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

Transferrin Receptor 1 (TfR1) and putative Stimulator of Fe Transport (SFT) represent two different proteins involved in iron metabolism in mammalian cells. The expression of TfR1 in the duodenum of subjects with normal body iron stores has been mainly localized in the basolateral portion of the cytoplasm of crypt cells, supporting the idea that this molecule may be involved in the sensing of body iron stores. In iron deficiency anemia TfR1 expression demonstrated an inverse relationship with body iron stores as assessed by immunohistochemistry with anti-TfR1 antibodies. In iron overload, TfR1 expression in the duodenum differed according to the presence or absence of the C282Y mutation in the HFE gene, being increased in HFE-related hemochromatosis and similar to controls in non-HFE-related iron overload. SFT is characterized by its ability to increase iron transport both through the transferrin dependent and independent uptake, and could thus affect iron absorption in the intestine. Immunohistochemistry using anti-SFT antibodies which recognize a putative stimulator of Fe transport of approximately 80 KDa revealed a localization of this protein in the apical part of the cytoplasm of enterocytes localized at the tip of the villi. The expression of the protein recognized by these antibodies was increased in iron deficiency, as well as in patients carrying the C282Y HFE mutation. Thus, the increased expression of both proteins only in patients with HFE-related hemochromatosis suggests that other factors should be involved in determining non-HFE-related iron overload.
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PMID:Transferrin receptor 1 (TfR1) and putative stimulator of Fe transport (SFT) expression in iron deficiency and overload: an overview. 1254 40

Juvenile or type 2 hemochromatosis (JH) is a genetic disease caused by increased intestinal iron absorption that leads to early massive iron overload. The main form of the disease is caused by mutations in a still unknown gene on chromosome 1q. Recently, we recognized a second type of JH with clinical features identical to the 1q-linked form, caused by mutations in the gene encoding hepcidin (HEPC). Hepcidin is a hepatic antimicrobial-like peptide whose role in iron homeostasis was first defined in animal models; deficiency of hepcidin in mice leads to iron overload, whereas its hepatic overexpression in transgenic animals causes iron deficiency. To define the prevalence of HEPC mutations in JH we screened the HEPC gene for mutation in 21 unrelated JH subjects. We identified a new mutation (C70R), which affects 1 of the 8 conserved cysteines that form the disulfide bonds and are critical for the stability of the polypeptide.
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PMID:Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). 1463 Aug 9

In the past seven years numerous genes that influence iron homeostasis have been discovered. Dr. Beutler provides a brief overview of these genes, genes that encode HFE, DMT-1, ferroportin, transferrin receptor 2, hephaestin, and hepcidin to lay the groundwork for a discussion of the various clinical forms of iron storage disease and how they differ from one another. In Section I, Dr. Beutler also discusses the types of hemochromatosis that exist as acquired and as hereditary forms. Acquired hemochromatosis occurs in patients with marrow failure, particularly when there is active ineffective erythropoiesis. Hereditary hemochromatosis is most commonly due to mutations in the HLA-linked HFE gene, and hemochromatosis clinically indistinguishable from HFE hemochromatosis is the consequence of mutations in three transferrin receptor-2 gene. A more severe, juvenile form of iron storage disease results from mutations of the gene encoding hepcidin or of a not-yet-identified gene on chromosome 1q. Autosomal dominant iron storage disease is a consequence of ferroportin mutations, and a polymorphism in the ferroportin gene appears to be involved in the African iron overload syndrome. Evidence regarding the biochemical and clinical penetrance of hemochromatosis due to mutations of the HFE gene is rapidly accumulating. These studies, emanating from several centers in Europe and the United States, all agree that the penetrance of hemochromatosis is much lower than had previously been thought. Probably only 1% of homozygotes develop clinical findings. The implications of these new findings for the management of hemochromatosis will be discussed. In Section II, Dr. Victor Hoffbrand discusses the management of iron storage disease by chelation therapy, treatment that is usually reserved for patients with secondary hemochromatosis such as occurs in the thalassemias and in patients with transfusion requirements due to myelodysplasia and other marrow failure states. Tissue iron can be estimated by determining serum ferritin levels, measuring liver iron, and by measuring cardiac iron using the MRI-T2* technique. The standard form of chelation therapy is the slow intravenous or subcutaneous infusion of desferoxamine. An orally active bidentate iron chelator, deferiprone, is now licensed in 25 countries for treatment of patients with thalassemia major. Possibly because of the ability of this compound to cross membranes, it appears to have superior cardioprotective properties. Agranulocytosis is the most serious complication of deferiprone therapy and occurs in about 1% of treated patients. Deferiprone and desferoxamine can be given together or on alternating schedules. A new orally active chelating agent ICL 670 seems promising in early clinical studies. In Section III, Dr. James Cook discusses the most common disorder of iron homeostasis, iron deficiency. He will compare some of the standard methods for identifying iron deficiency, the hemoglobin level, transferrin saturation, and mean corpuscular hemoglobin and compare these with some of the newer methods that have been introduced, specifically the percentage of hypochromic erythrocytes and reticulocyte hemoglobin content. The measurement of storage iron is achieved by measuring serum ferritin levels. The soluble transferrin receptor is a truncated form of the cellular transferrin receptor and the possible value of this measurement in the diagnosis of iron deficiency will be discussed. Until recently iron dextran was the only parental iron preparation available in the US. Sodium ferric gluconate, which has been used extensively in Europe for many years, is now available in the United States. It seems to have a distinct advantage over iron dextran in that anaphylactic reactions are much less common with the latter preparation.
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PMID:Iron deficiency and overload. 1463 76

