Higher Hepcidin Research Articles

Genetic analysis of TMPRSS6 gene in Saudi female patients with iron deficiency anemia

Objective/backgroundMutations in transmembrane protease serine 6 (TMPRSS6) gene induce high hepcidin level, which causes iron-refractory iron deficiency anemia (IRIDA) by preventing duodenal iron absorption. This study aims to identify the common genetic variations of the TMPRSS6 gene that affect iron levels among Saudi female patients with iron deficiency anemia (IDA). MethodsAll study participants were Saudi females (12–49 years old): 32 patients with IDA, 32 patients with IRIDA, and 34 healthy individuals comprising the control group. Hematological investigations, iron profile, serum hepcidin level, and TMPRSS6 gene transcription were determined. The TMPRSS6 gene was amplified, sequenced, and analyzed among all study participants. ResultsThe mean hepcidin and TMPRSS6 RNA transcription levels in IDA and IRIDA groups were significantly lower than those in the control group. TMPRSS6 gene sequence analysis detected 41 variants: two in the 5′ untranslated region (5′UTR), 17 in introns, and 22 in exons. Thirty-three variants were previously reported in the Single Nucleotide Polymorphism Database, and eight variants were novel; one novel variant was in 5′UTR (g.-2 T > G); five novel variants were detected in exons (p.W73X, p.D479N, p.E523K, p.L674L, and p.I799I). At the time of the sequence analysis of our samples, two variants—p.D479N and p.674L—were novel. However, these variants are present at a very low allele frequency in other populations (L674L, 0.00007761 and D479N, 0.000003980). ConclusionThis is the first study to investigate the genetic variants of TMPRSS6 gene in Saudi female patients with IDA. The generated data will serve as a reference for future studies on IDA in the Arab population.

Iron deficiency and risk factors in pre-menopausal females living in Auckland, New Zealand.

Iron deficiency is prevalent in New Zealand, with low dietary haem intake and blood loss previously identified as risk factors. However, the influence of the hormone hepcidin on iron status has not been investigated. Females (n=170) aged 18-45 residing in Auckland participated in a cross-sectional study. Iron status and inflammation were assessed with serum biomarkers including; serum ferritin, haemoglobin, soluble transferrin receptor, hepcidin, C-reactive protein and interleukin-6. Lifestyle factors were assessed using a series of validated questionnaires, including an iron food frequency questionnaire. Potential determinants of serum ferritin were identified using multiple linear regression analysis. Iron insufficiency was confirmed in 55.8% of participants (Serum ferritin <30 μg·L-1). Hepcidin levels were higher in those who were iron sufficient (Serum ferritin ≥30 μg·L-1) (6.62 nM vs 1.17 nM, p<0.001). South Asian females had higher hepcidin (8.78 nM) levels, compared to New Zealand Europeans (6.28 nM) (p=0.018), a result likely due to South Asians presenting with higher interleukin-6 (1.66 vs 0.63 pg·mL-1, p<0.001). Hepcidin (β=0.082, p<0.001) and frequency of meat intake (β=0.058, p=0.001) were identified as significant predictors of serum ferritin in New Zealand Europeans, while hepcidin was the only identified predictor in South Asians (β=0.138, p<0.001) and those of other ethnicities (β=0.117, p<0.002). This is the first study in New Zealand to show that hepcidin levels strongly predict serum ferritin in premenopausal females. Additionally, frequency of meat intake appears to be an important determinant of iron status in New Zealand Europeans.

A hepcidin-based approach for iron therapy in hemodialysis patients: A pilot study.

