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PubMed1982

Iron and isoferritins in iron overload.

1. The ferritin content of iron-overloaded tissues was higher than that of normal tissues. There was also an increased iron content of ferritin extracted from these tissues. 2. In the limited number of tissues that we examined haemosiderin deposition appeared to be greater in the iron-overloaded livers than in the iron-overloaded spleens. 3. Ferritins extracted from iron-overloaded liver, spleen and kidney had similar properties to those extracted from the corresponding normal tissues. 4. Ferritin from iron-overloaded heart had a greater proportion of more basic isoferritins than had ferritin from normal heart. 5. Immunoreactivity to heart and spleen ferritin antibodies, subunit composition, iron content and rate of iron uptake of both unfractionated ferritin and isoferritin fractions separated by ion exchange chromatography were related to the isoelectric point.

Chromatography, Ion Exchange↗
PubMed2004

Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis.

We report the identification of a novel mutation in ferroportin1 in an Australian family with autosomal dominant iron overload. The phenotype of iron overload in one member of this family is associated with high serum ferritin concentration and elevated transferrin saturation. The pattern of iron overload in the liver shows accumulation predominantly in parenchymal cells with some Kupffer cell iron loading. Although some cases of type 4 haemochromatosis have been associated with the development of liver fibrosis this is the first report of a patient with fully established cirrhosis at a relatively young age (32 years). The coexistence of sarcoidosis in this patient may contribute to the more severe phenotype. This report highlights the phenotypic variability that can occur in type 4 haemochromatosis. Some patients have predominant reticuloendothelial iron loading and normal transferrin saturation whereas others have predominant parenchymal iron loading and elevated transferrin saturation. The reasons for this variability remain to be determined. Interestingly this is the third mutation to affect asparagine 144, reinforcing the important role for this amino acid in the function of ferroportin1.

Adult↗
PubMed1978

Deferoxamine-chelatable iron in hemochromatosis and other disorders of iron overload.

Deferoxamine-chelatable iron was measured in 103 patients with known or suspected iron overload. All of 34 patients with untreated hemochromatosis had distinctly elevated values for deferoxamine-chelatable iron. The mean value in these cases was significantly greater than that in patients with cirrhosis, who had little or no stainable hepatic iron. In 15 patients with hemochromatosis who were tested sequentially during the course of phlebotomy therapy, deferoxamine-chelatable iron proved a reliable index of the degree of reduction of storage iron. In 22 additional patients with partially treated hemochromatosis and 14 with iron overload accompanying chronic anemia, this test correlated well with the magnitude of iron deposits in liver or bone marrow. In patients with unexplained elevations of serum iron, normal or only slightly elevated deferoxamine-chelatable iron correctly indicated that storage (hepatic) iron was not excessive. The test was more reliable than determination of serum iron or transferrin saturation as an indicator of increased storage iron. Elevated values could not be attributed to disturbed liver function. Determination of deferoxamine-chelatable iron is a safe, practical, and useful procedure for identifying persons with increased iron stores and for assessing the effect of phlebotomy therapy.

Adult↗
PubMed1996

Hepatotoxicity induced by iron overload and alcohol. Studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation.

BACKGROUND/AIMS: Clinical experience and studies with experimental animal models indicate a synergistic hepatotoxic effect of dietary iron overload and chronic alcohol ingestion. In order to elucidate the mechanism underlying this synergism, we examined the hepatic levels of ethanol-inducible cytochrome P450 2E1, glutathione and malondialdehyde, and the effect of iron chelation with desferrioxamine, in livers from rats treated with iron and/or ethanol. METHODS: Animals received diets with or without 2.5-3% carbonyl iron for 6-9 weeks, followed by an ethanol-containing diet or a liquid control diet for 5-9 weeks. Desferrioxamine was administered subcutaneously with mini-osmotic pumps. Alanine aminotransferase activity in serum and hepatic contents of glutathione and malondialdehyde were determined. The hepatic level of cytochrome P450 2E1 was determined with Western Blotting using a specific polyclonal antibody. RESULTS: The combination of iron and alcohol led to a marked increase in serum alanine aminotransferase activity as compared with all other treatment groups, and iron chelation with desferrioxamine reversed these increases. Treatment with alcohol alone led to slightly increased aminotransferases compared with controls. The level of cytochrome P450 2E1 was significantly elevated in microsomes isolated from ethanol-treated rats, but neither additional iron supplementation nor desferrioxamine influenced this level significantly. Glutathione contents were increased in the livers of animals treated with iron and/or ethanol. Malondialdehyde values were increased in iron-treated animals, whereas neither ethanol nor desferrioxamine altered malondialdehyde levels significantly. CONCLUSIONS: The toxic effects exerted by the combination of iron overload and chronic ethanol feeding on rat liver are dependent on a pool of chelatable iron. The hepatic level of cytochrome P450 2E1 is markedly induced by ethanol but not further altered by iron overload. Neither increased lipid peroxidation nor depletion of hepatic glutathione levels can explain the synergistic hepatotoxic effects of iron and ethanol in this model.

