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Background

Iron deficiency (ID) and iron deficiency anemia (IDA) are common nutritional disorders in children. Hepcidin, a peptide hormone produced in the liver, is a central regulator of systemic iron metabolism. We evaluated whether serum hepcidin levels can diagnose ID in children.

Methods

Sera from 59 children (23 males and 36 females; 5 months to 17 years) were analyzed for hepcidin-25 by ELISA. Patients were classified according to hemoglobin level and iron parameters as: IDA, (N=17), ID (N=18), and control (N=24).

Results

Serum hepcidin, ferritin, soluble transferrin receptor (sTfR), transferrin saturation, and hemoglobin levels differed significantly between groups (P<0.0001). Serum hepcidin and ferritin levels (mean±SD) were 2.01±2.30 and 7.00±7.86, 7.72±8.03 and 29.35±24.01, 16.71±14.74 and 46.40±43.57 ng/mL in the IDA, ID, and control groups, respectively. The area under the receiver operating characteristic curve for serum hepcidin as a predictor of ID was 0.852 (95% CI, 0.755-0.950). Hepcidin ≤6.895 ng/mL had a sensitivity of 79.2% and specificity of 82.8% for the diagnosis of ID. Serum hepcidin levels were significantly correlated with ferritin, transferrin saturation, and hemoglobin levels and significantly negatively correlated with sTfR level and total iron binding capacity (P<0.0001).

Conclusion

Serum hepcidin levels are significantly associated with iron status and can be a useful indicator of ID. Further studies are necessary to validate these findings and determine a reliable cutoff value in children.

Introduction. Anemia is a frequent problem in hospitalized geriatric patients, and the anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the 2 most prevalent causes. The aim of the study was to assess the possible role of serum hepcidin in the differential diagnosis between ACD and IDA. Methods. We investigated serum hepcidin, iron status, anemia, and C-reactive protein in 39 consecutive geriatric patients with ACD and IDA. Serum hepcidin levels were determined using a commercial ELISA kit (DRG Instruments, Marburg, Germany). We also measured hepcidin in 26 healthy controls. Results. The serum hepcidin levels were not significantly higher in the 28 patients with ACD as compared to the 11 patients with IDA. Conclusions. The serum hepcidin levels measured using the commercial ELISA kit (DRG) do not appear to increase in older patients with ACD. It should be noted that an assay-specific problem could explain our results.

Objective: Iron deficiency is a common complication in patients with polycythemia vera (PV). Hepcidin is a principal regulator of iron homeostasis. The aim of our study was to assess prohepcidin, a hepcidin precursor, and other iron status parameters in the serum of PV patients. Methods: The study was performed in 60 patients (F/M 26/34) aged 38~84 (66±10) years. The control group consisted of 20 healthy volunteers, age and sex matched. The following parameters were determined in blood serum samples: prohepcidin concentration, iron content, unsaturated iron binding capacity (UIBC), total iron binding capacity (TIBC), transferrin saturation (TfS), and concentrations of ferritin and soluble transferrin receptor (sTfR). Results: All PV patients showed significantly lower levels of prohepcidin, higher levels of sTfR and TIBC compared to the control group. 40% of the patients from the study group showed concentrations of ferritin below the normal range and significantly lower levels of serum iron and TfS, and significantly higher levels of sTfR, UIBC and TIBC in comparison with the rest of the study group. In this group of patients, prohepcidin concentrations were significantly lower than those in other patients. Conclusion: The results indicate that PV patients suffer from iron metabolism disorders. The decreased serum level of prohepcidin in PV patients may be a result of iron deficiency.

Background

The ideal screening test would be capable of identifying iron deficiency in the absence of anemia. We tried to detect role of urinary hepcidin-25 level in early prediction of iron deficiency in children.

