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PubMed1998

Activated hepatic stellate cells participate in liver fibrosis in a patient with transfusional iron overload.

We describe liver fibrosis caused by iron overload after a long history of blood transfusion in a patient with chronic renal failure. Pertinent laboratory data were: serum (s)-Fe 148 microg/dl; unsaturated iron binding capacity (UIBC) 14 microg/dl; s-ferritin 9350 ng/ml; human leukocyte antigen (HLA) A2, A24, B39, B55, Cw1, Cw7. Computed tomography revealed a high density in the liver, and laparoscopy revealed a brown liver. Liver histology showed bridging fibrosis from portal tracts. A heavy iron deposit was seen in Kupffer cells as well as in hepatocytes surrounded by fibrosis around the portal tracts. Immunocytochemistry revealed alpha-smooth muscle actin in many stellate cells distributed along the fibrotic area, and electron microscopy revealed infiltrating myofibroblastic stellate cells coexisting with collagen fibers around degenerated hepatocytes containing iron deposits. The findings are consistent with the notion that stellate cells play an important role in liver fibrogenesis in both genetic and transfusional iron overload hemochromatosis.

Adult↗
PubMed1986

Management of iron overload in dialysis patients.

Acquired hemosiderosis resulting from massive iron deposits in various organs, including heart, liver, and pancreas, may lead to architectural and functional disturbances of these organs. Even though iron overload can occur in nonuremic as well as in uremic individuals, the dialysis patient is at particular risk for developing hemosiderosis. Many dialysis patients receive exogenous iron from either oral iron therapy or blood transfusions. In addition, these patients seem to be at high risk for retaining iron. A diagnosis of excess iron deposition should be considered if the patient has unexplained cardiomyopathy, hepatic cirrhosis, proximal myopathy, diabetes mellitus, arthropathy, or immune dysfunction such as listeriosis. Several techniques are available for determining iron overload. Diagnostic tests include measuring serum ferritin levels, staining bone marrow preparations for excess iron, measuring tissue hemosiderin concentrations, magnetic resonance imaging, and the deferoxamine (DFO; Desferal) "challenge test." The simplest treatment for iron overload in nonuremic patients is removal of iron by venesection. However, in patients in whom venesection is not feasible, the chelating agent DFO can effectively remove excess iron. In the dialysis patient, DFO therapy can be combined with either dialysis or hemoperfusion to remove the iron-DFO complex that would otherwise be removed by the kidney. DFO therapy in the nondialyzed individual has proven to be successful, but before treatment, the benefits of the treatment must be weighed against possible adverse side effects such as cataracts, changes in color vision, and anaphylaxis. In the dialysis patient, indications for iron removal are less clearly defined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Iron overload in renal failure patients: changes since the introduction of erythropoietin therapy.

Iron overload was a common complication in patients with chronic renal failure treated with dialysis prior to the availability of recombinant human erythropoietin (rHuEPO) therapy. Iron overload was the result of hypoproliferative erythroid marrow function coupled with the need for frequent red blood cell transfusions to manage symptomatic anemia. The repetitive use of intravenous iron with or without the use of red blood cell transfusions also contributed to iron loading and was associated with iron deposition in liver parenchymal and reticuloendothelial cells; however, there were no abnormal liver function tests or evidence of cirrhosis unless viral hepatitis resulted from the transfusions. With rHuEPO therapy, the excess iron stores were shifted back into circulating red blood cells as the anemia was partially corrected, and red blood cells were lost from circulation by the hemodialysis procedure. After several years of rHuEPO therapy, most hemodialysis patients required iron supplements to replace the continuing blood losses related to hemodialysis. The potential complications of iron overload (parenchymal iron deposition, permanent organ damage, increased risk of bacterial infections, and increased free radical generation) are reviewed in the context of this setting.

Anemia↗
PubMed2005

Recent acquisitions in the management of iron overload.

Chronically transfused patients develop iron overload, which leads to organ damage and ultimately to death. The introduction of the iron-chelating agent desferrioxamine mesylate dramatically improved the life expectancy of these patients. However, the very demanding nature of this treatment (subcutaneous, continuous infusion via a battery-operated portable pump) has been the motivation for attempts to develop alternative forms of treatment that would facilitate the patients' compliance. In this review, we describe the most important advances in iron-chelation therapy.

Deferoxamine↗
PubMed1986

Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload.

A patient who developed severe iron overload cardiomyopathy is described. Venesection could not be performed because the patient had chronic anemia. Deferoxamine mesylate, a chelating agent, was administered daily for more than 2 years and produced significant improvement in ventricular function which was associated with a biopsy-proven decrease in myocardial iron stores. This is the first reported case in which a severe cardiomyopathy due to iron overload was reversed by chelation therapy alone.

