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PubMed2001

Venesection therapy of insulin resistance-associated hepatic iron overload.

BACKGROUND/AIMS: The association of hepatic iron overload with metabolic disorders has been coined as the insulin resistance-associated hepatic iron overload syndrome (IR-HIO). METHODS: Fifty-six IR-HIO patients were phlebotomized either weekly (n = 14) or bimonthly (n = 42) and compared with C282Y homozygotes and with ten IR-HIO patients treated by a low calorie diet alone. RESULTS: In venesected patients, the median amount of mobilized iron was 0.6 g in 2.8 months in females and 1.8 g in 5 months in males. Mobilized iron did not differ depending on the frequency of venesections or HFE genotype. When compared with C282Y homozygotes, IR-HIO patients had a similar amount of mobilized iron, but three-fold serum ferritin levels. The presenting symptoms (chronic fatigue and/or polyarthralgias) improved in 6/7 patients. Phlebotomies were well tolerated. In patients treated by a low calorie diet, serum ferritin levels remained stable. CONCLUSIONS: In IR-HIO patients, body iron stores are significantly increased, overestimated by serum ferritin, not modified by a low calorie diet, and safely removed by phlebotomies. Based on these data and on studies indicating that iron excess is associated with increased risk for hepatic fibrosis, cancer and cardiovascular disorders, venesection therapy can be recommended in IR-HIO patients.

Adult↗
PubMed2005

Iron in skin of mice with three etiologies of systemic iron overload.

In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe(-/-) mice, iron content in the epidermis and dermis was unexpectedly the same as in Hfe(+/+) mice, and there were no histological abnormalities detected after 30 wk. A high iron diet produced increased iron in the epidermis of both normal and Hfe(-/-) animals; a high diet increased iron in the dermis only in Hfe(-/-) mice. Increased skin iron was not associated with other histological changes, even after 19 wk. Parenteral administration of iron produced increased iron in the epidermis and dermis, and gave the skin a bronze hue. These results show that the amount and distribution of iron in the skin depends on the etiology of iron overload. It appears that neither Hfe deletion nor elevated skin iron alone can account for cutaneous manifestations reportedly seen in humans with hereditary hemochromatosis.

Animals↗
PubMed1997

Hyperferritinaemia in the absence of iron overload.

BACKGROUND: Serum ferritin is normally a marker of iron overload. Ferritin genes are sited at chromosomes 19 and 11. Regulation of ferritin synthesis involves an interaction between an iron regulatory protein (IRP) and part of the ferritin mRNA designated the iron regulatory element (IRE). A disorder of ferritin synthesis resulting in hyperferritinaemia in the absence of iron overload has been described recently. PATIENTS AND METHODS: Hyperferritinaemia in the absence of iron overload was detected in a patient who was investigated for possible haemochromatosis. Serum iron, transferrin saturation, and ferritin concentration were studied in 11 members of this patient's family from three generations. Eight members had DNA samples analysed by direct cycle sequencing of the 5' untranslated region of the L ferritin gene. RESULTS: Six of the family members studied had serum ferritin concentrations greater than 900 micrograms/l. However, serum iron and transferrin saturation were normal in these subjects who all had evidence of cataracts. Three affected family members who had genetic studies of the L ferritin gene on chromosome 19 had an A to G point mutation which was not found in unaffected members. CONCLUSIONS: There was complete concordance between a mutated IRE, cataracts, and hyperferritinaemia in three generations of this family. This family study confirms the finding that hereditary hyperferritinaemia in the absence of iron overload is an autosomal dominant inherited disorder.

Adult↗
PubMed2002

High prevalence of a screening-detected, HFE-unrelated, mild idiopathic iron overload in Northern Italy.

