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Hepcidin has a crucial role in iron homeostasis upon inflammatory conditions such as inflammatory bowel disease (IBD). Thus, we conducted a systematic review and meta‐analysis to determine the overall association between serum hepcidin concentrations and IBD. Based on the preferred reporting items for systematic review and meta‐analysis (PRISMA) protocols, an electronic literature search was conducted on PubMed/MEDLINE, Scopus, and Web of Science until June 2020. Studies were deemed eligible for inclusion if they met the following criteria: (1) diagnosis of IBD, (2) observational design, and (3) measured serum hepcidin and prohepcidin concentrations in IBD patients and control group. Overall, 10 studies including 1184 participants were evaluated. Random‐effects meta‐analysis revealed that subjects with IBD had 7.22 ng/mL (95% CI: 2.10, 12.34; p =.006) higher serum hepcidin concentrations compared to control groups. A nonsignificantly lower serum prohepcidin concentration (0.522 ng/mL, 95% CI: −1.983 to 0.939; p =.484) was found for IBD patients compared to healthy subjects. However, there was significant heterogeneity among the studies regarding both hepcidin (I2 = 98%, p <.001) and prohepcidin levels (I2 = 96%, p <.001), respectively. In an age‐based subgroup analysis, patients aged ≥18 years with IBD displayed higher serum hepcidin levels when compared to healthy individuals (22.36 ng/mL, 95% CI, 2.12–42.61; p =.030). Hepcidin concentrations are elevated in subjects with IBD; however, the clinical relevance of this finding requires further evaluation in future investigations as the increase is relatively small compared to the wide range of normal hepcidin values. [ABSTRACT FROM AUTHOR]

Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron-regulatory hormone, is a 25-amino-acid peptide with four intramolecular disulfide bonds circulating in blood. Its hormonal activity is indirect and consists of marking ferroportin-1 (an iron exporter) for degradation. Hepcidin biosynthesis involves the N-terminally extended precursors prepro-hepcidin and pro-hepcidin, processed by peptidases to the final 25-peptide form. A sequence-specific formation of disulfide bonds and export of the oxidized peptide to the bloodstream follows. In this study we considered the fact that prior to export, reduced hepcidin may function as an octathiol ligand bearing some resemblance to the N-terminal part of the α-domain of metallothioneins. Consequently, we studied its ability to bind Zn(II) and Cd(II) ions using the original peptide and a model for prohepcidin extended N-terminally with a stretch of five arginine residues (5R-hepcidin). We found that both form equivalent mononuclear complexes with two Zn(II) or Cd(II) ions saturating all eight Cys residues. The average affinity at pH 7.4, determined from pH-metric spectroscopic titrations, is 1010.1 M−1 for Zn(II) ions; Cd(II) ions bind with affinities of 1015.2 M−1 and 1014.1 M−1. Using mass spectrometry and 5R-hepcidin we demonstrated that hepcidin can compete for Cd(II) ions with metallothionein-2, a cellular cadmium target. This study enabled us to conclude that hepcidin binds Zn(II) and Cd(II) sufficiently strongly to participate in zinc physiology and cadmium toxicity under intracellular conditions. [ABSTRACT FROM AUTHOR]

Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron-regulatory hormone, is a 25-amino-acid peptide with four intramolecular disulfide bonds circulating in blood. Its hormonal activity is indirect and consists of marking ferroportin-1 (an iron exporter) for degradation. Hepcidin biosynthesis involves the N-terminally extended precursors prepro-hepcidin and pro-hepcidin, processed by peptidases to the final 25-peptide form. A sequence-specific formation of disulfide bonds and export of the oxidized peptide to the bloodstream follows. In this study we considered the fact that prior to export, reduced hepcidin may function as an octathiol ligand bearing some resemblance to the N-terminal part of the α-domain of metallothioneins. Consequently, we studied its ability to bind Zn(II) and Cd(II) ions using the original peptide and a model for prohepcidin extended N-terminally with a stretch of five arginine residues (5R-hepcidin). We found that both form equivalent mononuclear complexes with two Zn(II) or Cd(II) ions saturating all eight Cys residues. The average affinity at pH 7.4, determined from pH-metric spectroscopic titrations, is 1010.1 M−1 for Zn(II) ions; Cd(II) ions bind with affinities of 1015.2 M−1 and 1014.1 M−1. Using mass spectrometry and 5R-hepcidin we demonstrated that hepcidin can compete for Cd(II) ions with metallothionein-2, a cellular cadmium target. This study enabled us to conclude that hepcidin binds Zn(II) and Cd(II) sufficiently strongly to participate in zinc physiology and cadmium toxicity under intracellular conditions.

