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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepcidin, which has been recently identified both by biochemical and genomic approaches, is a 25 amino acid polypeptide synthesized mainly by hepatocytes and secreted into the plasma. Besides its potential activity in antimicrobial defense, hepcidin plays a major role in iron metabolism. It controls two key steps of iron bioavailability, likely through a hormonal action: digestive iron absorption by enterocytes and iron recycling by macrophages. In humans, this could explain that low levels of hepcidin found during juvenile haemochromatosis and HFE-1 genetic haemochromatosis are associated with an iron overload phenotype. Conversely, an increase of hepcidin expression is suspected to play a major role in the development of anemia of chronic inflammatory diseases. However, the regulatory mechanisms of hepcidin expression are multiple, including iron-related parameters, anemia, hypoxia, inflammation and hepatocyte function. Therefore, many physiological and pathological situations may modulate hepcidin expression and subsequently iron metabolism. A better knowledge of the biological effects of hepcidin and of its expression regulatory mechanisms will clarify the place of hepcidin in the diagnosis and treatment of iron-related diseases.
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PMID:Hepcidin in iron metabolism. 1597 53

Hepcidin, originally discovered in urine as a bactericidal peptide synthesized by hepatocytes was later proved to be a key regulator of iron metabolism at the whole body level, namely, in conditions of altered iron demand such as the increased or decreased total amount of body iron, inflammation, hypoxia and anemia. The major mechanism of hepcidin function seems to be the regulation of transmembrane iron transport. Hepcidin binds to its receptor, protein ferroportin, which serves as a transmembrane iron channel enabling iron efflux from cells. The hepcidin-ferroportin complex is then degraded in lysosomes and iron is locked inside the cells (mainly enterocytes, hepatocytes and macrophages). This leads to lowering of iron absorption in the intestine and to a decrease in serum iron concentration. Utilizing this mechanism, hepcidin regulates serum iron levels during inflammation, infection and possibly also in cancer. Under these conditions iron is shifted from circulation into cellular stores in hepatocytes and macrophages, making it less available for invading microorganisms and tumor cells. In anemia and hypoxia, hepcidin regulates the availability of iron for erythropoiesis. Hepcidin or hepcidin-related therapeutics could find a place in the treatment of various diseases such as hemochromatosis and anemia of chronic disease.
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PMID:Hepcidin: a direct link between iron metabolism and immunity. 1600 23

Multiple myeloma (MM) is a B cell lymphoproliferative disorder in which malignant plasma cells accumulate in the bone marrow and usually produce monoclonal immunoglobulin in excess. Interleukin-6 (IL-6), is known to be an essential survival factor of myeloma cells, high IL-6 levels being correlated with an adverse prognosis. IL-6 modulates the transcription of several liver-specific acute phase protein genes, including C-reactive protein and hepcidin. Anemia is one of the prominent features of MM, along with recurrent osteolytic lesions, bacterial infections and renal insufficiency. The current treatment strategies of MM related anemia are often inadequate and many patients rely on transfusions. Several causes have been implicated, but anemia of chronic disease (ACD) related to the inflammatory cytokines appears to be one of the main culprits. The pathogenesis of ACD had been poorly understood, but recently it has been shown that increased Il-6 upregulates the hepatic production of hepcidin, which, by binding to its cellular receptor, ferroportin, causes anemia by blocking iron export from enterocytes and macrophages. We hereby argue that by virtue of its biological characteristics, multiple myeloma should be an ideal clinical setting to test the role of hepcidin in the pathogenesis of ACD. Hepcidin levels should be higher in MM patients and might correlate with prognosis. Anemic MM patients should also be among those who would benefit mostly from hepcidin targeted therapies.
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PMID:Hepcidin and multiple myeloma related anemia. 1622 91

Most patients suffering from chronic infections, chronic inflammatory diseases, and some malignancies develop a mild to moderate anemia designated anemia of chronic disease or anemia of inflammation. Patients with this anemia have low serum iron, low to normal transferrin, and high to normal serum ferritin concentration. The anemia is caused by increased inflammatory cytokines, especially IL-6, inducing increased production of the iron-regulatory hormone hepcidin by hepatocytes. Hepcidin blocks the release of iron from macrophages, hepatocytes, and enterocytes, causing the characteristic hypoferremia associated with this anemia and iron-deprivation of the developing erythrocytes.
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PMID:Molecular pathogenesis of anemia of chronic disease. 1626 3

The anemia of chronic disease (ACD) results from 3 major processes: slightly shortened red cell survival, impaired reticuloendothelial system iron mobilization, and impaired erythropoiesis. Hepcidin is an acute-phase protein with specific iron regulatory properties, which, along with the anemia seen with increased hepcidin expression, have led many to consider it the major mediator of ACD. However, if hepcidin is the major factor responsible for ACD, then it should also contribute to the impaired erythropoiesis observed in this syndrome. Erythroid colony formation in vitro was inhibited by hepcidin at erythropoietin (Epo) concentrations less than or equal to 0.5 U/mL but not at Epo 1.0 U/mL. At Epo concentrations of 0.3 U/mL, HCD57 erythroleukemia cells exposed to hepcidin exhibit decreased expression of the antiapoptotic protein pBad compared with controls. These studies suggest that hepcidin may contribute to anemia in ACD not only through effects on iron metabolism, but also through inhibition of erythroid progenitor proliferation and survival.
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PMID:Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. 1633 70