Alanine Transaminase↗
PubMed1984

Screening for iron overload using transferrin saturation.

People with parenchymal iron overload exhibit an elevated serum iron concentration and a raised transferrin (TIBC) saturation early in the course of the disease. They can therefore be detected by simple laboratory tests before organ damage has occurred. In this study running for 2 months, 10512 samples from approximately 8750 patients and blood donors were examined in a county hospital in Central Sweden. Abnormal TIBC saturation (greater than 70%) was found in 1.7% of the samples. This abnormality was caused by physiological fluctuations in serum iron in 44%, liver disease in 22%, blood disorder in 10%, iron therapy in 10.5% and parenchymal iron overload in 11.5%. The diagnosis of iron overload was confirmed by measuring the serum ferritin concentration and by performing the desferrioxamine test, liver biopsy, quantitative phlebotomy and family studies including HLA typing. We found a prevalence of iron overload of 0.24%. This figure is almost certainly too low because some affected patients were probably lost because of TIBC desaturation induced by inflammatory conditions.

Adult↗
PubMed1990

Increased prooxidant action of hepatic cytosolic low-molecular-weight iron in experimental iron overload.

In the iron-loaded liver there may be an increase in the putative intracellular transit pool of iron, components of which could be catalytically active in stimulating lipid peroxidation. To study the levels of low-molecular-weight, catalytically active iron in the liver, cytosolic ultrafiltrates were tested in an assay containing rat liver microsomes and NADPH. Malondialdehyde production was used as an index of lipid peroxidation. This assay system was sensitive enough to detect 0.25 mumol/L ferrous iron; progressive but non-linear increases in malondialdehyde were produced as the iron concentration was increased to 5 mumol/L. Ultrafiltrates from hepatic cytosol of iron-loaded rats had greater prooxidant action than did those from controls. When added to the assay, deferoxamine, an iron chelator, completely suppressed the prooxidant action of hepatic ultrafiltrates, showing that this activity is iron-dependent. Deferoxamine administered intraperitoneally to control animals at a dose of 1 gm/kg completely inhibited the prooxidant effect of hepatic ultrafiltrates prepared from rats killed after 1, 2 and 3 hr. Partial inhibition was observed at 4 hr; by 6 hr the inhibitory effect of deferoxamine was completely lost. Administration of deferoxamine (1 gm/kg intraperitoneally, 1 hr before killing) completely inhibited the prooxidant action of hepatic ultrafiltrates in moderately iron-loaded rats and controls but had no protective effect in heavily iron-loaded rats. These results support the concept that iron overload results in an increase in a hepatic cytosolic pool of low-molecular-weight iron that is catalytically active in stimulating lipid peroxidation. This pool can be chelated transiently in vivo by deferoxamine in moderate, but not heavy, iron overload.

Animals↗
PubMed2005

Iron overload and tuberculosis: a case for iron chelation therapy.

Elevated levels of iron impair immune defence mechanisms, and specifically the macrophage function of innate immunity. Iron enhances Mycobacterium tuberculosis infection, M. tuberculosis replication, progression to clinical disease and death from tuberculosis (TB). Chelation of iron in individuals with an excessive iron burden may reduce M. tuberculosis viability and replication, restore host defence mechanisms and could find application in the prevention and treatment strategies in settings where both iron overload and TB are prevalent. The objective of this paper was to summarise recent literature on the role of iron in TB pathogenesis and to examine the potential of iron chelation therapy. The literature confirms a key role for iron in mycobacterial virulence. The ability of chelation to enhance host effector mechanisms and to inhibit replication of various pathogens justifies further studies into iron chelation as a potential additive therapy for TB.

