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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is hypothesized that a homozygous C282Y mutation of the HFE gene prohibits the assembly of the transferrin-receptor 1 (TFR1) with the divalent metal transporter (DMT1) as the main iron update complex in hepatocytes membrane. Thus, the cellular influx of transferrin-bound iron from the endosomal compartment into the cytasol is compromised. As a consequence, transferrin saturation increases while concomitantly a cytosolic iron deficiency state develops. This in turn triggers the suppression of hepcidin synthesis in hepatocytes. Its impaired release into the bloodstream, causes the increased intestinal iron absorption of hemochromatosis. Excessively absorbed iron cannot be used by the erythron as a surplus for hemoglobin synthesis and is therefore trapped in ferritin complexes of RES macrophages. The ferritin is thereafter released into the bloodstream and taken up by hepatocytes for final disposal. In the lysosomal compartment ferritin is degraded to hemosiderin. Here, the release of excessive iron molecules may induce cellular injury via free radicals. The phenotypic expression of genetic hemochromatosis may depend on the activity of the erythron to use transferrin-bound-iron for heme synthesis. Therefore, a high erythron requirement for iron can utilize excess iron and may represent the rationale of phlebotomy therapy in this disease.
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PMID:Liver and iron metabolism--a comprehensive hypothesis for the pathogenesis of genetic hemochromatosis. 1723 23

Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are the major cause of juvenile hemochromatosis (JH), a recessive disease leading to iron overload. Defective HJV reduces hepcidin up-regulation both in humans and in Hjv-deficient mice. To investigate the JH pathogenesis and the functional properties of human HJV we studied the biosynthesis and maturation of 6 HJV pathogenic mutants in HeLa and HepG2 cells. We show that proteolytic processing is defective in mutants F170S, W191C, and G320V, but not in G99V and C119F. Moreover, we show that mutants G99V and C119F are targeted to the cell surface, while F170S, W191C, G320V, and R326X (lacking the glycosilphosphatidylinositol [GPI] anchor) are mainly retained in the endoplasmic reticulum, although all mutants are released as soluble forms (s-HJV) in a proportion that is modulated by iron supplementation. Membrane HJV (m-HJV) is mainly composed of the cleaved protein, and its level is increased by iron in wild-type (WT) mice but not in the mutants. Altogether, the data demonstrate that the loss of HJV membrane export is central to the pathogenesis of JH, and that HJV cleavage is essential for the export. The results support a dual function for s- and m-HJV in iron deficiency and overload, respectively.
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PMID:Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. 1726

Twenty five years ago, Finch summarized knowledge gained primarily from studies of normal individuals, patients with hereditary hemolytic anemias, and patients with hemochromatosis [1]. Under conditions of basal erythropoiesis in normal subjects, plasma iron turnover (as an index of marrow erythropoietic response) is little affected, whether transferrin saturation ranges from very low to very high levels. In contrast, the erythropoietic response in individuals with congenital hemolytic anemia, in whom erythropoiesis is chronically raised up to sixfold over basal levels [2], is affected (and limited) by serum iron levels and by transferrin saturation [3]. Patients with hemochromatosis who underwent serial phlebotomy were observed to mount erythropoietic responses of up to eightfold over basal rates, attributed to the maintenance of very high serum iron and transferrin saturation levels in these patients [4], whereas normal individuals were shown to have difficulty providing sufficient iron to support rates of erythropoiesis greater than three times basal rates [5]. These observations led Finch to identify a "relative iron deficiency" state, also known as "functional iron deficiency," which he defined as circumstances in which increased erythron iron requirements exceed the available supply of iron [6]. In another clinical setting, patients undergoing autologous blood donation represent a model for perisurgical blood loss and the erythropoietic response. Insights gained over the last 20 years regarding the relationship between erythropoietin, iron, and erythropoiesis, along with implications for clinical management, will be reviewed.
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PMID:Erythropoietin and iron-restricted erythropoiesis. 1737 3

Iron deficiency, with or without iron-deficiency anemia, is so ubiquitous that it affects all populations of the world irrespective of race, culture, or ethnic background. Despite all the latest advances in modern medicine, improved nutrition, and the ready availability of cheap oral iron, there is still no good explanation for the widespread persistence of iron deficiency. It is possible that the iron deficiency phenotype is very prevalent because of many factors other than the commonly cited causes such as a decreased availability or an increased utilization of iron. Several thousand years ago, human culture changed profoundly with the agrarian revolution, when humans turned to agriculture. Their diet became iron deficient and new epidemic infections emerged due to crowding and lifestyle changes. There is convincing evidence that iron deficiency protects against many infectious diseases such as malaria, plague, and tuberculosis as shown by diverse medical, historical, and anthropologic studies. Thus, this change of diet increased the frequency of iron deficiency, and epidemic infections exerted a selection pressure under which the iron deficiency phenotype survived better. Multiple evolutionary factors have contributed in making iron deficiency a successful phenotype. We analyze some of the recent findings of iron metabolism, the theories explaining excessive menstruation in human primates, the unexplained relative paucity of hemochromatosis genes, the former medical practice of "blood-letting," and other relevant historical data to fully understand the phenomenon of iron deficiency. We suggest that, due to a long evolutionary persistence of iron deficiency, efforts at its prevention will take a long time to be effective.
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PMID:Nutritional iron deficiency: an evolutionary perspective. 1758 79