Methods

This is a case control study performed on 100 children in Hematology Unit of Pediatric Department, Zagazig University Hospital, Egypt. Our study included 25 cases of iron deficiency (ID) stage-1 (iron depletion), 25 cases ID stage-2 (iron-deficient erythropoiesis), 25 cases ID stage-3 (iron deficiency anemia) and 25 healthy children as a control group. Estimation of iron status parameters was done. Urinary hepcidin-25 level was detected.

Results

Urinary hepcidin-25 level was significantly lower in all stages of iron deficiency than in control group, more significant reduction in its level was observed with the progress in severity of iron deficiency. Urinary hepcidin showed significant positive correlation with hemoglobin, mean corpuscular volume, hematocrit value, serum iron and ferritin and transferrin saturation. In contrary, it showed significant negative correlation with serum transferrin and total iron binding capacity.

Urinary hepcidin at cutoff point ≤0.94 nmol/mmol Cr could Predict ID stage-1 with sensitivity 88% and specificity 88%. Cutoff point ≤0.42 nmol/mmol Cr could predict ID stage-2 with sensitivity 96% and specificity 92%. Cutoff point ≤0.08 nmol/mmol Cr could Predict ID stage-3 with Sensitivity 96% and specificity 100%.

Conclusions

We can conclude that detection of urinary hepcidin-25 level was a simple and non invasive test and could predict iron deficiency very early, before appearance of hematological affections.

Hepcidin is the key mediator of renal anemia, and reliable measurement of serum hepcidin levels has been made possible by the ProteinChip system. We therefore investigated the iron status and serum hepcidin levels of peritoneal dialysis (PD) patients who had not received frequent doses of an erythrocytosis-stimulating agent (ESA) and had not received iron therapy. In addition to the usual iron parameters, the iron status of erythrocytes can be determined by measuring reticulocyte hemoglobin (RET-He). The mean serum hepcidin level of the PD patients (n = 52) was 80.7 ng/mL. Their serum hepcidin levels were significantly positively correlated with their serum ferritin levels and transferrin saturation (TSAT) levels, but no correlations were found between their serum hepcidin levels and RET-He levels, thereby suggesting that hepcidin has no effect on the iron dynamics of reticulocytes. Since low serum levels of CRP and IL-6, biomarkers of inflammation, were not correlated with the serum hepcidin levels, there is likely to be a threshold for induction of hepcidin expression by inflammation.

Iron deficiency anemia (IDA) is one of the most prevalent micronutrient deficiencies particularly in the developing countries. While there is evidence of an altered immune profile in iron deficiency, the exact immunoregulatory role of iron is not known. Knowledge particularly in children, who are vulnerable to iron deficiency and infection, is lacking. We aimed to study the effects of IDA and its treatment with oral iron supplementation on cell-mediated immunity. The levels of T-lymphocytes, their CD4+, CD8+ and CD1a+ subsets, transferrin receptor (CD71) and serum ferritin were evaluated in 40 iron-deficient and 40 healthy children. The impact of oral iron supplementation for three months on the same parameters was also noted in children with IDA. The level of mature T-lymphocytes (CD4+ and CD8+) was significantly lower (P<0.001) while that of the immature T-cells (CD1a+) was significantly higher (p<0.001) in IDA children compared to the control. The mature T-cell count was significantly improved after iron therapy. In spite of significant reduction in the immature T-cells (CD1a+) level after iron supplementation, it was significantly higher than the control. The present study demonstrated that T-lymphocytes maturation was defective in IDA and improved partially after 3 months of iron supplementation. Therefore, longer time of iron therapy may be required to induce complete maturation of T-lymphocytes.

Background

Hepcidin, a key regulator of iron homeostasis, is increased in response to inflammation and some infections, but the in vivo role of hepcidin, particularly in children with iron deficiency anemia (IDA) is unclear. We investigated the relationships between hepcidin, cytokines and iron status in a pediatric population with a high prevalence of both anemia and co-morbid infections.

