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PubMed1984

Ultrastructural study of iron deposition in the eccrine sweat glands of patients with iron overload.

An ultrastructural study of eccrine sweat glands was carried out on three patients with iron overload (two with idiopathic haemochromatosis and one with transfusional haemosiderosis). In all three patients small electron-dense particles were seen in both eccrine sweat glands and macrophages. They appeared primarily in the clear cells of the eccrine sweat glands as membrane-bound irregularly shaped bodies, and were shown to contain iron by energy dispersive X-ray microanalysis. Iron aggregates in and around sweat glands were also seen on light microscopy.

Adult↗
PubMed1978

Serum ferritin concentration: a reliable guide to iron overload in uremic and hemodialyzed patients.

The inter-relationships between serum ferritin, hemoglobin, serum iron and total body iron stores were studied in 20 patients with chronic renal failure treated conservatively and in 20 patients on regular hemodialysis. There was no relationship between serum iron or transferrin and bone marrow iron deposits, but serum ferritin concentration was a good indicator of increased marrow iron stores. All patients with serum ferritin levels above 300 microgram/l had increased iron stores. Serum ferritin assay is a useful non-invasive technique for detecting iron overload in uremic and hemodialyzed patients.

Adolescent↗
PubMed2001

Iron overload and nitric oxide-derived oxidative stress following lung transplantation.

BACKGROUND: Reactive oxygen species (ROS) may contribute to airway injury and the development of the bronchiolitis obliterans syndrome (BOS) following lung transplantation (LT). Chemically active iron released from ferritin stores and nitric oxide (NO)-derived radicals may add to the oxidative burden. METHODS: We determined the concentrations of ferritin and the aqueous NO derivative nitrite (NO2(-)) within bronchoalveolar lavage fluid (BALF) of 14 stable LT recipients (ST) and 7 subjects with BOS and 21 normal controls. We also assessed the relationship between BALF ferritin and hemosiderin-laden macrophages (HLMs) using a hemosiderin score (HS) and determined BALF albumin concentration as a marker of microvascular leakage. RESULTS: BALF ferritin concentrations and HSs were significantly elevated in LT recipients overall compared with normal controls (p < 0.05). BALF NO2(-) levels were elevated in BOS subjects and STs compared with normal controls (p = 0.002 and p = 0.09, respectively), but there was no difference between transplant groups. BALF albumin concentrations were elevated in BOS patients compared with normal controls (p = 0.02) and ST (p = 0.05), but there was no difference between STs and controls. There was a significant relationship between BALF ferritin concentration and HS in LT recipients overall (r(s) = 0.7, p < 0.001). In BOS subjects, but not ST, BALF ferritin was significantly related to BALF albumin (r(s) = 0.8, p = 0.05) and there was a weak relationship with NO2(-) concentration (r(s) = 0.6, p = 0.1). BALF NO2(-) was strongly related to BALF % neutrophils in BOS subjects (r(s) = 0.9, p < 0.01), but there was no such relationship in STs. CONCLUSIONS: Our findings suggest that the allograft could be subject to significant iron-generated oxidative stress, which may be exacerbated by NO and neutrophil-derived ROS, particularly in BOS. Microvascular leakage may be a feature of established chronic rejection, which potentiates the iron overload and contributes to further airway damage and remodeling.

Adult↗
PubMed1982

Effect of ascorbic acid deficiency on serum ferritin concentration in patients with beta-thalassaemia major and iron overload.

The incidence of ascorbic acid (AA) deficiency and its effect on serum ferritin concentration relative to body iron stores was studied in 61 unchelated patients with beta-thalassaemia major. Thirty-nine (64%) of patients had subnormal leucocyte ascorbate concentrations without clinical evidence of scurvy. The lowest leucocyte ascorbate concentrations tended to occur in the most transfused patients. No correlation was found between the units transfused and serum ferritin concentration in the AA-deficient patients but a close correlation (r = +0.82; p less than 0.005) existed for the AA-replete group. Similarly a close correlation (r = +0.77; p less than 0.005) was obtained between liver iron concentration and serum ferritin in AA-replete patients but only a weak correlation (r = +0.385; p less than 0.025) existed for the AA-deficient group. When AA-deficient patients were treated with ascorbic acid, serum iron and percentage saturation of iron binding capacity rose significantly; serum ferritin rose in 13 of 21 patients despite the simultaneous commencement of desferrioxamine therapy. In contrast all three measurements tended to fall in AA-replete patients with ascorbic acid and desferrioxamine therapy. Thus, AA deficiency is commonly present in beta-thalassaemia patients with iron overload and may give rise to inappropriate serum ferritin concentrations in relation to body iron stores.

