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PubMed1980

[Hepatocyte changes in experimental iron overloading. An ultrastructural and microanalytic study].

In this paper the ultrastructural changes in hepatocytes which were experimentally induced by oral and parenteral iron overloading in Sprague-Dawley rats fed on a steatogenous U.A.R. 2-13 diet are analysed. The changes in the mitochondria consisted of flocculation, vesiculation and crystolysis. The R.E.G. showed marked phenomena of dilatation degranulation and fragmentation. The lysosomes became more numerous and increased their content of ferric macromolecules. Degenerative nuclear phenomena were also seen. A microanalytic study of the cellular organelles and nucleus was done relating the cellular lesion and the intracellular distribution of the iron.

Animals↗
PubMed1984

Iron overload and lysosomal stability in beta zero-thalassaemia intermedia and trait: correlation between serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels.

Increased iron storage represents a characteristic condition in patients with beta zero-thalassaemia intermedia. Iron overload is an important factor in cellular damage. Recent studies have shown an enhanced lysosomal fragility due to increased iron storage. 13 patients with beta-thalassaemia intermedia, aged 17-44 years, were studied. Both serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels were evaluated in all subjects studied. A significant linear correlation (P less than 0.05) between serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels were found.

Acetylglucosaminidase↗
PubMed1982

Normal serum ferritin levels in a patient with HEMPAS syndrome and iron overload.

Serum ferritin levels in a patient with HEMPAS syndrome (hereditary erythroblastic multinuclearity associated with positive acidified serum test) were correlated with body iron stores directly measured on spleen and liver biopsy specimens as well as by quantitative serial phlebotomy. Normal serum ferritin concentrations were found in the presence of a moderate excess in iron stores (approximately 6-12 times normal). They temporarily increased after transfusion and splenectomy with a prompt return to the normal range. As repeated phlebotomies over a period of nine months depleted the excess iron stores, the serum ferritin ultimately decreased to a subnormal concentration. The serum ferritin concentration was not a reliable index of increased body iron stores in this iron overloaded patient, but did reflect their depletion by serial phlebotomy.

Anemia, Dyserythropoietic, Congenital↗
PubMed2004

Iron overload and genotype 3 are associated with liver steatosis in chronic hepatitis C.

OBJECTIVE: To determine epidemiological, biochemical, virological, and histological factors associated with liver steatosis in chronic hepatitis C. SUBJECTS: The medical histories of 53 patients biopsied for chronic hepatitis C diagnosis between June 2000 and December 2002 were retrospectively studied. Epidemiological, biochemical, and virological data were collected. Patients with hepatitis B virus or human immunodeficiency virus coinfection were excluded. Liver biopsy specimens were reviewed and scored by one pathologist. Weight and height were measured at liver biopsy time. The statistic association between qualitative and quantitative variables and the presence of liver steatosis was studied. RESULTS: Steatosis was identified in 52% of biopsies. There was no statistic association with age, sex, method of transmission, duration of infection, alcohol consumption, other diseases, body mass index, glucose, triglycerides, cholesterol, AST, ALT, GGT, alkaline phosphatase, bilirubin, or viral load. Liver steatosis was associated with serum iron, transferrin saturation, and ferritin. Genotype 3 was also associated with steatosis. Piecemeal necrosis, hepatocellular injury, Kupffer cell hyperplasia, liver iron, and portal fibrosis were also associated with steatosis. A multivariate analysis showed that genotype 3, Kupffer cell hyperplasia, and liver iron were associated with the presence of steatosis. CONCLUSIONS: Liver steatosis in chronic hepatitis C associates with genotype 3, Kupffer cell hyperplasia, and iron overload. Hepatic steatosis also associates with greater inflammation and fibrosis, and must be considered to contribute to disease progression.

Adult↗
PubMed1987

Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload.