Methodology/Principal Findings

African refugee children <16 years were consecutively recruited at the initial post-resettlement health check with 181 children meeting inclusion criteria. Data on hematological parameters, cytokine levels and co-morbid infections (Helicobacter pylori, helminth and malaria) were obtained and urinary hepcidin assays performed. The primary outcome measure was urinary hepcidin levels in children with and without iron deficiency (ID) and/or ID anaemia (IDA). The secondary outcome measures included were the relationship between co-morbid infections and (i) ID and IDA, (ii) urinary hepcidin levels and (iii) cytokine levels. IDA was present in 25/181 (13.8%). Children with IDA had significantly lower hepcidin levels (IDA median hepcidin 0.14 nmol/mmol Cr (interquartile range 0.05–0.061) versus non-IDA 2.96 nmol/mmol Cr, (IQR 0.95–6.72), p<0.001). Hemoglobin, log-ferritin, iron, mean cell volume (MCV) and transferrin saturation were positively associated with log-hepcidin levels (log-ferritin beta coefficient (β): 1.30, 95% CI 1.02 to 1.57) and transferrin was inversely associated (β: −0.12, 95% CI −0.15 to −0.08). Cytokine levels (including IL-6) and co-morbid infections were not associated with IDA or hepcidin levels.

Conclusions/Significance

This is the largest pediatric study of the in vivo associations between hepcidin, iron status and cytokines. Gastro-intestinal infections (H. pylori and helminths) did not elevate urinary hepcidin or IL-6 levels in refugee children, nor were they associated with IDA. Longitudinal and mechanistic studies of IDA will further elucidate the role of hepcidin in paediatric iron regulation.

Background/Aims

Helicobacter pylori (H. pylori) infection appears to subvert the human iron regulatory mechanism and thus upregulates hepcidin, resulting in unexplained iron-deficiency anemia (IDA). We evaluated serum prohepcidin levels before and after eradication of H. pylori in IDA patients to assess whether it plays a role in IDA related to H. pylori infection.

Methods

Subjects diagnosed with unexplained IDA underwent upper gastrointestinal endoscopy and colonoscopy to confirm H. pylori infection and to exclude gastrointestinal bleeding. Blood was sampled before treatment to eradicate H. pylori and again 1 month later. Serum prohepcidin levels were measured using a commercial enzyme-linked immunosorbent assay kit.

Results

Serum prohepcidin levels decreased significantly after oral iron replacement combined with H. pylori eradication (p = 0.011). The reduction ratio of serum prohepcidin levels after the treatment did not differ among the combined oral iron replacement and H. pylori eradication groups, the H. pylori eradication only group, and the iron replacement only group (p = 0.894).

Conclusions

Serum prohepcidin levels decrease after both H. pylori eradication and oral iron administration, with improvement in IDA. Serum concentration of prohepcidin is related to the anemia status, rather than to the current status of H. pylori infection, in IDA patients.

Uremia is a state of heightened inflammatory activation. This might have an impact on several parameters including anemia management. Inflammation interferes with iron utilization in chronic kidney disease through hepcidin. We studied the body iron stores, degree of inflammatory activation, and pro-hepcidin levels in newly diagnosed patients with end-stage renal disease (ESRD), and compared them with normal population. In addition to clinical examination and anthropometry, the levels of iron, ferritin, C-reactive protein, tumor necrosis factor alfa, interleukin-6, and prohepcidin were estimated. A total of 74 ESRD patients and 52 healthy controls were studied. The ESRD patients had a significantly lower estimated body fat percentage, muscle mass, and albumin; and higher transferrin saturation (TSAT) and raised serum ferritin. Inflammatory activation was evident in the ESRD group as shown by the significantly higher CRP, IL-6, and TNF-α levels. The pro-hepcidin levels were also increased in this group. Half of the ESRD patients had received parenteral iron before referral. Patients who had received intravenous iron showed higher iron, ferritin, and TSAT levels. These patients also showed more marked inflammatory activation, as shown by the significantly higher CRP, TNF-α, and IL-6 levels. We conclude that our ESRD patients showed marked inflammatory activation, which was more pronounced in patients who had received IV iron. High hepcidin levels could explain the functional iron deficiency. The cause of the relatively greater degree of inflammatory activation as well as the relationship with IV iron administration needs further studies.