Present studies on serum hepcidin levels in patients with rheumatoid arthritis (RA) are inconsistent. We aimed to synthetically evaluate the relationship between hepcidin and RA, and the correlation of serum hepcidin levels and RA disease activity as well as anemia associated with RA. Multiple electronic databases were searched. Pooled standard mean difference (SMD) with 95% confidence interval (CI) and correlation coefficients between hepcidin levels and rheumatoid factor (RF), disease activity for 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) were calculated. Totally, 13 articles were available for this meta-analysis. The results revealed that serum levels of hepcidin were higher in RA patients compared to healthy controls (SMD = 0.573, 95% CI = 0.317 to 0.829, p <.001); RA patients with anemia had higher serum hepcidin levels than RA patients without anemia (SMD = 0.400, 95% CI = 0.080 to 0.720, p =.014); RA patients with pure ACD had higher serum hepcidin levels than RA patients with ACD and IDA (SMD = 0.658, 95% CI = 0.018 to 1.299, p =.044). Moreover, the result of correlation coefficients identified a significant positive correlation between hepcidin levels and RF, DAS28 as well as ESR. Serum hepcidin levels may be closely associated with the development of RA. [ABSTRACT FROM AUTHOR]

Recent research evidence suggests a central role for hepcidin in iron homeostasis. Hepcidin is a hormone synthesized in the liver. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. A 38-year-old female who presented with recurrent abdominal pain was found to have raised urinary porphyrins and a blood lead level of 779 µg/l. Her haemoglobin level was 8.3 g/dl. Her MCV was normal. Serum ferritin, B12 and folate were normal. Her serum prohepcidin level was 2,489 ng/ml (normal

A number of pathophysiological conditions are related to iron metabolism disturbances. Some of them are well known, others are newly discovered or special. Hepcidin is a newly identified iron metabolism regulating hormone, which could be a promising biomarker for many disorders. In this review, we provide background information about mammalian iron metabolism, cellular iron trafficking, and the regulation of expression of hepcidin. Beside these molecular biological processes, we summarize the methods that have been used to determine blood and urine hepcidin levels and present those pathological conditions (cancer, inflammation, neurological disorders) when hepcidin measurement may have clinical relevance. [ABSTRACT FROM AUTHOR]

Since the immune system is suppressed before bone marrow transplantation (BMT), severe infections might arise. This clinical article considers the role of prohepcidin, in addition to interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in infections occurring after BMT. Serum prohepcidin, IL-6, TNF-α, and C-reactive protein (CRP) levels were measured in 10 pediatric BMT patients by enzyme-linked immunosorbent assay before and after BMT. The results were evaluated statistically. As a result of the analysis, it was observed that there was a significant correlation between serum prohepcidin and IL-6, TNF-α, and CRP levels in the pretransplantation, posttransplantation, and discharge periods of the patients. The relationship between CRP levels and prohepcidin levels suggests that the serum prohepcidin level might be an important parameter for transplantation patients in consideration of infection. Verification of these results from future studies may confirm the clinical importance of hepcidin. [ABSTRACT FROM AUTHOR]