An inhibitor of hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was demonstrated in heat-treated extracts of livers from C57BL/10ScSn mice with iron overload after a single dose (100 mg/kg; 350 mumol/kg) of hexachlorobenzene (HCB). Inhibition was not due to accumulated uroporphyrin since this could be removed by a SEP-PAK C18 cartridge without affecting inhibitor activity. The presence of the inhibitor could be first demonstrated 2 weeks after mice received HCB and before major elevation of hepatic porphyrin levels. Maximum inhibitory potential was reached at about 8 weeks and was still detected 25 weeks after the chemical, thus paralleling the depression of enzyme activity reported previously [Smith, Francis, Kay, Greig & Stewart (1986) Biochem. J. 238, 871-878]. The inhibitor was not detected following treatment of mice with either iron or HCB alone or after the decarboxylase activity was destroyed in vitro by the combination of uroporphyrin and light. The formation of the inhibitor by inbred mouse strains nominally Ah-responsive (C57BL/6J, C57BL/10ScSn, BALB/c, C3H/HeJ, CBA/J and A/J) and Ah-nonresponsive (SWR, AKR, 129, SJL, LP and DBA/2) did not correlate fully with their reported Ah-phenotype. There was a correlation amongst the Ah-responsive strains only, with hepatic ethoxyphenoxazone de-ethylase activity induced in parallel experiments by treatment with beta-naphthoflavone. De-ethylase activity induced by HCB, however, was considerably less than that with beta-naphthoflavone, which has not been reported as porphyrogenic. Other polyhalogenated chemicals, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,2',3',4'-hexachlorobiphenyl and hexabromobenzene, also caused the formation of the inhibitor of uroporphyrinogen decarboxylase.

Animals↗
PubMed1985

Pathogenesis of hepatic fibrosis in experimental iron overload.

Significant increases in prolyl hydroxylase activity, a key enzyme in the collagen biosynthetic pathway, were noted in the hepatic homogenates of iron-loaded animals as compared to controls. The increase in prolyl hydroxylase activity was seen without any light microscopic histologic evidence of cell necrosis or accumulation of collagen in the livers from the iron-loaded animals. However, utilizing electron microscopy, collagen fibrils were demonstrated immediately adjacent to the hepatocytes in the iron-loaded animals but not the controls. No fibroblasts or inflammatory cells were noted in this area. There was no evidence of damage to the subcellular organelles of the iron-loaded hepatocytes. The hydroxyproline content of the iron-loaded livers was also shown to be increased. These experimental studies in conjunction with clinical observations described below suggest that in vivo iron overload may have a primary effect on stimulating collagen synthesis by hepatocytes.

Animals↗
PubMed2006

Secreted ferritin: mosquito defense against iron overload?

The yellow fever mosquito, Aedes aegypti, must blood feed in order to complete her life cycle. The blood meal provides a high level of iron that is required for egg development. We are interested in developing control strategies that interfere with this process. We show that A. aegypti larval cells synthesize and secrete ferritin in response to iron exposure. Cytoplasmic ferritin is maximal at low levels of iron, consists of both the light chain (LCH) and heavy chain (HCH) subunits and reflects cytoplasmic iron levels. Secreted ferritin increases in direct linear relationship to iron dose and consists primarily of HCH subunits. Although the messages for both subunits increase with iron treatment, our data indicate that mosquito HCH synthesis could be partially controlled at the translational level as well. Importantly, we show that exposure of mosquito cells to iron at low concentrations increases cytoplasmic iron, while higher iron levels results in a decline in cytoplasmic iron levels indicating that excess iron is removed from mosquito cells. Our work indicates that HCH synthesis and ferritin secretion are key factors in the response of mosquito cells to iron exposure and could be the primary mechanisms that allow these insects to defend against an intracellular iron overload.

Aedes↗
PubMed1971

Relationship of hepatic iron concentration to histochemical grading and to total chelatable body iron in conditions associated with iron overload.

A simple method based on atomic absorption spectrophotometry and using protein concentration as the reference standard was used for measuring the total tissue iron concentration in needle liver biopsy specimens from 47 patients with varying levels of body iron stores. The values obtained showed a close correlation over a wide range with measurements of total chelatable body iron stores. A comparison with the histochemical assessment of iron deposition showed that only those with grades 3 and 4 had significant increases in iron concentration which is in accord with other clinical observations in such patients. A liver biopsy can thus be of value in the quantitative determination of total body iron overload as well as in the diagnosis of underlying liver disease.

Biopsy↗
PubMed1990

Hemoglobin H disease complicated iron overload and HLA expression in Chinese.

HLA-A,B antigens were typed in 15 patients with Hemoglobin H disease; 10 of them had iron overloading. No significant HLA antigen specificity was identified to be at risk as compared with 170 controls. However, HLA-A11 was suggested to have significant negative risk, and may have a protective effect. (RR = 0.1, p = 0.0015). It seems that increased iron absorption in Hemoglobin H disease is not genetically associated with idiopathic hemochromatosis and certain HLA antigen expressions.