Hepcidin regulation by competing stimuli such as infection and iron deficiency has not been studied in infants and it’s yet unknown whether hepcidin regulatory pathways are fully functional in infants. In this cross-sectional study including 339 Kenyan infants aged 6.0±1.1 months (mean±SD), we assessed serum hepcidin-25, biomarkers of iron status and inflammation, and fecal calprotectin. Prevalence of inflammation, anemia, and iron deficiency was 31%, 71%, 26%, respectively. Geometric mean (±SD) serum hepcidin was 6.0 (±3.4) ng/mL, and was significantly lower in males than females. Inflammation (C-reactive protein and interleukin-6) and iron status (serum ferritin, zinc protoporphyrin and soluble transferrin receptor) were significant predictors of serum hepcidin, explaining nearly 60% of its variance. There were small, but significant differences in serum hepcidin comparing iron deficient anemic (IDA) infants without inflammation to iron-deficient anemic infants with inflammation (1.2 (±4.9) vs. 3.4 (±4.9) ng/mL; P<0.001). Fecal calprotectin correlated with blood/mucus in the stool but not with hepcidin. Similarly, the gut-linked cytokines IL-12 and IL-17 did not correlate with hepcidin. We conclude that hepcidin regulatory pathways are already functional in infancy, but serum hepcidin alone may not clearly discriminate between iron-deficient anemic infants with and without infection. We propose gender-specific reference values for serum hepcidin in iron-replete infants without inflammation.

This longitudinal study investigated the rates of iron-deficiency (ID) and iron-deficiency anemia (IDA) among prenatally cocaine-exposed and nonexposed two- and four-year-old children and assessed their relationships to neurodevelopmental outcomes. The sample consisted of 143 two-year-old (70 exposed and 73 nonexposed) and 274 four-year-old (139 exposed and 135 nonexposed) low socioeconomic status children recruited from an ongoing longitudinal study. Hematological assessments included hemoglobin, serum ferritin, mean corpuscular volume, transferrin saturation, and blood lead levels. The neurodevelopmental outcomes consisted of the Bayley Mental (MDI) and Motor (PDI) Development indices at two years, and the Wechsler Preschool and Primary Scales of Intelligence (WPPSI) and the Peabody Developmental Motor Scales (PDMS) at four years. The rate of IDA in four-year-old children was significantly greater among the cocaine-exposed compared to the nonexposed group (p = .026), while the rates at two years were not significant. Exposure to IDA at two years was associated with a significant decrease in concurrent motor scores (p = .011) after adjustment for relevant covariates. Peak exposure to IDA, defined as being anemic at 2 and/or 4 years of age, was associated with a significant (p < .05) decrease in Full Scale IQ after adjustment. Cocaine exposure was not a significant predictor of Full Scale IQ with the inclusion of peak IDA and lead in the model. These findings indicate the need for greater pediatric surveillance of IDA and lead in cocaine-exposed infants, in order to reduce long-term neuropsychological deficits.

