Iron Retention Research Articles

Erythrocyte Transfusions and Serum Prohepcidin Levels in Premature Newborns With Anemia of Prematurity

Hepcidin is a regulatory peptide hormone acts by limiting intestinal iron absorption and promoting iron retention. Determining the level of hepcidin in anemia of prematurity might be important in preventing iron overload. This study aimed to determine serum levels of prohepcidin in newborns with anemia of prematurity, to assess the effect of a single erythrocyte transfusion on serum prohepcidin levels, and to determine the possible relationships between prohepcidin levels and serum iron and complete blood count parameters. Nineteen premature newborns with anemia of prematurity who had been treated with erythrocyte transfusions were included in this study. Just before, and 48 hours after, each transfusion, venous blood samples were collected from patients. Serum prohepcidin levels before and after erythrocyte transfusion were 206.5+/-27.3 and 205.7+/-47.1 ng/mL, respectively; no statistically significant differences were found. No significant differences existed before or after transfusion regarding serum total iron and ferritin levels, iron-binding capacity, or mean corpuscular hemoglobin concentration. No significant correlations existed between serum prohepcidin levels and other parameters, either before or after transfusions. Our results showed that there were no statistically significant differences between serum prohepcidin levels before and after a single erythrocyte transfusion in premature newborns.

Hepcidin targets ferroportin for degradation in hepatocytes

Hepcidin, a circulating regulatory hormone peptide produced by hepatocytes, functions as the master regulator of cellular iron export by controlling the amount of ferroportin, an iron exporter present on the basolateral surface of intestinal enterocytes and macrophages. Hepcidin binding to ferroportin induces its internalization and degradation, resulting in cellular iron retention and decreased iron export. Whether hepatocytes express ferroportin that could be targeted by hepcidin has remained a subject of debate. Here, we describe a hepatocyte culture system expressing high levels of ferroportin, and demonstrate that both endogenously secreted and synthetic hepcidin are fully active in down-regulating membrane-associated ferroportin. In agreement with this result, ferroportin is stabilized in liver hepatocytes of hepcidin-deficient mice and accumulates in periportal areas, supporting the centrolobular iron deposition observed in these mice. In conclusion, we show that hepcidin can trigger ferroportin degradation in hepatocytes, which must be taken into account when considering hepcidin therapeutics.

Patterns of hepatic iron distribution in patients with chronically transfused thalassemia and sickle cell disease

Patients with sickle cell disease (SCD) appear to be at lower risk of endocrinopathies and cardiac dysfunction than those with thalassemia major (TM). Circulating redox active iron is lower in these patients, possibly due to increased systemic inflammation and circulating cytokines. Hepcidin synthesis is upregulated during chronic inflammation, reducing intestinal iron absorption and promoting retention of iron in the reticuloendothelial cells. Hence, we hypothesized that livers of patients with SCD would exhibit greater iron deposition in sinusoidal spaces relative to hepatocytes and less in portal tracts when compared to patients with TM. To test this hypothesis, iron scoring analysis was performed on 70 clinically indicated liver biopsy specimens from children and young adults with the two syndromes. Sinusoidal scores were lower in around 1 of 4 patients with TM but the relative iron loading in hepatocytes, and portal tracts was identical in both diseases. Sinusoidal iron burdens saturated at low hepatic iron concentration (HIC) while hepatocyte and portal iron depots increased proportionally to HIC. Liver fibrosis was increased in patients with TM regardless of their chronic hepatitis status. Overall, liver iron distribution was relatively insensitive to differences in disease type and to the presence or absence of hepatitis.

Addition of milk or caseinophosphopeptides to fruit beverages to improve iron bioavailability?

