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PubMedDate not supplied

Serum type III procollagen peptide in alcoholic liver disease and idiopathic hemochromatosis: its relationship to hepatic fibrosis, activity of the disease and iron overload.

To assess the value of type III procollagen peptide (sPIIIP) as a marker of hepatic fibrosis, sera from 73 patients with alcohol-related liver disease and 30 patients with idiopathic hemochromatosis (IHC) were studied by a specific radioimmunoassay. sPIIIP was increased in 87% of 30 patients with cirrhosis, in 16% of 32 with steatofibrosis but in none of 11 with steatosis. There was a significant correlation with histologic hepatocellular necroinflammation (r = 0.42, p less than 0.01), but not with hepatic fibrosis. sPIIP was increased in 33% of 30 patients with IHC, whether or not they had cirrhosis or fibrosis, and whatever the level of iron overload or the extent of the hepatic deterioration. IHC patients with increased levels of sPIIIP had a higher prevalence of superimposed hepatic damage than did those with normal procollagen levels (p less than 0.05). Our findings, therefore, weaken the diagnostic value of sPIIIP as an index of connective tissue deposition in the liver, and suggest that, at least in alcohol-related liver disease and IHC, hepatocellular necroinflammation influences the results.

Adult↗
PubMed1979

Detection of early cardiac dysfunction in patients with severe beta-thalassemia and chronic iron overload.

To detect early left ventricular dysfunction, we used radionuclide cineangiography to determine left ventricular ejection fraction during exercise in 24 patients with transfusion-dependent, congenital anemias, 21 of whom had severe beta thalassemia. Ejection fraction at rest was normal in 21 patients (greater than 45 per cent) and in all patients was 53 +/- 2 per cent (mean +/- S.E.M.)--not significantly different from the value in normal subjects. However, ejection fraction during exercise was normal in only 11 patients (53 +/- 3 per cent in all patients, P less than 0.001 as compared with the normal value). All eight patients who had received fewer than 100 transfusions but only three of 16 (19 per cent, P less than 0.001) who had received 100 or more transfusions had normal responses during exercise. Whereas echocardiographic fractional shortening at rest was normal in 16 of 19 patients studied, eight patients with normal fractional shortening had abnormal ejection-fraction responses to exercise. Thus, radionuclide cineangiography during exercise is a highly sensitive technique for detecting preclinical myocardial dysfunction in patients with systemic iron overload.

Adolescent↗
PubMed2003

Current directions in hemochromatosis research: towards an understanding of the role of iron overload and the HFE gene mutations in the development of clinical disease.

Since the discovery of a candidate gene (HFE) thought to be involved in the development of hereditary hemochromatosis, there has been much interest in the potential use of genetic testing as a screening tool for the disease in the general population. However, a recent study suggests that less than 1% of subjects who are homozygous for the gene mutations will go on to develop the full-blown disease of hereditary hemochromatosis, historically termed "bronzed diabetes." The study also suggests that homozygotes have no higher risk of mortality or of any clinically significant morbidity than normal control subjects. This conclusion contradicts earlier findings that linked iron overload and HFE mutations to a number of devastating diseases, including cardiovascular disease, diabetes, and cancer.

Genetic Predisposition to Disease↗
PubMed1996

Continuous low-dose subcutaneous desferrioxamine (DFO) to prevent allergic manifestations in patients with iron overload.

In some patients compliance to subcutaneous desferrioxamine therapy is reduced because of allergic symptoms. Effective drug desensitization consists of bringing patients to tolerate the same mode of administration. We evaluated three thalassemic patients with severe allergies to desferrioxamine. Each patient received weekly three prefilled infusors with desferrioxamine 4 g/48 m1/48 h for s.c. therapy. Follow-up was performed for 12 consecutive weeks. During follow-up no allergic events were noted. The s-ferritin levels decreased from 2583 micrograms/l +/- 485 to 1916 micrograms/l +/- 275 (mean decrease 25.8%, p = 0.038). Compliance to the infusional system was excellent. Our results show that continuous infusion of desferrioxamine using a new infusional delivery system is effective in preventing allergic reactions and in reducing iron overload.

Adult↗
PubMed1985

Impaired phagocytic activity of neutrophils in patients receiving haemodialysis: the critical role of iron overload.

