Regulation Of Iron Absorption Research Articles

Intestinal Iron Absorption: Regulation by Dietary & Systemic Factors

Iron is an essential trace metal in human metabolism. However, imbalances in iron homeostasis are prevalent worldwide and have detrimental effects on human health. Humans do not have the ability to remove excess iron and therefore iron homeostasis is maintained by regulating the amount of iron entering the body from the diet. Iron is present in the human diet in number of different forms, including heme (from meat) and a variety of non-heme iron compounds. While heme is absorbed intact, the bioavailability of non-heme iron varies greatly depending on dietary composition. A number of dietary components are capable of interacting with iron to regulate its solubility and oxidation state. Interestingly, there is an emerging body of evidence suggesting that some nutrients also have direct effects on the expression and function of enterocyte iron transporters. In addition to dietary factors, body iron status is a major determinant of iron absorption. The roles of these important dietary and systemic factors in regulating iron absorption will be discussed in this review.

Hepcidin and Hfe in iron overload in β‐thalassemia

Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with beta-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in beta-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in beta-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries.

Advancements in anemias related to chronic conditions

Anemia of chronic disease (ACD), the most frequent anemia among hospitalized patients, occurs in chronic inflammatory disorders, such as chronic infections, cancer and autoimmune diseases. Different causes contribute to ACD including diversion of iron traffic, diminished erythropoiesis, blunted response to erythropoietin, erythrophagocytosis, hematologic malignancies and solid tumors. A particular case of ACD is represented by anemia of chronic kidney disease (CKD). ACD is characterized by hyposideremia and altered iron transport. Cytokines are implicated in the ACD by reducing erythropoiesis and increasing iron sequestration in the reticuloendothelial system. The regulation of iron absorption across the epithelium of the proximal small intestine is essential for maintaining body iron concentrations within a physiologically defined range. Hepcidin controls cellular iron efflux by binding to the iron export protein ferroportin, causing ferroportin to be phosphorylated and degraded in lysosomes. Finally, hepcidin inhibits iron release from the reticulo-endothelial system. Increased expression of hepcidin leads to decreased iron absorption and iron deficient anemia. Hepcidin, therefore, is a negative regulator of iron transport in plasma. Causes of anemia in patients with CKD are multifactorial, but the most well-known cause is inadequate erythropoietin production. In these patients, anemia increases the risk of either cardiovascular disease or renal failure.

Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable‐isotope appearance curves, increases plasma hepcidin

Plasma hepcidin appears to be a major regulator of iron absorption and homeostasis, but there are few data in humans.We aimed to see if circulating hepcidin predicted iron bioavailability and to measure the plasma hepcidin response to varying amounts of absorbed iron.In study 1, women (n = 98) with serum ferritin concentrations < 25 or > 40 μg/L were given stable isotope–labeled meals with ferrous sulfate (FeSO4), ferrous fumarate (FeC4H2O4), or ferric pyrophosphate (FePPi). Then, plasma hepcidin and iron absorption were measured. In study 2, iron‐sufficient men (n = 4) were given oral doses of 3.8 mg and 60 mg iron as labeled FeSO4. The stable isotope appearance and the plasma hepcidin curve were measured over 6 h.In study 1, plasma hepcidin and ferritin strongly correlated (r = 0.79, P < 0.001). Plasma hepcidin significantly, but modestly, predicted iron bioavailability from FeSO4 and FeC4H2O4 (r = 20.51 and 20.46, respectively; P < 0.0001) but not from FePPi (r = 20.30, P = 0.056). In study 2, the 3.8 mg dose increased circulating absorbed iron to 0.42 μmol/L but did not increase plasma hepcidin. The 60 mg dose increased mean circulating absorbed iron to 5.9 μmol/L and produced a ~30% increase in plasma hepcidin at 6 h (P < 0.01).Plasma hepcidin is only a modest predictor of dietary iron bioavailability. Oral iron loading increases circulating hepcidin.The ETHZ and DSM Nutritional Products financially supported this study.