Abstract A study has been made of the influence of caseinophosphopeptides (CPPs) added to a fruit beverage versus milk based fruit beverages upon iron retention, transport and uptake, using a combined simulated gastrointestinal digestion/Caco-2 cell system. Grape concentrate, orange concentrate, and apricot puree were used for sample formulation. Eight samples were assayed with/without added Fe sulphate (3 mg/100 ml fruit beverage) and/or added Zn sulphate (1.6 mg/100 ml fruit beverage), with/without skimmed milk (11% v/v). The addition of milk to fruit beverages exerted a positive effect on iron retention, transport and uptake versus fruit beverages, and this effect was greater than that of CPPs added to soluble fractions of fruit beverages. The addition of CPPs to soluble fractions of fruit beverages improved iron transport. Iron supplementation increased Fe retention, transport and uptake – the effect being more notable in samples with milk. Zinc supplementation did not affect Fe retention, transport or uptake.

Regulation of serum hepcidin levels in sickle cell disease

The peptide hormone hepcidin exerts its function by binding to the transmembrane cellular iron exporter ferroportin and inducing its internalization and degradation, resulting in decreased intestinal iron uptake and iron retention in the reticulo-endothelial (RE) macrophages. Inflammatory cytokines

Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications

AbstractThe anemia of chronic disease (ACD) is characterized by macrophage iron retention induced by cytokines and the master regulator hepcidin. Hepcidin controls cellular iron efflux on binding to the iron export protein ferroportin. Many patients, however, present with both ACD and iron deficiency anemia (ACD/IDA), the latter resulting from chronic blood loss. We used a rat model of ACD resulting from chronic arthritis and mimicked ACD/IDA by additional phlebotomy to define differing iron-regulatory pathways. Iron retention during inflammation occurs in macrophages and the spleen, but not in the liver. In rats and humans with ACD, serum hepcidin concentrations are elevated, which is paralleled by reduced duodenal and macrophage expression of ferroportin. Individuals with ACD/IDA have significantly lower hepcidin levels than ACD subjects, and ACD/IDA persons, in contrast to ACD subjects, were able to absorb dietary iron from the gut and to mobilize iron from macrophages. Circulating hepcidin levels affect iron traffic in ACD and ACD/IDA and are more responsive to the erythropoietic demands for iron than to inflammation. Hepcidin determination may aid to differentiate between ACD and ACD/IDA and in selecting appropriate therapy for these patients.

Performance Traits and Metabolic Responses in Goats (Capra hircus) Supplemented with Inorganic Trivalent Chromium

The effects of supplemental chromium (Cr) as chromic chloride hexahydrate in incremental dose levels (0, 0.5, 1.0, and 1.5 mg/day for 240 days) on metabolism of nutrients and trace elements were determined in dwarf Bengal goats (Capra hircus, castrated males, average age 3 months, n = 24, initial mean body weight 6.4 +/- 0.22 kg). Live weight increased linearly (p < 0.05) with the level of supplemental Cr. Organic matter and crude protein digestibility, intake of total digestible nutrients, and retention of N (g/g N intake) increased (p < 0.05) in a dose-dependent linear manner. Serum cholesterol and tryacylglycerol concentrations changed inversely with the dose of supplemental Cr (p < 0.01). Supplemental Cr positively influenced retention of copper and iron (p < 0.05) causing linear increase (p < 0.01) in their serum concentrations. It was concluded that Cr supplementation may improve utilization of nutrients including the trace elements and may also elicit a hypolidemic effect in goats. However, further study with regards to optimization of dose is warranted.

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.