Adult↗
PubMed1984

NMR imaging of the liver in two cases of iron overload.

Two cases of iron overload in the liver are presented--one of hemochromatosis with associated hepatoma and one of hemosiderosis with probable androgen dependent multicentric hepatic adenomas. Nuclear magnetic resonance scans displayed the tumours as well as low liver parenchymal signal intensity on the saturation-recovery, inversion-recovery, and spin-echo pulse sequences probably as a result of decreased tissue T1 and T2.

Adenoma↗
PubMed1992

Transport of siderotic Kupffer cells to the lung and bronchial excretion of iron in experimental iron-overload.

In 3,5,5-trimethylhexanoylferrocene-induced iron overload of rats, three different types of iron-loaded macrophages and derivatives thereof were found in the lungs. On the basis of their localization and of their pattern of iron load it was possible to distinguish: (1) Resident macrophages, showing an alveolar localization and a moderate iron content represented by lysosomal ferritin and haemosiderin. (2) Liver-derived macrophages and giant cells, as well as fragments of them. They showed an exclusive localization in capillaries and alveolar septa, and high concentrations of free ferritin molecules in addition to polymorphous ferritin- and haemosiderin-containing siderosomes. (3) Monocyte-derived intravascular pulmonary macrophages. Initially, they contained iron only as lysosomal aggregates of ferritin and haemosiderin, as a result of phagocytosis of liver-derived macrophageal cell fragments. Later in iron overload, they also showed free ferritin molecules in the cytosol and fused intrapulmonarily to giant cells. The resident as well as the liver-derived siderotic pulmonary macrophages provide a way for iron excretion through the airways.

Animals↗
PubMed1996

Iron overload disorders among Hispanics--San Diego, California, 1995.

Approximately 1.5 million persons in the United States are affected by iron overload diseases, which are primarily caused by hereditary hemochromatosis--the most common genetic disorder in the United States. Hereditary hemochromatosis is characterized by increased iron absorption in the gastrointestinal tract, which may cause lifelong excessive iron absorption and accumulation and serious health effects, including arthritis, cirrhosis, diabetes, impotence, heart failure, and death. Hereditary hemochromatosis is an autosomal recessive disease; the estimated prevalence of the homozygous genotype is 1:200 - 1:250 persons, and 10% of persons are carriers. Although the disease was previously believed to affect primarily white males of northern European descent, recent data indicate hereditary hemochromatosis also occurs among blacks. Moreover, iron overload diseases are underdiagnosed among whites and may not be considered in other racial/ethnic groups (e.g., Hispanics) even when compatible symptoms and clinical findings are present. As part of a joint demonstration project during August-October 1995 to determine the overall prevalence of iron overload, CDC reviewed data from a health-maintenance organization (HMO) in San Diego, California; the prevalence among Hispanics appeared similar to that for non-Hispanic whites. This report presents the preliminary findings of an analysis of the prevalence of iron overload among Hispanics and compares these findings with nationally representative data from the Third National Health and Nutrition Examination Survey (NHANES III). These findings indicate that the prevalence of possible iron overload among Hispanic clients of the HMO based on initial screening was consistent with the nationwide prevalence of possible iron overload based on a single screening test for Hispanics of Mexican descent and non-Hispanic whites.

California↗
PubMed1998

Time course study of the influence of acute iron overload on Kupffer cell functioning and hepatotoxicity assessed in the isolated perfused rat liver.

This study tested the hypothesis that acute iron overload (500 mg/kg) alters Kupffer cell functioning by promoting free radical reactions associated with the respiratory burst of liver macrophages, assessed in the isolated perfused rat liver under conditions of Kupffer cell stimulation by carbon infusion and inactivation by gadolinium chloride pretreatment. Total serum and hepatic iron levels were markedly enhanced compared with control values 2 to 24 hours after iron treatment. Total liver O2 uptake progressively increased by iron overload reaching a maximum at 6 hours after treatment, an effect that was completely blocked by GdCl3. Concomitantly, carbon-induced GdCl3-sensitive liver O2 uptake was either enhanced by 119% at 2 hours after iron overload, diminished compared with control values at 4 hours, or abolished at 6 hours. Iron-overloaded rats showed a marked increase in liver sinusoidal lactate dehydrogenase efflux at 4 and 6 hours after treatment, an effect that is exacerbated by carbon infusion and reduced (69%-89%) by GdCl3 pretreatment. Both basal and carbon-induced lactate dehydrogenase effluxes returned to control values at 24 hours after iron overload concomitantly with depression of the basal O2 uptake, without development of iron-induced GdCl3-sensitive respiration or Kupffer cell activation by carbon infusion. It is concluded that iron overload induces a derangement in the Kupffer cell functional status represented by early increases in macrophage-dependent respiratory activity, which may contribute to the concomitant liver injury that developed and to the impairment of both hepatic respiration and the macrophage response to particle stimulation observed at later times after treatment.