BACKGROUND AND OBJECTIVES: In Italy, typical HFE mutations account for only 64% of the cases with overt hereditary hemochromatosis (HH), and a common HFE-unrelated disease was hypothesized. DESIGN AND METHODS: One thousand and fifty potential blood donors were screened by iron tests, C282Y and H63D HFE mutation analysis in a region in North Italy. Subjects with repeated fasting transferrin saturation of 45% or more and no secondary iron overload were defined as probands with idiopathic iron overload. To assess the inheritance of iron overload, relatives of probands were screened. RESULTS: The overall frequency of probands with idiopathic iron overload was 3.43% (95% confidence interval, 2.32 to 4.52). Of these, 8.4% had genotypes associated with HH (compound heterozygous for H63D/C282Y or homozygous for H63D HFE mutations), and 91.6% had atypical genotypes: 47.2% were heterozygous for C282Y or H63D HFE mutations, and 44.4% had wild type/wild type genotype. A family history of iron overload was proven in 33.3% of probands with atypical genotypes (1.04% of the overall population). Pedigree analysis excluded linkage of heterozygous HFE mutations with iron overload (cumulative lod score 2.41) and documented a recessive non-HLA-linked locus accounting for iron overload in wild type/wild type genotypes. None of the probands had clinical signs of iron accumulation; in males, serum ferritin positively correlated with age (r=0.63, p<0.01), and the regression model predicted a serum ferritin of 700 ng/mL at the age of 58. INTERPRETATION AND CONCLUSIONS: In Northern Italy an HFE-unrelated, mild idiopathic iron overload is highly prevalent. A recessive locus accounts for iron overload in at least 1.04% of the overall population.

Adolescent↗
PubMed2000

Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation.

Previously, we found appreciable hepatic iron deposition in one third of our patients undergoing liver transplantation (LTx) with approximately 10% of cases having quantifiable iron in the range of that seen in hereditary hemochromatosis (HHC). The aim of this study was to compare clinical outcome in liver transplant patients with and without iron overload. We also sought to determine the prevalence of HFE mutations in liver transplant patients with iron overload. Of 456 consecutive liver transplants, 41 explants had an hepatic iron index (HII) greater than 1.9, and these cases were compared to 41 matched liver transplant recipients without increased hepatic iron. Posttransplantation complications, along with patient and graft survival were monitored. HFE gene testing was performed using DNA-based techniques. Kaplan-Meier 5-year patient survival after LTx was significantly lower in cases with hepatic iron overload compared to matched controls without iron excess (48% vs. 77%; P =.045). Fatal infections (especially fungal) were more common in patients with iron overload (24% vs. 7%; P =.03). Of the 41 patients with a liver explant HII greater than 1.9, only 4 were C282Y homozygotes. Patients with severe hepatic explant iron overload undergoing LTx have a reduced survival compared to liver transplant recipients without explant iron excess. The reduced survival was attributable mainly to fatal bacterial and fungal infections. Despite the iron overload, HFE gene mutations were uncommon in patients with hepatic explant hemosiderosis.

Female↗
PubMed2001

Noninvasive methods for quantitative assessment of transfusional iron overload in sickle cell disease.

Because optimal management of iron chelation therapy in patients with sickle cell disease and transfusional iron overload requires accurate determination of the magnitude of iron excess, a variety of techniques for evaluating iron overload are under development, including measurement of serum ferritin iron levels, x-ray fluorescence of iron, magnetic resonance imaging, computed tomography, and measurement of magnetic susceptibility. The most promising methods for noninvasive assessment of body iron stores in patients with sickle cell anemia and transfusional iron overload are based on measurement of hepatic magnetic susceptibility, either using superconducting quantum interference device (SQUID) susceptometry or, potentially, magnetic resonance susceptometry.

Anemia, Sickle Cell↗
PubMed2005

Iron overload promotes Cyclin D1 expression and alters cell cycle in mouse hepatocytes.

BACKGROUND/AIMS: Patients exhibiting hepatic iron overload frequently develop hepatocellular carcinoma. An impaired expression of hepatic genes could be involved in this phenomenon. Our aim was to identify, during iron overload, hepatic genes involved in cell cycle which are misregulated. RESULTS: Mouse iron overload was obtained by carbonyl-iron supplementation or iron-dextran injection. As expected, liver iron overload was associated to both hepatomegaly and hepatocyte polyploidisation. Hepatic gene expression was investigated using macroarray hybridizations. Cyclin D1 mRNA was the only gene whose expression increased in both models. Its overexpression was confirmed by real-time quantitative PCR. Immunobloting analysis demonstrated a strong increase of Cyclin D1 protein expression in iron-overloaded hepatocytes. This overexpression was correlated with early abnormalities in their cell cycle progression judged, in vitro, on DNA synthesis and mitotic index increase. CONCLUSIONS: Our data demonstrates that Cyclin D1, a protein involved in G1-phase of cell cycle, is overexpressed in the iron-overloaded liver. This iron-induced expression of Cyclin D1 may contribute to development of cell cycle abnormalities, suggesting a role of Cyclin D1 in iron-related hepatocarcinogenesis.