The link between Helicobacter pylori and iron deficiency (ID) or iron deficiency anemia (IDA) has been investigated recently. We suggested that IDA/ID associated with H. pylori infection might be mediated by inflammation-driven hepcidin production. Patients with complaints of recurrent abdominal pain and dyspepsia aged between 7-16 years were included in this study. Patients were divided into two groups according to H. pylori status in upper gastrointestinal endoscopy. Group I who had H. pylori gastritis ( n = 50) received triple antibiotic therapy. Group II ( n = 50) who had H. pylori-negative gastritis only received proton pump inhibitor. Thirty healthy children with the similar age and gender were included in the study as a control group. Complete blood count, serum iron levels, iron-binding capacity, ferritin levels, prohepcidin and interleukin-6 (IL-6) values were evaluated in all children at the first visit. Initial tests were repeated after H. pylori eradication. Initial levels of ferritin ( p = 0.002), prohepcidin ( p = 0.003), and IL-6 ( p = 0.004) were found significantly lower in group I compared to group II and the control group. The mean prohepcidin level was lower in the anemic H. pylori-positive group than in non-anemic H. pylori-positive group; however, the difference was not statistically significant. While significant increases in hematocrit and mean corpuscular volume were observed, no significant difference was found in serum ferritin, prohepcidin, or IL-6 level after eradication treatment in H. pylori-positive group. Conclusion: H. pylori-induced gastritis appears to cause an increase in prohepcidin levels and a decrease in ferritin levels, supporting our hypothesis; but this relationship has not been proven. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to compare pro-hepcidin, hemoglobin (Hb) concentration, hematocrit (Hct), C-reactive protein (CRP), IL-6 and iron status parameters in preeclamptic (PE) and healthy pregnant women, and to examine the relationship between serum pro-hepcidin levels and iron parameters of preeclampsia (PE). Methods: In a prospective controlled study, we collected serum from women with normal pregnancy ( n = 37) and from women with PE ( n = 30) at the Department of Obstetrics and Gynecology at Turgut Ozal University between February 2010 and January 2013. Pro-hepcidin, hemoglobin (Hb) concentration, hematocrit (Hct), CRP, IL-6 and iron status parameters were measured in all patients and compared between groups. Results: Levels of serum prohepcidin in PE and control groups were similar and amount 69.4 ± 19.7 and 71.9 ± 22.1 ng/ml, respectively. The difference was not statistically significant ( p: 0.694). On the other hand, the study group had a statistically lower iron binding capacity (IBC), total iron binding capacity, transferin, total protein, albumin levels ( p < 0.05). No significant differences were found among prohepcidin, Hb concentration, Hct, iron, ferritin, IL-6, urea and creatine in both the groups. Conclusion: In pregnancies complicated by PE with normal values of hemoglobin and hematocrit, serum prohepcidin concentrations are similar to those observed in healthy pregnant women. The analysis revealed no significant correlations between prohepcidin level and serum iron, serum ferritin or transferrin in the PE. [ABSTRACT FROM AUTHOR]

Background/aim: To investigate whether spontaneous preterm labor (PTL) with intact membranes is associated with changes in maternal serum prohepcidin concentrations. Materials and methods: The study consisted of patients with spontaneous PTL with intact membranes (n = 25), a control group of healthy pregnant women between the 24th and 37th gestational weeks (n = 22), and uncomplicated term pregnancies in spontaneous labor (n = 19). Blood samples were collected from patients at the time of clinical diagnosis. Levels of prohepcidin, hemoglobin, serum ferritin, serum iron, unsaturated iron binding capacity, total iron binding capacity, transferrin and transferrin saturation, C reactive protein, and interleukin-6 were measured. Results: Patients with spontaneous PTL had significantly lower maternal serum prohepcidin concentrations than term delivery and control subjects. Conclusion: Maternal serum prohepcidin concentration is lower in patients with spontaneous PTL compared to term delivery and control subjects. This suggests that measuring maternal serum prohepcidin concentrations in PTL may be a feasible method for understanding etiologic causes of spontaneous preterm delivery, but, before suggesting this as a course of action, low levels of prohepcidin in patients with PTL need to be more fully investigated. [ABSTRACT FROM AUTHOR]

Introduction: Hepcidin, a small peptide hormone synthesized in the liver, plays central role in regulation of iron metabolism. Hepcidin generation in chronic kidney disease (CKD) is dependent on iron status, anemia, inflammation, and hypoxia and erythropoietin levels. In our study, the relationship between Prohepcidin levels and inflammation and iron indices in non-diabetic uremic patients was investigated. Methods: This study has a cross-sectional design which includes four groups: Non-diabetic 21 patients with stage 4 CKD (predialysis), 20 hemodialysis (HD) and 21 peritoneal dialysis (PD) patients and 17 healthy volunteers as the control group. Complete blood count, iron, total iron binding capacity (TIBC), ferritin, high-sensitive C-reactive protein (hsCRP), fibrinogen, parathyroid hormone, interleukin (IL)-6 and Prohepcidin levels were recorded. Results: Serum Prohepcidin levels in the predialysis, HD, PD and the control groups were 119.6 ± 45.1 ng/mL, 140.2 ± 41.8 ng/mL, 148.2 ± 35.0 ng/mL and 93.8 ± 21.9 ng/mL, respectively ( p < 0.001). Prohepcidin was positively correlated with urea ( r = 0.345, p = 0.002), creatinine ( r = 0.465, p < 0.001), phosphorus ( r = 0.253, p = 0.025), hsCRP ( r = 0.275, p = 0.019), duration of dialysis treatment ( r = 0.443, p < 0.001), fibrinogen ( r = 0.467, p < 0.001) and IL-6 ( r = 0.615, p < 0.001) levels. A negative correlation was detected between Prohepcidin levels and albumin ( r = −0.286, p < 0.001), TIBC ( r = −0.573, p < 0.001), GFR ( r = −0.473, p < 0.001), hemoglobin ( r = −0.351, p = 0.002) and hematocrit ( r = −0.342, p = 0.002) levels. Discussion: Prohepcidin levels increase with deepening anemia and show positive correlation with inflammatory markers. Therapeutic interventions regarding Prohepcidin action on inflammatory status may play a role in the treatment of anemia due to inflammation. Functional iron deficiency is frequent in uremic patients. It may be beneficial to measure Prohepcidin level together with ferritin among these patients. [ABSTRACT FROM AUTHOR]