The regulation of intestinal iron absorption is not fully understood. Hepcidin, a liver-produced peptide, has recently been identified as a negative regulator of iron absorption in various conditions associated with altered iron metabolism (e.g. inflammation, anaemia, hypoxia). It is not clear whether these perturbants share a common signalling pathway. In this study, the importance of the cytokine interleukin-6 (IL-6) was investigated in the hypoxic mouse model. Hypoxia was associated with increased levels of circulating IL-6, decreased liver hepcidin mRNA and increased iron absorption (especially MT). A significant positive correlation existed between the total iron uptake and IL-6 levels in circulation. IL-6 per se, though inducing hepcidin mRNA, failed to affect basal iron absorption. The adaptive response to absorption following the hypoxic exposure was, however, more prominent if mice had been treated concurrently with IL-6. This enhancement in absorption occurred even though hepcidin mRNA was not significantly changed. Similar prominent responses were seen with both human and mouse IL-6. Anti-IL-6 antiserum normalised iron absorption in mice exposed to hypoxia, because of a reduction in the MT. These data indicate that IL-6 can influence iron absorption (especially MT) during the hypoxic exposure, but via a mechanism independent of hepcidin.
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PMID:Role of interleukin-6 in hypoxic regulation of intestinal iron absorption. 1635 43

Hepcidin, a small peptide synthesized in the liver, controls extracellular iron by regulating its intestinal absorption, placental transport, recycling by macrophages, and release from stores. Hepcidin inhibits the cellular efflux of iron by binding to and inducing the degradation of ferroportin, the sole iron exporter in iron-transporting cells. In turn, hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Hepcidin is markedly induced during inflammation, trapping iron in macrophages, decreasing plasma iron concentrations, and contributing to the anemia of inflammation. Hepcidin deficiency due to the dysregulation of its synthesis causes most known forms of hemochromatosis.
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PMID:Iron imports. IV. Hepcidin and regulation of body iron metabolism. 1640 89

Anemia of chronic disease (ACD) is frequently found in patients with chronic immune activation. Since most studies on ACD pathophysiology were performed with cell culture or animal models but not in humans, we examined 37 ACD patients suffering from autoimmune diseases or infections, 10 subjects with iron-deficiency anemia (IDA), 10 anemic patients with hereditary spherocytosis (HS), and 27 age-matched controls. Although hemoglobin concentrations were comparable between ACD and IDA patients, the latter presented with significantly higher serum erythropoietin concentrations than ACD patients. The significant negative correlation between erythropoietin and hemoglobin levels observed in IDA patients was also found in a group of anemic but not hypoferremic hereditary spherocytosis subjects, but not in ACD patients. Increased serum concentrations of the hepcidin precursor prohepcidin were paralleled by a decreased expression of the iron exporter ferroportin in circulating monocytes of ACD patients. In the latter cells, increased amounts of the iron storage protein ferritin and a reduced activity of iron-regulatory protein indicated monocyte iron accumulation. Our data indicate that hypoferremia in ACD may result from downregulation of ferroportin expression by hepcidin and cytokines with subsequent iron retention in monocytes. Together with a diminished erythropoietin formation, the impaired iron recirculation from monocytes may be central in the pathophysiology of ACD in humans.
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PMID:Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. 1643 84

Hepcidin, a key regulator of iron metabolism, decreases intestinal absorption of iron and its release from macrophages. Iron, anemia, hypoxia, and inflammation were reported to influence hepcidin expression. To investigate regulation of the expression of hepcidin and other iron-related genes, we manipulated erythropoietic activity in mice. Erythropoiesis was inhibited by irradiation or posttransfusion polycythemia and stimulated by phenylhydrazine administration and erythropoietin. Gene expression of hepcidin and other iron-related genes (hemojuvelin, DMT1, ferroportin, transferrin receptors, ferritin) in the liver was measured by the real-time polymerase chain reaction. Hepcidin expression increased despite severe anemia when hematopoiesis was inhibited by irradiation. Suppression of erythropoiesis by posttransfusion polycythemia or irradiation also increased hepcidin mRNA levels. Compensated hemolysis induced by repeated phenylhydrazine administration did not change hepcidin expression. The decrease caused by exogenous erythropoeitin was blocked by postirradiation bone marrow suppression. The hemolysis and anemia decrease hepcidin expression only when erythropoiesis is functional; on the other hand, if erythropoiesis is blocked, even severe anemia does not lead to a decrease of hepcidin expression, which is indeed increased. We propose that hepcidin is exclusively sensitive to iron utilization for erythropoiesis and hepatocyte iron balance, and these changes are not sensed by other genes involved in the control of iron metabolism in the liver.
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PMID:Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. 1649 4

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
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PMID:Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. 1703 97


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