Animals↗
PubMed1995

Chronic iron overload causes activation of rat lipocytes in vivo.

Chronic iron overload can result in hepatic fibrosis and cirrhosis. Activated lipocytes, through increased production of collagen and extracellular matrix, play an important role in hepatic fibrogenesis in several types of experimental liver injury, but their contribution to hepatic injury after iron overload is unknown. This study examines the effect of iron overload on lipocyte activation, in vivo. Male Sprague-Dawley rats were fed a chow diet supplemented with 1% carbonyl iron for up to 20 mo. Controls were fed the chow diet alone. Lipocytes were prepared by sequential pronase and collagenase perfusion of the livers, followed by density-gradient centrifugation. Lipocyte activation was assessed by immunohistochemistry of liver sections and by Western blot analysis of alpha-smooth muscle actin expression in freshly isolated lipocytes. In addition, to measure the biosynthetic capability of these lipocytes, collagen and noncollagen protein production was determined after 3 days in culture, using [3H]proline incorporation. The hepatic iron concentration was increased by eightfold in the iron-loaded rats, and lipocytes from these animals expressed alpha-smooth muscle actin. Collagen production was increased by 2.5-fold, and noncollagen protein production was elevated by twofold in lipocytes isolated from iron-loaded rats. In the iron-loaded livers, autofluorescent material with the characteristics of lipofusion was present in periportal zones. Chronic iron overload expression results in the activation of lipocytes, as determined by increased expression of alpha-smooth muscle actin and by increased production of both collagen and noncollagen protein. This activation may contribute to iron-induced hepatic fibrogenesis.

Actins↗
PubMed1998

Dual-energy CT in the diagnosis and quantification of fatty liver: limited clinical value in comparison to ultrasound scan and single-energy CT, with special reference to iron overload.

BACKGROUND/AIMS: It has been suggested that dual-energy CT could differentiate irregular fatty liver from other hypodense lesions. We compared dual-energy CT to ultrasound scan and single-energy CT in the diagnosis and quantification of fatty liver, with special reference to iron overload. METHODS: Twenty-seven patients were included according to ultrasound: fatty liver (n=16) and normal liver (n=11). Single and dual-energy CT were performed. Attenuation measurements of hepatic lobes and control tissues were taken at 140 kV and 80 kV CT-guided liver biopsy was done in fatty liver patients, the degree of infiltration was estimated, and the histologic iron overload determined (iron overload, n=11; iron-free, n=5). RESULTS: The mean changes in attenuation for the right hepatic lobe were: normal liver: -0.8 (ns); iron overloaded fatty liver: 1.5 (ns); and iron-free fatty liver: 7.7 (p<0.0053). A spleen-liver attenuation differential threshold of 12H (140 kV, single-energy CT) and a right hepatic lobe 140 kV to 80 kV attenuation differential threshold of 9 H (dual-energy CT) were specific for fatty liver. Histology confirmed all cases of fatty liver diagnosed by ultrasound, independently of iron overload. Ultrasound did not differentiate cases of irregular from diffuse fatty liver detected on CT. Iron overload produced a masking effect in CT, decreasing its sensitivity: fatty liver was diagnosed in 67% of cases by single-energy CT and in 20% by dual-energy CT. Degree of fatty infiltration correlated with single-energy CT. CONCLUSIONS: Ultrasound diagnosed fatty liver best. Single-energy CT quantifies fatty infiltration, and best differentiates the irregular from the diffuse forms. Dual-energy CT is limited by poor sensitivity, especially in iron overload.

Adult↗
PubMed2003

Iron overload in adult Hfe-deficient mice independent of changes in the steady-state expression of the duodenal iron transporters DMT1 and Ireg1/ferroportin.