Background: Hepcidin, a key regulator of iron homeostasis, increases when inflammation and some infections occur. It plays a critical role in macrophage iron retention, which underlies inflammation/infection caused anemia. It is known that Helicobacter pylori (HP) may lead to iron deficiency (ID) due to occult blood loss or reduced iron absorption. This study investigates the role of prohepcidin, hepcidin's precursor, in ID and ID anemia (IDA) with a concurrent HP infection. Methods: In this prospectively designed study, 15 patients with IDA and a concurrent HP infection (group 1), 11 patients with an ID and a concurrent HP infection (group 2), and 18 patients with HP infection (group 3) were observed. All groups received only HP eradication therapy. Twenty-five age- and sex-matched children without ID/IDA and HP infection were included in the study as the control group. In all groups and control group, measurements were taken for pre- and posttreatment hemoglobin, serum prohepcidin, serum ferritin, serum iron (SI), transferrin saturation, erythrocyte sedimentation rate, fibrinogen, and C-reactive protein levels. Results: The pretreatment prohepcidin levels were significantly higher only in group 1 compared to the control group ( P < .05). In group 1, a significant increase in hemoglobin and SI levels and a significant reduction in prohepcidin levels were additionally observed following HP eradication treatment ( P < .05). However, in groups 2 and 3, significant differences in hemoglobin, iron, and prohepcidin levels between pre- and posttreatment were not observed. Conclusion: Elevated serum prohepcidin might indicate the role of inflammation in the etiology of anemia concurrent with HP. [ABSTRACT FROM AUTHOR]

To analyze the interconnection between erythropoiesis and iron metabolism, one of the issues raised in this study was to know iron bioavailability under physiopathological conditions. Our aim was to understand the functional axis response composed of erythropoietin (Epo)-hepcidin-ferroportin (FPN), when 2 dysfunctional states coexist, using an animal model of iron overload followed by hypoxia. FPN and prohepcidin were assessed by immunohistochemistry using rabbit anti-mouse FPN polyclonal and prohepcidin monoclonal antibodies. Goat-labeled polymer − horseradish peroxidase anti-rabbit EnVision + System (DAB) was used as the secondary antibody. Epo levels were measured by ELISA. Tissue iron was studied by Prussian blue iron staining. Erythropoietic response was assessed using conventional hematological tests. Iron overload increased prohepcidin that remained high in hypoxia, coexisting with high levels of Epo in hypoxia, with or without iron overload. In hypoxia, FPN was clearly evident in reticuloendothelial macrophages, more than in hypoxia with iron overload. Interestingly, duodenal FPN was clearly identified on the basolateral membrane in hypoxia, with or without iron overload. Our data indicate that 2 signals could induce the cell-specific response as follows: ( i) iron signal, induced prohepcidin, which reduced reticuloendothelial FPN and reduced iron availability; and ( ii) hypoxia signal, stimulated Epo, which affected iron absorption by stabilizing duodenal FPN and allowed iron supply to erythropoiesis independently of store size. [ABSTRACT FROM AUTHOR]

Hepcidin is the major regulatory peptide hormone of iron metabolism, encoded by the HAMP (hepcidin antimicrobial peptide) gene. Hepcidin is expressed mainly in hepatocytes, but is also found in the blood in both a mature and prohormone form. Although, the function of mature hepcidin and the regulation of the HAMP gene have been extensively studied, the intracellular localization and the fate of prohepcidin remains controversial. In the present study, we propose a novel role for prohepcidin in the regulation of its own transcription. Using indirect immunofluorescence and mCherry tagging, a portion of prohepcidin was detected in the nucleus of hepatocytes. Prohepcidin was found to specifically bind to the STAT3 (signal transducer and activator of transcription 3) site in the promoter of HAMP. Overexpression of prohepcidin in WRL68 cells decreased HAMP promoter activity, whereas decreasing the amount of prohepcidin caused increased promoter activity measured by a luciferase reporter-gene assay. Moreover, overexpression of the known prohepcidin-binding partner, α-1 antitrypsin caused increased HAMP promoter activity, suggesting that only the non-α-1 antitrypsin-bound prohepcidin affects the expression of its own gene. The results of the present study indicate that prohepcidin can bind to and transcriptionally regulate the expression of HAMP, suggesting a novel autoregulatory pathway of hepcidin gene expression in hepatocytes. [ABSTRACT FROM AUTHOR]

