Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertrophic cardiomyopathy is a common complication of Friedreich's ataxia (FRDA). Histological sections reveal abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue. Scattered muscle fibers display perinuclear collections of minute iron-positive granules that lie in rows between myofibrils. Frataxin deficiency in FRDA causes mitochondrial iron dysmetabolism. We studied total iron and the iron-related proteins ferritin, mitochondrial ferritin, divalent metal transporter 1 (DMT1), and ferroportin in FRDA hearts by biochemical and histological techniques. Total iron in the left ventricular wall of FRDA patients (30.7+/-19.3 mg/100 g dry weight) was not significantly higher than normal (31.3+/-24.1 mg/100 g dry weight). Similarly, cytosolic holoferritin levels in FRDA hearts (230+/-172 microg/g wet weight) were not significantly elevated above normal (148+/-86 microg/g wet weight). The iron-positive granules exhibited immunoreactivity for cytosolic ferritin, mitochondrial ferritin, and ferroportin. Electron microscopy showed enhanced electron density of mitochondrial deposits after treatment with bismuth subnitrate supporting ferritin accumulation. The inflammatory cells in the endomysium were reactive for CD68, cytosolic ferritin, and the DMT1 isoform(s) translated from messenger ribonucleic acids containing iron-responsive elements (DMT1+). Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis.
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PMID:Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. 1713 88

Cardiac damage caused by iron overload toxicity is the main cause of death in thalassemia patients. Biopsy samples of poorly chelated thalassemia patients who suffered congestive cardiac failure (CCF) show extensive iron deposition in the myocardium. In one patient who survived CCF, a cardiac biopsy was performed during the removal of a thrombus caused by a port-a-cath, which was used for the administration of intravenous (iv) deferoxamine (DFO). Ultrastructural pathology studies of the cardiac biopsy indicated extensive iron deposition in myocytes with accumulation of iron mainly in lysosomes, leading in some cases to their disruption. Damage to other intracellular components of the myocytes and loss of myofibers was also observed. The patient became intolerant to iv and subcutaneous (sc) DFO 2 years after the CCF, and was then treated with deferiprone (L1) for 7 years. Within 1 year of L1 treatment at 75-80 mg/kg/day, serum ferritin levels were reduced to <0.45 mg/L and she became asymptomatic, needing no further drugs for her cardiomyopathy. Lowering the L1 dose to 50-70 mg/kg/day caused an increase in serum ferritin levels. Maintenance of normal iron stores during the last 3 years as detected by cardiac and liver magnetic resonance imaging (MRI) T2 and T2* and normalization of serum ferritin levels (<0.15 mg/L) was observed following L1 therapy at 80-85 mg/kg/day. Deferiprone (>80 mg/kg/day) appears to be effective in the rapid clearance of cardiac iron, in the reversal of iron overload related cardiomyopathy, in the maintenance of normal iron stores and the overall long-term survival of thalassemia patients.
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PMID:Myocyte damage and loss of myofibers is the potential mechanism of iron overload toxicity in congestive cardiac failure in thalassemia. Complete reversal of the cardiomyopathy and normalization of iron load by deferiprone. 1827 79

As a means to manage cardiac conditions, we determined the effects of high-dose intravenous (IV) deferoxamine in 15 thalassaemia patients with cardiomyopathy and high ferritin and haemoglobin levels. The patients received IV deferoxamine, 130 mg/kg per day over 10-14 hours (maximum 5 g) for 5 consecutive days. All patients underwent a full evaluation before receiving deferoxamine, and 2 days and 1 month after completing the treatment. Visual and auditory examinations were done to detect any side-effects. After treatment, cardiovascular symptoms decreased considerably and systolic function showed significant improvement, but there was no significant effect on diastolic function, electrocardiography and physical findings. There were no significant side-effects reported.
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PMID:High-dose deferoxamine treatment (intravenous) for thalassaemia patients with cardiac complications. 1829 Mar 97

