Systemic iron delivery is mediated by the basolateral iron exporter ferroportin. A major source of daily iron is provided by iron recycling macrophages. Red blood cells are lysed, and iron is released from hemoglobin by heme oxygenase Iron can then be stored in ferritin and exported to the bloodstream by ferroportin via a similar process described above for duodenal enterocytes.
Ferroportin, the only known mammalian iron exporter, therefore functions as a major gatekeeper controlling iron entry into the bloodstream. Transferrin-bound iron is the main form of iron present in the bloodstream under normal conditions. Transferrin can carry up to 2 iron molecules and maintains iron in a redox inert state. Transferrin delivers iron to tissues for uptake by the ubiquitously expressed transferrin receptor 1 TFR1.
Circulating ferritin mainly originates from macrophages 27 and generally correlates with body iron stores, although its levels can also be influenced by inflammation, infection, liver disease, and malignancy among other conditions. Additional circulating carriers of iron include the heme and hemoglobin scavengers hemopexin and haptoglobin. Circulating iron is delivered to erythrocytes and other cells in the body via specific uptake mechanisms Figure 2. Iron then enters the so-called chelatable or labile-iron pool and is either utilized directly, trafficked to the mitochondria for incorporation into the heme or iron sulfur cluster synthesis pathways, stored in an inert form in cytosolic or mitochondrial ferritin as described above, or exported out of the cell.
Intracellular trafficking and transport across the mitochondrial membranes requires additional specialized proteins including the cytosolic iron chaperone poly rC binding proteins 30 , the mitochondrial chaperone frataxin 31 , and mitochondrial iron and heme transporters such as mitoferrins 32 and feline leukemia virus type C receptor 1B FLVCR1B.
Iron enters into cells primarily by transferrin receptor 1 TFR1 -mediated endocytosis. TF and TFR1 are recycled back to the cell membrane for further cycles. In the cytosol, iron enters the labile iron pool LIP , and is then utilized, stored, or exported out of the cell. Cytoplasmic iron transport is assisted in some cases by the chaperone poly rC binding protein 1 PCBP1.
Excess iron in the cytosol is stored safely in ferritin. A mitochondrial form of ferritin MTFT is also expressed in some cell types. When the demand arises, ferritin can be targeted for autophagic turnover by nuclear receptor coactivator 4 NCOA4 to release iron into the cytosolic LIP. Since IRPs target proteins that are also key mediators of systemic iron homeostasis, IRPs may also influence systemic iron balance.
This leads to an increase in iron uptake and a decrease in iron storage and export. At the systemic level, the iron hormone hepcidin is a major regulator of body iron balance Figure 4 5. Hepcidin controls iron entry into circulation from absorptive enterocytes, iron recycling macrophages, and hepatocytes by binding to ferroportin and inducing its internalization and degradation in lysosomes.
In contrast, lowering hepcidin levels promotes iron availability. Secreted by the liver, hepcidin is a key iron hormone controls iron entry into circulation from absorptive enterocytes and iron-recycling macrophages by inducing FPN degradation. Iron loading and inflammation stimulate hepcidin transcription to prevent iron overload and sequester iron from pathogenic microorganisms left panel.
Iron deficiency and erythropoietic drive inhibit hepcidin transcription to provide adequate iron for erythropoiesis and other body requirements right panel. Mediators of hepcidin regulation by iron, inflammation, and erythropoietic drive are indicated. The liver is the major source of circulating hepcidin that regulates systemic iron balance. In particular, iron loading stimulates hepcidin expression, whereas iron deficiency inhibits hepcidin as a feedback mechanism to maintain normal body iron levels. Enhancers of erythropoietic drive, such as anemia, erythropoietin administration, and hypoxia suppress hepcidin expression to increase the availability of iron for red blood cell production.