Hepcidin is a key factor that regulates iron homeostasis. In hemodialysis patients (HD), a high hepcidin level may decrease intestinal iron absorption and reduce the efficacy of Oral iron vs Intravenous iron therapy. Whether the hepcidin level in HD could guide oral iron therapy is unclear. We report a monocentric study on nine "erythropoietin (EPO)-free" patients (without recombinant human EPO [rHU-EPO] for at least 6 months) and normal hepcidin level (<20 ng mL) during the study. After 15 days of washout, oral iron (ferrous sulfate 80 mg/day) was introduced. The primary end point was the hemoglobin response and iron store at 3 months. Nine patients (8 men, 1 woman) with a median age of 62 years (range 42-79) were included. After 1 week of treatment, the median transferrin saturation index increased from 15% (range 6-61) to 34% (range 13-42), P = 0.62, reflecting intestinal absorption. The median ferritin level remained stable 80 μg/L (35-293) vs 82 μg/L (range 37-496) between M0 and M3, P = 0.43. During the 3-month study, median hemoglobin level increased from 11.5 d/dL (range10.4-13.7) to 12.8 g/dL (range 11.1-15.2), P = 0.01. No major side effects were observed. Quality of life assessed by the SF-36 criteria was similar during the 3-month study. Oral iron therapy is effective and safe in EPO-free patients with normal hepcidin levels. These findings suggest that serum hepcidin may be a marker for defining iron therapy strategies in HD patients. HD patients treated with rHU-EPO and with normal hepcidin levels could benefit from oral iron treatment.

Relationship between Cardiac Geometry and Serum Hepcidin in Chronic Kidney Disease: Analysis from the KNOW-CKD Study.

BackgroundFew studies have examined the relationship between cardiac function and geometry and serum hepcidin levels in patients with chronic kidney disease (CKD). We aimed to identify the relationship between cardiac function and geometry and serum hepcidin levels.MethodsWe reviewed data of 1,897 patients in a large-scale multicenter prospective Korean study. Logistic regression analysis was used to identify the relationship between cardiac function and geometry and serum hepcidin levels.ResultsThe mean relative wall thickness (RWT) and left ventricular mass index (LVMI) were 0.38 and 42.0 g/m2.7, respectively. The mean ejection fraction (EF) and early diastolic mitral inflow to annulus velocity ratio (E/e′) were 64.1% and 9.9, respectively. Although EF and E/e′ were not associated with high serum hepcidin, RWT and LVMI were significantly associated with high serum hepcidin levels in univariate logistic regression analysis. In multivariate logistic regression analysis after adjusting for variables related to anemia, bone mineral metabolism, comorbidities, and inflammation, however, only each 0.1-unit increase in RWT was associated with increased odds of high serum hepcidin (odds ratio, 1.989; 95% confidence interval, 1.358–2.916; P < 0.001). In the subgroup analysis, the independent relationship between RWT and high serum hepcidin level was valid only in women and patients with low transferrin saturation (TSAT).ConclusionAlthough the relationship was not cause-and-effect, increased RWT was independently associated with high serum hepcidin, particularly in women and patients with low TSAT. The relationship between cardiac geometry and serum hepcidin in CKD patients needs to be confirmed in future studies.

The significance of serum hepcidin on iron status in overweight and obese patients with iron-deficiency anemia

BACKGROUND: Deficiency of iron is one of the most prevalent nutritional disorders, and obesity is an increasing nutritional problem, but only a few studies mention a possible association between them in Iraq. Adipocytes secrete adipokines, some of them are related to the inflammatory response in addition to hepcidin, a hormone that mediates iron metabolism. OBJECTIVES: This study aimed to assess the significance of serum hepcidin in obese patients with iron deficiency. PATIENTS MATERIALS AND METHODS: Ninty patients were separated into Group 1 (normal weight), Group 2 (30 overweight), and the Group 3 (30 obese). All patients were investigated by complete blood count, serum hepcidin, iron, total iron-binding capacity, and ferritin using the standard laboratory techniques. RESULTS: There were no significant differences among the groups regarding the severity of anemia, red cell indices, white blood cells, and platelets count. The obese group had significantly higher serum hepcidin and ferritin (P = 0.003, 0.040, respectively), while serum iron is lower. Serum hepcidin positively correlated with the serum ferritin but inversely correlated with serum iron. Increased hepcidin level in obesity could be related to inflammatory adipokines that effect on hepatic hepcidin transcription and hepcidin mRNA expression, in addition to the nonhepatic production of hepcidin in an autocrine manner; hepcidin, in turn, is responsible for low serum iron, but a high ferritin level in correlation to high hepcidin may explain by low-grade chronic inflammation associated with obesity. CONCLUSIONS: The severity of iron-deficiency anemia is not affected by body weight; however, significantly higher serum hepcidin and ferritin in the obese patient with a lower serum iron should be considered during the assessment of iron status in those patients.

