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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25-amino-acid peptide hepcidin is up-regulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it was considered the most common disease among Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and only its genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype. Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias. While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.
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PMID:Iron storage disease: facts, fiction and progress. 1754 May 89

Epidemiological studies and experimental data suggest iron involvement in atherosclerosis. The relation between iron and atherosclerosis is complex and remains contradictory. In thalassemia patients, non transferrin bound iron (NTBI) and free hemoglobin (Hb) are present in plasma and may accelerate atherogenesis, but its progression may be inhibited by iron chelators. The mechanism whereby iron may stimulate atherogenesis has been intensively investigated. Non transferrin bound iron and sera from subjects with hemochromatosis induced endothelial activation with expression of vascular adhesion molecules and endothelial inflammatory chemokines. Such events could be inhibited by iron chelators and oxygen radical scavengers with intracellular activity. Iron chelators may be effective in preventing vascular damage in patients with high concentrations of NTBI as found in thalassemia.
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PMID:Can iron chelators influence the progression of atherosclerosis? 1827 90

Iron (Fe) overload diseases, such as beta-thalassemia (thal) major and hemochromatosis, have been treated for several decades by chelating therapy with desferrioxamine (DFO). However, drawbacks associated with that drug led to the development of new chelating drugs. The 3-hydroxy-4-pyridinones emerged as highly effective Fe chelators, and deferiprone (L1) has been approved as a Fe chelating drug. The most recent strategy for Fe overload problems is based on the replacement of monotherapies by a combination therapy with both chelators. Following a similar chelating strategy, we present herein the results of animal tests with a combination of two different hydroxypyridinone-based chelators. Both are of the 3-hydroxy-4-pyridinone (HP) type, but with one and two HP chelating units, and extra functional groups to account for differentiation in their physicochemical and biological properties, namely chelating efficacy and bioavailability. Animal studies have shown that the simultaneous administration of this pair of HP chelators, under appropriate proportion, to metal-loaded mice, could speed up metal excretion. This may be rationalized by adjuvant and eventual synergistic effects, due to complementary accessibility of each chelator to different cellular compartments.
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PMID:A new approach for potential combined chelation therapy using mono- and bis-hydroxypyridinones. 1827 92

Heme-regulated eIF2alpha kinase (HRI) is essential for regulating globin translation in iron deficiency and in beta-thalassemia. We investigated the role of heme-regulated eIF2alpha kinase in hemoglobin and red blood cell production as well as in iron homeostasis in a mouse model of iron overload. We show that HRI deficiency does not significantly affect red cell parameters of hemochromatosis (HFE(-)(/)(-)) mice. Importantly, heme-regulated eIF2alpha kinase deficiency exacerbates decreases in hepcidin expression and splenic macrophage iron in HFE(-)(/)(-) mice. Furthermore, the serum level of bone morphogenic protein 2, which positively regulates hepcidin, is reduced in heme-regulated eIF2alpha kinase deficiency, but not in HFE deficiency.
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PMID:Deficiency of heme-regulated eIF2alpha kinase decreases hepcidin expression and splenic iron in HFE-/- mice. 1836 82

ABSTRACT Genetically modified rice that incorporates twofold to threefold increased amounts of iron is being developed. The product could provide improved nutrition to iron-deficient persons but may be a health hazard to large numbers of humans who are prone to iron overload. Clinical disorders such as African siderosis, beta-thalassemia, hemochromatosis, and alcoholic siderosis are of special concern. Conditions associated with iron loading include fatigue and depression; arthritis; endocrine disorders such as stunted growth, impotence, and diabetes; gastrointestinal maladies; infections and malignancies; several neurological diseases; and, not least, cardiovascular system decay. Therefore, it would be prudent to label sacks of iron-enriched rice to indicate that "this product may be dangerous to persons with iron loading conditions".
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PMID:Iron-enriched rice: the case for labeling. 1923 76

Osteoporosis is a remarkably frequent complication of iron loading conditions such as thalassemia, sicklemia, African siderosis, hemochromatosis, smoking, alcoholism, HIV infection, and cessation of menstruation. The metal suppresses osteoblast formation of bone and may also stimulate osteoclast resorption of bone. Iron also inhibits anterior pituitary synthesis of gonadotrophs. This, in turn, results in depressed formation of gonadal hormones. The tendency of iron-loaded persons to become osteoporotic may be enhanced by gonadal hormone deficiency. Iron binding agents that could specifically withhold excess skeletal iron (and be excreted as the iron chelate) might have therapeutic utility.
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PMID:Role of iron in osteoporosis. 1933 60

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.
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PMID:Iron overload in the Asian community. 1957 77