Patients suffering from hereditary hemochromatosis (HH) show progressive iron overload as a consequence of increased duodenal iron absorption. It has been hypothesized that mutations in the HH gene HFE cause misprogramming of the duodenal enterocytes towards a paradoxical iron-deficient state, resulting in increased iron transporter expression. Previous reports concerning gene expression levels of the duodenal iron transporters DMT1 and IREG1 in HH patients and animal models are controversial, however, and in many cases only mRNA expression levels were investigated. To analyze the duodenal expression of DMT1, Ireg1, Dcytb, and hephaestin and the association with iron overload in adult Hfe(-/-) mice, an Hfe(-/-) mouse line was generated. Duodenal DMT1 and Ireg1 protein levels, duodenal DMT1, Ireg1, Dcytb, hephaestin, and TfR1 mRNA levels, and hepatic hepcidin mRNA levels were quantified and the correlation to liver iron contents was calculated. We report that duodenal DMT1 and Ireg1 mRNA levels and DMT1 and Ireg1 protein levels remained unaffected by the Hfe deletion. Furthermore, duodenal hephaestin and TfR1 mRNA expression and hepatic hepcidin mRNA expression remained unaltered, while the duodenal mRNA expression of the brush border ferric reductase Dcytb was significantly increased in Hfe(-/-) mice. We found no correlation between the expression level of any of the analyzed transcripts and the liver iron content. In conclusion, the lack of correlation between DMT1 and Ireg1 protein expression and the liver iron content suggests that elevated duodenal iron transporter expression is not required for high liver iron overload. Hfe(-/-) mice do not necessarily display features of iron deficiency in the duodenum, indicated by an increase in mRNA and protein levels of DMT1 and Ireg1. Rather, the duodenal ferric reductase Dcytb may act as a possible mediator of iron overload in Hfe deficiency.

Animals↗
PubMed2000

A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.

Considering that the development of hepatic lesions related to iron overload diseases might be a result of abnormally expressed hepatic genes, we searched for new genes up-regulated under the condition of iron excess. By suppressive subtractive hybridization performed between livers from carbonyl iron-overloaded and control mice, we isolated a 225-base pair cDNA. By Northern blot analysis, the corresponding mRNA was confirmed to be overexpressed in livers of experimentally (carbonyl iron and iron-dextran-treated mice) and spontaneously (beta(2)-microglobulin knockout mice) iron-overloaded mice. In addition, beta(2)-microglobulin knockout mice fed with a low iron content diet exhibited a decrease of hepatic mRNA expression. The murine full-length cDNA was isolated and was found to encode an 83-amino acid protein presenting a strong homology in its C-terminal region to the human antimicrobial peptide hepcidin. In addition, we cloned the corresponding rat and human orthologue cDNAs. Both mouse and human genes named HEPC are constituted of 3 exons and 2 introns and are located on chromosome 7 and 19, respectively, in close proximity to USF2 gene. In mouse and human, HEPC mRNA was predominantly expressed in the liver. During both in vivo and in vitro studies, HEPC mRNA expression was enhanced in mouse hepatocytes under the effect of lipopolysaccharide. Finally, to analyze the intracellular localization of the predicted protein, we used the green fluorescent protein chimera expression vectors. The murine green fluorescent protein-prohepcidin protein was exclusively localized in the nucleus. When the putative nuclear localization signal was deleted, the resulting protein was addressed to the cytoplasm. Taken together, our data strongly suggest that the product of the new liver-specific gene HEPC might play a specific role during iron overload and exhibit additional functions distinct from its antimicrobial activity.

Animals↗
PubMed2000

Transfusion iron overload in adults with acute leukemia: manifestations and therapy.

BACKGROUND: Hepatic dysfunction occurs commonly among persons successfully treated for acute leukemia, and iron overload is a possible cause of hepatic and other abnormalities in these patients. METHODS: We identified 5 adults 40+/-13 (mean +/- S.D.) years of age who developed transfusion iron overload in association with successful chemotherapy of de novo acute leukemia. None had evidence of hemochromatosis, viral hepatitis, or other primary hepatic disorders. RESULTS: The mean serum ferritin concentration of our patients was 1531+/-572 ng/mL. Other abnormalities associated with transfusion iron overload were increased stainable iron in bone marrow macrophages, elevated serum concentrations of hepatic enzymes, hyperpigmentation, hyperferremia, elevated iron saturation of serum transferrin, and increased stainable iron in Kupffer cells and hepatocytes. Rheumatologic, endocrinologic, or cardiac abnormalities attributable to iron overload were not observed. Therapeutic phlebotomy was initiated after chemotherapy; recovery of hemoglobin concentrations after phlebotomy permitted weekly treatment in each case. This yielded an average of 28+/-9 units per patient (range 15-35 units). Abnormalities associated with transfusion iron overload resolved after iron depletion therapy. The mean leukemia-free survival of our patients is 96+/-36 months (range 40-125 months). CONCLUSIONS: Our data and those of others suggest that 15 to 20% of adults who are long-term survivors of acute leukemia develop iron overload, often with hepatic abnormalities. Iron overload is a relatively common sequela to successful management of acute leukemia in adults for which routine evaluation should be performed and for which therapeutic phlebotomy should be used as treatment.