The aim of the study is to investigate the role of circulating prohepcidin and hepcidin, which are homeostatic regulators of iron metabolism and mediators of inflammation, in anemia associated with Behcet's disease (BD) and the differential diagnosis of healthy controls. Twenty patients with BD and twenty healthy controls were included in this prospective study. Laboratory tests including complete blood count, serum prohepcidin, hepcidin, iron, total iron binding capacity (TIBC), transferrin, ferritin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were determined. Serum prohepcidin and hepcidin levels in patients with BD were significantly higher than healthy group. In the group with BD positive correlation was determined between the values of serum prohepcidin, hepcidin, hemoglobin, total binding capacity and ferritine. Serum prohepcidin and hepcidin levels are closely associated with disease activity in patients and might play a role in the pathobiology of chronic disease anemia associated with patients with BD. [ABSTRACT FROM AUTHOR]

Background: Prohepcidin, a liver-derived peptide with antimicrobial properties, is regulated by factors such as iron load and inflammation. Hepcidin is a central player in iron homeostasis. It downregulates the iron exporter ferroportin, thereby inhibiting iron absorption, release and recycling. Thus, prohepcidin increases the possibility of ironlimited erythropoiesis and development of anemia. In end-stage renal disease (ESRD), plasma hepcidin levels are elevated, which may contribute to iron deficiency in these patients. This study was undertaken to investigate the relationship between prohepcidin and serum biochemical parameters related to anemia and inflammation in the aforesaid patients. Methods: Fifty-four stable patients with uremia who were on chronic hemodialysis were enrolled in the study. The patients were withheld from intravenous iron two weeks prior to laboratory measurements. Later, (total) prohepcidin was measured by ELISA method as were other parameters including serum iron, TIBC, TSAT, Hct, ferritin, albumin, CRP, ESR, cholesterol and triglyceride. Results: Serum prohepcidin levels were higher than normal values in the patients, but they were not correlated to the serum iron, TIBC, TSAT, Hct, ferritin, albumin, cholesterol and triglyceride (p>0.05). No significant association were also found with ESR (p=0.97, r= -0.005) or CRP (p=0.053, r =0.26). Conclusion: Serum prohepcidin level was higher in chronic hemodialysis patients but it was not predictive of iron status or inflammatory conditions in these patients. Confirmation of these results may necessitate studies with larger sample sizes or measurement of the biologically active form of hepcidin. [ABSTRACT FROM AUTHOR]

Abstract: Anemia in cancer patients can result from a complex interaction of numerous factors including iron deficiency, inflammation, toxicity related to therapy and effect of cancer on the marrow. Determining effective anemia treatment can therefore be complex, requiring a combination of diagnostic tests. Research on iron metabolism has highlighted the importance of hepcidin and its potential role in development of anemia of inflammation (AI). Hepcidin is a peptide that controls iron flow, is induced by inflammation and is speculated to cause the sequestration of iron in patients with inflammation. In the present study, serum hepcidin concentration determined by LC-MS/MS was shown to correlate with inflammatory markers in patients with anemia of cancer (AoC). In the absence of a widely-available serum hepcidin detection assay, detection of prohepcidin using a commercial assay has been used for several years as a surrogate for measuring serum hepcidin concentration. Analysis of prohepcidin concentration did not reveal any correlation with hepcidin or with inflammatory markers in patient samples and our data suggest that prohepcidin may not be stable in serum. Algorithms to sub-classify AoC patients showed that hepcidin was strongly associated with the population subset with inflammation and without iron deficiency. Serum hepcidin concentrations may therefore be a good predictor of AI, useful in diagnosis of anemia etiology and in treatment determination. [ABSTRACT FROM AUTHOR]

This study highlights the iron profile of myelodysplastic patients in the era of hepcidin and its pro-hormone, pro-hepcidin. Previous studies have focused on the anemia of chronic renal failure, thalassemia, and hemochromatosis. We determined if pro-hepcidin played a role in iron overload in patients with myelodysplasia (MDS). Thirty adult patients with MDS and 20 healthy adults (controls) were selected. Our results revealed a statistically significant difference in pro-hepcidin levels between the two tested groups (Z = 2.9, p = 0.003). There was a weak positive correlation between pro-hepcidin and hematocrit (HCT; r = 0.49, p = 0.02) in the healthy group only. Neither age, subtypes of MDS, gender, soluble transferrin receptor (sTFR) or ferritin affected the pro-hepcidin level in patients with MDS. The role of ineffective erythropoiesis in the regulation of pro-hepcidin is superior to the role of chronic blood transfusion therapy. [ABSTRACT FROM AUTHOR]