Hemoglobin and zinc protoporphyrin (ZPP) tests are commonly used to screen for iron deficiency, but little research has been done to systematically evaluate the sensitivity and specificity of these two tests. The goal of this study was to evaluate the effectiveness of zinc protoporphyrin/heme (ZPP/H) ratio as a point-of-service screening test for iron deficiency among preschool-aged children by comparing the sensitivity and specificity of hemoglobin, ZPP/H ratio, and serum ferritin (SF). Also completed were assessments for the prevalence of anemia, iron deficiency (ID), and iron deficiency anemia (IDA) with indicators of ferritin models. This study was carried out with 95 children ages 3 to 6 y. Anthropometric measurements were assessed, and blood samples were analyzed for hemoglobin, SF, transferrin saturation (TS), and ZPP. Anemia was common and the prevalences of anemia, ID, and IDA were 14.7%, 12.6%, and 5.2%, respectively. The ZPP/H ratio was strongly and significantly correlated with hemoglobin. And ZPP/H ratio was a more sensitive test for ID than hemoglobin or SF measurement, correctly identifying more than twice as many iron-deficient children (sensitivity of 91.7%, compared to 41.7% for hemoglobin and SF). However, ZPP/H ratio had lower specificity (60.2%, compared to 89.1% for hemoglobin or 96.4% for SF) and resulted in the false identification of more subjects who actually were not iron deficient than did hemoglobin or SF. Low hemoglobin concentration is a late-stage indicator of ID, but ZPP/H ratio can detect ID at early stages and can be performed easily at a relatively low cost. Therefore, ZPP/H ratio can serve as a potential screening test for pre-anemic iron deficiency in community pediatric practices.

BACKGROUND

Low serum hepcidin levels provide a physiologic response to iron demand in patients with iron deficiency (ID). Based on a discovery of suppressed hepcidin expression by a cytokine named growth differentiation factor 15 (GDF15), it was hypothesized that GDF15 may suppress hepcidin expression in humans with ID due to blood loss.

STUDY DESIGN AND METHODS

To test this hypothesis, GDF15 and hepcidin levels were measured in peripheral blood from subjects with iron-deficient erythropoiesis before and after iron supplementation.

RESULTS

Iron variables and hepcidin levels were significantly suppressed in iron-deficient blood donors compared to healthy volunteers. However, ID was not associated with elevated serum levels of GDF15. Instead, iron-deficient subjects’ GDF15 levels were slightly lower than those measured in the control group of subjects (307 ± 90 and 386 ± 104 pg/mL, respectively). Additionally, GDF15 levels were not significantly altered by iron repletion.

CONCLUSIONS

ID due to blood loss is not associated with a significant change in serum levels of GDF15.

The aim of this study was to analyze the relationship between serum pro-hepcidin concentration and the anemia profiles of rheumatoid arthritis (RA) and to estimate the pro-hepcidin could reflect the disease activity of RA. RA disease activities were measured using Disease Activity Score 28 (DAS28), tender/swollen joint counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Anemia profiles such as hemoglobin, iron, total iron binding capacity (TIBC), ferritin, and transferrin levels were measured. Serum concentration of pro-hepcidin, the prohormone of hepcidin, was measured using enzyme-linked immunosorbent assay (ELISA). Mean concentration of serum pro-hepcidin was 237.6±67.9 ng/mL in 40 RA patients. The pro-hepcidin concentration was correlated with rheumatoid factor, CRP, ESR, and DAS28. There was a significant correlation between pro-hepcidin with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. The pro-hepcidin concentration was significantly higher in the patients with active RA (DAS28>5.1) than those with inactive to moderate RA (DAS28≤5.1). However, the pro-hepcidin concentration did not correlate with the anemia profiles except hemoglobin level. There was no difference of pro-hepcidin concentration between the patients with anemia of chronic disease and those without. In conclusion, serum concentration of pro-hepcidin reflects the disease activity, regardless of the anemia states in RA patients, thus it may be another potential marker for disease activity of RA.

Most of the techniques for measuring iron stores such as serum iron concentration, iron binding capacity, serum ferritin level, liver biopsy can be troublesome or invasive for patients with thalassemia. The salivary iron measurement could be of potential advantage being an easy and non invasive approach for diagnosis of iron deficiency and iron overload . The aim of this study was to compare the levels of iron and ferritin in saliva and serum of patients affected by thalassemia or iron deficiency anemia. For this purpose, 96 patients with iron overload (71 with thalassemia major, 10 with thalassemia intermedia and 15 with thalassemia trait), 30 patients with iron deficiency anemia, and 35 healthy children as control group were involved in this study. Their saliva and serum iron and ferritin levels were measured. Iron and ferritin levels were higher in iron overload groups than in control group and lower in iron deficiency group (p<0.05). Furthermore serum and saliva iron and ferritin levels paralleled in all groups. In conclusion, iron and ferritin saliva can be routinely used for diagnosis of both iron overload and deficiency; furthermore this procedure may be an important advantage for blood donors being easily available and not invasive.