Seasonal iron overload in Svalbard reindeer was studied by light and electron microscopy and by X-ray microanalysis. The hepatic iron overload was of two types. The first type was characterized by massive siderosis of both parenchymal and non-parenchymal cells caused by a diet very rich in iron but low in energy and protein. Hepatocytes contained a moderate amount of free ferritin particles in the cytosol together with numerous siderosomes. This pattern is similar to that seen in primary haemochromatosis and thalassaemia. Kupffer cells contained large quantities of cytosolic ferritin, siderosomes and lysosomes with disintegrating red blood cells as seen in thalassaemia. The second type was characterized by massive non-parenchymal siderosis caused by an energy- and protein-poor diet with normal iron concentration. Hepatocytes contained little cytosolic ferritin and few siderosomes, but there were abundant electron-dense bodies without iron (i.e., autophagosomes). Kupffer cells were as described above. Ferritin was also present within the duodenal mucosa of these animals, located within enterocytes and lamina propria macrophages, as well as in the extracellular space and capillary and lacteal lumina. Ferritin was also present in the acinar cells of submucosal Brunner's glands. Changes consistent with exchange of ferritin particles between different cell types were observed. The role of ferritin as a possible iron transporter in this condition is discussed.
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PMID:Iron distribution in the liver and duodenum during seasonal iron overload in Svalbard reindeer. 1934 12

Homozygous beta-thalassemia is a common genetic disorder in the Arabian Peninsula and an important cause of morbidity in Kuwait. The anemia is so severe that chronic blood transfusions, and the resulting iron overload, cause a shift in immunoregulatory balances and a deficiency in zinc. It was reported that individual immunological profile of CD8+ T-lymphocytes may have a modifying effect on the severity of iron overload in HFE homozygous hemochromatosis patients, with low numbers being negatively correlated with the total amount of body iron stores. This has not been tested in thalassemia major patients. This study was designed to utilize flow cytometric immunophenotyping to characterize effects of regular blood transfusion, and high serum ferritin levels because of irregular use of iron chelation therapy on T lymphocytes (CD2, CD3, CD4 and CD8), B lymphocytes (CD19) and natural killer cells (CD56) and zinc levels in the blood of patients with thalassemia major (n = 49) and healthy normal controls (n = 60) in Kuwait. None of the patients had active infections. T-cell markers' percentage levels were comparable between patients and controls (P > 0.05), while B cell marker (CD19) was significantly higher in patients (P = 0.007). Patients had lower percentage levels of CD56 cells (P = 0.007) and normal serum zinc. All patients had high serum ferritin levels with no significant correlation to CD8+ T lymphocytes (P > 0.05). High iron stores did not have an effect on T lymphocytes' profile, with normal zinc levels perhaps related to non compliance with chelation therapy. The high B cell marker may be indicative of stimulation of antibody producing cells as a result of regular blood transfusions.
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PMID:Investigation of the distribution of lymphocyte subsets and zinc levels in multitransfused beta-thalassemia major patients. 1945 75

Excess iron is found in brain nuclei from neurodegenerative patients (with Parkinson's, Alzheimer's and Huntington's diseases) and also in the liver and spleen of cirrhosis, hemochromatosis and thalassaemia patients. Ferritin, the iron-storing protein of mammals, is known to darken T(2)-weighted MR images. Understanding NMR tissue behavior may make it possible to detect those diseases, to follow their evolution and finally to establish a protocol for non-invasive measurement of an organ's iron content using MRI methods. In this preliminary work, the MR relaxation properties of embalmed iron-containing tissues were studied as well as their potential correlation with the iron content of these tissues. Relaxometric measurements (T(1) and T(2)) of embalmed samples of brain nuclei (caudate nucleus, dentate nucleus, globus pallidus, putamen, red nucleus and substantia nigra), liver and spleen from six donors were made at different magnetic fields (0.00023-14 T). The influence of the inter-echo time on transverse relaxation was also studied. Moreover, iron content of tissues was determined by inductively coupled plasma atomic emission spectroscopy. In brain nuclei, 1/T(2) increases quadratically with the field and depends on the inter-echo time in CPMG sequences at high fields, both features compatible with an outer sphere relaxation theory. In liver and spleen, 1/T(2) increases linearly with the field and depends on the inter-echo time at all fields. In our study, a correlation between 1/T(2) and iron concentration is observed. Explaining the relaxation mechanism for these tissues is likely to require a combination of several models. The value of 1/T(2) at high field could be used to evaluate iron accumulation in vivo. In the future, confirmation of those features is expected to be achieved from measurements of fresh (not embalmed) human tissues.
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PMID:Variable-field relaxometry of iron-containing human tissues: a preliminary study. 1957 79


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