Divalent Metal‐Dependent Regulation of Hepcidin Expression by MTF‐1

There appears to be cross‐talk between metal ions and their acquisition pathways. In particular, zinc and iron reciprocally inhibit each other's uptake. Hepcidin, a small acute phase and antimicrobial peptide, is the principle regulator of iron absorption. This peptide is induced by inflammation and infection, but is repressed by anaemia and hypoxia, suggesting a complex array of regulatory pathways underlying its expression. Here we further reveal that it also appears to be a sensor of other divalent metal ions, principally zinc and cadmium. Using 1.8kb of the human hepcidin promoter tagged with luciferase as a reporter, we show that hepcidin transcription can be significantly modulated by zinc and cadmium levels. This process is entirely dependent on functional metal response elements (MREs) that recruit the MRE‐binding transcription factor MTF‐1 to the promoter, as ascertained by site‐directed mutagenesis. Analysis of hepcidin expression both at the mRNA and protein levels in hepatoma cells suggests that its induction by zinc is rapid; paradoxically, cobalt and iron significantly decreased its mRNA levels. Taken together, these data show that hepcidin may be a pleiotropic sensor of divalent metals some of which are xenobiotic environmental toxins.

Decreased Prohepcidin Levels in Patients with HBV-Related Liver Disease: Relation with Ferritin Levels

Levels of prohepcidin, a homeostatic regulator of iron absorption, are altered in chronic hepatitis C and liver cirrhosis. However, data on the potential alterations of prohepcidin in patients with HBV-related liver disease are scarce. We investigated whether serum prohepcidin is related to iron overload and perenchymal dysfuction in HBV-related liver disease. Three groups of subjects were studied: 66 patients with chronic hepatitis B, 32 patients with HBV-related cirrhosis, and 42 healthy controls without evidence of liver disease. Serum levels of prohepcidin were determined by enzyme-linked immunosorbent assay. Serum prohepcidin levels were significantly lower in patients with HBV-related cirrhosis (175.85 ± 71.5 ng/ml) than in patients with chronic hepatitis B (209.02 ± 62.7 ng/ml P < 0.05) and controls (222.4 ± 128.4 ng/ml, P < 0.05). After adjustment for potential confounders, prohepcidin was found to be an independent predictor of ferritin levels in multiple linear regression analysis (β = -1.10, t = -3.11, P < 0.01). These results demonstrate that prohepcidin levels are reduced in patients with HBV-related cirrhosis and are an independent correlate of serum ferritin.

Regulatory mechanisms of intestinal iron absorption—Uncovering of a fast‐response mechanism based on DMT1 and ferroportin endocytosis

Knowledge on the intestinal iron transport process and the regulation of body iron stores has greatly increased during the last decade. The liver, through the sensing of circulating iron, is now recognized as the central organ in this regulation. High iron levels induce the synthesis of hepcidin, which in turn decreases circulating iron by inhibiting its recycling from macrophages and its absorption at the intestine. Another mechanism for the control of iron absorption by the enterocyte is an active Iron Responsive Element (IRE)/Iron Regulatory Protein (IRP) system. The IRE/IRP system regulates the expression of iron uptake and storage proteins thus regulating iron absorption. Similarly, increasing evidence points to the transcriptional regulation of both divalent metal transporter 1 (DMT1) and ferroportin expression. A new mechanism of regulation related to a phenomenon called the mucosal block is starting to be unveiled. The mucosal block describes the ability of an initial dose of ingested iron to block absorption of a second dose given 2-4 h later. Here, we review the mechanisms involved in the expression of DMT1 and ferroportin, and present recent evidence on the molecular components and cellular processes involved in the mucosal block response. Our studies indicate that mucosal block is a fast-response endocytic mechanism destined to decrease intestinal iron absorption during a high ingest of iron.

Crosstalk between Iron Metabolism and Erythropoiesis

Iron metabolism and erythropoiesis are inextricably linked. The majority of iron extracted from circulation daily is used for hemoglobin synthesis. In the last 15 years, major advances have been made in understanding the pathways regulating iron metabolism. Hepcidin is a key regulator of iron absorption and recycling and is itself regulated by erythropoiesis. While several viable candidates have been proposed, elucidating the “erythroid regulator” of hepcidin continues to generate significant experimental activity in the field. Although the mechanism responsible for sensing iron demand for erythropoiesis is still incompletely understood, evaluating diseases in which disordered erythropoiesis and/or iron metabolism are showcased has resulted in a more robust appreciation of potential candidates coordinated erythroid iron demand with regulators of iron supply. We present data drawn from four different conditions—iron deficiency, congenital hypotransferrinemia, beta-thalassemia, and hereditary hemochromatosis—both in human and non-human models of disease, together suggesting that erythroid iron demand exerts a stronger influence on circulating iron supply than systemic iron stores. Greater understanding of the interplay between the key factors involved in the regulation of iron metabolism and erythropoiesis will help develop more effective therapies for disorders of iron overload, iron deficiency, and hemoglobin synthesis.