Chelating Agents↗
PubMed2005

Hepatic iron overload in alcoholic end-stage liver disease is associated with iron deposition in other organs in the absence of HFE-1 hemochromatosis.

BACKGROUND: End-stage cirrhosis in the absence of hereditary hemochromatosis (HHC) can be associated with moderate to marked hepatic iron overload, especially in liver disease as a result of alcohol and/or hepatitis C. However, no published studies have addressed extrahepatic iron deposition in this setting. METHOD: A retrospective case series from three autopsied patients who died from end-stage cirrhosis associated with significant hepatic iron overload. Histology of vital organs was performed to detect extrahepatic iron deposition. HFE genotyping for the C282Y and H63D mutations was determined from archival tissue. Hepatic iron index and hepatic iron concentration (HIC) were quantified from formalin-fixed, paraffin-embedded tissue. Medical records were reviewed for possible causes of iron overload. RESULTS: Two patients were H63D heterozygous (H63D +/-) and one was wild type (C282Y -/-, H63D -/-). Histology revealed evidence of stainable iron in the heart and pancreas of all three subjects. Additionally, stainable iron was seen in the stomach in one subject and in the thyroid, pituitary, choroid plexus and testes in another subject. HIC ranged from 4354 to 6834 microg/g dry weight and HII from 1.8 to 2.2 (micromol/g/years). CONCLUSION: Iron overload secondary to end-stage liver disease can be associated with iron deposition in other organs in the absence of HFE-1 HHC.

Adult↗
PubMed1981

Lipid peroxidation in iron-overloaded spleens.

1. Iron-overloaded spleens from thalassaemic subjects showed a greatly increased susceptibility to free-radical oxidation (peroxidation) in vitro. 2. Iron content was the main but not the only variable governing susceptibility. Added ascorbate had a dose-dependent action either as an antioxidant or as a pro-oxidant, the direction of its effect depending mainly on the degree of iron overload. This has therapeutic implications.

Adolescent↗
PubMed1995

Transferrin receptor distribution and iron deposition in the hepatic lobule of iron-overloaded rats.

Under the condition of obvious iron-overload, there is a zonal hemosiderin (iron) deposition in hepatic lobules. The deposition is heaviest in the periportal (zone 1) and lightest in the perivenous (zone 3) hepatocytes. However, the mechanism for this pattern of iron deposition is obscure. Hepatic tissues from control, iron-deficient or iron-overloaded Wistar rats were used to study its pathogenesis. Iron-deficiency was induced by a low iron regimen. Iron-overload was produced by repeated intraperitoneal injections of ferric nitrilotriacetate (Fe(3+)-NTA) for 1-4 months. Liver tissues of the rats were immunohistochemically and histochemically stained for transferrin receptor (TfR), transferrin (Tf), ferritin (Ft), and iron. The staining intensity of TfR, Tf and Ft increased in hepatocytes of iron-deficient rats and decreased in that of the iron-overloaded in comparison with the control rats. TfR staining was strong in zone 1, with gradual transition into weak staining in zone 3 hepatocytes of the rat liver. TfR located primarily on the hepatocyte membrane. Tf had both membranous and cytoplasmic distribution. Many hepatocytes in group B had strong cytoplasmic Tf staining. Conversely, only a few hepatocytes had weakly stained cytoplasmic Tf in group C. Hepatocytes and Kupffer cells were Ft positive in control rats. Ft was distributed only in the cytoplasm. The staining intensity of Ft was stronger in zone 3 than in zone 1 hepatocytes of iron-deficient rats. In iron-overloaded rats, the iron deposition was severe in zone 1 and mild in zone 3 hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Influence of iron overload on manganese, zinc, and copper concentration in rat tissues in vivo: study of liver, spleen, and brain.