Acute Disease↗
PubMed2006

Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease.

Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P = <0.001) and growth failure (33% vs. 7%, P < 0.001), versus Tx-SCD. Fifty-six per cent of Thal had more than one endocrinopathy compared with only 13% of Tx-SCD (P < 0.001). In contrast, Tx-SCD was not different from non-Tx-SCD. Multivariate analysis indicated that endocrinopathy was more likely in Thal than SCD [Odds Ratio (OR) = 9.4, P < 0.001], with duration of chronic transfusion a significant predictor (OR = 1.4 per 10 years of transfusion, P = 0.04). Despite iron overload, endocrinopathy was not increased in Tx-SCD versus non-Tx-SCD, suggesting that the underlying disease may modulate iron-related endocrine injury. However, because transfusion duration remained a significant predictor of endocrinopathy, these data should be confirmed in SCD subjects that have been chronically transfused for longer periods of time.

Adult↗
PubMed1997

Ultrastructural sequences during liver iron overload in genetic hemochromatosis.

BACKGROUND/AIMS: The pathway through which iron contributes to liver cell damage and cirrhosis in genetic hemochromatosis is not clear. The objective of the present study was to describe the ultrastructural changes in liver biopsies of patients in various stages of this condition and to correlate these with clinical, histopathological and biochemical data. METHODS: Liver biopsies from 20 patients with genetic hemochromatosis were examined by transmission electron microscopy. The use of unstained thin (60 nm) sections facilitated the identification and localization of the electron-opaque compounds ferritin and hemosiderin in various liver cells. Stained thin sections permitted evaluation of the concomitant subcellular damage and collagen deposition. The ultrastructural observations were corroborated with the histopathological findings and biochemical data. RESULTS: All patients had liver iron overload, which was classified as mild, moderate or severe. In the stage of mild overload (hepatic iron concentration HIC 93.5+/-23.3 micromol/g and hepatic iron index HII 2.3+/-0.7), cytosolic ferritin and scarce pericanalicular lysosomes (siderosomes) were seen in periportal hepatocytes (acinar zone 1), without evidence of organelle damage, and in the absence of sinusoidal cell siderosis. In moderate overload (HIC 190.8+/-41.5 micromol/g and HII 4.3+/-1.9), ferritin was identified in hepatocytes of all acinar zones, and the pericanalicular siderosomes were abundant, especially in acinar zone 1. Single hepatocytes showed organelle damage and occasional sinusoidal cells showed siderosis. In severe overload (HIC 308+/-49.0 micromol/g and HII 7.5+/-1.7), hepatocytes of all acinar zones were filled with large, hemosiderin-containing siderosomes, and changes in mitochondria, smooth and rough endoplasmic reticulum and nuclei were conspicuous. Marked sinusoidal cell siderosis and collagen deposition were observed predominantly in this stage. CONCLUSIONS: Electron microscopy has shown that during the long, latent stage of "compensated" genetic hemochromatosis, hepatocytes display only minimal subcellular changes, other than iron overload. "Decompensated" overload, characterized by extensive subcellular pathology and focal necrosis, is reached when 1) the hepatocytic siderosis is generalized (i.e. beyond pericanalicular polarization of siderosomes in hepatocytes, and beyond zone 1 in the acinus); and 2) there is evidence of massive siderosis of sinusoidal cells. These findings support the concept of a critical level of hepatic iron concentration beyond which organelle damage is conspicuous and liver cell injury may become irreversible.

Adult↗
PubMedDate not supplied

[The urinary elimination of cobalt 57 in iron-deficiency anemia and in iron-overload states].