More than 25 years ago, the iron hypothesis proposed that a state of sustained iron depletion or mild iron deficiency exerts a primary protective action against ischemic heart disease. Iron depletion leads to a decreased availability of redox-active iron in vivo. The amount of free iron available at sites of oxidative or inflammatory injury appears to be a function of the stored iron level. Depletion of iron levels by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduce atherosclerotic lesion size and increase plaque stability. In homozygous hemochromatosis there is commonly a defect that inhibits iron retention in macrophages. This defect may explain why atherosclerotic lesions appear to be less prevalent in this disorder. Findings of the "FeAST" trial have been recently reported. The trial assessed the potential benefit of mild iron reduction therapy in secondary prevention of cardiovascular disease. It was therefore not a fully valid test of primary prevention as postulated by the iron hypothesis. However, although no overall statistically significant cardiovascular benefit was found, in the youngest quartile at entry there were highly significant reductions in all cause mortality and in combined death plus non-fatal myocardial infarction and stroke in association with iron reduction therapy. The FeAST trial adds urgency to the initiation of new studies to assess the impact of maintenance of complete iron depletion in the primary prevention of cardiovascular diseases.
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PMID:[Current status of the iron hypothesis of cardiovascular diseases]. 1768 84

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

Hepcidin is a small protein comprised of 25 amino acids, synthesized in the liver. It was first described in 2001 as a component of the innate immunity due to its antimicrobial activity. Soon after, hepcidin was recognized as a key component in iron homeostasis, involved in maladies of iron overload or iron deficiency. Hepcidin acts by binding to the transmembrane protein ferroportin, in charge of exporting iron from cells. Upon binding to ferroportin, the latter is internalized into cytoplasmic lysosomes and is hydrolyzed, thus iron is accumulating in cells, and hypoferremia ensues. In hereditary and juvenile types of hemochromatosis, iron overload could be partially due to the down-regulation of hepcidin by the mutated genes HFE and HJV. In ferroportin disease, hepcidin synthesis is not inhibited, yet cells are still overloaded with iron due to mutations in ferroportin, preventing the binding of hepcidin and iron export from cell to the blood. Hepcidin has also been implicated in the scenario related to as "anemia of inflammation". In this condition significant hypoferremia develops as a result of acute sepsis, but also in wake of infections, chronic inflammation, rheumatic diseases and in certain malignancies. Such scarcity of iron leads to anemia that may not be corrected by erythropoietin treatment, and hepcidin synthesis in such anemic state is dramatically elevated. Future therapeutic approach may attempt administering synthetic hepcidin, or its antagonists, to correct states of iron overload or scarcity.
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PMID:[Hepcidin--the discovery of a small protein with a pivotal role in iron homeostasis]. 1848 71

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

Hepcidin, a 25-amino-acid antimicrobial peptide, is the central regulator of iron homeostasis. Hepcidin transcription is upregulated by inflammatory cytokines, iron, and bone morphogenetic proteins and is downregulated by iron deficiency, ineffective erythropoiesis, and hypoxia. The iron transporter ferroportin is the cognate receptor of hepcidin and is destroyed as a result of interaction with the peptide. Except for inherited defects of ferroportin and hepcidin itself, all forms of iron-storage disease appear to arise from hepcidin dysregulation. Studies using multiple approaches have begun to delineate the molecular mechanisms that regulate hepcidin expression, particularly at the transcriptional level. Knowledge of the regulation of hepcidin by inflammation, iron, erythropoiesis, and hypoxia will lead to an understanding of the pathogenesis of primary hemochromatosis, secondary iron overload, and anemia of inflammatory disease.
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PMID:Regulation of hepcidin and iron-overload disease. 1940 Jun 94

Hemoglobin (Hb) levels and mean corpuscular volume (MCV) are abnormal in some persons with hemochromatosis or thyroid disorders. We sought to determine whether serum free thyroxine (T4) affects erythrocyte measures in euthyroid adults with or without C282Y homozygosity. We evaluated 488 white HFE C282Y homozygotes and controls (no HFE C282Y or H63D; normal serum iron measures) identified in screening; we excluded those with thyroid disorders, anemia, erythrocytosis, or serum ferritin (SF) <34 pmol/l. In the remaining 141 C282Y homozygotes and 243 controls, we evaluated correlations of log(10) free T4 with Hb, RBC, MCV, and red blood cell distribution width (RDW). C282Y homozygotes had lower mean age, higher mean Hb, MCV, and log(10) SF, and lower mean RBC and RDW than controls; mean log(10) free T4 did not differ significantly. In HFE C282Y homozygotes, there was no significant correlation of log(10) T4 with erythrocyte measures. In controls, there was a positive correlation of log(10) T4 with Hb (P = 0.0096) and a negative correlation with RDW (P = 0.0286). Among euthyroid white adults without iron deficiency, there are significant correlations of log(10) free T4 with Hb and RDW in controls, but not in HFE C282Y homozygotes.
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PMID:Relationships of serum free thyroxine and erythrocyte measures in euthyroid HFE C282Y homozygotes and control subjects: the HEIRS study. 1970 67


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