Diagnose der Rheuma-Anämie

Anaemia of chronic disease is frequently accompanied by marked disturbances in iron metabolism driven, to a large part, by liver-derived hepcidin. Typically, there is reduced iron resorption from the intestine as well as increased uptake and retention of iron within cells of the reticuloendothelial system, resulting in a diversion of iron from the circulation to storage sites with a subsequent lack of iron for red progenitor cells and iron-deficient erythropoesis. In addition, gastrointestinal blood loss may aggravate the availability of iron. By using biochemical markers and special red blood cell indices, all three compartments of iron metabolism can be readily monitored. Serum ferritin represents storage iron, whereas the transferrin saturation (TSAT) is a measure for the amount of iron bound to transferrin. Determination of red cell indices such as% hypochromic erythrocytes or reticulocyte hemoglobin (CHr) or the soluble transferrin receptor (sTfR) provides direct information on iron availability for erythropoesis. An absolute iron deficiency is characterised by a serum ferritin<30 μg/L and reduced haemoglobin levels (iron deficiency anaemia). A latent iron deficiency is characterised by reduced iron stores with still normal haemoglobin values. Patients suffering from chronic inflammation might become anaemic (Hb reduced) in the presence of adequate iron stores (ferritin normal), due to hepcidin-mediated retention of iron in the reticuloendothelial system and subsequent iron-deficient erythropoesis. Iron-restricted blood formation may also occur during epoetin treatment, when the pharmacologically stimulated erythropoesis needs more iron than transferrin (low TSAT) is able to deliver to the bone marrow. Both scenarios would ultimately lead to iron-deficient erythropoesis, which is also called functional iron deficiency. Normally it is not necessary to determine all iron parameters in each and every case. The simultaneous evaluation of storage iron (ferritin) and iron availability to the bone marrow (% hypochromic red cells, CHr or sTfR) appears to be a rational first step to characterise complex disturbancies of iron homeostasis.

Chronische Entzündungsanämie – Epiphänomen oder Adaptationsmechanismus der Entzündung?

Die chronische Entzündungsanämie (anaemia of chronic disease, ACD) ist die häufigste Anämie bei hospitalisierten Patienten und findet sich vor allem bei Personen, die an chronischen Infektionen, Autoimmunerkrankungen und malignen Tumoren leiden. Alle der ACD zugrunde liegenden pathophysiologischen Mechanismen sind durch die mit jener der Grundkrankheit assoziierten Immunaktivierung bedingt. Zytokine und Akutphaseproteine führen zu einer Retention von Eisen im retikuloendothelialen System und damit zu einer eisenlimitierten Erythropoese, da Eisen nicht für die Hämbiosynthese im Knochenmark zur Verfügung steht. Ferner hemmen vor allem pro-inflammatorische Zytokine die Proliferation und Differenzierung von erythroiden Vorläuferzellen, die Bildung und biologische Wirkung von Erythropoetin und führen wohl auch zu einer direkten Schädigung von Erythrozyten durch die Bildung von Radikalen und dadurch zu einer verminderten Lebensdauer der Erythrozyten. Die Entwicklung der ACD hat auch potentielle Vorteile, da durch die Limitierung der Eisenverfügbarkeit das Wachstum von eingedrungenen Pathogenen blockiert wird. Weiters führt der Entzug von Eisen zu einer Stärkung der durch IFN-γ induzierten Immunabwehrmechanismen von Makrophagen, da Eisen einen negativen Effekt auf pro-inflammatorische, zellvermittelte Immuneffektorwege ausübt. Während diese Strategie bei Infektion und Tumorerkrankungen wichtig ist, erweißt sich diese bei Autoimmunerkrankung wohl als kontraproduktiv. Während die alleinige therapeutische Gabe von Eisen zur Anämiebehandlung bei ACD Patienten mit Infektionen und Tumorerkrankungen aufgrund der Wachstumsförderung von Pathogenen sowie der durch das Metall vermittelten negativen immunologischen Effekte im Regelfall kontraindiziert ist, kann diese umgekehrt bei Patienten mit Erkrankungen des rheumatischen Formenkreises aufgrund der immunsupprimierenden Eigenschaften des Metalls positive Effekte auf die Krankheitsaktivität ausüben, was klinisch zu verifizieren sein wird.

