a dominant transmission the genetical analysis of these families lead to further strong argument in favour of recessive inheritance of idiopathic haemochromatosis.

Adolescent↗
PubMed1972

An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload.

An immunoradiometric assay for human ferritin has been developed. Concentrations of ferritin in the serum of male and female controls and patients with iron deficiency and iron overload were measured.Male controls were found to have a significantly higher mean concentration of serum ferritin than females. Patients with iron deficiency had significantly lower levels than normals of either sex and patients with iron overload had greatly elevated serum ferritin concentrations. It is thought that the serum ferritin concentration may reflect the iron stores of the body.

Anemia, Hypochromic↗
PubMed2006

Dual function of fish hepcidin: response to experimental iron overload and bacterial infection in sea bass (Dicentrarchus labrax).

The role of hepcidin in iron metabolism regulation and bacterial infection has been the focus of recent attention. However, in spite of the growing number of hepcidin genes known from different organisms, little is known about its putative dual function in fish. The aim of this study was to characterize the sea bass hepcidin gene and to study its role in iron metabolism and infection. The novel sea bass hepcidin gene was found to be organized into two introns and three exons with several copies present in the genome. The transcript showed a constitutive low basal expression being mainly expressed in liver and encoding a putative 85 residues long peptide. Fish were submitted either to iron status modulation or bacterial infection and the hepcidin transcript levels were analysed along with a number of other parameters. Liver hepcidin expression was found to increase in both the iron-overloaded and infected fish, while in the iron-deficient fish no alteration in expression levels was detected. These results point to the evolutionary conservation of hepcidin's dual functions.

Amino Acid Sequence↗
PubMed1992

Assessment of liver iron overload in thalassemic patients by MR imaging.

The use of MR imaging has been proposed for the assessment of the hepatic iron overload in transfusion-dependent thalassemic patients treated with desferrioxamine. The aim of the study was to correlate serum ferritin levels and MR signal intensity of the liver parenchyma. Results on 12 patients showed that the ratios between the signal intensity of liver parenchyma and muscle and fat are promising parameters for predicting iron overload.

Adolescent↗
PubMed1984

Effects of iron overload on bone remodeling in pigs.

For study of the effects of an iron overload on bone remodeling, 5 control pigs were compared with 5 pigs given a total dose of 10.8 g of parenteral iron in 36 days. Treated pigs developed an iron tissue overload demonstrated by a marked increase in bone and liver iron. Except for a modest increase in SGOT, there was no biochemical or histologic sign of liver damage. Serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were unchanged in the treated pigs. There was no accumulation of iron in the parathyroid glands and the serum immunoreactive parathyroid hormone level was unchanged in the treated animals. Bone histomorphometry after double tetracycline labeling showed that in the treated pigs osteoblast cell surfaces, double and total labeled surfaces, appositional rate, and formation at tissue level were significantly decreased, and reversal surfaces were increased. Mineralization was not impaired because the osteoid thickness was unchanged. From the morphometric measurements it was concluded that osteoblast recruitment and the collagen synthesis rate were decreased. Mean wall thickness, which indicates the amount of bone synthesized, was also lowered. In contrast, the osteoclastic resorption surfaces and the depth of lacunae resulting from osteoclast resorption were unchanged by treatment. Despite this imbalance between formation and resorption, trabecular bone mass estimated on trabecular bone volume and bone ash was unchanged after 36 days' treatment. Perls' stain revealed that iron deposits were present in osteoblast and osteoclast cells and also inside the bone matrix, because there was a linear deposit along the trabecular surfaces, cement line, and osteoid-mineralized bone interface. Therefore, because treatment induced no modification of the major humoral regulators of bone metabolism, it is suggested that iron, which was present in bone cells and matrix, could play a role in bone remodeling.

Alanine Transaminase↗