Iron metabolism and iron-refractory iron deficiency anemia

Hepcidin is a key molecule that regulates iron metabolism in the body. Iron refractory iron deficiency anemia (IRIDA) is a genetic disorder caused by a defect in the TMPRSS6 gene encoding matriptase-2, a transmembrane serine protease that physiologically inhibits hepcidin production. In patients with IRIDA, the iron uptake in the intestine is remarkably reduced, and iron deficiency anemia (IDA) develops. However, in contrast to the ordinary IDA, high hepcidin levels in IRIDA keep the serum ferritin levels normal or sometimes high. Due to the malabsorption of iron in the intestine, IRIDA is refractory to oral iron supplementation, but partially responds to parenteral iron administration. A high hepcidin level gives IRIDA a lot of similarities with anemia of chronic disease, and a differential diagnosis between the two disorders needs careful inspection. Diagnosis of IRIDA needs genetic testing that is hardly available in most facilities, and therefore its clinical features are not fully understood.

Higher Hepcidin Levels in Adolescents With Obesity Are Associated With Metabolic Syndrome Dyslipidemia and Visceral Fat, Irrespective of Iron Status

Higher Hepcidin Levels in Adolescents With Obesity Are Associated With Metabolic Syndrome Dyslipidemia and Visceral Fat, Irrespective of Iron Status

Disbalanced Erythroid Ferroportin Expression Contributes to Ineffective Erythroid Output in Anemia of Chronic Disease

Iron is essential for proper red blood cell development. During erythroid maturation in the bone marrow iron dependency starts at the basophilic stage, and lasts until the reticulocyte stage. Thereby the majority of iron is delivered in a Tf-TfR dependent manner and is incorporated in hemoglobin of developing red cells. Just recently, it has been discovered that erythroblasts and mature red blood cells not only incorporate iron but also express the sole known iron exporter, ferroportin (Fpn), throughout their development, and thus can also effectively export iron that is not used for heme synthesis. Fpn surface expression is regulated via hepcidin, a hepatocyte-derived peptide, which binds directly to surface-Fpn, inducing its internalization and consequent degradation in lysosomes. Among patients suffering from anemia of chronic disease (ACD), hepcidin is constantly induced due to long-lasting inflammation, leading to impaired iron export capacity. While splenic tissue iron overload, which is associated with the restricted capacity of red pulp macrophages to export recycled iron form degraded erythrocytes is well established, the effect of high hepcidin levels in ACD and its consequences on developing erythroblasts in the bone marrow has not been investigated. First we induced chronic kidney disease (CKD) in C57BL/6 mice via an Adenine - diet. Alongside microcytic anemia, reduced Tf-saturation, increased hepcidin levels and splenic tissue iron overload, we found a ~38% increase in tissue iron content in bone marrows of CKD mice compared to control mice. In parallel, Western blot analysis revealed massively reduced Fpn protein levels in the bone marrow. Moreover, the individual iron-dependent erythroblast precursor populations (i.e. basophilic, polychromatic, orthochromatic erythroblasts and reticulocytes) showed higher levels of intracellular iron as measured by Calcein fluorescence via flow cytometry. We could further corroborate these results by Western blot analysis and flow cytometric work-up of reticulocytes and mature red blood cells in the blood stream, both revealing highly reduced Fpn protein levels on these cells in mice suffering from CKD. Based on these findings we performed additional experiments to investigate the detrimental effect of iron overload on erythroid development and to exclude the possibility of a direct inflammation-regulated process in the CKD model. Therefor we established an iron-overload mouse model via repeated parenteral iron dextran applications. Despite significantly increased Tf-saturation levels as well as hepatic hepcidin levels (&amp;gt;4-fold) and reduced bone marrow Fpn protein levels among iron-treated mice, iron overload led to higher stress levels among erythroid precursor populations. In detail, we could demonstrate via flow cytometry that higher intracellular iron pools (measured by Calcein), correlated with higher levels of mitochondrial stress and higher levels of lipid peroxidation (determined by mean fluorescence intensity of MitoSOX and Bodipy 581/59, respectively). These data indicate that iron is a critical regulator of stress during erythroid development and can be regulated via the hepcidin-Fpn axis. In conclusion, we clearly show that Fpn expression on erythroid precursor cells is inversely regulated to systemic hepcidin levels and affects the erythropoietic bone marrow iron content. Moreover our results reveal a novel model for ineffective erythroid output in patients suffering from ACD due to hepcidin-triggered Fpn internalistation. Based on our data, anti-hepcidin treatment strategies are promising to overcome restricted erythropoiesis, which will be evaluated in future experiments. Disclosures Theurl: Kymab Ltd: Consultancy, Equity Ownership.