Divalent metal-dependent regulation of hepcidin expression by MTF-1

Hepcidin is a small acute phase peptide that regulates iron absorption. It is induced by inflammation and infection, but is repressed by anaemia and hypoxia. Here we further reveal that hepcidin transcription also involves interactions between functional metal response elements (MREs) in its promoter, and the MRE-binding transcription factor-1. Analysis of hepcidin mRNA and protein levels in hepatoma cells suggests that its expression may be regulated by divalent metal ions, with zinc inducing maximal effects on hepcidin levels. These data suggest that this peptide may be a pleiotropic sensor of divalent metals, some of which are xenobiotic environmental toxins.

Iron Metabolism and Erythropoietic Stress in Myelodysplastic Syndromes.

Abstract 1752Poster Board I-778Iron overload (IO) occurs in a large proportion of patients affected by myelodysplastic syndromes; however data on the mechanisms responsible for IO and on the consequences on organ damages are scanty. IO in MDS may result both from ineffective erythropoiesis and from reiterative transfusions. The role of iron chelation therapy in MDS is deduced from thalassemia experience. We evaluated parameters of iron metabolism and erythropoiesis in 171 consecutive chelation naïve MDS patients. Patients were classified according WHO criteria, and prognostic scores evaluated according IPSS and WPSS criteria. CMML patients (n= 7) were also included in the analysis. Serum ferritin, iron, transferrin, transferrin saturation and non-transferrin-bound iron (NTBI) were measured. Growth-differentiation factor-15 (GDF-15) and hepcidin-25 were also determined, parallel to hemoglobin, endogenous erythropoietin (EPO) and LDH. All the parameters studied were highly variable within the analyzed cohort, as expected due to the great heterogeneity of MDS. As already observed, ferritin levels were higher than normal range in MDS patients (1091 ± 1135 ng/ml) and significantly increased in transfused ones (1890,55 ± 1833 ng/ml). EPO production was stimulated in all MDS patients (215, 40; range 85-1011 U/L), respect to normal range, and physiologically inversely correlated with hemoglobin levels (p<0.001). Serum EPO was lower in IPSS low risk patients than in IPSS high risk ones. Analysis of variance among different WHO subtypes indicated that RAEB-2 patients had the highest levels of EPO, 5q- patients had significantly increased levels of EPO (313; 67,7-836 U/L), while RARS and RA patients did not show significantly higher EPO than other WHO MDS subtypes. NTBI was found elevated in all MDS patients (0,35 ± 1,73 microM) respect to normal subjects (-0,72 ± 0,39 microM). NTBI levels did not correlate with disease duration, nor with patient age. NTBI was significantly elevated in RARS patients (2,37; -0,8-9,3 microM) compared to other WHO subtypes (0,123; -2,3 - 4,5 microM). An increasing trend was observed in MDS patients with high and very high WPSS score. Consistently, toxic iron was significantly increased in transfused MDS patients (1,214; -1,38-9,26 microM) vs non transfused ones (-0,052; -2,23 - 5,84 microM). GDF-15, a marker of erythropoietic stress, was significantly increased in MDS patients (9429; 302-87758 pg/ml) compared to normal subjects (450 ± 50 pg/ml). Transfused patients had higher GDF-15 values vs non-transfused patients (12458,0; 838-74717 pg/ml vs 6623,15; 302-43816 pg/ml respectively). GDF-15 levels did not correlate with disease duration, age, WHO subtypes, or IPSS and WPSS prognostic scores. A correlation between NTBI and: ferritin (p< 0.001), GDF-15 (p= 0.048) and transferrin saturation (p<0.001) was observed. Serum hepcidin-25, measured by mass spectrometry, was significantly elevated in IPSS low risk MDS patients (9,48; 1,06-38,35 nM) respect to normal (4,62 3.01–7.02 nM), with the exception of RARS patients, where hepcidin-25 was significantly lower (3,71 ± 1,33 nM) than normal, with high GDF-15 (8027,82 ± 7086,32 pg/ml). Hepcidin was found significantly increased in CMML, RAEB-1 and unclassifiable MDS patients (19,1 nM), while patients with RCMD had less high levels (8,27 ± 6,63 nM). Hepcidin levels did not show linear correlation with GDF-15, NTBI, and ferritin. LDH was not correlated with NTBI, GDF-15, hepcidin, EPO and ferritin. These observations indicate that in MDS patients iron homeostasis is altered although the clear relationship among the different players (hepcidin, GDF-15, EPO) is not yet fully understood. Many factors may be involved, including the intervention of pro-inflammatory cytokines as stimulators of hepcidin production in MDS, counterbalancing GDF-15 effect. The “ferrostat“ mechanism seemed to be maintained only in RARS patients who had the highest levels of NTBI and elevated GDF-15, with consequent repression of hepcidin production. Our results suggest that the regulation of iron absorption in MDS may be altered by the concomitant effect of several parameters acting at different rates in the various subtypes of dysplasia: GDF-15, induced by the expanded erythroid dysplastic compartment, but also EPO, hypoxia, generation of ROS and production of cytokines. The significance of each of these molecules needs to be further investigated. DisclosuresNo relevant conflicts of interest to declare.