Adolescent↗
PubMed2006

Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis.

AIMS/HYPOTHESIS: We recently demonstrated that humans with hereditary haemochromatosis have decreased insulin secretory capacity with a compensatory increase in insulin sensitivity. We therefore determined how these measures change after correction of tissue iron overload. SUBJECTS AND METHODS: Five non-diabetic subjects who had been studied previously at the time of initial diagnosis by means of the OGTT and frequently sampled intravenous glucose tolerance tests (FSIVGTT) underwent phlebotomy to normalise their serum ferritin. After normalisation of ferritin they were studied again (33+/-4 months after the initial studies) by OGTT and FSIVGTT. RESULTS: Normalisation of tissue iron stores resulted in an average 1.8-fold increase in the integrated area under the insulin curve during OGTT (p<0.0001), but no significant change in the area under the glucose curve (10% decrease, p=0.32). After phlebotomy, there was a 2.2-fold increase in insulin secretory capacity as determined by FSIVGTT (acute insulin response to glucose [AIRg], p<0.02) but a concomitant 70% fall in insulin sensitivity (Si, p<0.05). The disposition index (AIRgxSi) was unchanged (5% increase, p=0.90). BMI and fasting glucose were unchanged. At the time of diagnosis of haemochromatosis, four of the subjects had IGT. After normalisation of ferritin, two achieved NGT and two remained with IGT, despite 2.5- and 3.7-fold increases in insulin secretory capacity. CONCLUSIONS/INTERPRETATION: Insulin secretory capacity improves after normalisation of iron stores in subjects with hereditary haemochromatosis. Glucose tolerance status improves incompletely because of decreased insulin sensitivity after phlebotomy. We conclude that tissue iron levels are an important determinant of insulin secretion and insulin action.

Blood Glucose↗
PubMed1990

Familial iron overload with possible autosomal dominant inheritance.

A 96 member Melanesian kindred with 31 cases of iron overload is reported. Liver biopsies from 19 of these patients showed features similar to those of genetic haemochromatosis in Caucasians, but in contrast to the previous reported HLA-linked autosomal recessive pattern of inheritance for haemochromatosis, this family shows a pattern that is most consistent with autosomal dominant inheritance. This is suggested by involvement of three and possibly four consecutive generations, with a high frequency of transmission from parents to children and equal gender distribution. Linkage and segregation analysis supported dominant inheritance, with no demonstrable HLA linkage.

Female↗
PubMed1994

Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.

BACKGROUND: To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. METHODS: At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. RESULTS: The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P < 0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun chelation therapy later and used less deferoxamine in relation to their transfusional iron load (P < 0.001). CONCLUSIONS: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.

Adolescent↗
PubMed2002

Antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria, cholestasis, iron overload, and lactic acidosis in the newborn infant.

OBJECTIVE: A prenatal diagnosis of the fetus for a mother of two previously deceased infants who died from the recently described autosomal recessive disease (OMIM 603358). The infants presented with intrauterine growth retardation, aminoaciduria, cholestasis, iron overload, severe lactic acidosis, and early death (GRACILE syndrome). STUDY DESIGN: DNA was extracted from the fibroblasts and tissue samples of the deceased infants, parental leukocytes, and from a chorion villus biopsy in the next pregnancy. Haplotypes were determined using the relevant markers flanking the disease-associated region of chromosome 2. RESULTS: Both deceased infants were homozygous for the four critical markers. The fetal haploptypes were identical to those of the siblings and the pregnancy was terminated. The iron content of the fetal liver was increased (5000 microg/g) compared with the controls, with a marked iron accumulation in the Kupffer cells. CONCLUSIONS: Antenatal diagnosis can be performed based on linkage analysis in families with at least one affected child because the disease locus has been assigned to a restricted chromosomal region. Typical histological abnormalities may be present in early fetal life.