Iron deficiency is a common cause of anemia. In end-stage renal disease (ESRD), iron deficiency impairs the therapeutic efficacy of recombinant erythropoietin. Oral or parental iron supplements usually are effective in treating iron deficiency anemia (IDA). Some patients, however, respond poorly to iron supplements and are diagnosed as having iron-refractory iron deficiency anemia (IRIDA). The disease represents a medical challenge but its underlying mechanism was unclear. Hepcidin is a central player in iron homeostasis. It down-regulates the iron exporter ferroportin, thereby inhibiting iron absorption, release and recycling. In ESRD, plasma hepcidin levels are elevated, which contributes to iron deficiency in patients. Matriptase-2, a liver transmembrane serine protease, has been found to have a major role in controlling hepcidin gene expression. In mice, defects in the Tmprss6 gene encoding matriptase-2 result in high hepcidin expression and cause severe microcytic anemia. Similarly, mutations in the human TMPRSS6 gene have been identified in patients with IRIDA. Thus, matriptase-2 is critical for iron homeostasis and may play a role in renal disease.

Iron deficiency anemia is the most frequent micronutrient deficiency in the developing countries like India especially affecting pregnant women and young children. Iron is an essential element involved in myelin formation, neurotransmitter synthesis and neuro-metabolism. Several behavioural disturbances have been reported in iron deficient children. In the present study, we determined the prevalence of iron deficiency anemia in children with behavioural disorders and assessed the improvement in terms of symptoms (by child behaviour check list), haematological parameters and iron status after treatment with oral iron. In this prospective study, 44 children in the age group of 3–12 years who were diagnosed with behavioural disorders were evaluated. Complete blood counts using automated hematology analyzer and iron parameters (serum iron, total iron binding capacity, % transferrin saturation and serum ferritin) were measured in all the patients to assess the prevalence of iron deficiency in these children. Thirty age matched controls were also studied. Iron deficiency was found in 32 (73%) children, as assessed by transferrin saturation <16% and/or serum ferritin <16 μg/l. Following treatment with iron for 100 ± 10 days, there was a statistically (P ≤ 0.05) significant improvement in the clinical features, haematological profile and iron status. The presence of iron deficiency in children with behavioural disorders and subsequent improvement in clinical features, haematological profile and iron status suggests a possible causal relationship between iron deficiency and behavioural disorders.

Hepcidin is the main regulator of systemic iron homeostasis and is primarily produced by the liver but is also expressed, at the mRNA-level, in periphery tissues including the subcutaneous and visceral adipose tissue. Obesity is associated with elevated hepcidin concentrations and iron depletion suggesting that the exaggerated fat mass in obesity could contribute significantly to circulating hepcidin levels consequently altering iron homeostasis. The objective of this study was to determine if abdominal subcutaneous adipose tissue (AbScAT) releases hepcidin in vivo and if release is modified by obesity. Arterio-venous differences in concentrations of hepcidin were measured across AbScAT in 9 obese and 9 lean adults. Overall (n = 18), mean plasma hepcidin concentrations were significantly higher in arterialized compared to AbScAT venous samples [mean difference (arterialized-AbScAT venous plasma hepcidin) = 4.9 ± 9.6 ng/mL, P = 0.04]. Net regional release was not calculated because mean venous plasma hepcidin concentrations were lower than mean arterialized concentrations indicating no net release. Significant correlations between AbScAT venous and arterialized plasma hepcidin concentrations with anthropometric variables were not observed. Findings from this vein drainage study suggest there is no net release of hepcidin from the AbScAT depot and thereby no ability to signal systemically, even in obesity.

Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P < .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P < .0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT.

The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency. Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies. Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo. Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations. A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron. The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states. These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders.

The results of recent randomized, controlled trials in patients with chronic kidney disease and anemia have suggested that hyporesponsiveness to erythropoiesis stimulating agents (ESA) is a significant predictor of poor patient outcomes. Functional iron deficiency (FID) is the most common cause of suboptimal ESA response, and intravenous iron administration (IVFe) efficiently raises hemoglobin (Hb) concentrations even under the condition of FID. Consequently, renal anemia correction has conceptually shifted from ‘higher Hb values with high ESA doses’ to ‘prevention of ESA hyporesponsiveness with IVFe’. The discovery of hepcidin has profoundly changed our understanding of the place of FID in renal anemia therapy. Hepcidin reduces the abundance of iron transport proteins which facilitate iron absorption from the gut and iron mobilization from macrophages. Serum hepcidin is mainly modulated by iron stores, as is serum ferritin. High hepcidin or ferritin levels block intestinal iron absorption and iron recycling in macrophages and decrease iron availability for erythropoiesis, leading to FID. Iron administration, especially IVFe, increases hepcidin levels and concomitantly inhibits iron supply to erythroid cells. This in turn could lead to a vicious circle, exacerbating FID and increasing iron demand. Therefore, physicians should be cautious with unrestricted IVFe to chronic kidney disease patients with FID.

Abstract

Maintenance of proper “labile iron” levels is a critical component in preserving homeostasis. Iron is a vital element that is a constituent of a number of important macromolecules, including those involved in energy production, respiration, DNA synthesis, and metabolism; however, excess “labile iron” is potentially detrimental to the cell or organism or both because of its propensity to participate in oxidation–reduction reactions that generate harmful free radicals. Because of this dual nature, elaborate systems tightly control the concentration of available iron. Perturbation of normal physiologic iron concentrations may be both a cause and a consequence of cellular damage and disease states. This review highlights the molecular mechanisms responsible for regulation of iron absorption, transport, and storage through the roles of key regulatory proteins, including ferroportin, hepcidin, ferritin, and frataxin. In addition, we present an overview of the relation between iron regulation and oxidative stress and we discuss the role of functional iron overload in the pathogenesis of hemochromatosis, neurodegeneration, and inflammation. Antioxid. Redox Signal. 10, 997–1030.

Introduction

Iron Transport

Nonintestinal iron transport by transferring

Iron-bound transferrin binds the transferrin receptor for cellular iron uptake

Regulation of transferrin receptor 1 by iron regulatory element–iron regulatory protein system

Transcriptional regulation of transferrin receptor 1

Differential regulation of transferrin receptor 1 and transferrin receptor 2

Transferrin receptor 1 is regulated by hereditary hemochromatosis protein

Transferrin-independent cellular iron uptake

Intestinal iron absorption

Regulation of divalent metal transporter 1

Ferroportin is responsible for cellular iron efflux

Ferroportin associates and cooperates with ceruloplasmin

Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

Hepcidin

Iron Storage and Ferritin

Structure, tissue distribution, and importance of cytoplasmic ferritin

Iron efflux and ferritin degradation

Serum ferritin and ferritin receptor

Mitochondrial ferritin

Nuclear ferritin

Regulation of Ferritin

Iron-mediated ferritin regulation

Ferritin regulation by reactive oxygen species

Ferritin transcriptional regulation by cytokines

Ferritin regulation in erythroleukemic cells

Frataxin and Iron Homeostasis

Frataxin and Friedreich ataxia

Frataxin and mitochondrial iron traffic

Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

Frataxin gene regulation

Treatments

Functional Iron Overload and Human Health

Hereditary hemochromatosis

Mutant iron-responsive element-mediated iron overload

Iron regulation and neurodegeneration

Conclusions and Future Directions

Objective

Assess ex vivo whole-blood (WB) cytokine production and its association with iron status and serum hepcidin in obese versus non-obese women. Determine the change in ex vivo WB cytokine production six months after restrictive bariatric surgery in the obese group. Subjects: 17 obese (BMI: 46.6 ±7.9 kg/m2) and 19 non-obese (BMI: 22.5 ± 3.0 kg/m2), pre-menopausal women; frequency matched for hemoglobin, age and race.