Inflammatory cytokines stimulate hepcidin expression to limit the supply of iron to pathogenic microorganisms in the context of infection, but this also leads to hypoferremia and iron restricted erythropoiesis in chronic inflammatory diseases including CKD. Given the essential functions of iron but the toxicity associated with iron excess, abnormalities in iron homeostasis are associated with a number of diseases. The most widely recognized clinical manifestation of iron deficiency is anemia. Iron deficiency can be due to insufficient dietary iron absorption to meet the body iron needs from nutritional deficiency, malabsorption e.
In addition to true iron deficiency, where total body iron levels are reduced, anemia can also be caused by functional iron deficiency, characterized by reduced levels of circulating iron that limit erythropoiesis despite adequate or high stores of total body iron. This is a characteristic feature of anemia of chronic disease or anemia of inflammation associated with a number of chronic diseases including autoimmune disorders, malignancy, and CKD.
Hepcidin excess and functional iron deficiency in CKD can also be influenced by reduced renal clearance of this small peptide hormone. More rarely, iron deficiency anemia can be a consequence of mutations in genes involved in duodenal iron uptake, iron mobilization from body stores, or erythroid iron uptake or utilization, including DMT1 SLC11A2 , ceruloplasmin CP , transferrin TF. Mutations in the hepcidin regulatory gene, TMPRSS6 , lead to iron refractory iron deficiency anemia due to inability to suppress hepcidin production in the liver Figure 4.
Major causes of systemic iron overload are hereditary hemochromatosis, iron loading anemias thalassemias, congenital dyserythropoietic anemias, sideroblastic anemias, myelodysplastic syndromes , and transfusional or other secondary forms of iron overload. Hereditary hemochromatosis is due to mutations in genes encoding hepcidin itself HAMP or mutations in the genes that are the major inducers of hepcidin expression in response to iron: Mutations in the hepcidin-binding site of ferroportin that render it resistant to hepcidin-mediated degradation cause a similar phenotype.
Iron loading anemias are disorders characterized by ineffective erythropoiesis, resulting in hepcidin suppression, dietary hyperabsoprtion of iron and secondary iron overload. This stimulates erythropoietin production and expansion of immature erythroid precursors, but erythropoiesis remains ineffective and anemia persists.
The expanded erythroid precursor population secretes an excess of the erythroid regulator s that normally suppress hepcidin to increase iron availability for red blood cell production, thereby resulting in excessive iron absorption and iron overload.
One such erythroid regulator of hepcidin was recently identified as erythroferrone Figure 4. Transfusional iron overload was previously common in the dialysis patient population before the advent of treatment with erythropoiesis stimulating agents. In the wake of studies raising safety concerns for ESAs when used to target higher hemoglobin levels and changes for dialysis reimbursement, intravenous iron supplementation transiently increased and average ferritin levels remain persistently higher in dialysis patients in the United States.
The liver is a main storage depot for iron and is the primary organ that clears excess circulating NTBI in conditions of iron overload. In secondary iron overload where hepcidin is upregulated and ferroportin expression is reduced, iron accumulates in adipocytes and contributes to insulin resistance by reducing production of the insulin-sensitizing hormone adiponectin. Iron accumulation is associated with cardiomyopathy, which is a major cause of morbidity and mortality in these patients.
Iron deficiency also has adverse consequences on the heart, an organ with high energy demands. An unresolved question is whether iron also has a role in promoting atherosclerosis, which was originally postulated over 30 years ago. Large prospective randomized trials are awaited to provide further clarification. In aceruloplasminemia, the loss of ceruloplasmin ferroxidase activity impairs astrocyte iron export and incorporation into extracellular transferrin for uptake by neurons.
This leads to a combination of oxidative damage from iron overload in astrocytes and possibly also toxicity from neuronal iron deficiency. APP has been reported to stabilize the iron exporter ferroportin to facilitate iron egress from neurons. Second, cancer cells have an enhanced dependence on iron to maintain their rapid growth rate.
Interestingly, multiple cancer cell types exhibit altered expression of iron homeostasis proteins that favor iron accumulation, including increased expression of TFR1 to increase iron uptake , decreased expression of ferroportin to reduce iron export , and increased hepcidin production for autocrine downregulaton ferroportin expression to reduce iron export.