A Comparison of Serum Hepcidin and GDF15 Expression in Cases of Iron Depletion Due to Blood Loss.

Abstract 4043Poster Board III-978Iron depletion affects billions worldwide, and anemia develops when iron stores become insufficient to maintain normal erythropoiesis. Hepcidin is a negative regulator of iron absorption in the body. Low serum hepcidin levels provide a physiological response to iron demand in patients with iron deficiency. Based on a recent discovery of elevated growth differentiation factor 15 (GDF15) as a pathological suppressor of hepcidin in cases of thalassemia (Tanno et al. 2007), it was hypothesized that GDF15 may be elevated under physiological circumstances such as iron deficiency, but this area of research remains controversial. Here GDF15 and hepcidin levels were measured in the peripheral blood of subjects with iron-depleted erythropoiesis, and monitored in patients receiving iron replacement therapy. Initially, clinical studies were performed to measure GDF15 in the serum of iron-depleted blood donors (n = 10) and healthy volunteers (n = 10). Iron depletion was defined for this study as serum ferritin level (<10 ng/ml) and transferrin saturation (<15%). When compared to the control group, hemoglobin and RBC counts were also significantly reduced (p< 0.01) among the iron-depleted group. Serum hepcidin levels were also significantly reduced in the iron-depleted group (<5 ng/ml) compared to healthy volunteers (46 ± 41 ng/ml, p < 0.01). However, the GDF15 levels were not elevated in the iron-depleted group. Instead, iron-depletion was associated with a slight decrease in serum GDF15 (304 ± 90 pg/ml) compared to that in the control group (386 ± 104 pg/ml, p = 0.084). In three additional patients with iron depletion due to menstrual blood loss, serum GDF15 and hepcidin levels were monitored during oral iron replacement. In association with normalization of the ferritin and transferrin saturation, hepcidin levels increased in each patient, but GDF15 levels remained stable (202 ± 15 pg/ml versus 215 ± 23 pg/ml). In summary, iron depletion due to blood loss was not associated with increased GDF15, and there was no obvious correlation between GDF15 and hepcidin expression at the time of depletion or during iron replacement therapy. The data support the hypothesis that GDF15 elevation contributes to the pathological suppression of hepcidin and iron overload in cases of ineffective erythropoiesis rather than the physiological suppression of hepcidin in cases of iron depletion. Disclosures:No relevant conflicts of interest to declare.

Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable-isotope appearance curves, increases plasma hepcidin