Acute Disease↗
PubMed2005

Serum iron levels and hepatic iron overload in nonalcoholic steatohepatitis and chronic viral hepatitis.

Our objective was to determine the effect of serum iron levels and hepatic iron overload on hepatocellular damage in nonalcoholic steatohepatitis (NASH) and to compare this with chronic viral hepatitis. Twenty-five patients who had elevated transaminase levels on at least two occasions, without any evidence of viral and autoimmune hepatitis and diabetes, without a history of significant alcohol use, and with a liver biopsy consistent with NASH were enrolled in the study. Twenty-five patients with chronic viral hepatitis (13 patients with chronic hepatitis C and 12 with chronic hepatitis B) who were not under any antiviral treatment were taken as controls. Metabolic factors were studied in the NASH and chronic hepatitis groups. Biopsy specimens were stained with hematoxylin-eosin, and the grade of steatosis and the stage of fibrosis were evaluated as I, II, or III, I being mild and III being severe. Iron overload in the hepatic tissue was studied by Prussian blue staining. Serum ALT, AST, ALP, GGT, globulin, and ferritin levels were comparable in both steatohepatitis and chronic viral hepatitis groups. However, patients with chronic hepatitis had a lower albumin level and a higher serum iron level, with higher transferrin saturation. Among patients with NASH, mild, moderate, and severe steatosis was found in 7, 10, and 8 patients, respectively. Inflammatory infiltration was grade I in 24 patients and grade III in 1 patient. Fibrosis was mild in 12 patients and 13 patients had no fibrosis. Among patients with chronic viral hepatitis, inflammatory infiltration of grade I was seen in 11 patients, grade II in 11 patients, and grade III in 3 patients. Fibrosis was mild in 9 patients, moderate in 13 patients, and severe in 2 patients; 1 patient had no fibrosis. Compared to patients with NASH, those with chronic viral hepatitis cases had more severe inflammatory infiltration and fibrosis (P < 0.01). While five patients with chronic viral hepatitis had mild iron overload, patients with NASH had no hepatic paranchymal iron overload. Neither NASH nor chronic viral hepatitis revealed a relationship between hepatic iron overload and disease activity. This suggests that the iron overload actually may be a result of hemachromatosis gene mutation. The absence of hepatic parenchymal iron overload in the NASH group and only mild iron accumulation in the chronic hepatitis group may be explained by a lower frequency of the gene mutation in our country.

Adult↗
PubMed1987

Iron overload and mobilization in long-term hemodialysis patients.

Iron overload from repeated transfusions of RBCs in long-term hemodialysis patients is a problem of increasing clinical significance. We report on the prevalence of and diagnostic criteria for identification of hemodialysis patients with iron overload. In 150 unselected hemodialysis patients, 62 (41%) had ferritin levels greater than 2,000 ng/mL (normal = 10 to 360 ng/mL). In 16 of these patients, accurate transfusion histories were obtained and ferritin levels correlated with calculated transfusional iron burden (r = 0.553, P less than .05). These patients could be divided into two distinct groups on the basis of their response to a single dose (2 g, IV) of deferoxamine: "high" responders had twice the level of feroxamine (the chelated product of deferoxamine and iron) of the "low" responders (P less than .001). High responders also had significantly higher prevalence of the "hemochromatosis" alleles A3, B7, and B14 than a large group of dialysis patients awaiting transplantation (71% v 37%, P less than .001). In two patients with iron overload and clinically significant bone disease, bone histology revealed prominent iron staining at the calcification front. We conclude that transfusional iron overload is a significant clinical problem in long-term hemodialysis patients, that may also be associated with bone pathology.

Adult↗
PubMed2005

Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia.

Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver disease and severe iron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis. Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis. An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed1980

Studies on the concentration and intracellular localization of iron proteins in liver biopsy specimens from patients with iron overload with special reference to their role in lysosomal disruption.