For example, in breast cancer, low tumor expression of ferroportin is associated with metastatic progression and reduced survival, while high tumor expression of ferroportin and low expression of hepcidin predicts a favorable prognosis. Iron and iron-induced reactive oxygen species have been implicated in the pathogenesis of multiple models of acute kidney injury AKI. More recently, a specific iron-dependent type of regulated cell death due to lipid peroxide accumulation, termed ferroptosis, has been identified and is implicated the pathogenesis of renal ischemia-reperfusion injury.
Pathogenic microorganisms, like humans, require iron for survival and proliferation, and have evolved a number of mechanisms for obtaining iron from their human hosts. It has been hypothesized that one function of the hepcidin-ferroportin system in humans is to restrict iron availability in the context of infection by sequestering iron in macrophages and reducing circulating iron levels. For example, intracellular organisms that resides in macrophages, such as Salmonella , may have increased pathogenicity in this context.
CKD patients are prone to iron deficiency anemia and functional iron deficiency as a consequence of hepcidin excess, and intravenous iron administration is a mainstay of anemia management in this patient population. Although both iron deficiency and iron excess are associated with numerous adverse health consequences in many different organ systems, data are limited to understand the optimal iron treatment strategy for CKD patients.
There are many key areas for future research. We need better diagnostic parameters for accurately gauging iron status and a better understanding of the risks versus benefits of intravenous iron administration, differences among available iron preparations, and optimal dosing regimens and treatment targets for iron administration. Fundamental research, animal studies, and larger prospective randomized controlled trials in human patients with hard clinical outcomes are needed to improve our knowledge and evidence based practice moving forward.
SD has nothing to declare. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jun 1. Som Dev and Jodie L. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Hemodial Int. See other articles in PMC that cite the published article. Abstract Iron is an essential element for numerous fundamental biologic processes, but excess iron is toxic. This is why the knowledge of the iron content of various aliments as well as of the factors influencing its absorption should be improved [ 74 ].
Finally, from a hematologist point of view, universal iron fortification of the food may be problematic, notably for individuals with hemochromatosis and other iron loading diseases [ 75 ]. Even if iron fortification of food has been recognized by some authors as a suitable strategy to combat iron deficiency, some health authorities have abandoned it. Readers interested in iron fortification, iron food, and other deviancies are referred to the recent reviews published in [ 67 , 76 ]. Iron absorption is the result of complex mechanisms that takes place in the upper parts of the gut, notably in the duodenum and the proximal jejunum [ 16 , 77 ] fig.
Regulation of iron absorption and exportation by enterocytes. Both heme and non-heme iron are absorbed by specific pathways, including divalent metal transporter-1 DMT-1 and heme carrier protein HCP1 , in association with the ferrireductase, duodenal cytochrome B Dcytb. Within the cell, iron can be stored within the ferritin molecule. The metal is exported by the protein ferroportin FPN1 , and transported into the blood by transferrin.
In presence of hepcidin, ferroportin is internalized and degradated. Thus, iron exportation is blocked. Inversely, in the absence of hepcidin, ferroportin is maintained on the cell membrane, and iron transportation is facilitated illustrations used elements from Servier Medical Art: Non-heme iron is associated with various storage proteins, including ferritin, whereas heminic iron is present within hemoproteins such as Mb or Hb.
It is important to note that non-heme iron is captured by several complexes which can interfere with its absorption, notably plant-derived phytates or tannins [ 78 ]. Ascorbic acid and other acidic components derived from the diet can increase iron absorption. Nevertheless, it is known that different pathways exist for the absorption of non-heme iron and heme iron. The distinction is of potential interest, because it has been shown that high heme iron intake leads to increased body iron stores which are significantly associated with higher risk to develop type 2 diabetes mellitus [ 79 ].