BackgroundPlasma hepcidin appears to be a major regulator of iron absorption and homeostasis, but there are few data in humans. ObjectivesWith the use of iron stable isotopes, we aimed to determine whether circulating hepcidin predicts dietary iron bioavailability, to quantify the amount of absorbed iron after oral iron loading, and to measure the plasma hepcidin response. DesignIn the first study, young women (n = 98) with an iron status varying from iron deficiency anemia to iron sufficiency (women with serum ferritin concentrations 25–40 ¼g/L were not included) were given stable isotope–labeled test meals (n = 196) containing ferrous sulfate, ferrous fumarate, or ferric pyrophosphate, after which plasma hepcidin and iron bioavailability were measured. In the second study, iron-sufficient men (n = 4) were given 3.8- and 60-mg oral doses of labeled ferrous sulfate. The stable isotope appearance curve was determined, and the plasma hepcidin response was measured over 6 h. ResultsIn study 1, plasma hepcidin and plasma ferritin were strongly correlated (r = 0.79, P < 0.001). Plasma hepcidin significantly, but modestly, predicted iron bioavailability from ferrous sulfate and ferrous fumarate (r = −0.51 and −0.46, respectively; P < 0.0001) but not from ferric pyrophosphate (r = −0.30, P = 0.056, respectively). In study 2, the 3.8-mg dose increased mean circulating absorbed iron to a peak of 0.42 ¼mol/L at 60 min but did not increase plasma hepcidin, The 60-mg dose increased mean circulating absorbed iron to a peak of 5.9 ¼mol/L at 120 min and produced an ≈30% increase in mean plasma hepcidin at 6 h (P < 0.01). ConclusionsPlasma hepcidin is only a modest predictor of dietary iron bioavailability in humans. Oral iron loading, measured by stable-isotope appearance curves, increases circulating hepcidin.

Mutation analysis of hepcidin and ferroportin genes in Italian prospective blood donors with iron overload

Maintenance of iron balance is essential for humans and requires the coordinate regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages, and from storage in hepatocytes. Hepcidin, a recently identified antimicrobial peptide produced in the liver, has been shown to play a central role in the homeostatic regulation of iron absorption and distribution [1]. It is a negative regulator of iron absorption in the small intestine and of iron release from macrophages engaged in the recycling of iron senescent erythrocytes [2]. The human hepcidin gene contains three exons that encode a 72-aa precursor (pro-hepcidin) with a characteristic furin cleavage site immediately N-terminal to the 25-aa major hepcidin species found in plasma and urine [3]. Recently, hepcidin has been shown to regulate iron homeostasis by interaction with ferroportin, an iron cellular exporter highly expressed in absorptive enterocytes, macrophages, hepatocytes, and placental cells [4].

Regulation of Intestinal Iron Absorption: The Mucosa Takes Control?

Two studies (Shah et al., 2009; Mastrogiannaki et al., 2009) show that the hypoxia inducible factor HIF-2alpha is a major player in regulating iron absorption by directly controlling the transcription of iron transporters in the intestine in response to changes in mucosal iron or oxygen levels. The HIF-2alpha mechanism has major effects on iron metabolism which can override the well-known hepcidin-ferroportin regulatory axis.

HFE-associated hereditary hemochromatosis

In populations of northern European descent, the p.C282Y mutation in the HFE gene is highly prevalent, and HFE-associated hereditary hemochromatosis is the most common type of inherited iron overload disorder. Inappropriate low secretion of hepcidin, which negatively regulates iron absorption, is postulated to be the mechanism for iron overload in this condition. The characteristic biochemical abnormalities are elevated serum transferrin-iron saturation and serum ferritin. Typical clinical manifestations include cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated serum aminotransferase levels, diabetes mellitus, restrictive cardiomyopathy and arthropathy of the second and third metacarpophalangeal joints. Most patients are now diagnosed before the development of these clinical features. Molecular genetic tests are currently available for genotypic diagnosis. In selected individuals, diagnosis might require liver biopsy or quantitative phlebotomy. Iron depletion by phlebotomy is the mainstay of treatment and is highly effective in preventing the complications of iron overload if instituted before the development of cirrhosis. Genetic testing is currently not recommended for population screening because of low yield as the majority of the healthy, asymptomatic p.C282Y homozygotes do not develop clinically significant iron overload. HFE gene testing remains an excellent tool for the screening of first-degree relatives of affected probands who are p.C282Y homozygotes.

SELDI-TOF MS detection of urinary hepcidin

Hepcidin is a 25-residue hepatic peptide that regulates iron absorption from the diet and tissue iron distribution. Inappropriately low Hepcidin expression is implicated in the pathogenesis of hereditary hemochromatosis and iron-loading anemias, like the thalassemias. Increased hepcidin expression mediates iron retention in the anemias of inflammation and plays a pathogenic role in iron-refractory iron-deficiency anemia (IRIDA). Because of its clinical importance, Hepcidin is expected to be a useful biomarker for diagnosis and management of iron-related disorders. So far an ELISA for human hepcidin and SELDI-TOF-MS based approaches have been applied to monitor urinary and/or serum hepcidin levels. Here we report a modified protocol for SELDI-TOF based detection of human, urinary hepcidin. We show that CM10 Proteinchips are superior to NP20 Proteinchips commonly used in previously reported protocols to sensitively and accurately detect urinary hepcidin. Application of this modified hepcidin assay accurately detects increased hepcidin levels in the urine of sepsis patients.