Heart failure due to myocardial iron overload remains the leading cause of death in patients with transfusion-dependent anemias. Iron overload-induced cardiomyopathy is reversible if intensive chelation therapy is instituted on time. Thus, early detection of myocardial iron deposition is imperative to prevent overt heart failure. Conventional cardiac monitoring, including physical examination, electrocardiography, echocardiography or serum ferritin levels fail to predict manifest or subclinical myocardial involvement resulting from iron overload. Cardiovascular magnetic resonance imaging T2* (cMRI-T2*, pronounced T2 star) times correlate well with myocardial iron levels. This timely review focuses on the utility of cMRI-T2*, for the preclinical detection of myocardial iron overload and monitoring of myocardial iron content during chelation therapy.
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PMID:Quantification of myocardial iron overload by cardiovascular magnetic resonance imaging T2* and review of the literature. 1841 44

An African American male of West Indies descent was diagnosed to have elevated transferrin saturation, hyperferritinemia, severe iron deposition in hepatocytes, and hepatic cirrhosis at age 4. He was treated with serial phlebotomy to maintain a normal serum ferritin concentration thereafter. We evaluated him at age 23 and confirmed that he had normal serum ferritin levels, severe iron deposition in hepatocytes, hepatic cirrhosis, and portal hypertension. He did not have endocrinopathy, cardiomyopathy, or arthropathy. He was homozygous for the novel hemojuvelin (HJV) premature stop-codon mutation R54X (exon 3; c.160A-->T). He did not have either HFE C282Y, H63D, or S65C, or deleterious coding region mutations of SLC40A1, TFR2, or HAMP. His erythrocyte measures and hemoglobin electrophoresis were consistent with alpha-thalassemia trait. We conclude that homozygosity for HJV R54X accounts for his severe, early age-of-onset hemochromatosis; his phenotype was probably modified by serial phlebotomy therapy.
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PMID:Early age-of-onset iron overload and homozygosity for the novel hemojuvelin mutation HJV R54X (exon 3; c.160A-->T) in an African American male of West Indies descent. 1849 90

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.
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PMID:The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. 1862 80

Defects in frataxin result in Friedreich ataxia, a genetic disease characterized by early onset of neurodegeneration, cardiomyopathy, and diabetes. Frataxin is a conserved mitochondrial protein that controls iron needed for iron-sulfur cluster assembly and heme synthesis and also detoxifies excess iron. Studies in vitro have shown that either monomeric or oligomeric frataxin delivers iron to other proteins, whereas ferritin-like frataxin particles convert redox-active iron to an inert mineral. We have investigated how these different forms of frataxin are regulated in vivo. In Saccharomyces cerevisiae, only monomeric yeast frataxin (Yfh1) was detected in unstressed cells when mitochondrial iron uptake was maintained at a steady, low nanomolar level. Increments in mitochondrial iron uptake induced stepwise assembly of Yfh1 species ranging from trimer to > or = 24-mer, independent of interactions between Yfh1 and its major iron-binding partners, Isu1/Nfs1 or aconitase. The rate-limiting step in Yfh1 assembly was a structural transition that preceded conversion of monomer to trimer. This step was induced, independently or synergistically, by mitochondrial iron increments, overexpression of wild type Yfh1 monomer, mutations that stabilize Yfh1 trimer, or heat stress. Faster assembly kinetics correlated with reduced oxidative damage and higher levels of aconitase activity, respiratory capacity, and cell survival. However, deregulation of Yfh1 assembly resulted in Yfh1 aggregation, aconitase sequestration, and mitochondrial DNA depletion. The data suggest that Yfh1 assembly responds to dynamic changes in mitochondrial iron uptake or stress exposure in a highly controlled fashion and that this may enable frataxin to simultaneously promote respiratory function and stress tolerance.
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PMID:Assembly of the iron-binding protein frataxin in Saccharomyces cerevisiae responds to dynamic changes in mitochondrial iron influx and stress level. 1878 75