Non-enhanced ultrafiltration of iron(III) with commercial ceramic membranes

Membranes are nowadays being developed as a mature technology to deal with polluted waters containing heavy metals. Nanofiltration membranes have classically been employed for this purpose. However, it was recently shown that a 5 kDa ceramic ultrafiltration membrane could be successfully used to recover iron(III) from aqueous solutions even at acidic pH, although the mechanisms associated with the retention of iron were not clearly established. This paper aims to highlight the phenomena associated with the retention of iron(III) species by commercial ceramic ultrafiltration membranes. The results show that iron(III) retention by ceramic membranes is strongly influenced by the molecular weight cut-off of the membranes and their material, although even 50 kDa molecular weight cut-off membranes are capable to efficiently retain iron species. A retention mechanism based on iron-membrane adsorption seems to be the most likely for explaining iron rejection when using UF membranes. However, charge repulsion phenomena and sieving effects may also contribute to the rejection of iron(III). The occurrence of mononuclear hydrolysed iron species, which can result in the formation of polynuclear species in the neighbourhood of the membrane surface could definitively contribute to the high retention of iron(III) shown by ceramic ultrafiltration membranes.

New Pharmacological Concepts for the Treatment of Iron Overload Disorders

Imbalances of iron homeostasis cause frequent clinical syndromes. Iron deficiency affects almost 25% of the global population and approximately one billion people suffer from iron deficiency anaemia. Moreover, the anaemia of chronic disease, which develops primarily in subjects suffering from malignancies, infections and autoimmune disorders is pivotally caused by an iron-limited erythropoiesis, which arises from iron retention within cells of the reticulo endothelial system. In contrast, one of the most frequent inherited disorders in people of Northern-Western European origin is hereditary hemochromatosis (HH). HH leads to progressive iron overload in parenchymal organs with subsequent organ failure. In addition, secondary iron overload develops in patients receiving repetitive blood transfusion for the treatment of genetic hemoglobinopathies or for the correction of anaemia in cancer or myelodysplastic syndromes. Due to the discovery of new genes, our knowledge on the regulation of iron homeostasis has dramatically expanded which offers avenues for new treatment options. This is of importance, since some of these clinical syndromes (e.g. anaemia of chronic disease or secondary iron overload) are not sufficiently treatable with current medications (e.g. iron chelators, iron, erythropoietin) in many patients. In addition, some patients with iron deficiency face side effects from iron therapy or refuse phlebotomy for treatment of HH. Thus, new treatment strategies for iron metabolism disorders or improvement of existing concepts are necessary. This review discusses established, approaching and future putative treatment strategies and concepts for combating iron metabolism disorders.

Evaluation of Mitigation Methods to Manage Contaminant Transfer in Urban Watersheds

Abstract Three case studies on trace metal contamination in urban stormwater are presented from the Greater Vancouver area of British Columbia. In the first case study, the spatial and temporal variability in trace metals in sediments were determined in the completely urbanized Brunette watershed. A natural lake in the middle of the watershed acts as a sediment detention system, and an analysis of the sediment core showed the historic accumulation of metal and selective organic contaminants in sediments since the early 1800s. Suspended sediments transported during storm events showed significantly higher concentrations of trace metals than bedload sediments, and the largest proportion of the geochemically active metals was found to be associated with the organic-sulphur-based fraction. Benthic organism survival tests showed mixed results with lower survival and growth in urban sediments than in control sediments from a forested watershed. In the second case study, significant correlations were obtained between percent impervious cover and trace metal concentrations in 28 subwatersheds with various degrees of urbanization. It is shown that imperviousness combined with traffic density can significantly improve the prediction of metal contamination in highly urbanized watersheds. In the third case study five urban stormwater detention systems were examined over one year to determine how effective these systems were in removing metal contamination. The results were highly variable depending on a wide range of physical conditions, land use activities, traffic volume, and detention system designs. The range of total metal detention was between −15 to +72% for copper (Cu), lead (Pb), and zinc (Zn), while iron (Fe) and manganese (Mn) retention was generally poor. Labile Zn was more effectively retained in four of the five ponds, and a significant relationship was found between percent imperviousness, traffic volume, and Zn concentrations in water, sediment, and labile form.