Brain iron homeostasis and neurodegenerative disease

AD= : Alzheimer disease; APP= : amyloid precursor protein; ATP= : adenosine triphosphate; BBB= : blood–brain barrier; DMT1= : divalent metal transporter-1; FA= : Friedreich ataxia; FTL= : ferritin light chain; FTH= : ferritin heavy chain; NBIA= : neurodegeneration with brain iron accumulation; NTBI= : non–transferrin-bound iron; PANK2= : pantothenate kinase 2; PD= : Parkinson disease; PKAN= : pantothenate kinase–associated neurodegeneration; TfR1= : transferrin receptor 1. Iron is essential for multiple functions in the CNS, including DNA synthesis, gene expression, myelination, neurotransmission, and mitochondrial electron transport. Several proteins implicated in brain iron homeostasis are involved in disorders associated with abnormal iron metabolism. A basic understanding of mechanisms of iron homeostasis is of clinical relevance, as either accumulation or depletion of intracellular iron may impair normal function and promote cell death. Iron accumulates in selective brain regions during aging, in acquired neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD), and in genetic disorders such as neurodegeneration with brain iron accumulation (NBIA). Dysregulation of iron homeostasis is also a critical feature of Friedreich ataxia (FA). The link between iron and neurodegenerative disease provides potential therapeutic targets for these disorders. Brain iron metabolism and its implications in neurodegeneration have been the subjects of excellent reviews.1–6 Some general concepts, unresolved issues, and clinical correlations are briefly discussed here. The CNS is separated from the systemic circulation by the blood–brain barrier (BBB), a tight epithelial barrier analogous to that of the mammalian duodenum, which is the site of absorption of dietary iron. After absorption, iron in its oxidized (ferric) form binds to serum transferrin and is distributed throughout the general circulation. The presence of a BBB explains the relative independence of the brain iron from the total body iron content. This is reflected by the absence of brain iron overload in mouse models and in humans with hemochromatosis due to mutations of the HFE gene, encoding a protein that regulates iron absorption.1,2 ### Incorporation and transport of iron in the nervous system. Iron incorporation and transport in the brain depends on interactions between the endothelial cells and astrocytes (figure). Brain endothelial cells express the transferrin receptor 1 (TfR1) in their luminal membrane; this receptor binds iron-loaded transferrin and internalizes this complex in endosomes. Within the endosomes, …

What regulates the iron regulator?