Anemia is a common clinical problem in end-stage renal disease (ESRD). Despite adequate erythropoiesis-stimulating agent (ESA) supplementation, some ESRD patients still have suboptimal hemoglobin levels, and iron deficiency and inflammation are recognized as the two most common causes. Hepcidin, a newly discovered key regulator of iron homeostasis, is found to be accumulated in ESRD. As it controls iron uptake and release, better reflecting real-time iron demand and availability, hepcidin might become a target in the management of iron deficiency and ESA resistance in dialysis patients. For their pleiotropic functions apart from lipid-modulation, statins are also used as anti-inflammatory or immune-modulating agents. In this study, we applied simvastatin for the purpose of influencing serum prohepcidin level in a group of maintenance hemodialysis patients. Thirty-three ESRD patients undergoing hemodialysis were enrolled and assigned to experimental and hemodialysis control groups according to their lipid profile. Nineteen healthy adults were chosen as a normal control group. The subjects in the experimental group took 20 mg simvastatin orally per night for eight weeks, and those in the hemodialysis control group took no statins or any other lipid-modulating drugs. Before and after the experiment, the serum prohepcidin concentrations, plasma IL-6, and serum C-reactive protein (CRP), ferritin, hemoglobin, albumin, total cholesterol, glycerinate, and LDL and HDL cholesterol levels were determined. Of the 33 hemodialysis patients, the serum prohepcidin concentration was (175.8 ± 52.9) ng/mL, significantly higher than that in the normal control group (149.5 ± 24.2) ng/mL ( P = 0.048). In the experimental group, the serum prohepcidin level was (156.7 ± 51.9) ng/mL before treatment, and (190.6 ± 49.6) ng/mL after eight weeks ( P = 0.127). In the hemodialysis control group, the serum prohepcidin level was (190.6 ± 49.6) ng/mL at the beginning, and (193.5 ± 36.0) ng/mL after eight weeks ( P = 0.728). In the experimental group, after taking simvastatin for eight weeks the serum total cholesterol and triglyceride levels had lowered by 18.6% ( P = 0.004) and 55.1% ( P = 0.007), respectively. The plasma IL-6, serum CRP, ferritin, hemoglobin, albumin, and LDL and HDL cholesterol levels in both the hemodialysis group remained unchanged. According to our preliminary study, eight weeks of 20 mg simvastatin did not significantly change the serum prohepcidin, high-sensitive CRP, or IL-6 concentrations in the group of maintenance hemodialysis patients. [ABSTRACT FROM AUTHOR]

Hepcidin is a small defensin-like peptide, the production of which by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. Kidneys are involved in not only the synthesis of hepcidin, but they also may be involved in its elimination. A cross-sectional study was performed to assess prohepcidin and hepcidin in serum, urine, and ultrafiltrate/peritoneal effluent in relation to type of renal replacement therapy and prohepcidin and hepcidin correlations with renal function, iron status, and markers of inflammation. Methods. Prohepcidin and hepcidin high-sensitivity CRP, TNF alpha, and IL-6 were measured using commercially available kits in 102 patients on hemodialyses, 17 on hemodiafiltration, 44 on peritoneal dialyses, and 22 healthy volunteers. Results. In hemodialyzed and peritoneally dialyzed patients with residual renal function, serum prohepcidin (264.21 ± 95.84 vs. 341.84 ± 90.45 ng/mL, p < 0.01; 142.76 ± 57.87 vs. 238.42 ± 84.32 ng/mL, p < 0.01, respectively) and hepcidin (178.89 ± 89.87 vs. 295.76 ± 129.65 ng/mL, p < 0.01; 108.43 ± 75.49 vs. 186.53 ± 119.62 ng/mL, p < 0.01, respectively) were significantly lower than in anuric patients. In peritoneal effluent, prohepcidin level was significantly higher than in ultrafiltrate of HD/HDF patients. In multiple regression analysis, residual renal function, ferritin, and hsCRP were predictors of hepcidin in hemodialyzed patients, while residual renal function and ferritin were predictors of hepcidin in peritoneally dialyzed patients. Conclusions. Residual renal function seems to play a pivotal role in hepcidin levels in dialyzed patients. In addition, the presence of low-grade inflammation, more pronounced in anuric patients, and functional iron deficiency may also contribute to the elevated hepcidin. The removal of prohepcidin with ultrafiltrate/peritoneal effluent may partially explain its lower concentration in peritoneal dialysis and hemodiafiltration. [ABSTRACT FROM AUTHOR]