The beneficial effect of Mediterranean dietary patterns on dietary iron utilization in male adolescents aged 11–14 years

The effects of a diet based on Mediterranean patterns on iron bioavailability and iron status in adolescents were studied. The study was divided into two periods: basal period, in which 21 male adolescents consumed their habitual diet (basal diet); and nutritional intervention period, during which an experimental diet based on the Mediterranean model was consumed. Dietary iron utilization was studied by means of iron intake and iron output in faeces and urine, and iron status was analysed in fasting blood samples collected at the end of each period. No differences in total iron intake were found between diets, but consumption of the experimental diet increased iron absorption and retention compared with the basal diet. Biochemical parameters related to iron metabolism did not vary after the intervention period, although serum ferritin tended to increase. Therefore, a diet based on Mediterranean dietary patterns may improve dietary iron utilization during adolescence and may prevent iron deficiency.

HFE-Related Hemochromatosis: The Haptoglobin 2-2 Type Has a Significant but Limited Influence on Phenotypic Expression of the Predominant p.C282Y Homozygous Genotype

Phenotypic expression of the common p.C282Y/p.C282Y HFE-related hemochromatosis genotype is heterogeneous and depends on a complex interplay of genetic and non-genetic factors. Haptoglobin has a crucial role in free hemoglobin iron recovery, and exists as three major types: Hp1-1, Hp2-1 and Hp2-2. Hp2-2 favors endocytosis of hemoglobin iron in monocytes/macrophages, resulting in partial iron retention and increased intracellular ferritin levels. This situation is generally not expected to severely affect iron homeostasis, but was found to correlate with elevated serum iron indices in healthy men. Whether the Hp2-2 genotype acts as a modifier in HFE-related hemochromatosis is unclear. In this study we investigated influence of Hp2-2 and of potential confounders on the iron indices of 351 p.C282Y homozygous patients. We conclude that there is a cause-and-effect relationship between the Hp2-2 genotype and increased iron indices in p.C282Y homozygous patients. The Hp2-2 effect is, however, limited and only apparent in males.

Iron oxide coating of geosynthetic fibers for water treatment applications

Polypropylene fibers present favorable physical, hydraulic and specific surface area properties for use as a raw material or substrate in developing a novel iron-oxide-coated medium for the adsorption of heavy metals from drinking water. However, polypropylene fibers have not been explored for their ability to retain iron oxide coating under realistic flow rates for water treatment. This study evaluated the ability of polypropylene to retain its coating under flow rates used in water treatment, through column studies. A full factorial experimental design was used to evaluate the effects of flow rate, packing scheme (in-plane or cross-plane) and location within the column on iron retention. The polypropylene mat achieved an iron density of 86 mg Fe/g medium of material and retained 73% of this coating after being subjected to hydraulic flows in the cross-plane direction several times those used in water treatment. This is substantially higher than the amount of iron retained on sand as reported by previous researchers. Further investigation should evaluate pre-treatment methods which may facilitate strong chemical bonds between the iron and fiber to create a more consistent coating.

Emergency Laparoscopic-Assisted Gastrotomy for the Treatment of an Iron Bezoar

Iron ingestion accounts for approximately 3% of calls to poison control centers. The profound local and systemic effects of an iron overdose have an associated mortality rate of 5%. Laparotomy and gastrotomy has been reported as a life-saving maneuver to extract the retained iron aggregates that are notoriously resistant to, removal by conventional emesis or lavage techniques. In this paper, we describe, for the first time, the use of laparoscopic-assisted gastrotomy in the treatment of an iron overdose. A 14-year-old girl attempted suicide by means of a polydrug drug overdose, which included ferrous fumarate, at a calculated potentially lethal dose of 70 mg/kg. A gastric iron bezoar was seen on plain radiograph. The regional poison control center recommended surgical removal of the retained iron tablets. Upper endoscopy confirmed the retention of iron and showed its dense adherence to the gastric mucosa. A 5-mm laparoscope was introduced at the umbilicus, and the stomach was grasped by an instrument introduced through a left-upper quadrant incision. The incision was then enlarged to allow the formation of a gastrotomy. The iron bezoar was removed with the aid of digital disimpaction and copious saline irrigation. The patient made a rapid postoperative recovery prior to undergoing psychiatric treatment. We conclude that laparoscopic-assisted gastrotomy is a simple and safe option in the acute management of a retained iron bezoar.