Measurements

At baseline control and ex vivo stimulated IL-6, IL-10, IL-22, IFNγ, and TNFα from heparinized WB cultures, hemoglobin from finger-stick and transferrin receptor, hepcidin, CRP, IL-6, HOMA-IR from fasted serum samples and anthropometric parameters were assessed in the women. All parameters were reassessed six-months following restrictive bariatric surgery in the obese women only.

Results

Whole blood ex vivo LPS and ZY stimulated production of IL-6, TNFα and IFNγ was reduced, IL-22 increased, and IL-10 was unaffected in obese compared with the non-obese women. Furthermore, ex vivo stimulated production of IL-6 and TNFα normalized, but IFNγ production remained unchanged with weight loss following restrictive bariatric surgery. In the obese women, serum transferrin receptor (a marker of iron status) and serum hepcidin were correlated with ex vivo stimulated IFNγ production at baseline.

Conclusion

Ex vivo LPS and ZY stimulated cytokine production from WB cultures was altered in pre-menopausal women with morbid obesity. Significant weight loss resulted in normalization of some but not all observed alterations. Furthermore, iron status and serum hepcidin were associated with ex vivo LPS and ZY stimulated IFNγ in obesity.

PURPOSE:

This study was designed to evaluate the levels of hepcidin in the serum of patients with chronic obstructive pulmonary disease (COPD).

METHODS:

In the study, 74 male patients (ages 45-75) in a stable period for COPD were grouped as Group I: Mild COPD (n:25), Group II: Moderate COPD (n:24), and Group III: Severe COPD (n:25). Healthy non-smoker males were included in Group IV (n:35) as a control group. The differences of hepcidin level among all the groups were examined. Also, in the patient groups with COPD, hepcidin level was compared with age, body mass index, cigarette (package/year), blood parameters (iron, total iron binding capacity, ferritin, hemoglobin, hematocrit [hct]), respiratory function tests, and arterial blood gas results.

RESULTS:

Although there was no difference between the healthy control group and the mild COPD patient group (P=0.781) in terms of hepcidin level, there was a difference between the moderate (P=0.004) and the severe COPD patient groups (P=0.002). The hepcidin level of the control group was found to be higher than the moderate and severe COPD patient groups. In the severe COPD patients, hepcidin level increased with the increase in serum iron (P=0.000), hct (P=0.009), ferritin levels (P=0.012), and arterial oxygen saturation (SaO2, P=0.000).

CONCLUSION:

The serum hepcidin level that is decreased in severe COPD brings into mind that it may play a role in the mechanism to prevent hypoxemia. The results suggest that serum hepcidin level may be a useful marker in COPD. Larger prospective studies are needed to confirm our findings between hepcidin and COPD.

In this case report we describe the relationship between ferritin levels and hepcidin in a patient with alcohol-related spur cell anemia who underwent liver transplantation. We demonstrate a reciprocal relationship between serum or urinary hepcidin and serum ferritin, which indicates that inadequate hepcidin production by the diseased liver is associated with elevated serum ferritin. The ferritin level falls with increasing hepcidin production after transplantation. Neither inflammatory indices (IL6) nor erythropoietin appear to be related to hepcidin expression in this case. We suggest that inappropriately low hepcidin production by the cirrhotic liver may contribute substantially to elevated tissue iron stores in cirrhosis and speculate that hepcidin replacement in these patients may be of therapeutic benefit in the future.