The authors used the 57 Co urinary excretion test to assess the intestinal absorption of iron in anemia associated with hypoferrinemia and in iron overload states. Among the anemia associated with hypoferrinemia, a high elimination of 57 Co had been found in all patients (15) with post-haemorrhagic iron deficiency anemia. Conversely, this elimination was very low in all 10 patients with anemia due to chronic inflammatory diseases. Moreover the test detected few iron deficiency anemia due to a decreased intestinal absorption of iron. In the iron overload states, the test had been performed in 2 subgroups of patients : chronic anemic patients with transfusional iron overload and hemochromatosis without anemia. In the transfusional iron overload group, 19 patients with thalassemia major who are routinely transfused have a moderate decrease of the 57 Co excretion. This finding probably reflects a continuing intestinal absorption of iron. On the other hand, 6 patients with acquired idiopathic sideroblastic anemia have a very low excretion. In the non anemic hemochromatosis, a high urinary level of 57 Co was present in 5 patients with idiopathic hemochromatosis when it was lower and variable in 6 patients with alcoholic siderosis. Using Wilcoxon, Mann and Whitney's non parametric test, there is a significant difference between the results of both groups. So, in idiopathic hemochromatosis, the high urinary level of 57 Co reflects an inappropriately high absorption of iron in spite of the iron overload and the test may be of value in detecting asymptomatic carriers of the disease.

Adolescent↗
PubMed2005

Iron overload and chelation.

Iron is one of the most common elements in nature. As a transition metal it is very efficient in electron transport and redox reactions. The proteins and enzymes in which iron is an essential component play a key role in respiration, energy production, detoxification of harmful oxygen species and cell replication. Despite the abundance of iron in nature, the solubility of its stable ferric form is extremely low. Hence, living organisms were compelled to develop efficient mechanisms for iron transport and storage.

Chelation Therapy↗
PubMed2002

Differential effects of iron overload on GST isoform expression in mouse liver and kidney and correlation between GSTA4 induction and overproduction of free radicles.

We have investigated the effect of iron overload on the expression of mouse GSTA1, A4, M1, and P1 in liver, the main iron storage site during iron overload, and in kidney. In iron-overloaded animals, mRNA and protein levels of GSTA1, A4, and M1 were increased in liver. In kidney, GSTA4 protein level was also increased while, unexpectedly, GSTA1 and M1 expression was strongly decreased. We showed, by immunohistochemistry, that GSTA4 was more abundant in hepatocytes of periportal areas and in convoluted proximal tubular cells in normal liver and kidney, respectively. In iron-overloaded mice, GSTA4 staining was more intense in cells that preferentially accumulated iron, and conjugation of 4-hydroxynonenal, a specific substrate of GSTA4, was enhanced in both organs. Moreover an acute exposure of primary cultures of mouse hepatocytes to iron-citrate strongly induced oxidative stress and cellular injury and resulted in an increase in GSTA4 expression, while cotreatment with iron-citrate and either desferrioxamine or vitamin E prevented both toxicity and GSTA4 induction. These data demonstrate that GSTA1 and M1 are differentially regulated in liver and kidney while GSTA4 is induced in both organs during iron overload. Moreover, they support the view that iron-induction of GSTA4 is related to an overproduction of free radicals.

Animals↗
PubMed2003

Optical mapping reveals conduction slowing and impulse block in iron-overload cardiomyopathy.

Cardiac disease with arrhythmia or heart failure is the leading cause of death in patients with thalassemia major and a major complication of other forms of iron overload. Current antiarrhythmic treatment does not appear to alter the clinical course. Using a gerbil model of iron-overload cardiomyopathy, we previously observed a reduction in the fast inward sodium current in isolated cardiomyocytes. Electrocardiograms (ECGs) in the same gerbil model indicate PR-interval prolongation, QRS-interval widening, and arrhythmias. We hypothesize that such changes in the ECG in this model are the result of abnormal action-potential conduction at the level of the whole heart. To test this hypothesis, we took ECGs and recorded action potentials using high-resolution optical mapping from the anterior surface of 9 iron-overloaded and 9 age-matched control ventricular-paced, Langendorff-perfused gerbil hearts. The iron-overloaded gerbils received weekly iron-dextran injections of 800 mg/kg for 14 to 18 weeks. ECGs showed QRS- and PR-interval prolongation in iron-treated gerbils compared with that in controls. In addition, atrioventricular block was observed in 2 of 6 iron-treated gerbils but not in controls. Conduction velocity was significantly slower in iron-treated gerbils than in controls. At normal pacing rates, abnormal activation patterns caused by stable regions of conduction block were observed in iron-overloaded gerbils (33%) but not in controls. Such abnormal impulse conduction may be a mechanism of increased arrhythmia vulnerability in iron-overload cardiomyopathy.

Action Potentials↗
PubMed1993

Iron overload in multiply transfused patients who are HIV seropositive.