Abortion, Induced↗
PubMed1999

Effects of dietary iron overload on progression in chemical hepatocarcinogenesis.

AIM: The present study was undertaken to investigate possible effects of dietary iron during the progression step in hepatocarcinogenesis. METHODS: Two experiments were performed, in which preneoplastic foci were produced in rat liver using the Solt & Farber protocol, with diethylnitrosamine as initiator and partial hepatectomy + 2-acetylaminofluorene as promoter. Two weeks after promotion, animals were fed 1.25-2.5% dietary carbonyl iron or a control diet until sacrifice. In the first experiment, animals were killed at different time points when they developed an abdominal mass in combination with weight loss. In the second experiment, animals were sacrificed 45 weeks post-promotion. Liver tumours were counted and histologically graded. Tumour levels of ubiquinone-9 and alpha-tocopherol were determined with HPLC, and labelling and apoptotic indices calculated using immunohistochemistry. The number and area of glutathione S-transferase 7,7 (GST-7,7)-positive foci were determined. RESULTS: In experiment number 1, survival and tumour differentiation were similar in iron-treated animals and controls. In the second experiment, iron-treated rats had an increased number of GST-7,7-positive foci compared to controls. Number and size of carcinomas were similar between the groups, whereas tumour differentiation was higher in rats exposed to iron. Cell proliferation, apoptosis and concentrations of alpha-tocopherol in tumours were not altered by iron. The ratio of reduced/oxidized ubiquinone-9 was decreased in tumours from iron-treated animals. CONCLUSION: In this model, dietary iron overload resulted in an increased number of preneoplastic foci but did not enhance the progression of these into hepatocellular carcinomas. Iron decreased the ratio of reduced/oxidized ubiquinone-9 in tumours, indicating that neoplastic liver cells utilize intracellular ubiquinones as a defense mechanism against iron-induced oxidative stress.

2-Acetylaminofluorene↗
PubMed1980

[Treatment of iron overload due to repeated transfusions with subcutaneous infusions of desferrioxamine (author's transl)].

The urinary excretion of iron has been studied in 23 cases of iron overload (20 thalassemia major, 2 pure red cell aplasia, 1 congenital sideroblastic anemia) after 12 hour subcutaneous infusions of 0.5 g, 1 g, 2 g and 3 g of desferrioxamine (D). The urinary excretion of iron was correlated with the dose of D and the serum ferritin. Continuous subcutaneous infusion of 0.5 g and 1 g D over 12 hours increased the mean urinary iron excretion from 6.6 to 12 mg/day and 9.9 to 18 mg/day respectively compared with intramuscular injection of a similar dose. The test doses of D have been used to determine the dose of D necessary to balance the iron received in transfusion and the iron excreted in the urine. Five children treated for between 7 and 12 months demonstrated that the treatment is effective. Serum ferritin levels decreased and the children were in negative iron balance. Using a portable constant infusion pump subcutaneous infusions can be given at home.

Adolescent↗
PubMed1997

Clinics in diagnostic imaging (29). Thalassaemia major with iron overload.

A 5-year-old girl presented with lethargy, anaemia and facial distortion. Both parents had beta-thalassaemia minor. Radiographs confirmed the characteristic features of thalassaemia major. A treatment regime comprising regular blood transfusions was commenced. The basis of the radiographic changes and the current role of magnetic resonance imaging, particularly with respect to assessing iron overload, are emphasized.

Blood Transfusion↗
PubMed1993

Hepatotoxicity associated with dietary iron overload in mice.

1. Weanling male CD-1 mice were fed 120 (control), 5000 and 8000 mg of iron kg-1 for seven weeks. The haematocrit (P = 0.265), water consumption (P = 0.170) and percentage body weight ratios of kidney, spleen and heart were not affected by iron supplementation. 2. Iron supplementation reduced weight gain (P = 0.023), increased weight of liver (P = 0.0001), the iron deposition index and concentration of iron in the liver (P < 0.01). A strong correlation between liver iron concentration and level of iron in the diet (r = 0.989) was observed. Histologically, the deposition of iron was restricted to the hepatocytes, Kupffer cells and splenic macrophages. 3. Consumption of 5000 and 8000 mg of iron kg-1 resulted in hepatic damage, as judged by elevated serum alkaline phosphatase and alanine aminotransferase activities (P < 0.05). 4. This study indicates that prolonged feeding of excess dietary iron has the potential to cause hepatic accumulation of iron with resultant liver toxicity, and that mice may be a suitable model to study the mechanisms of dietary iron overload.