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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

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. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hepcidin is the key regulator of iron metabolism. Iron supplementation is often introduced in dialyzed patients to replete or to maintain iron stores, particularly in patients treated with erythropoietic-stimulating agents. The present study was aimed to assess possible relation between hepcidin and erythropoietin therapy, with particular attention being paid to erythropoietin-hyporesponsiveness in hemodialyzed patients. Prohepcidin and hepcidin were studied using commercially available kits from DRG Instruments GmbH, Germany (ELISA method) and Bachem, UK (RIA method). TNFα and IL-6 were studied using kits from and R&D (Abington, UK), and hsCRP was studied using kits from American Diagnostica, USA. Hyporesponsive patients to erythropoietin therapy had significantly lower serum albumin, cholesterol, LDL, hemoglobin, hematocrit, and residual renal function, and significantly higher serum ferritin, hsCRP, IL-6, TNFα, and erythropoietin dose. The difference in serum prohepcidin and hepcidin did not reach statistical significance; however, there was a tendency toward higher values of both prohepcidin and hepcidin in hyporesponsive patients. In conclusion, though hyporesponsiveness to erythropoietin therapy occur in dialyzed patients, it is mainly associated with subclinical inflammation than with hepcidin excess. Further studies are needed to develop a reliable and reproducible assay to elucidate the potential contribution of hepcidin to hyporesponsiveness during erythropoietin therapy. [ABSTRACT FROM AUTHOR]

Abstract: Hepcidin is a small liver-derived peptide central in the regulation of systemic iron homeostasis. Although the gene regulation has been extensively studied at transcriptional level, the corresponding effects on the production of bioactive peptide are largely unknown. We therefore applied a proteomics-based approach by combining immunocapture with time-of-flight mass spectrometry to characterize hepcidin-25 produced by hepatocyte-derived cell lines. Similar to its transcriptional regulation, mature hepcidin-25 was strongly secreted upon stimulation with BMPs and IL-6. The immunocaptured peptide down-modulated iron-exporter ferroportin on the monocyte/macrophage surface. Further mass spectrometry-based analyses indicated that hepcidin-25 in its bioactive conformation was very stable in serum and urine and not converted into its smaller isoforms. Hepcidin-25 was processed in the Golgi apparatus from its precursor, while the unprocessed prohepcidin was secreted only when furin-like protease activity was intracellularly inhibited. Furthermore, the amounts of hepatocytic secretion of hepcidin-25 are highly correlated with the gene transcript levels. An unexpected observation was the synergistic effect of BMPs and IL-6 on hepcidin-25 secretion, which points towards cross-talk between iron and inflammatory stimuli. The study underscores hepcidin-25 quantification as a valuable tool to unravel regulatory pathways in iron metabolism. [Copyright &y& Elsevier]

Abstract: Familial amyloidosis TTR V30M (FAP-I) usually presents as a sensorimotor and autonomic neuropathy. Anemia was first described in this disease more than 20 years ago and classified as an anemia of chronic disease. However, so far no studies have addressed the role of inflammatory proteins in this disease. The anemia affects 24.8% of symptomatic FAP-I Portuguese patients, and is associated with low serum erythropoietin levels, independently of the presence of clinical nephropathy. In this study we evaluate the role of systemic inflammation on the erythropoietin production and anemia genesis in FAP-I. Data from 24 FAP-I patients (50% with anemia) and 33 healthy controls were analysed. Laboratory data included hemoglobin, hematocrit, ferritin, transferrin saturation, soluble transferrin receptors (sTR), prohepcidin, hepcidin-25, C-reactive protein (CRP), interleukin-6 and erythropoietin levels. In general, FAP-I patients presented significantly lower hemoglobin, hematocrit and observed/expected erythropoietin levels. Mean sTR was lower in FAP-I patients than in controls (2.36±1.3 vs 2.96±0.8 mg/l, P =0.055) correlating with hemoglobin and hematocrit. As expected, sTR were positively correlated with erythropoietin both in controls and in FAP-I patients. No significant differences on CRP, interleukin-6, transferrin saturation, ferritin and hepcidin-25 were found between anemic and non-anemic FAP-I patients and between non-anemic FAP-I patients and healthy controls. In all groups, a positive correlation was observed between hepcidin-25 and ferritin. Surprisingly, significantly lower prohepcidin levels were found in FAP-I patients, with or without anemia, not correlated with serum hepcidin-25 levels. In general, the decreased observed/expected EPO levels in FAP-I correlated with the prohepcidin levels, therefore raising the possibility that a common defect in these two hormones may be somehow involved in the genesis of the disease. [Copyright &y& Elsevier]