Hepcidin mediates hypoferremia and reduces the growth potential of bacteria in the immediate post-natal period in human neonates

Septicemia is a leading cause of death among neonates in low-income settings, a situation that is deteriorating due to high levels of antimicrobial resistance. Novel interventions are urgently needed. Iron stimulates the growth of most bacteria and hypoferremia induced by the acute phase response is a key element of innate immunity. Cord blood, which has high levels of hemoglobin, iron and transferrin saturation, has hitherto been used as a proxy for the iron status of neonates. We investigated hepcidin-mediated redistribution of iron in the immediate post-natal period and tested the effect of the observed hypoferremia on the growth of pathogens frequently associated with neonatal sepsis. Healthy, vaginally delivered neonates were enrolled in a cohort study at a single center in rural Gambia (N = 120). Cord blood and two further blood samples up to 96 hours of age were analyzed for markers of iron metabolism. Samples pooled by transferrin saturation were used to conduct ex-vivo growth assays with Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli and Klebsiella pneumonia. A profound reduction in transferrin saturation occurred within the first 12 h of life, from high mean levels in cord blood (47.6% (95% CI 43.7–51.5%)) to levels at the lower end of the normal reference range by 24 h of age (24.4% (21.2–27.6%)). These levels remained suppressed to 48 h of age with some recovery by 96 h. Reductions in serum iron were associated with high hepcidin and IL-6 levels. Ex-vivo growth of all sentinel pathogens was strongly associated with serum transferrin saturation. These results suggest the possibility that the hypoferremia could be augmented (e.g. by mini-hepcidins) as a novel therapeutic option that would not be vulnerable to antimicrobial resistance. Trial registration: The original trial in which this study was nested is registered at ISRCTN, number 93854442.