Alanine Transaminase↗
PubMed2004

Bone metabolism and oxidative stress in postmenopausal rats with iron overload.

Osteoporosis is associated with many etiological causes such as nutrition, cytokines, hormones, and aging. Recently, reactive oxygen species (ROS) are considered to be responsible for the aging process and osteoporosis. We investigated the relationship between ROS and bone metabolism in young female and postmenopausal rats, by using dietary iron overload and several indices including bone metabolic markers, oxidative stress and antioxidant markers, and cytokines. Postmenopausal rats exhibited significant decreases in serum alkaline phosphatase activity and the level of osteocalcin as bone formation markers compared with young female rats; however, urinary excretion of deoxypyridinoline, a bone resorption marker, did not change. On the other hand, a 5% iron lactate diet for 4 weeks in postmenopausal rats led to significantly increased excretion of urinary deoxypyridinoline and 8-hydroxy-2'-deoxyguanosine (8-OHdG) but not serum alkaline phosphatase activity. Interestingly, the diet induced significant increases of serum osteopontin and TGF-beta1, augumenting osteoclast-mediated bone resorption through the RANK/RANKL pathway [J. Clin. Invest. 112 (2003) 181]. TGF-beta1 showed a negative correlation with serum glutathione peroxidase (GPx) activity (r = -0.674, P < 0.003), but a positive correlation with the serum iron level (r = 0.836, P < 0.0001). Taken together, these results suggest for the first time that oxidative stress could be involved in the pathogenesis of metabolic bone diseases such as osteoporosis as demonstrated by analysis of the relationship between bone metabolism and oxidative stress.

Animals↗
PubMed1984

Iron overload in three generations of a family with hemoglobin Olympia.

Erythrocytosis, increased whole blood oxygen affinity, and iron overload were found in a 37-yr-old man. Electrophoretic techniques to demonstrate a hemoglobin variant showed no abnormality. Structural studies of the hemoglobin from this patient revealed an abnormal hemoglobin previously described as Hemoglobin Olympia, a high-affinity variant. Study of three generations in this family showed increased hepatic iron or iron absorption in some members of all three generations studied. The findings in this family are consistent with an increase in iron absorption due to the consequences of Hemoglobin Olympia and the heterozygous state for hemochromatosis (allele for hemochromatosis associated with HLA-A3, B7) or the presence in the family pedigree of three different alleles for hemochromatosis (alleles for hemochromatosis associated with HLA-A3. B7, HLA-A3, B15, and HLA-A9, B44) with the heterozygous state being manifest with increased iron absorption.

Absorption↗
PubMed1981

[Experimental studies on metabolism of iron overload in dogs with carbon tetrachloride induced chronic hepatic injury (author's transl)].

In order to clarify the influence of iron overload in the liver, histological and histochemical examinations were performed on the dogs to which colloidal iron (chondroitin sulfuric iron) as well as inorganic iron (ferrous sulfate) was intravenously administered for a long period. The experimental animals were firstly divided into two groups were respectively subdivided into three groups; the two corresponding to the injected irons and the one with no iron injection. Also the liver iron content was measured by atomic absorption spectrophotometry when the animals were sacrificed. The results were summarized as follows: 1) Even in the group in which only CCl4 was given without any iron solution, positive iron granules were found in Kupffer cells or macrophages at the central necrotic zone of hepatic lobules. The liver iron content was 80.15 +/- 25.74 microgram/100mg wet weight and higher than that of 35.20 +/- 6.13 micro/100mg.w. w. in normal control group, however, there were no significant difference between these two values (Fig. 1). 2) In the group in which only colloidal iron was given, iron deposition was limited to the Kupffer cells and did not appear in hepatocytes unless the liver content reached to 978.0 microgram/100mg.w.w.. On the contrary, in the group in which only inorganic iron was given, positive iron granules were already found in hepatocytes at the peripheral zone of hepatic lobules with liver iron content of 157.7 microgram/100mg.w.w.. 3) In the group in which inorganic iron was administered with CCl4, positive iron granules were found in hepatocytes, even though the level of liver iron content was as low as 81.86 microgram/100mg.w.w. being far lower than that in the group without CCl4. 4) Liver iron content was well correlated with the duration of administration of iron solution, irrespective the kinds of injected iron. And the slope of the regression line in the group in which only colloidal iron was given was steeper than that in the group in which only inorganic iron was administered (Fig. 2). And also the slope of the regression line in the group in which colloidal iron was administered with CCl4 was steeper than that in the group without CCl4 (Fig. 3). 5) In the group in which colloidal iron was administered with CCl4, marked iron deposition was observed in Kupffer cells or macrophages at the central necrotic zone of hepatic lobules, and accompanied by hepatic fibrosis in chronic cases. These results indicate that the long-term administration of colloidal iron may accelerate the hepatic fibrosis when chronic hepatic injury co-existed, even if it seems that it is mostly metabolized in reticuloendothelial system of the liver.