Although hemochromatosis and pathological situations due to chronic iron overload have been extensively described, there is little information about the influence of iron on other trace elements in the cell. The aim of this study was to investigate changes in the concentration of zinc, manganese, and copper in the liver, spleen, and brain of rats after iron overload. Iron overload in Wistar rats was achieved by iron-supplemented diet or by intraperitoneal or intravenous injection of polymaltose iron. Iron, zinc, manganese, and copper were determined by atomic absorption spectrophotometry. Iron overload in rats, regardless of the route of its application, resulted in an increase not only of iron but also of zinc and manganese in the liver and the spleen, whereas the content of these metals in the brain did not change. The copper content of the liver, spleen, and brain remained the same after iron overload. The increase of zinc and manganese in the liver and spleen following iron overload was probably a result not only of increased intestinal absorption but also of increased uptake from the cell. This is also supported by the fact that no increase in the zinc and manganese concentrations occurred in the brain since, despite iron overload, the iron content remained constant.

Animals↗
PubMed1988

Structural specificity of haemosiderin iron cores in iron-overload diseases.

Haemosiderin iron cores isolated from patients with secondary haemochromatosis have a goethite-like (alpha-FeOOH) crystal structure whereas those from patients with primary haemochromatosis are amorphous Fe (III) oxide. Haemosiderin cores isolated from normal human spleen are crystalline ferrihydrite (5Fe2O3.9H2O). The disease-specific structures are significantly different from the ferrihydrite structure of associated ferritin cores. The results are important in understanding the biological processing of iron in pathological states and in the clinical treatment of iron-overload diseases.

Crystallization↗
PubMed2002

Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease.

BACKGROUND: Hepatic iron overload is often seen in alcoholic liver disease (ALD). We previously reported that the expression of 4-hydroxy-2-nonenal-protein adducts, which is a lipid peroxidative product and can be used as a marker of radical-mediated cellular damage, was increased in iron-overloaded hepatocytes with ALD. However, the mechanism of hepatic iron overload in ALD has not been clarified. In this study, to elucidate the mechanism of hepatic iron overload in ALD, we immunohistochemically investigated the expression of transferrin receptor (TfR), which mainly acts for cellular iron uptake. METHODS: Hepatic tissues were obtained from 31 patients with ALD and 5 normal livers by percutaneous needle biopsy under laparoscopy or ultrasound guidance. Chemical detection of hepatic iron accumulation was performed by Perls' Prussian blue stain. Immunohistochemical detection of TfR expression was done using human monoclonal anti-TfR antibody (TR104) according to the avidin-biotin complex method with alkaline phosphatase. RESULTS: Excess iron accumulation was found in 22 hepatic tissues with ALD but not in any normal hepatic tissues. TfR expression was increased in hepatocytes of 18 hepatic tissues with ALD but was not detected in any normal hepatic tissues. The mean duration of abstinence of patients who demonstrated positive TfR expression in hepatocytes was significantly shorter than that of patients who demonstrated negative TfR expression (positive: 14 days; negative: 30 days). However, total ethanol consumption, daily ethanol intake, and serum aspartate aminotransferase and gamma-glutamyl transpeptidase values on admission were not significantly correlated with TfR expression in hepatocytes. CONCLUSIONS: The up-regulation of TfR expression in hepatocytes is implicated in hepatic iron overload in ALD, and habitual alcohol drinking is an important factor for the induction of TfR expression.

Alcoholism↗
PubMed1996

A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload.

Fifteen iron-overloaded thalassaemia major (TM) patients and two homozygous sickle cell patients (SCD) were treated continuously for 7d each week with the novel 48 h continuous subcutaneous (s.c.) desferrioxamine (DFX) delivery device (code C1083, Baxter) and 10 TM patients received the 24 h continuous intravenous (i.v.) DFX delivery device (code C1071). The 27 patients had previously received conventional s.c. DFX for 8-10h on 5 or more days each week. The serum non-transferrin bound iron (NTBI) levels fell significantly in both groups within 12h of commencing the continuous infusion. In the s.c. group the mean level fell from 4.2 to 2.0 mumol/l (P = 0.001), whereas in the i.v. group the mean level fell from 3.6 to 0.1 mumol/l (P = 0.006) the initial levels being measured 12h after stopping conventional s.c. DFX. After 4 weeks there was a significant fall in serum ferritin in both groups (P = 0.009). The new DFX delivery device is effective at removing toxicfree iron from plasma and reducing body iron. Moreover, it is preferred by patients with much improved compliance compared to the conventional s.c. DFX pump.