Although it generally does not improve performance, iron is often used by elite athletes. The physiologic changes induced by exercise can mimic iron deficiency and decrease hemoglobin and ferritin concentrations. Determination of serum transferrin receptor concentrations may identify true iron deficiency, which occurs particularly in young athletes. In contrast, increased iron stores in the body are a frequent finding in elite athletes who have used long-term iron supplementation. Elite runners have increased intestinal blood loss, but this usually can be compensated by enhanced absorption of dietary iron. The combination of exercise-induced hemolysis with enhanced intestinal blood loss in various endurance sports leads to severe abnormalities of routine tests, and extreme physical activity may be responsible for positive fecal occult blood determinations. Indiscriminate iron supplementation carries the risk of inducing hemochromatosis in individuals homozygous for the widespread C282Y allele of the HFE gene. This polymorphism is common and can be found in about 1% of individuals of Northern European descent; moreover, iron supplementation can modify the presentation of important underlying diseases such as celiac disease or colon carcinoma. In conclusion, iron supplements should be prescribed for athletes with iron-deficiency anemia and carefully monitored if given for prophylaxis; unless a therapeutic response occurs, investigations to establish the cause of iron deficiency should be initiated.
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PMID:Iron supplementation in athletes--first do no harm. 1521 43

Diagnosing disorders of iron metabolism the concentration of the iron storing protein ferritin reflects the body's iron reserves much better than does serum iron concentrations or transferring saturation. Merely in the event of acute phase reactions is the validity of the ferretin level compromised. This applies in particular to the redistribution of iron in anemia caused by inflammatory conditions or malignancies, as also, though less markedly, to functional iron deficiency in renal anemia. Here, an additional diagnostic work-up, in particular when EPO/iron therapy is applied. Iron overload should be recognized already in the latent state before organ damage occurs. Clinically and chemically confirmed iron overload that cannot be ascribed to hematological disease, iron replacement of transfusions, should prompt a molecular-biological analysis of hemochromatosis-associated genetic defects.
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PMID:[Diagnosing disorders of iron metabolism. Begin with ferritin]. 1562 34