THE ASSOCIATION BETWEEN LEVELS OF HEPCIDIN, IRON STATUS AND MICRO-INFLAMMATION MARKERS AMONG HAEMODIALYSIS

Hepcidin is a polypeptide that regulates iron homeostasis and could serve as an indicator of functional iron deficiency in patients with end-stage renal disease (ESRD); this may also aid in the assessment of patient's response to erythropoietin (EPO). Erythropoietin is a cytokine glycoprotein secreted by the kidney in response to cellular hypoxia; it stimulates the production of red blood cells (erythrocytes) in the bone marrow. The present study was aimed to investigate serum levels of hepcidin, iron status and inflammation markers such as C-reactive protein (CRP) in patients with ESRD on maintenance HD and to observe the correlation of serum hepcidin with conventional iron and inflammatory markers. A total of 59 patients on maintenance HD were enrolled; 29 age and sex-matched healthy subjects were included as controls. Laboratory tests including complete blood count, creatinine, urea, albumin, BUN, serum hepcidin, serum ferritin, serum iron and CRP were performed. The serum hepcidin levels was measured by a competitive enzyme-linked immunosorbent assay (C-ELISA). Serum hepcidin levels were significantly higher in patients with ESRD than in the control group (63.7±47.4 ng/mL: 11.5± 26.3 ng/mL respectively P&lt;0.001). The hemoglobin and serum iron levels in the patient group were significantly lower than in the control group. Higher feritine levels were found in hemodialysis patients (448.5±710 ng/mL): ( 98.3±83 ng/mL) of controls (P =0.01). A positive and significant correlation was observed between the values of serum hepcidin and CRP. Serum hepcidin and high-sensitivity C-reactive protein levels were significantly higher in maintenance haemodialysis patients (case=21.2±28.6 mg/L:control=2.9±2.7 mg/L, P=0.001). In conclusion, higher hepcidin levels are found in ESRD patients and serum hepcidin levels are associated with iron status and micro-inflammation (defined as hsCRP &lt; 6mg/l, in maintenance haemodialysis patients). Also, our findings suggest that hepcidin might play a role in the pathophysiology of anemia associated with chronic diseases as ESRD. As well as, ELISA method for measuring serum hepcidin should facilitate the routine measurement of hepcidin in clinical practice.&#x0D; Peer Review History: &#x0D; UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.&#x0D; Received file &#x0D; &#x0D; Average Peer review marks at initial stage: 5.5/10&#x0D; Average Peer review marks at publication st0ge: 8.5/10&#x0D; Reviewer(s) detail:&#x0D; Name: Hebatallah Ahmed Mohamed Moustafa&#x0D; Affiliation: Heliopolis University Cairo, Egypt&#x0D; E-mail: anasweety2003@yahoo.com&#x0D; &#x0D; Name: Dr. Heba M. Abd El-Azim &#x0D; Affiliation: Damanhour University, Egypt&#x0D; E-mail: h_m_abdelazim@hotmail.com&#x0D; Comments of reviewer(s): &#x0D;

Hepcidin and iron: novel findings for elite female rugby Sevens players.

Iron deficiency is a common deficiency disease worldwide with athletes at increased risk. A proposed new mechanism of exercise-induced iron deficiency in athletes involves the iron-regulatory hormone hepcidin, however, there is limited information on this amongst elite athletes. This study describes iron status in elite female rugby Sevens players. Blood samples were collected at the start and mid-season and analyzed for serum iron, serum ferritin (SF), soluble transferring receptor (sTfR), high sensitivity C-reactive Protein (hsCRP) and hepcidin. Of the 17 players 18% were iron deficient (SF<30 µg/L) with 29-35% of players with sub-optimal iron stores at some point during the study (SF<45 µg/L). Serum hepcidin was strongly correlated with SF (r=0.61, P=0.0001). Some elite female rugby Sevens players have sub-optimal iron stores over the course of a season.

Hepcidin and Anemia: A Tight Relationship

Hepcidin, the master regulator of systemic iron homeostasis, tightly influences erythrocyte production. High hepcidin levels block intestinal iron absorption and macrophage iron recycling, causing iron restricted erythropoiesis and anemia. Low hepcidin levels favor bone marrow iron supply for hemoglobin synthesis and red blood cells production. Expanded erythropoiesis, as after hemorrhage or erythropoietin treatment, blocks hepcidin through an acute reduction of transferrin saturation and the release of the erythroblast hormone and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis, limiting iron consumption, increases transferrin saturation and stimulates hepcidin transcription. Deregulation of hepcidin synthesis is associated with anemia in three conditions: iron refractory iron deficiency anemia (IRIDA), the common anemia of acute and chronic inflammatory disorders, and the extremely rare hepcidin-producing adenomas that may develop in the liver of children with an inborn error of glucose metabolism. Inappropriately high levels of hepcidin cause iron-restricted or even iron-deficient erythropoiesis in all these conditions. Patients with IRIDA or anemia of inflammation do not respond to oral iron supplementation and show a delayed or partial response to intravenous iron. In hepcidin-producing adenomas, anemia is reverted by surgery. Other hepcidin-related anemias are the “iron loading anemias” characterized by ineffective erythropoiesis and hepcidin suppression. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and some forms of hemolytic anemias as pyruvate kinase deficiency. The paradigm is non-transfusion-dependent thalassemia where the release of erythroferrone from the expanded pool of immature erythroid cells results in hepcidin suppression and secondary iron overload that in turn worsens ineffective erythropoiesis and anemia. In thalassemia murine models, approaches that induce iron restriction ameliorate both anemia and the iron phenotype. Manipulations of hepcidin might benefit all the above-described anemias. Compounds that antagonize hepcidin or its effect may be useful in inflammation and IRIDA, while hepcidin agonists may improve ineffective erythropoiesis. Correcting ineffective erythropoiesis in animal models ameliorates not only anemia but also iron homeostasis by reducing hepcidin inhibition. Some targeted approaches are now in clinical trials: hopefully they will result in novel treatments for a variety of anemias.