Adult↗
PubMed1998

Development of iron chelators to treat iron overload disease and their use as experimental tools to probe intracellular iron metabolism.

The development of an orally effective iron (Fe) chelator for the treatment of Fe overload diseases such as beta-thalassemia has been a difficult challenge. Even though the drug in current clinical use, desferrioxamine (DFO), is efficient and remarkably free of toxicity, it suffers from not being orally effective and requiring long subcutaneous infusion to mobilize sufficient quantities of Fe. In addition, DFO is very expensive, which precludes it from treating most of the world's thalassemic population. Therefore, the development of an economical and orally effective Fe chelator is of great importance. Despite the screening of a wide range of structurally diverse ligands from both natural and synthetic sources, few compounds have been promising enough to proceed to clinical trials. In the current review, the properties of an ideal chelator are discussed, followed by a description of the most successful ligands that have been identified. Apart from the use of Fe chelators as therapeutic agents, some of these compounds have also been useful as experimental probes to investigate cellular Fe metabolism. We describe here the most important of these studies.

Deferoxamine↗
PubMed1991

Liver iron overload and desferrioxamine treatment of porphyria cutanea tarda.

The aim of this paper is to evaluate invasive and non-invasive indices of iron store and compare the effectiveness of different ferrodepletive protocols in 150 patients with porphyria cutanea tarda (PCT). Iron removal was performed either by intensive phlebotomy (22 cases) or slow subcutaneous and high intravenous doses of desferrioxamine (18 and 5 cases, respectively), and several laboratory parameters were studied; among these, oligo-elements and urinary porphyrins (detected by HPLC) were taken into account before and after the treatments. Serum iron, transferrin saturation, ferritin (RIA) and nuclear magnetic resonance results were compared with invasive findings in order to detect the metal deposition in liver tissue (atomic absorption concentration, optic or electron-microscopic detection). Liver iron overload was observed in 95% of cases. Full normalization of the disease took place by all the treatments, even if it required slightly more time in the phlebotomy group. We may conclude that ferrodepletive treatments are highly effective in PCT and, considering the fact that siderosis and liver damage always accompany the disease, these treatments are proposed as first choice in such cases.

Bloodletting↗
PubMed1983

Insulin resistance and iron overload.

Glucose tolerance tests performed in 15 patients (10 males and 5 females, age range 6-34 years, mean 16 years) with transfusional iron overload revealed fasting and subsequent blood glucose concentrations within the normal range in all except one patients who was overtly diabetic. However, in all patients except one, blood glucose concentration at 2 hours was higher than the respective fasting glucose concentration. All but two of the patients (one of whom was diabetic) showed fasting and post glucose hyperinsulinism. All the patients had hepatic dysfunction of varying severity. It is hence suggested that the initial disturbance of carbohydrate metabolism in transfusional siderosis is insulin resistance, similar to that found in chronic liver disease. Overt diabetes is probably a later event, occurring when sufficient damage to pancreatic cells has occurred and appropriate hyperinsulinaemia cannot be sustained.

Adolescent↗
PubMed1992

Liver tissue injury secondary to iron overload in beta-thalassemia/hemoglobin E disease.

Liver tissues from 17 patients with advanced stages of beta-thal/Hb E disease were examined by light and electron microscopy, with emphasis on cellular damage due to excess iron overload. Various histochemical stains were performed to grade degrees of iron deposition and fibrosis, and to demonstrate hepatitis B surface antigen, in Kupffer cells as well as macrophages. The results of light and electron microscopic studies were correlated. There was a variation in the distribution of hepatic iron and the severity of fibrosis. In most of the cases ballooning degeneration of the hepatocytes, increase in number of lysosomes, hemosiderin and ferritin in hepatocytes as well as in the sinusoidal lining cells were found. The ferro-acidophilic body, representing another important form of hepatocellular necrosis also occurred. So far no precise mechanisms can be concluded.

Adolescent↗
PubMedDate not supplied

[Evaluation of iron overload in thalassemia].

