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

Hepcidin is a small cystein-rich cationic peptide produced mainly by the liver. It was initially isolated from human plasma and exhibited antimicrobial activity. Recently, several lines of evidence have suggested that hepcidin is a key regulator of iron metabolism at the whole body level and is relative to inflammation, infection, hypoxia and anemia. Hepcidin, is implicated in duodenal iron absorption and iron mobilization from reticuloendothelial macrophages. The major mechanism of hepcidin function seems to be the regulation of transmembrane iron transport. As both iron deficiency and iron excess are associated with cellular dysfunction, so hepcidin or hepcidin-related therapeutics could find a place in the treatment of various diseases such as hemochromatosis and anemia of chronic disease. To elucidate biological function of hepcidin further and use it for other research, it is necessary to produce enough hepcidin through DNA recombinant technique. As a highly successful system for the production of a variety of heterologous proteins, the methylotrophic Pichia pastoris system has the probability for a high level production of hepcidin. The subject of this paper is to summarize the regulation of hepcidin gene expression and the understanding of functions of hepcidin. At last, giving a prospect of production hepcidin by gene engineer.
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PMID:[Properties and advance of hepcidin]. 1675 11

Caucasian South African patients with multiple sclerosis (MS) were screened for the most common hereditary haemochromatosis (HH) mutations, H63D and C282Y, in order to determine the impact of iron overload on clinical outcome of MS. DNA screening for mutations H63D and C282Y in 118 apparently unrelated MS patients did not reveal significant differences in allele frequencies in comparison with a control group from the same population. Of 17 MS patients heterozygous for C282Y, 3 had below normal and none had above normal transferrin saturation levels. One of the index MS patients, and subsequently also her sister who also has MS, tested positive for two copies of mutation C282Y. Determination of iron status revealed high serum ferritin and transferrin saturation levels in both patients. However, the index patient, being unaware of her C282Y status, had received treatment for iron deficiency in the past and her MS symptoms were less severe than those of her sister who has been wheelchair bound for the past 12 years and who did not take iron supplements. Lack of clinical manifestation of HH without any signs of organ damage in the C282Y homozygous MS patients is in accordance with a role of iron dysregulation in the aetiology of MS.
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PMID:Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis. 1685 Feb 57

The discovery in recent years of a plethora of new genes whose products are implicated in iron homeostasis has led to rapid expansion of our knowledge in the field of iron metabolism and its underlying complex regulation in both health and disease. Abnormalities of iron metabolism are among the most common disorders encountered in practical medicine and may have significant negative impact on physical condition and life expectancy. Basic insights into the principles of iron homeostasis and the pathophysiological and clinical consequences of iron overload, iron deficiency and misdistribution are thus of crucial importance in modern medicine. This review summarizes our current understanding of human iron metabolism and focuses on the clinically relevant features of hereditary and secondary hemochromatosis, iron deficiency anemia, anemia of chronic disease and anemia of critical illness. The interconnections between iron metabolism and immunity are also addressed, in as much as they may affect the risk and course of infections and malignancies.
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PMID:Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis. 1695 74

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

Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43-82 microg/L for women, 165-242 microg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 microg/L for women (<47 microg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9-47.5 for women, 60.6-3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4-1.8 for women, 1.2-1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement.
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PMID:Bivariate mixture modeling of transferrin saturation and serum ferritin concentration in Asians, African Americans, Hispanics, and whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. 1820 77

Hemochromatosis is caused by mutations in HFE, a protein that competes with transferrin (TF) for binding to transferrin receptor 1 (TFR1). We developed mutant mouse strains to gain insight into the role of the Hfe/Tfr1 complex in regulating iron homeostasis. We introduced mutations into a ubiquitously expressed Tfr1 transgene or the endogenous Tfr1 locus to promote or prevent the Hfe/Tfr1 interaction. Under conditions favoring a constitutive Hfe/Tfr1 interaction, mice developed iron overload attributable to inappropriately low expression of the hormone hepcidin. In contrast, mice carrying a mutation that interferes with the Hfe/Tfr1 interaction developed iron deficiency associated with inappropriately high hepcidin expression. High-level expression of a liver-specific Hfe transgene in Hfe-/- mice was also associated with increased hepcidin production and iron deficiency. Together, these models suggest that Hfe induces hepcidin expression when it is not in complex with Tfr1.
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PMID:The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. 1831 26


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