Adolescent↗
PubMed1988

Effect of the combination of clavulanic acid and cephalothin on an experimental infection with Yersinia enterocolitica in iron-overloaded mice.

Iron-overloaded mice were infected with a virulent strain of Yersinia enterocolitica by the oral route to study the effect of antimicrobial treatments. The effects of therapy were assessed by enumeration of viable yersiniae in Peyer's patches and in ileal contents. Combinations of cephalothin and clavulanic acid showed therapeutic effects, which were interpreted as in-vivo synergism, since each component alone was ineffective. Ceftazidime, which is relatively beta-lactamase resistant, showed in-vivo activity similar to that of the combination of cephalothin and clavulanic acid. These results suggest that clavulanic acid is able to protect cephalothin against Y. enterocolitica beta-lactamases in vivo, as has been shown previously in vitro.

Animals↗
PubMed1994

Magnetic resonance imaging of transfusional hepatic iron overload.

The transfusional iron overload in 11 adult patients suffering from haematological malignancy was studied in 14 consecutive 1.0 Tesla magnetic resonance imaging (MRI) studies. Routine T1- and T2-weighted spin echo sequences and a fat suppressed sequence (STIR) were used. The ratio from a region of interest of the liver parenchyma and from a manganese chloride reference phantom was measured. There was a definite difference between the signal ratio from the haematological patient group and the control group (p = 0.0001). The patients showed a diminished signal ratio in all pulse sequences used. There was a statistically significant inverse linear correlation between the number of transfused red cell units and the signal ratio in the T1-weighted (p = 0.03) and the T2-weighted (p = 0.03) images. A definite decrease of the effect is found after 20-30 red cell unit transfusions in T2-weighted and STIR images.

Adult↗
PubMed1995

[Transferrin receptor and iron deposition pattern in the hepatic lobules of the iron-deficient and iron-overloaded rats].

Wistar rats were made iron deficient by a low iron regimen. Iron overload was produced by repeated intraperitoneal injections of ferric nitrilotriacetate (Fe(3+)-NTA) for one to four months. Hepatic tissues from these iron deficient, overloaded and control rats were examined for transferrin receptor (TfR), transferrin (Tf) and iron after immunohistochemical staining. TfR and Tf were mainly distributed in the peripheral part of the lobule (zone 1) in the normal, iron deficient and iron-overloaded rats. The staining intensity decreased from zone 1 to zone 3. The staining intensity of TfR was strongest in iron-deficiency rat hepatic cells, weakest in iron-overloaded rat hepatic cells when compared with controls. The difference of Tf staining between the three groups of rats was similar to that of TfR. In the iron-overloaded rats, the staining intensity of iron was stronger in zone 1 than in zone 2 and 3, similar to the distribution pattern of TfR and Tf. These findings suggest that (1) iron uptake in hepatic cells in vivo is regulated and mediated by TfR and Tf, (2) the expression pattern of TfR and Tf in zone 1 to zone 3 liver cells may result in the progressive decrease of iron deposition in the hepatic lobules of the iron overloaded rats.

Anemia, Iron-Deficiency↗
PubMed1994

Etiologies, consequences, and treatment of iron overload.

From a global perspective, severe systemic iron overload occurs predominantly in individuals affected by geographically specific genetic mutations that permit the daily absorption from the diet of more iron than is physiologically needed. Two main types of hereditary iron overload are well recognized: (1) HLA-linked hemochromatosis in populations derived from Europe and (2) iron overload complicating thalassaemia major and intermedia syndromes in Southeast Asia, the Middle East, and the Mediterranean. Another very common form of iron overload occurs in Africa and is clearly related to high dietary iron content; recent evidence suggests that a genetic predisposition may also contribute to the pathogenesis. Patients with iron overload may develop multiorgan system toxicity; aggressive therapy with phlebotomy or iron chelation to remove excess iron from the body prevents organ damage and prolongs life.

Animals↗