Hepcidin in the diagnosis of iron disorders
In contrast, total dietary iron, non-heme iron, and intake of iron supplements were not associated with type 2 diabetes mellitus. Several well regulated gate keeper proteins are expressed in the duodenum enterocytes and are differently regulated as compared to the same proteins in liver cells. Of note, ferric reductase activities due to duodenal cytochrome B [ 82 ] and STEAPs six transmembrane epithelial antigen of the prostate proteins [ 83 ] are present on the brush border of duodenum allowing reduction of ferric to ferrous iron, thus facilitating its absorption by DMT1.
Heme iron is an important nutritional source of iron in carnivores and omnivores that is more readily absorbed than non-heme iron derived from vegetables and grain. Most heme is absorbed in the proximal intestine, with absorptive capacity decreasing distally, and the role of specific proteins such as hephaestin has been deciphered [ 84 , 85 ]. HCP1, which presents homology to bacterial metal-tetracycline transporters, mediates heme uptake by the cells at the luminal brush border membrane of duodenal enterocytes. Once iron is present in the enterocyte, its fate de pends on the iron pool within the cell.
Iron has to be exported from cells to the circulation, and a specific protein, FPN1, has been identified in this function. FPN1 is a multipass protein found in the basolateral membrane of the enterocytes. Furthermore, FPN1 is the unique iron export membrane protein that is present in large quantities on macrophages. Over-expression of FPN1 is induced by cellular iron, and it is suppressed by hepcidin. Hepcidin binds to cell surface FPN1 inducing its internalization which is followed by lysosomal degradation [ 21 ]. Thus, as a consequence, the iron efflux from enterocytes or macrophages is suppressed, leading to reduced iron absorption by duodenal enterocytes.
Deletion of the FPN1 gene results in a complete block of iron exportation associated with accumulation of the metal within enterocytes and macrophages [ 86 ].
Overview of Iron Metabolism in Health and Disease
Without activity of ferroxidases, FPN1 is internalized and degraded [ 87 , 88 ]. Thus, the ferroxidases at the cell surface mediate stability of FPN1. In humans with aceruloplasminemia, anemia is associated with impaired cellular iron export [ 89 ]. As previously mentioned, HCP1, which is also a ferroxidase, has also an important role during iron export from intestinal enterocytes and its subsequent loading to Tf. Structurally, the ectodomain of HCP1 resemble Cp [ 90 ]. Tf is the main protein involved in iron transport in plasma.
The diagnostic value of Tf has just been reviewed [ 91 ]. It proved to be a useful parameter for assessing both iron deficiency and iron overload. The saturation of Tf is a strong indicator of iron overload. However, from a physiological point of view, the iron binding capacity of plasma Tf is often exhausted, with concomitant generation of non-Tf-bound iron NTBI as observed in transfused patients.
Physiology of Iron Metabolism
Using fluorescent tracing of labile iron in endosomal vesicles and cytosol, Kloss-Brandstatter et al. Erythrocyte precursors restrictively take up iron by using Tfr, notably Tfr1, whereas hepatocytes and other non-erythroid cells are also able to use NTBI. Iron-Tf binds to Tfr, and the complexes are internalized within the cell by the endosomal recycling vesicles. Thus, the Tf cycle is dependent on the Tf-Tfr complex trafficking, involving internalization of the complex within endosome, followed by iron release upon acidification of the endosome and recycling of the Tf-Tfr complex to the cell surface.
Each of these steps is mediated by a specific pathway and specific machinery [ 93 , 94 , 95 ]. Finally, at the cell surface, at neutral pH, Tf dissociates from Tfr, and is used to repeat the iron cycle. In addition, Tfr is cleaved and shed as a soluble form sTfr into the extracellular and intravascular space. This shedding of Tfr1 is known for more than 30 years, and its assessment is well accepted as a diagnostic marker of iron-depleted erythropoiesis [ 96 , 97 , 98 ].