The aim of the paper is to assess the value of a series of clinical and laboratory indices used in determining the degree of iron overload in homozygous beta-thalassaemic patients. 155 thalassaemic patients of different age in chelation with subcutaneous infusions of desferrioxamine for a period of 2-7 years have been studied. Calculation of the total iron accumulated and the iron load per kg of body weight in patients undergoing chelation requires an exact knowledge of their compliance and faecal and urinary iron elimination, and is clearly open to many errors. Despite this, usefull information can be derived from its determination. We have found, for example, that serious organ damage tends to appear when iron accumulation exceeds 1 g/kg. In addition, the serum ferritin and the evaluation of the growth have been proved to be the most important and helpful indices for checking the effectiveness of the chelation therapy and forecasting the appearance of the serious complications as diabetes or hypothyroidism.

Adolescent↗
PubMed1991

Direct evidence for in vivo hydroxyl-radical generation in experimental iron overload: an ESR spin-trapping investigation.

Although the hydroxyl radical is often implicated as the species responsible for the initiation of oxidative damage in iron-overload conditions, no ESR evidence for the formation of the radical in vivo has been reported. We have employed a secondary radical-trapping technique in which the hydroxyl radical reacts with dimethyl sulfoxide to form the methyl radical, which is then detected as its adduct of the spin trap N-t-butyl-alpha-phenylnitrone in the bile of animals given an intragastric dose of ferrous sulfate. The identity of this adduct was verified by isotope-substitution techniques. We show that unless measures are taken to inactivate the iron excreted in the bile of treated animals, reactions between iron, oxygen, dimethyl sulfoxide, N-t-butyl-alpha-phenylnitrone, and bile components lead to the formation of artifacts during sample collection.

2,2'-Dipyridyl↗
PubMed2006

Iron Overload (with Attention to Genetic Testing and Diagnosis/Management of HFE Wild Type Patients).

The discovery of the HFE, HJV, HAMP, TfR2, and SLC40A1 genes and preliminary understanding of their roles in iron homeostasis have contributed tremendously to our understanding of the pathogenesis of genetic hemochromatosis. Although several new models of iron metabolism have been proposed, some key "sensor" steps of iron absorption in the enterocytes and of iron storage in hepatocytes and other cells remain unclear. A diagnosis of non-HFE genetic hemochromatosis should be considered in patients with unexplained iron overload who do not have the common mutations in the HFE genes. Phenotypic evaluation such as liver biopsy and measurement of hepatic iron concentration remain important in non-HFE hemochromatosis because mutations in other genes are rare and there are no other available noninvasive tests to confirm the diagnosis. Phlebotomy remains the mainstay of therapy also for non-HFE hemochromatosis. However, phlebotomy may not be well tolerated in certain forms of non-HFE hemochromatosis such as "ferroportin disease."

Journal Article↗
PubMed1997

Differential induction of polyamine oxidase activity in liver and heart of iron-overloaded rats.

The present study was undertaken to investigate the effect of iron dextran treatment on polyamine oxidase (PAO) activity, iron accumulation, and lipid peroxidation in livers and hearts of rats. PAO catalyzes oxidative deamination of polyamines, the cellular aliphatic cations. This reaction produces highly toxic hydrogen peroxide, 3-acetamidopropanal, and precursors of higher polyamines. The rats were given iron dextran daily for 7 d. In iron-dextran-treated rats, a marked increase in the hepatic level of iron was associated with enhanced lipid peroxidation and increased PAO activity. Though iron accumulation and lipid peroxidation in the iron-treated rats increased significantly in the heart, PAO activity remained unchanged. The paraffin sections of livers stained with Perls iron stain showed the presence of iron in macrophages and hepatocytes. The sections of hearts showed iron deposits only in macrophages, while myocytes showed no iron staining. These results show that although iron dextran treatment results in accumulation of iron in both liver and heart, it induces PAO activity only in liver. The significance of increased PAO activity in lipid peroxidation and fibrosis in iron-mediated injury is discussed.

Animals↗
PubMed1999

Iron overloading inhibits dentine mineralization.

The present study reveals the inhibitory effect of iron intoxication on the process of dentine mineralization. Wistar rats were injected intraperitoneally with iron dextran at 0.88 g/kg body weight per day for 10 days during the period of odontogenesis. An age-matched group was injected intraperitoneally with bisodium etidronate (EHBP) at 20 mg/kg body weight per day for 10 days. Another age-matched group was treated with similar amounts of saline intraperitoneally and considered as control. At the end of the experimental period the animals intoxicated with iron exhibited non-mineralized dentine and mineralized bone. The animals treated with EHBP showed non-mineralized dentine and bone. These findings would suggest the existence of different mineralization mechanisms for bone and dentine.

Alveolar Process↗