Effects of the Aspergillus fumigatus siderophore systems on the regulation of macrophage immune effector pathways and iron homeostasis

The saprophytic fungus Aspergillus fumigatus is the most prevalent airborne fungal pathogen, which is responsible for invasive aspergillosis in immunocompromised patients. Iron plays an essential role for the growth and proliferation of A. fumigatus. This fungus synthesizes three major siderophores. It excretes triacetylfusarinine C to capture iron, while it accumulates ferricrocin and hydroxyferricrocin for hyphal and conidial iron storage, respectively. Herein, we investigated the role of the siderophore system of A. fumigatus in the modulation of immune effector pathways and iron homeostasis in macrophages. We set up a co-culture system consisting of the murine macrophage cell line RAW264.7 and either A. fumigatus wild type or a siderophore-deficient mutant (Δ sidA). We used real-time quantitative RT-PCR and Western blot analyses to study the expression of macrophage iron metabolism and innate immune response genes in response to pathogen challenge. Infection of macrophages with A. fumigatus wild type, but not with the Δ sidA mutant, induced expression of TNF and phagocyte oxidase subunit 47 at the transcriptional level. Moreover, infection with A. fumigatus wild type, but not with the Δ sidA mutant, compromised macrophage iron homeostasis. Infection with wild-type A. fumigatus decreased expression of the two cellular iron importers, the divalent metal transporter-1 and the transferrin receptor, and the only known iron exporter ferroportin. At the same time, it increased macrophage iron retention and ferritin synthesis. These data indicate that A. fumigatus affects the regulation of macrophage iron homeostasis and innate immune effector pathways via its siderophore system. The changes in immune response may be a consequence of macrophage iron restriction.

Selectively Enhanced Retention of Neutral Iron(II) Complex in RP-LC with o-Hydroxy Pyrimidylazo Compounds as Precolumn Derivatizing Reagent

The diazo component of o-hydroxy heterocyclic azo compounds showed a remarkable effect on the retention of their neutral complexes of iron and nickel as a precolumn derivatizing reagent in the separation of metal ions by RP-HPLC using an octadecyl-bonded silica gel column. High resolutions of iron and nickel complexes were obtained with pyrimidyl derivatives. Acetonitrile-water or acetone-water was more suitable as a mobile phase than alcohol-water with regard to the separation of these metal ions. Thermodynamic study showed that the difference in transfer enthalpies of iron and nickel complexes from the mobile phase to the stationary phase dominated the resolution of two complexes with pyrimidyl compounds. High resolutions obtained by use of pyrimidyl compounds were ascribed to selectively enhanced retention of the iron complexes from the comparison with the retentions of the zinc complexes.

A purple acidophilic di-ferric DNA ligase from Ferroplasma.

We describe here an extraordinary purple-colored DNA ligase, LigFa, from the acidophilic ferrous iron-oxidizing archaeon Ferroplasma acidiphilum, a di-ferric enzyme with an extremely low pH activity optimum. Unlike any other DNA ligase studied to date, LigFa contains two Fe(3+)-tyrosinate centers and lacks any requirement for either Mg(2+) or K(+) for activity. DNA ligases from closest phylogenetic and ecophysiological relatives have normal pH optima (6.0-7.5), lack iron, and require Mg(2+)/K(+) for activity. Ferric iron retention is pH-dependent, with release resulting in partial protein unfolding and loss of activity. Reduction of the Fe(3+) to Fe(2+) results in an 80% decrease in DNA substrate binding and an increase in the pH activity optimum to 5.0. DNA binding induces significant conformational change around the iron site(s), suggesting that the ferric irons of LigFa act both as structure organizing and stabilizing elements and as Lewis acids facilitating DNA binding at low pH.