Animals↗
PubMed1994

Erythropoietin treatment in haemodialysis patients with iron overload.

Erythropoietic response to exogenously administered recombinant human erythropoietin (rHuEpo) was examined in 11 maintenance haemodialysis patients with iron overload (IO). All had required numerous blood transfusions earlier (> 12 units/year). Diagnosis of IO was established by high serum ferritin (SF) levels (> 1,100 micrograms/l), high hepatic CT density (> 70 Hounsfield units; HU) and excessive iron stores in bone marrow aspirate (grade 6). None of the patients had osteitis fibrosa cystica, aluminium intoxication, haemoglobinopathy or haemochromatosis alleles (HLA A3, B7 and B14). All patients responded to rHuEpo treatment (target haemoglobin level of 9-10 g/dl). None of the patients required iron supplementation or developed 'functional anaemia'. During 30 +/- 3 months of therapy, the initial maintenance dose of rHuEpo (103 +/- 12 units/kg/week) and median SF levels (2,250 micrograms/l) fell (50 +/- 8 units/kg/week and 1,060 micrograms/l, respectively) (p = 0.0003 and 0.0007). The initial and final rHuEpo doses correlated well with the respective SF levels (r = 0.89, p < 0.001). The maintenance dose of rHuEpo required for patients with IO at the start of the treatment period was significantly higher than that (50 +/- 5 units/kg/week) required by a control group of patients with adequate iron stores (SF = 100-600 micrograms/l) who were matched for age, sex and frequency of previous blood transfusions (p = 0.002). The findings suggested that excessive IO caused relative resistance to erythropoiesis on exogenous administration of rHuEpo and that iron supplementation was not warranted during rHuEpo therapy in those patients.

Adult↗
PubMed2001

C282Y and H63D mutations in the HFE gene have no effect on iron overload disorders in Japan.

OBJECTIVE: The gene responsible for hereditary hemochromatosis close to the human leukocyte antigen A locus was previously identified and designated as HFE. This study was performed to evaluate the clinical significance of two mutations, C282Y and H63D of HFE, in Japanese patients with hepatic iron overload. PATIENTS AND METHODS: We examined C282Y and H63D in 11 patients with primary hemochromatosis, 94 patients with chronic hepatitis C, 54 patients with miscellaneous liver diseases, and 151 healthy volunteers. The HFE gene region of DNA samples extracted from peripheral leukocytes was amplified by polymerase chain reaction. Restriction enzyme analysis was performed using SnaBI for C282Y and BclI for H63D. Direct sequence analysis was then performed when products suggested the presence of a mutation. RESULTS: All the subjects studied were free from C282Y. None of the patients with hemochromatosis had H63D. One patient with chronic hepatitis C was homozygous, and 4 patients were heterozygous for H63D. Two patients with alcoholic liver disease were heterozygous for H63D. The prevalence of chromosomes with H63D was 6/188 (3.2%) in patients with chronic hepatitis C, 2/108 (1.9%) in patients with miscellaneous liver diseases, and 8/302 (2.6%) in healthy volunteers. These differences were not significant. CONCLUSION: Our results suggested that neither C282Y nor H63D in HFE affect Japanese patients with hemochromatosis or chronic hepatitis C.

Adult↗