Very recently, the cleavage site as well as the cleaving proteases of membrane Tfr1 have been identified [ 99 ]. Only ferric iron is transported to the cytoplasm or to mitochondria. It is therefore mandatory to reduce ferrous irons; a family of ferrireductase has been identified.
DMT1 is also an essential protein involved in iron transportation from vacuole into the cytoplasm [ ]. In macrophages, another protein Nramp1 is involved [ , ]. Due to its toxicity, iron within the cytoplasm is associated with proteins such as poly RC -binding protein 1 [ ], functioning as cytosolic iron chaperone in the delivery of iron to ferritin.
Within the ferritin molecule, iron is stored in the ferric form associated with hydroxide and phosphate anions [ ]. Each ferritin molecule can sequester up to approximately 4, iron atoms. Ferritin also has enzymatic properties, converting ferric to ferrous iron, as iron is internalized and sequestered in the ferritin mineral core. Small quantities of ferritin are also present in human serum and are elevated in conditions of iron overload and inflammation.
De Domenico et al. An interesting observation was made by Mikhael et al. For decades, serum ferritin has been used for assessing iron disorders, and its value as a marker of body iron has been recently reviewed [ ]. Several genetic alteration of ferritin genes have been reported [ ], notably in association with a specific neurological disease [ ]. Erythroid precursors need much more iron than any other type of cells in the body, and, as previously mentioned, they take up iron almost exclusively through Tfr1.
Iron transport into mitochondria is provided by mitoferrin-1, the mitochondrial iron transporter 1 of erythroid precurors [ ]. Mitoferrin-1 interacts with an ATP-binding transporter and binds to ferrochelatase to form an oligomeric complex [ ], allowing iron uptake and heme biosynthesis. Erythroid cells contain adaptative mechanisms to face iron deficiency and a class of kinases activated by different cellular stresses.
HRI-deficient mice have allowed identifying HRI as a protector of apoptosis and being involved in the formation of microcytes. Several groups reported on the genetic polymorphism of the proteins involved in iron homeostasis, but not related to iron deficiency or overload [ , , ]. Genetic analysis of iron deficiency in mice has been evaluated [ ]. This study revealed that polymorphisms in multiple genes cause individual variations in iron regulation, especially in response to dietary iron challenge.
In humans, genome-wide association studies found linkage of various gene polymorphism single nucleotide polymorphism; SNP and iron status, notably polymorphism of the gene coding for Mt2 [ 56 , , , , ]. Other investigators showed an association between Mt2 polymorphism and the risk to develop type 2 diabetes [ 52 ]. The authors observed that individuals homozygous for iron-lowering alleles of Mt2 had a reduced risk of iron overload and of type 2 diabetes.
In a genome-wide association study looking at heme iron uptake polymorphisms, no significant association with type 2 diabetes and iron metabolic pathways were identified [ ]. In an analysis of several genes modulating iron status, Pelucchi et al. Iron is a key player in hemoglobin synthesis an erythrocyte production. At the same time, it is a potent poison to mammalian cells and an indispensable nutrient for many disease-causing germs and microbes. Therefore, its metabolism in mammalians is very complex and stringently controlled by many different genes and proteins.
Identification of the genes and their polymorphic alleles may shed light into the metabolic interplay of relevant proteins. BF also received research grants from Vifor Pharma. National Center for Biotechnology Information , U. Journal List Transfus Med Hemother v. Published online May Author information Article notes Copyright and License information Disclaimer. Received Oct 8; Accepted Dec 4. This article has been cited by other articles in PMC.
Summary A revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. Iron, Metabolism, Transfusion medicine. Introduction Various tests have been developed to evaluate iron metabolism and iron stores, and nowadays bone marrow examination has been replaced by the measurement of blood ferritin [ 1 ]. Iron Metabolism and Proteins The physiology of iron trafficking and metabolism has been well evaluated over the last 20 years, and several comprehensive reviews have been published on the subject [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ].