The metabolic burst (as measured by the spontaneous and stimulated nitroblue tetrazolium tests), the phagocytosis of heat inactivated bakers' yeast and of Staphylococcus aureus, the killing of Staph aureus, and the myeloperoxidase activity of polymorphonuclear neutrophils were studied in 11 patients receiving maintenance haemodialysis. Of these patients, six were polytransfused and had high serum ferritin concentrations (mean 5940 (SD 2925) micrograms/l; group 1), and five had normal serum ferritin values (mean 171 (116) micrograms/l; group 2). Patients in group 1 had a history of more infectious episodes (0.167 v 0.025 per patient per month) and significantly more genitourinary infections (p = 0.015) than those in group 2. Phagocytosis and myeloperoxidase activity were severely reduced in group 1 but normal in group 2. Percentages of neutrophils ingesting one or more particles together with the index of phagocytosis in patients' serum were inversely correlated with serum ferritin concentrations. Four patients in group 1 were treated with desferrioxamine, and after six to 18 weeks of treatment phagocytosis and myeloperoxidase activity had returned to normal in three of them. These data suggest that in patients receiving haemodialysis iron overload due to multiple transfusions plays an important part in the mechanisms underlying the susceptibility to bacterial infections, mediated at least partially through impaired neutrophil function.

Adult↗
PubMed2001

Iron deficiency and iron overload: effects of diet and genes.

Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some FIFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

Anemia, Iron-Deficiency↗
PubMed1991

Is dehydroepiandrosterone-sulphate a possible pathogenetic factor in osteopenia of patients with iron overload?

Bone metabolism studies were performed on 5 patients with transfusional haemosiderosis (2 male, 3 female; mean age: 30.8 years) and 5 patients with idiopathic haemochromatosis (2 male, 3 female; mean age: 48.8 years). In the majority of the patients, the modern osteodensitometric method showed a significant decrease of the mineral content of the trabecular and cortical bones. Low calcitonin and dehydroepiandrosterone-sulphate concentrations were measured in the majority of the patients with calcipenic osteopathy. Besides marked bone loss, hypogonadotropic hypogonadism was found in 3 male patients, while normal LH, FSH concentration values were measured in 3 female patients. The prolactin concentration was normal in all 6 patients. The authors suppose that besides the already known pathogenetic factors, insufficient calcitonin effect and especially the partial lack of dehydroepiandrosterone-sulphate can play a role in the development of bone loss connected with iron overload. Further study with a greater number of patients is required to support the above findings.

Adult↗
PubMedDate not supplied

Toxic effects of high-dose deferoxamine treatment in patients with iron overload: an electrophysiological study of cerebral and visual function.

BACKGROUND AND METHODS: It is well known that deferoxamine (DFO) treatment in thalassemia major can produce ocular toxicity. In one experience, Visual evoked potentials (VEPS) to pattern reversal were formed to be altered in 4 out of 10 patients under conventional treatment with DFO, before supplementary high-dose i.v. deferoxamine. In all 4 cases the alterations consisted of bilaterally delayed P100 latency, always obtained by stimulation with high spatial frequency (15' checks) and associated in three cases with low spatial frequency (55'). Computerized EEG (cEEG) studies showed a generalized increase of slowing activity. All patients underwent high-dose DFO treatment. RESULTS: At the control performed at the end of treatment in all 4 cases with previous VEP alterations, a further delay in P100 latency was observed bilaterally while two of the six patients, without previous involvement, showed delayed responses when using checks of 15'. The EEG slowing activity was not modified. Three weeks after terminating i.v. DFO therapy, the patients were still under subcutaneous treatment (50 mg/kg/day); a more evident VEP recovery towards the initial values was observed in those patients without initial alterations. No significant changes were found between electrophysiological parameters and serum ferritin levels. CONCLUSIONS: Our results indicate that high-dose DFO therapy in patients with iron overload induces reversible visual impairment without significant changes in brain electrical activity. The employment of VEP in intensive chelation programs in thalassemia major is discussed.

Adolescent↗
PubMed2006

Risk of iron overload in carriers of genetic mutations associated with hereditary haemochromatosis: UK Food Standards Agency workshop.

The UK Food Standards Agency convened a group of expert scientists to review current research investigating diet and carriers of genetic mutations associated with hereditary haemochromatosis. The workshop concluded that individuals who are heterozygous for the C282Y mutation of the HFE gene do not appear to respond abnormally to dietary Fe and therefore do not need to change their diet to prevent accumulation of body Fe.

Atherosclerosis↗
PubMedDate not supplied

Genome-linked toxic responses to dietary iron overload.