Type IV hemochromatosis is associated with dominant mutations in the SLC40A1 gene encoding ferroportin (FPN). Known as the "ferroportin disease," this condition is typically characterized by high serum ferritin, reduced transferrin saturation, and macrophage iron loading. Previously FPN expression in vitro has been shown to cause iron deficiency in human cell lines and mediate iron export from Xenopus oocytes. We confirm these findings by showing that expression of human FPN in a human cell line results in an iron deficiency because of a 3-fold increased export of iron. We show that FPN mutations A77D, V162delta, and G490D that are associated with a typical pattern of disease in vivo cause a loss of iron export function in vitro but do not physically or functionally impede wild-type FPN. These mutants may, therefore, lead to disease by haploinsufficiency. By contrast the variants Y64N, N144D, N144H, Q248H, and C326Y, which can be associated with greater transferrin saturation and more prominent iron deposition in liver parenchyma in vivo, retained iron export function in vitro. Because FPN is a target for negative feedback in iron homeostasis, we postulate that the latter group of mutants may resist inhibition, resulting in a permanently "turned on" iron exporter.
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PMID:In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. 1569 71

Although the recent identification of several genes has extended our knowledge on the maintenance of body iron homeostasis, their tissue specific expression patterns and the underlying regulatory networks are poorly understood. We studied C57black/Sv129 mice and HFE knockout (HFE -/-) variants thereof as a model for hemochromatosis, and investigated the expression of iron metabolism genes in the duodenum, liver, and kidney as a function of dietary iron challenge. In HFE +/+ mice dietary iron supplementation increased hepatic expression of hepcidin which was paralleled by decreased iron regulatory protein (IRP) activity, and reduced expression of divalent metal transporter-1 (DMT-1) and duodenal cytochrome b (Dcytb) in the enterocyte. In HFE -/- mice hepcidin formation was diminished upon iron challenge which was associated with decreased hepatic transferrin receptor (TfR)-2 levels. Accordingly, HFE -/- mice presented with high duodenal Dcytb and DMT-1 levels, and increased IRP and TfR expression, suggesting iron deficiency in the enterocyte and increased iron absorption. In parallel, HFE -/- resulted in reduced renal expression of Dcytb and DMT-1. Our data suggest that the feed back regulation of duodenal iron absorption by hepcidin is impaired in HFE -/- mice, a model for genetic hemochromatosis. This change may be linked to inappropriate iron sensing by the liver based on decreased TfR-2 expression, resulting in reduced circulating hepcidin levels and an inappropriate up-regulation of Dcytb and DMT-1 driven iron absorption. In addition, iron excretion/reabsorption by the kidneys may be altered, which may aggravate progressive iron overload.
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PMID:Regulatory networks for the control of body iron homeostasis and their dysregulation in HFE mediated hemochromatosis. 1574 72

We evaluated the analytical performance of a new, commercial, fully automated immunoturbidimetric assay for the determination of ferritin [FER-Latex(X2)CN SEIKEN, Denka Seiken, Japan] in serum on the Olympus AU2700 analyzer. The new assay is a latex-enhanced turbidimetric immunoassay with an analysis time of 10 min. The linearity of the assay was confirmed up to 2505 pmol/L (R2=0.999). The detection limit and the functional sensitivity were both 4.5 pmol/L. The intra- and inter-assay imprecision (CV) at 67, 506, 2186 pmol/L was < 1.8% and < 2.5%, respectively. Verification of the traceability to a WHO standard (80/578) showed a recovery of 102.6% (target value 449 pmol/L). No hook effect was observed in samples containing up to 33,705 pmol/L. The assay showed good correlation with the Beckman Immage nephelometric system (r=0.999). Hemoglobin (< or = 9.8 g/L), total bilirubin (< or = 113 micromol/L), conjugated bilirubin (< or = 109 micromol/L) and rheumatoid factor (< or = 5.2x10(5) IU/L) did not interfere with the assay. The reference interval (2.5-97.5 percentile) was 72-521 pmol/L for men and 27-267 pmol/L for women. The reference interval in patients with anemia, malignant tumors and hemochromatosis was 5.6-52, 130-2436 and 1465-2903 pmol/L, respectively. On the basis of the receiver operating characteristic curve, the 90% sensitivity cut-off value to distinguish between patients with and without iron deficiency was 40 pmol/L. The new latex turbidimetric procedure for ferritin assay is an attractive alternative that avoids the need for dedicated instrumentation.
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PMID:Preliminary evaluation of the performance of a new, highly sensitive commercial immunoassay for serum ferritin determination. 1620 2

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

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


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