Early in my career, we were pretty ignorant about iron (we did not pump it yet), although we did know a few things. We were aware that the daily intake of iron is (should be) about 10 mg and that 1–2 mg of this iron was absorbed. Iron traveled in the blood bound to a carrier protein called “transferrin” and was stored in various places, such as the reticulo-endothelial system (RES) and bone marrow. As a matter of fact, the court-of-last-appeals for iron deficiency was the staining of bone marrow for iron with “Prussian blue”. We were aware that 200 billion erythrocytes were produced daily and that this production would take about 20 mg elemental iron, more than was absorbed. Thus, active recycling had to take place. Total body iron stores were known to be about 5 g and that half this amount resided in the erythrocytes. We were aware of hereditary hemochromatosis (HH), a favorite examination issue by oral examiners who generally had never ever seen a case either. And we knew about the poor Bantus and their ironcontaining cooking-pots. That was about it, although the iron storage mechanism and the way to measure it, namely ferritin, were introduced about 10 years later. The rest was a mystery, including the other common anemia, termed the “anemia of chronic disease”, that not even our smartest professors understood. Fortunately, all that ignorance is behind us, or at any rate, much of it is. Hepcidin (also known as HFE2) is a hepatic iron regulatory hormone that maintains systemic iron homeostasis. Hepcidin is made by the liver and secreted into the blood stream, where it binds to the iron exporter ferroportin that is located on macrophages, hepatocytes, and intestinal enterocytes. Hepcidin causes ferroportin to be internalized and proteolyzed (chewed up). As a result, hepcidin reduces gastrointestinal iron absorption and macrophage-mediated iron recycling. If hepcidin is so critical to iron-metabolic regulation, then the regulation of hepcidin is critical for our understanding how this very basic portion of human physiology works. In this issue, Casanovas et al. shed light on this question [1]. As is now commonly the case, the understanding of a rare Mendelian disease, HH, led the way. We now know that HH can be caused by mutations in a membrane protein encoded by a gene that is similar to those coding MHC class I-type proteins. The protein product associates with beta2-microglobulin (beta2M) and is called “HFE” although I am uncertain why. HFE is thought to regulate iron absorption by influencing the interaction of the transferrin receptor with transferrin. The HH phenotype is also produced by mutations in transferrin receptor 2 (TfR2), hemojuvelin (HJV), or hepcidin itself. Mutations in any of these proteins results in increased duodenal iron absorption, increased macrophage iron release, increased serum iron levels, and liver iron overload. HJV is a member of the “repulsive guidance molecule” (RGM) family, which also includes the bone-morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Babitt et al. [2] reported that HJV is a BMP coreceptor and that HJV mutants associated with the HH phenotype have impaired BMP signaling ability. They showed that BMP upregulates hepatocyte hepcidin expression, a process enhanced by HJV, and that is blunted in hepcidin genedeleted hepatocytes. Their data suggested a mechanism by which hepcidin mutations cause hemochromatosis, namely HJV dysfunction decreases BMP signaling, thereby lowering hepcidin expression. Babbitt et al. [3] next showed that BMP-2 administration increases hepcidin expression and J Mol Med (2009) 87:447–449 DOI 10.1007/s00109-009-0453-4

Regulering av jernbalansen

The regulation of iron absorption has previously been considered <<an enigma>>. Recent research has given us interesting information on the regulation of the iron metabolism and pathological iron overload; the present article aims at providing an overview of these topics. The article is based on a review of literature retrieved from PubMed. The peptide hepcidin binds to ferroportin on membranes of enterocytes, macrophages and hepatocytes. The complex is internalised and degraded and this results in decreased export of iron to the circulation, and thus a lower level of plasma iron. Hepcidin production is up-regulated in iron overload and down-regulated with iron deficiency. The liver proteins human haemochromatosis protein (HFE), transferrin receptor 2 (TfR2), haemojuvelin (HJV) and bone morphogenetic protein (BNP) are necessary regulators for activation of the hepcidin synthesis. Lack of or mutations in the genes for these proteins, e.g. the HFE mutation C282Y in primary haemochromatosis, reduces the synthesis of hepcidin. Iron regulatory proteins (IRP) may bind to iron responsive elements (IRE) of ferritin-mRNA and transferritin-mRNA and regulate the protein synthesis. Regulation of uptake, utilization, release and storage of iron occurs at the gene level. Hepcidin is currently considered to be the <<key regulator>> of the iron balance. Intracellular iron balance is maintained by iron regulating proteins. Synthesis of ferritin increases with high iron levels, while synthesis of TfR1 is reduced. The opposite occurs with a low iron level.

Serum Prohepcidin and Hepcidin in Hemodialyzed Patients Undergoing Iron Therapy

Hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from the macrophages. Iron supplementation is often introduced in dialyzed patients to replete or to maintain iron stores, particularly in patients treated with erythropoietin-stimulating agents. The aim of this study was to assess hepcidin levels in 12 hemodialyzed (HD) patients (6 females, 6 males, mean age 64 years, mean time on HD 36 months) before and after intravenous iron therapy. Prohepcidin and hepcidin were studied using commercially available kits from DRG Instruments GmbH, Marburg, Germany (ELISA method), and Bachem, St. Helens, UK (RIA method). Soluble receptor of transferrin was studied using a kit from R&D, Abington, UK. We found a significant rise in hemoglobin concentration, hematocrit, ferritin, serum iron, transferrin saturation and a fall in soluble receptor of transferrin. Serum hepcidin and prohepcidin as well as urinary prohepcidin increased significantly after the therapy. In conclusion, hepcidin levels are influenced by iron supplementation in HD patients. Further examinations of hepcidin as a marker of iron deficiency using new validated measurement techniques are required. It remains to be seen if assay of hepcidin will be of help in identifying patients unresponsive to oral iron or requiring intravenous iron supplementation.