Open in a separate window. Iron Regulatory Proteins Iron is present in many different types of cells, having specific functions such as iron supply or iron storage. Iron in the Body Males contain about 4, mg of iron, of which 2, mg are within erythrocytes; 1, mg is stored in splenic and hepatic macrophages, and the rest is distributed in various proteins such as Mb, cytochromes, or other ferroproteins.
Iron in the Food; Unusual Aspects Iron is the most abundant element on earth, with potential of high toxicity to living cells. Intestinal Iron Exportation Once iron is present in the enterocyte, its fate de pends on the iron pool within the cell. Iron Transportation in Blood and Import Tf is the main protein involved in iron transport in plasma.
Intracellular Iron Storage Only ferric iron is transported to the cytoplasm or to mitochondria. HRG1 solute carrier family 48 [heme transporter], member 1; amino acids; HRG1 may also be functional in enterocytes. Illustration of splenic macrophages phagocytizing damaged red blood cells RBCs. Similar to erythrocytes, divalent metal ion transporter—1 DMT1 is internalized concurrent with this process. With digestion of the RBC, heme is released.
Ferrous iron that exits the cell via ferroportin is oxidized to ferric iron for loading onto transferrin via the action of ceruloplasmin. Just as in enterocytes, ferrous iron can be stored as ferric iron within ferritin or hemosiderin, or ferrous iron can be exported outside the macrophage by ferroportin. Also, similar to enterocytes, hepcidin regulates ferroportin expression in macrophages; increased hepcidin leads to increased internalization and degradation of ferroportin with reduced iron export from the macrophage to transferrin. One difference between iron transport in enterocytes and macrophages is that in the spleen the oxidation of ferrous iron to ferric iron to load iron from macrophages onto transferrin is accomplished by the plasma protein ceruloplasmin, which is a ferrioxidase.
Ceruloplasmin amino acids; Copper is transported in the plasma by albumin and transcuprein. Overall, transferrin-bound ferric iron from the splenic macrophages is delivered back to the bone marrow for erythropoiesis. Hepatic cells monitor several aspects of TBI. Hepatocytes regulate iron absorption and recycling via their production and secretion of hepcidin. When hepcidin binds to ferroportin, iron release from cells expressing ferroportin as the iron transport protein eg, duodenal enterocytes [the major site of iron absorption] and splenic macrophages is impaired as ferroportin is internalized and degraded Figure The nascent 84 amino acid 9.
In the 20— and 25—amino-acid sequences, there are 4 disulfide bonds 66—82; 69—72; 70—78; and 73— A 22—amino-acid sequence has also been reported. Only the 25—amino-acid form is bioactive; it is present in picomolar concentrations in the plasma. Measurement of hepcidin has been challenging; clinically robust assays are not yet available. Line drawing of the currently understood tertiary structure of hepcidin.
Hepcidin binds to ferroportin to initiate the internalization and metabolism of ferroportin. Consequently, cellular release of iron is reduced. There are 4 major mechanisms regulating hepcidin secretion: With sterile or nonsterile injury, macrophages act as sentinel cells and detect pathogen-associated molecular patterns PAMPs and danger- or damage- associated molecular patterns DAMPs via pattern-recognition receptors PRRs such as toll-like receptors TLRs , chemokine receptors, integrins, the inflammasome, and various other receptors.
IL-6 binding to the hepatic IL-6 receptor IL-6R increases hepcidin release and lowers the concentration of plasma ferric iron that is normally transported by transferrin. Hepatic uptake of iron and iron sensing are afforded by TfR1 and transferrin receptor 2 TfR2; Figure If there is a higher level of transferrin saturation by ferric iron, this is detected by TfR1 and HFE, which correspondingly increase hepcidin concentrations; this reduces iron absorption from the gut and iron recycling from splenic macrophages.
Depiction of how hepatocytes monitor transferrin saturation via transferrin receptor 1 TfR1 and transferrin receptor 2 TfR2. HFE is involved in this process. Mutations in HFE cause classic type 1 hemochromatosis; a lack of perception of transferrin saturation causes hepcidin deficiency and excess absorption of dietary iron, leading to TBI overload. Mutations in TfR2 type 3 hemochromatosis produce iron overload clinically similar to type 1 hemochromatosis.