Liver biopsies were collected from control subjects and patients with iron overload due to either primary or secondary haemochromatosis. They were analysed for iron proteins by cation exchange chromatography and flameless atomic absorption spectrophotometry. In control tissue the transferrin fraction contains 25%, ferritin 50% and haemprotein and haemosiderin 10--15% each, of the total iron. In iron overloaded tissue the ferritin and haemosiderin iron increases approximately 10- and 100-fold, respectively, compared with control tissue. There was a close positive correlation between enhanced lysosomal fragility as determined by measurements of latent N-acetyl-beta-glucosaminidase and haemosiderin content of the tissue; it is suggested that the haemosiderin is responsible for the lysosomal disruption and hence the tissue damage in iron overload. Studies were performed on the intracellular localization of ferritin and of total iron in biopsy extracts from control subjects and from patients with iron overload. In control tissue, ferritin contains most of the iron and is apparently free in the cytosol. In iron overload, ferritin is the major iron protein in the post-nuclear supernatant sedimenting into the gradient as the free protein. There are, however, significant amounts of immunoreactive ferritin deeper in the gradients but this cannot be assigned to any particular subcellular organelle. The extreme fragility of lysosomes in iron overloaded human tissue makes isolation of these organelles for detailed biochemical analysis extremely difficult.

Acetylglucosaminidase↗
PubMedDate not supplied

Mutation analysis of the transferrin receptor-2 gene in patients with iron overload.

Three mutations in the transferrin receptor-2 gene have recently been identified in four Sicilian families with iron overload who had a normal hemochromatosis gene, HFE (C. Camaschella, personal communication). To determine the extent to which mutations in the transferrin receptor-2 gene occur in other populations with iron overload, we have completely sequenced this gene in 17 whites, 10 Asians, and 8 African Americans with iron overload and a C282C/C282C HFE genotype, as well as 4 subjects without iron overload and homozygous for the mutant HFE C282Y genotype, 5 patients with iron overload and homozygous for the mutant HFE C282Y genotype, and 5 normal individuals. None of the individuals exhibited the Sicilian mutations, Y250X in exon 6, M172K in exon 4, and E60X in exon 2. One iron-overloaded individual of Asian descent exhibited a I238M mutation which was subsequently found to be a polymorphism present in the Asian population at a frequency of 0.0192. The presence of the I238M mutation was not associated with an increase in ferritin or transferrin saturation levels. Three silent polymorphisms were also identified, nt 1770 (D590D) and nt 1851 (A617A) and a polymorphism at nt 2255 in the 3' UTR. Thus, mutations in the transferrin receptor-2 gene were not responsible for the iron overload seen in our subjects.

DNA Mutational Analysis↗
PubMed1998

Formation of liver microsomal MDA-protein adducts in mice with chronic dietary iron overload.

Lipid peroxidation has been proposed to be a major mechanism involved in the pathophysiology of hepatic iron overload. Hepatic microsomal lipid peroxidation has been demonstrated in animals with dietary iron overload, and major products of lipid peroxidation with known cytotoxicity, such as malondialdehyde (MDA), may be involved in iron-induced hepatocellular injury by covalent binding to microsomal proteins. This investigation examined whether DBA/2Ibg mice fed a diet enriched with ferrocene-iron for 16 weeks, results in hepatic lipid peroxidation, and if liver microsomes contain proteins adducted by MDA. Chronic iron feeding to mice resulted in a severe hepatic iron overload with hepatic stores of iron 12-fold greater than those measured in control mice and a three-fold increase in hepatic concentrations of MDA, indicating the occurrence of iron-induced lipid peroxidation in vivo. Hepatic collagen content was increased by over three-fold (p < 0.05) in iron-fed mice as compared to control animals, suggesting increased fibrogenesis. Using rabbit antiserum specific for MDA amine protein adducts and immunoprecipitation-Western blotting, we documented formation of 10 liver microsomal proteins adducted by MDA in iron overload mice (approximate molecular weights; 214, 140, 129, 121, 103, 83, 62, 60, 48, and 43-kD). Control mice did not exhibit positive immunostaining for these protein adducts. The incubation of synthetic MDA with liver microsomes isolated from untreated mice demonstrated formation of MDA-adducted proteins with molecular weights comparable to those detected following in vivo iron overload. The data from this animal study are the first to demonstrate that lipid-derived aldehydes produced from hepatic iron overload in vivo, covalently bind and hence, chemically modify numerous proteins in microsomes. These data suggest that MDA modified proteins in microsomes may play a role in a sequence of events that lead to cell injury during metal-induced liver damage.

Animals↗