The aim of our study was to assess possible relations between prohepcidin, iron status and inflammatory markers in hemodialysis (HD) patients, as well as its association with resistance to recombinant human erythropoietin (rhEPO) therapy. Fifty HD patients and 25 healthy controls were enrolled in the study. Among HD patients, 25 were non-responders and 25 were responders to rhEPO therapy. Complete blood cell count, reticulocyte count, and circulating levels of ferritin, iron, transferrin saturation, C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (s-IL2R), soluble transferrin receptor (s-TfR), IL-6 and prohepcidin were measured in all patients and controls. HD patients showed higher circulating levels of ferritin, s-TfR, CRP, IL-6, s-IL2R and prohepcidin, and lower levels of transferrin compared to healthy controls. Higher levels of s-TfR, CRP and lower levels prohepcidin were observed among non-responders compared to responders. Prohepcidin levels correlated negatively with s-TfR and reticulocyte count. The weekly rhEPO/kg dose was found to be positively correlated with CRP, hemoglobin and s-TfR. In conclusion, our data show that a close interaction exists between inflammation, iron status and prohepcidin serum levels that ultimately regulate intracellular iron availability. Prohepcidin and s-TfR, together with CRP, may prove to be good markers of resistance to rhEPO therapy in HD patients. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Although hepcidin is proposed as a regulator of iron absorption, this has not been assessed in humans. Objective: Our objective was to assess the relation between serum or urinary prohepcidin and iron absorption in healthy premenopausal women. Design: The subjects were 28 healthy women aged 22-51 y with normal hemoglobin concentrations (120-152 g/L). Absorption of 0.5 mg Fe with 0.2 μCi 59Fe tracer, both as FeSO4, was measured by whole-body scintillation counting 13 d after oral administration. Fasting blood and urine samples were collected the day of and 16 wk after the absorption measurement. Serum and urinary prohepcidin concentrations were measured by an enzyme-linked immunosorbent assay by using an antibody against amino acid residues 28-47 of the proregion. Results: Mean ( ± SD) iron absorption was 36 ± 19% (range: 4-81%), and serum ferritin (geometric x) was 27 μg/L (range: 4-122 μg/L), as commonly observed in healthy premenopausal women. Serum prohepcidin was 196 μg/L (range: 99-376 μg/L) and, in contrast with urinary prohepcidin, was relatively consistent for the women between 0 and 16 wk. Serum prohepcidin correlated directly with serum ferritin (R2 = 0.28, P < 0.01) but was unrelated to 59Fe absorption, in contrast to serum ferritin (R2 = 0.33, P < 0.01). Conclusions: Serum prohepcidin concentrations were relatively stable within subjects and correlated with serum ferritin. However, unlike serum ferritin, neither serum nor urinary prohepcidin concentrations were related to iron absorption in healthy women. [ABSTRACT FROM AUTHOR]

Objective:Prohepcidin (Pro-Hep), synthesized in the liver, is the prohormone of hepcidin (Hep), which reduces iron absorption in the gut; its synthesis is enhanced by inflammation and is reduced during hypoxia. We aimed to study the hypothesis that infants born small for gestational age (SGA) have reduced cord blood concentrations of Pro-Hep.Study Design:Cord blood was collected from 20 SGA (term and near term >35 week gestation) infants and 20 appropriate for gestational age (AGA) controls. We excluded infants exposed to maternal chronic diseases, smoking, diabetes, alcohol or drug use. Both groups had a 1 min Apgar score above or equal to 7 and had normal cord blood pH (above 7.25). ELISA was used to determine serum concentrations of Pro-Hep and erythropoietin (EPO). Circulating CD71+/CD45−/SSClow cells were measured by flow cytometry as an index of erythroid progenitors.Result:There were no significant differences between groups in terms of hemoglobin concentrations, and Pro-Hep. In contrast, EPO levels and circulating CD71+/CD45−/SSClow erythroid progenitors were significantly higher in the SGA group. These differences remained significant even after controlling for gestational age and gravidity.Conclusion:Contrary to EPO upregulation during intrauterine growth restriction (IUGR), and higher concentrations of circulating erythroid progenitors, Pro-Hep concentration is not affected by IUGR. [ABSTRACT FROM AUTHOR]