Intestinal Inflammation Differentially Influences Iron Homeostasis in WT versus Hepcidin KO Rats

IntroductionThe chronic anemia associated with IBD in humans may result from trans‐activation of the the iron‐regulatory hormone (Hamp) by pro‐inflammatory cytokines in hepatocytes. High hepcidin decreases serum iron by blunting intestinal iron absorption and impairing release of storage iron, thus decreasing iron delivery to the erythroid marrow and causing anemia. Pharmacological targeting of hepcidin offers an attractive therapeutic approach to mitigate IBD‐associated anemia. Testing of such interventions has mainly utilized mouse models of hereditary hemochromatosis (HH). Collectively, these mice have inappropriately low (or absent) hepcidin expression, and concomitant increases in intestinal iron absorption leading to iron overload. However, since iron metabolism in mice and humans varies notably, development of complementary experimental models is imperative.ObjectiveWe created a novel model of HH, the Hamp KO rat, and utilized the DSS model of colitis for this investigation. We hypothesized that Hamp levels would increase in rats with colitis (due to pro‐inflammatory cytokine signaling), which would then blunt intestinal iron absorption and cause anemia (thus modeling human IBD). We further postulated that iron absorption would be unaffected by inflammation in Hamp KO rats, thus preventing the development of anemia.MethodsIntestinal inflammation was induced by providing DSS (4% w/v) in drinking water for 7 days. Standard bioassays were utilized to track iron loading. Iron absorption was assessed by oral‐intragastric gavage of an 59Fe transport solution.ResultsHamp−/− rats displayed multi‐visceral iron overload, and intestinal iron absorption was increased (≈2.5 fold). DSS treatment caused similar pathological changes in the duodenum and colon of Hamp KO rats and WT littermates. Systemic inflammation was not observed in any experimental animals. DSS exposure decreased TSAT, and serum and splenic nonheme iron in both genotypes. In WT animals, DSS exposure: 1) decreased blood hemoglobin levels by ≈15%; 2) reduced liver hepcidin expression by ≈60%; 3) and increased intestinal iron absorption by &gt;2‐fold. Conversely, in Hamp−/− rats, DSS treatment increased blood hemoglobin levels and decreased iron absorption by ≈2.5‐fold. Moreover, the distribution of absorbed 59Fe in blood and many tissues was different between genotypes after DSS txt.ConclusionsDespite the lack of systemic inflammation, iron homeostasis was perturbed in WT rats by DSS‐induced enteritis. Reduced hepcidin expression likely resulted from anemia and/or iron depletion of serum and spleen. This may explain why iron absorption increased, since a relative state of iron deficiency may have existed after DSS exposure. In the KOs, intestinal inflammation altered iron homeostasis in distinct ways. This differential response to DSS may relate to the iron‐overload phenotype of the KO rats, or alternatively, it could reflect a role for hepcidin in mediating the pathophysiologic response to intestinal inflammation. Future studies in iron‐depleted Hamp KO rats may allow for a better understanding of the role of hepcidin in regulating iron homeostasis in IBD.Support or Funding InformationNIH Grant R01 DK074867 and R01 DK109717 (to JFC)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High serum hepcidin is associated with the occurrence of anemia in anti-myeloperoxidase antibody-associated vasculitis with normal kidney function: a cross-sectional study.