As cellular iron increases, bone morphogenetic protein 6 BMP-6 is secreted Figure HJV is a —amino acid protein Depiction of hepatocyte monitoring of tissue iron content. This process is afforded by the secretion of bone morphogenetic protein 6 BMP Hemojuvelin HJV is involved in this signaling process.
Mutations in hemojuvelin and hepcidin cause hemochromatosis in children eg, type 2 [juvenile] hemochromatosis. The erythropoietic activity of the bone marrow influences the liver and regulates hepcidin release. Ultimately, more transferrin-bound ferric iron is made available to erythroblasts.
Signals that may suppress hepatic hepcidin release include growth differentiation factor—15 GDF and twisted gastrulation protein homolog 1 TWSG1 , both of which are secreted by the bone marrow with increased erythropoiesis. This mechanism explains cases of acquired iron overload in various types of anemia in the absence of chronic transfusion therapy.
Examples of nontransfusion iron overload anemias include thalassemia, X-linked sideroblastic anemia, sickle-cell anemia, pyruvate kinase deficiency, hereditary spherocytosis, and congenital dyserythropoietic anemia. Just as enterocytes and renal peritubular cells monitor their cellular oxygen tension, hepatocytes also monitor intracellular hepatocyte oxygen tension. Hypoxia allows HIFs to increase the expression of a membrane protease namely, matriptase-2 that cleaves hemojuvelin, reducing BMP-6R signaling.
HIFs also increase furin, a proprotein convertase that cleaves hemojuvelin, releasing a hemojuvelin decoy receptor for BMP Maltriptase-2 a transmembrane protease, serine 6 is encoded on chromosome 22q1, consists of amino acids, and has a molecular weight of 90 kDa.
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In the secretory pathway within cells, the proteolytic maturation of proprotein substrates is catalyzed by furin. Low transferrin saturation, hepatocyte oxygen tension, and hepatocyte tissue iron content, along with increased erythropoietic activity, reduce hepcidin concentrations in the plasma, permitting increased iron absorption from the gut and increased iron recycling from splenic macrophages Table 1 , Figure In non—transfusion induced iron overload, a deficiency of hepcidin causes pathologic iron overload from hyperabsorption of iron.
The opposite events namely, increased transferrin saturation, increased hepatocyte oxygen tension, increased hepatocyte tissue iron content, and decreased erythropoietic activity increase hepcidin levels, leading to decreased iron absorption from the gut and decreased iron recycling from splenic macrophages Table 1 , Figure A pathologic excess of hepcidin causes deficient iron absorption from the gut, impaired release of iron from splenic macrophages, and iron-restricted anemia. Hepcidin deficiency allows excess iron absorption; therefore, nature has selected iron excess over iron deficiency, most likely because iron is not abundant in the human diet.
Nutritional iron deficiency is common worldwide. Depiction of iron cycling and hepcidin deficiency with decreased plasma hepcidin concentrations. A , The normal state of iron cycling. B , hepcidin deficiency. Decreased plasma hepcidin concentrations permit hyperabsorption of iron and iron overload. Depiction of iron cycling and hepcidin deficiency with increased plasma hepcidin concentrations.
B , Hepcidin excess. Increased plasma hepcidin concentrations impair iron availability to the bone marrow, causing iron-restricted anemia. Although the pathophysiologic nature of iron overload is beyond the scope of this review, 39 , 40 iron homeostasis is important to understand the range of disorders that involve iron deficiency or iron excess. Factors that reduce hepcidin, including essentially any form of chronic liver disease, can lead to the hyperabsorption of iron and to iron overload. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Close mobile search navigation Article navigation. Cells of the Iron Circuit. Abstract Iron is one of the most important nonorganic substances that make life possible. View large Download slide.
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