Given the reported association of cardiac complications with hereditary hemochromatosis and the high carrier frequency of HFE gene mutations in the natural population, it seems reasonable that such mutations might appear more frequently than expected among symptomatic cardiac patients. Thus, H63D, C282Y, and S65C mutations and their possible associations were examined in 477 Caucasian males undergoing coronary angiography. Genotypes were analyzed for differences between ferritin and transferrin levels, coronary artery disease (CAD), cardiomyopathy (CM), and cardiovascular disease (CVD) mortality. No significant differences were found in ferritin levels between those with or without HFE mutations (C282Y P = 0.632, H63D P = 0.765, S65C P = 0.568, and HFE mutation P = 0.568); however, there was a significant difference (P = 0.005) in mean transferrin levels between those with (252 microg/l) and without (275 microg/l) C282Y. No relationship between HFE mutations and CAD (C282Y, P = 0.402; H63D, P = 0.112; S65C, P = 0.170) or CVD death (C282Y, P = 0.560; H63D, P = 0.682; S65C, P = 0.664) was demonstrated using logistic regression. However, an association between S65C and CM was found (odds ratio 4.4; 95% confidence interval 1.3-13.3, P = 0.018). This suggests that the S65C allele may contribute to the development of CM, but that these three HFE mutations do not appear to play a significant role in development of ischemic heart disease.
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PMID:HFE mutations in heart disease. 1881 May 84

We experienced an 81 year-old man with heart failure and macrocytic anemia. His serum ferritin level was extremely high (> 3,000 ng/mL). Echocardiography showed a normal left ventricular (LV) ejection fraction (EF), although the total ejection isovolume index (TEI index) was markedly elevated (0.60). In a cardiac catheterization study, cardiac index, pulmonary arterial wedge pressure, LV wall motion, and coronary arteries were shown to be normal. However, atrial pacing demonstrated a negative force-frequency relationship (a decrease in arterial blood pressure with higher pacing rates). Pathological study showed hemosiderin accumulation in his liver, but not in his myocardial tissue. As earlier studies have reported that iron may play an important role in oxidative cell damage and that this ion can enter cardiomyocytes through L-type Ca(2+) channels, we started an iron chelating agent (deferoxamine) and a calcium channel blocker (verapamil) in this case. Eighteen months later, his serum ferritin levels fell significantly without any changes in anemia. The TEI index was normalized (0.21) and the atrial pacing provoked a less negative force-frequency relationship. Thus, this combination treatment may be effective in iron overload cardiomyopathy at its early stage, when LV diastolic dysfunction is dominant and LV systolic dysfunction is only latent.
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PMID:A case of iron overload cardiomyopathy: beneficial effects of iron chelating agent and calcium channel blocker on left ventricular dysfunction. 1995 79

Genetic hemochromatosis is classified into four subtypes of which only type 1 is of clinical importance in Caucasians. Type 1 is due to an autosomal recessive inborn error of metabolism; the homozygous C282Y mutation of the HFE gene on chromosome 6 accounts for more than 90% of the clinical phenotype in populations of Celtic origin. The mutation leads to an inadequately high intestinal iron absorption which may finally cause iron overload in and damage to various organs. Type 2 is the juvenile form of iron overload which leads to a severe phenotype prior to age 30 with cardiomyopathy and hypogonadism. The corresponding mutations are located in the hemojuveline and hepcidin genes. Typ 3 has mainly been described in Italian families and refers to mutations in transferrin receptor 2 gene. Histopathologic and clinical consequences of type 3 hemochromatosis are similar to those seen in type 1. Types 2 and 3 are autosomal recessive traits. Type 4 hemochromatosis follows an autosomal dominant trait; the corresponding mutation affects the basolateral iron carrier ferroportin 1. Diagnosis of hemochromatosis is based on determinations of serum ferritin and transferrin saturation with the latter being more sensitive and specific. In case of a homozygous C282Y gene test, liver biopsy is not required for diagnosis. Liver biopsy is, however, recommended in C282Y homozygotes at ferritin values > 1,000 ng/ml because of an increased risk for liver fibrosis. Phlebotomy treatment is the standard care to remove iron in genetic hemochromatosis. Patients treated in the early noncirrhotic stage have a normal life expectancy. Thus, future efforts should aim at early diagnosis. Iron removal also improves the outcome in cirrhotic patients. Liver carcinoma may develop in cirrhotic patients despite iron depletion. Liver cancers without cirrhosis are so rare that screening is only recommended in cirrhotic patients.
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PMID:[Hereditary hemochromatosis]. 2003 60


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