Genome-related differences to Fe overload between and within rodent species were evaluated in the present study. Male B6C3F1 mice, yellow and black C5YSF1 mice, and Fischer 344 (F344) rats were fed AIN-76A diets containing 35 (control), 1,500, 3,500, 5,000, or 10,000 micrograms carbonyl Fe/g for 12 wk. No effects on body weight gain were observed in the B6C3F1 and black C5YSF1 mice, whereas at all doses of Fe above the control, weight gain was reduced in yellow C5YSF1 mice and F344 rats. At the 10,000 micrograms Fe/g dose, 9 of 12 rats died, but there was no mortality among the mice. In all animals, there was a dose-related increase in liver nonheme Fe, and the Fe was stored in hepatocytes predominantly in the periportal region. There was significant hypertrophy of the hepatocytes in both B6C3F1 mice and F344 rats fed the 10,000 micrograms Fe/g diet. PCNA assays showed significant stimulatory effects of the high dose of Fe on hepatocyte proliferation in the F344 rats and the C5YSF1 mice but not in the B6C3F1 mice. In the rat, there was pancreatic atrophy with loss of both endocrine and exocrine tissue. Morphometric evaluation of pancreas showed fewer beta cells in B6C3F1 and yellow C5YSF1 mice but not in the black C5YSF1 mice. There were fewer islets in the yellow C5YSF1 mice, and total and mean islet areas were smaller than in the control mice. Rats in the 10,000 micrograms Fe/g dose group had markedly exacerbated dose-dependent nephropathy and changes in glomerular and tubular epithelium associated with Fe accumulation. The rats also showed degeneration of the germinal epithelium of the testis, formation of multinucleated giant cells, and lack of mature sperm.

Animals↗
PubMed1999

An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload.

The aim of this study is to establish a good animal model for esophageal adenocarcinoma (EAC) and to test the hypothesis that iron over-nutrition enhances EAC formation. With rats, esophagogastroduodenal anastomosis (EGDA) was accomplished by anastomosing the duodenum to the gastroesophageal junction. Iron supplementation was given by i.p. injection of iron dextran (4 mg Fe/kg/week). This model mimics the development of human EAC by introducing mixed reflux of gastric and duodenal contents. At 40 weeks after surgery, the body weight, food intake, hemoglobin, total serum iron, transferrin saturation, serum albumin, and plasma levels of alpha-tocopherol, gamma-tocopherol and retinol of the EGDA rats were not significantly different from those of the non-operated controls. The animals generally had only mild esophagitis, except that the area surrounding the anastomosis opening had more severe esophagitis. Columnar-lined esophagus (CLE), CLE with dysplasia, and EAC were diagnosed in 53.5, 34.9 and 25.6%, respectively, of the 43 rats. Intraperitoneal iron supplementation significantly enhanced esophageal lesions with CLE, CLE with dysplasia, and EAC to 78.0, 53. 7 and 53.7%, respectively, of the 41 rats. All the tumors were well-differentiated mucinous adenocarcinomas at the squamocolumnar junction area, where most iron deposition was observed. EGDA avoids nutritional problems seen in other animal models for EAC. We believe that direct anastomosis of squamous epithelium to columnar epithelium and mixed reflux of gastric and duodenal contents lead to the formation of CLE and EAC. With this model, we demonstrated that iron supplementation significantly enhanced EAC formation, suggesting that iron over-nutrition could also be a risk factor for human EAC.

Adenocarcinoma, Mucinous↗
PubMed1985

Studies on the effect of iron overload on rat cortex synaptosomal membranes.

Iron as ferrous ammonium sulfate was injected into the cerebral spinal fluid of rats. After three consecutive days of injection of 4 mumol of iron, the total iron content of brain cortex synaptosomes from the iron-treated animals was 2-fold higher than that from control animals receiving the saline vehicle only. Spin label studies of the synaptosomal membranes demonstrated that the lipid region of the membranes became more rigid and, in addition, the mobility of labeled SH groups of membrane proteins decreased after the iron treatment. The cholesterol content was significantly higher in iron-treated animals as compared to controls. Centrophenoxine pretreatment (100 mg/kg body weight daily for 6 weeks) diminished the iron effects. Synaptosomal membrane alterations observed after iron treatment were similar to changes observed previously during aging. This lends support to the notion that free-radical induced damage occurs in brain membranes with increasing age.

Animals↗
PubMed1991

[Nuclear magnetic resonance and iron overload in thalassemia].

We assessed the iron load content in 36 beta-thalassemia patients by NMR correlating the results with serum ferritin levels. 22 of them were affected by beta-thalassemia major on hyper-transfusional regimen (Group A), 4 by beta-thalassemia intermedia (Group B) and 10 by beta-thalassemia major, who had been previously bone marrow transplanted (Group C). In A and C Groups the liver showed the lowest signal intensity on spin echo images (p less than 0.01; p less than 0.06, respectively). A significant correlation between the summation of signals obtained from all the examined organs and serum ferritin levels was observed by evaluating both all the patients globally (r = 0.78; p less than 0.001) and the A and C Group patients. This correlation was confirmed only in the liver both in all the patients (r = 0.77; p less than 0.001) and in A and C Group patients, when the signals obtained from each organ were evaluated.

Adolescent↗