AIMS: To assess histologically the amount of iron deposited in liver biopsy specimens from HIV positive patients; and to perform estimations of liver iron on tissue from patients with an increase in parenchymal stainable iron. To correlate the amount of blood transfused and the degree of iron overload. METHODS: Liver biopsy specimens (n = 120) from 109 HIV positive patients, 74 of whom had AIDS, were examined retrospectively and the amount of iron, as visualised with Perls's stain, was graded. Fibrosis was assessed using connective tissue stains. Estimations of liver iron were performed on tissue retrieved from paraffin wax blocks in cases with histological grade 3 or 4 iron overload. The amount of blood transfused before liver biopsy was determined from the notes for each patient. RESULTS: Fifteen of the 120 liver biopsy specimens had significantly increased amounts of iron in their hepatocytes, as assessed histologically, and this was confirmed in seven cases by measurement of liver iron. There was a close correlation between the amount of blood transfused and the degree of iron overload. In the initial biopsy specimens only one case showed portal tract expansion. Three of the five patients who had repeat biopsies, however, showed progressive fibrosis. CONCLUSION: Multiply transfused HIV positive patients may develop clinically important iron overload and are at risk of developing progressive fibrosis. Superimposed liver disease, especially viral hepatitis, in these high risk patients may exacerbate the effects of the iron overload.

Adult↗
PubMed2003

[Influences of iron overload on lipid peroxidation in rats and inhibiting effects of antioxidant vitamins].

In order to explore the influences of iron overload on lipid peroxidation of rats and the inhibiting effects of antioxidant vitamins such as vitamin E and beta-carotene on the influences induced by iron overload, eighty male Wistar rats were randomly divided into 8 groups according to the weight. The diets of the former 4 groups differed only in iron concentration (50, 200, 350 or 500 mg/kg diet). The diet of the latter 4 groups were consistent with the former 4 groups respectively, but complemented with vitamin E(100 mg/kg diet) and beta-carotene (25 mg/kg.BW) at the same time. After Eight weeks, the levels of serum iron, blood lipid including total cholesterol TC, triglyceride TG, high density lipoprotein HDL, low density lipoprotein LDL, vitamin E, vitamin A, serum malondialdehyde (MDA) and oxidized low density lipoprotein (OX-LDL), the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined. Results showed that the iron overload increased the levels of MDA, OX-LDL and LDL in serum, especially in the group of rat with 500 mg/kg diet. The activity of GSH-Px increased irritably and the contents of Vitamin E and Vitamin A decreased significantly. Complementing antioxidant vitamins decreased the levels of MDA, OX-LDL and LDL and increased HDL and the activity of GSH-Px decreased compared with the corresponding iron overload groups. It was concluded that iron overload could promote lipid peroxidation reaction especially in 10 folds of physiologic dose and the activities of antioxidant enzymes increased at the same time to keep the body homeostasis. Antioxidant vitamins may play a role through non-enzymatic reactive system to inhibit the above changes.

Animals↗
PubMed2005

Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study.

BACKGROUND: Recently it has been found that iron is an important element in the natural history of hepatitis C. Serum markers of iron stores are frequently increased in chronic hepatitis C virus (HCV)-infected carriers but the real impact of the hepatic iron overload is poorly understood. The purpose of the present paper was to determine the prevalence of iron overload and to study the relationship between hepatic iron concentration (HIC) and clinical, biochemical and histological characteristics in chronic HCV-infected carriers. METHODS: Patients presenting with anti-HCV and HCV-RNA were included. Hepatic iron concentration was determined in liver tissue by atomic absorption spectrophotometry. The association between HIC and age, gender, risk factor of transmission, duration of infection, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, iron and serum ferritin, transferrin saturation, HCV-RNA level, grading of inflammatory activity, staging of fibrosis, hepatic steatosis, and stainable iron was analyzed. Statistical analysis included the Mann-Whitney test and a multiple linear regression model. RESULTS: Ninety-six patients (58% male) with a mean age of 44 +/- 10 years were studied. Serum iron, ferritin and transferrin saturation were elevated in 28%, 27% and 12.5% of patients, respectively. Stainable iron was detected in few patients (15.6%). Higher grades of stainable iron (2 and 3) were observed in only 7%. The HIC (>30 mmol/g dry weight) was elevated in five patients (5%). Neither grading nor staging were related to HIC. Higher HIC were observed in male patients (P < 0.001), in patients with elevated serum ferritin (P = 0.001) and in patients with stainable iron (grades 2 and 3; P = 0.001). Multiple linear regression analysis showed that only stainable iron was independently correlated with HIC (P = 0.003). CONCLUSIONS: Iron overload in chronically HCV-infected patients was uncommon and hepatic iron content seemed not to be related to the liver damage process. In the eventuality of iron overload, histochemical liver iron is a useful marker to estimate HIC.

Adult↗