The etiology of anemia in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been elucidated. In this cross-sectional study, we tried to investigate the relationship between serum hepcidin and anemia in myeloperoxidase (MPO)-ANCA-AAV. Data of 64 newly diagnosed AAV patients who did not have kidney dysfunction or hemorrhage were analyzed. Serum hepcidin was measured with enzyme linked immunosorbent assay. Twenty-three of 64 patients had anemia. Compared with patients without anemia, patients with anemia had higher Birmingham vasculitis activity score [10 (3, 23) vs. 5 (3, 17), p = 0.020], lower levels of serum iron (5.83 ± 1.63 vs. 9.76 ± 1.54, p < 0.001) and higher levels of ferrtin [358.00 (59.85, 1314.10) vs. 151.05 (43.00, 645.30), p = 0.006]. All 64 patients had increased levels of serum hepcidin compared with normal controls, while patients with anemia had higher serum hepcidin than patients without anemia (85.30 ± 16.92ng/mL vs. 53.48 ± 13.32ng/mL, p < 0.001). In the multivariable analysis, the level of hemoglobin correlated with the levels of serum iron (r = 0.344, p = 0.026) and hepcidin (r = - 0.353, p = 0.022). Low level of serum iron was related to high level of serum hepcidin (r = - 0.472, p = 0.001). Immunosuppressive treatment induced rapid decrease of hepcidin and increase of serum iron on the 1st month, while the recovery of hemoglobin was relatively slow. This study indicated that in MPO-AAV without kidney dysfunction or hemorrhage, the existence of anemia is associated with high level of hepcidin which induces low serum iron and the abnormality of iron utilization.

Studying anemia of chronic disease and iron deficiency in patients with rheumatoid arthritis by iron status and circulating hepcidin.

Anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the two most important types of anemia in rheumatoid arthritis (RA). Functional iron deficiency in ACD can be attributed to overexpression of the main iron regulatory hormone hepcidin leading to diversion of iron from the circulation into storage sites resulting in iron-restricted erythropoiesis. The aim is to investigate the role of circulating hepcidin and to uncover the frequency of IDA in RA. The study included 51 patients with RA. Complete blood counts, serum iron, total iron binding capacity, ferritin, and hepcidin-25 were assessed. ACD was found in 37.3% of patients, IDA in 11.8%, and combined (ACD/IDA) in 17.6%. Serum hepcidin was higher in ACD than in control and the other groups (P≤0.001). It was strongly and positively correlated with ferritin (P<0.001), while hemoglobin, serum iron, and total iron binding capacity were negatively correlated with hepcidin (P=0.016, 0.022 and <0.001, respectively). High serum hepcidin was significantly associated with ACD in RA. IDA alone or combined with ACD was encountered in about a third of patients.

PLASMA FERRITIN AND HEPCIDIN LEVELS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Iron disorder and abnormal expression of hepcidin play important roles in many diseases, but it is still unclear in type 2 diabetes mellitus (T2DM). We aimed to assess iron, ferritin and hepcidin levels in plasma of with or without T2DM and evaluated increased body iron stores as risk factor for developing T2DM. Plasma samples were collected from 88 participants, who were categorized into 2 groups based on the presence or absence of T2DM. Demographics and general health parameters were recorded. Chemiluminescence microparticle immunoassay and enzyme-linked immunosorbent assay were used to detect iron, ferritin and hepcidin concentrations. The geometric mean±SD of the plasma level of hepcidin, ferritin, iron and insulin among T2DM comparing with that of healthy controls were evaluated. Plasma ferritin and hepcidin levels in T2DM group were higher than in the control group (P &lt; 0.05). The geometric mean ± SD of hepcidin and ferritin for T2DM were 41.1±23.3 μg/L and 227.2±156.1 ŋg/L respectively; higher than the 15.2±2.3 μg/L and 114.4±60.4 ŋg/L of controls respectively. There was a significant associated between high level of plasma hepcidin (OR=2.75) and ferritin (OR=2.24); with T2 DM. In conclusion: the regulation of body iron, an essential but also toxic element is strictly controlled by a small peptide hormone hepcidin. The present data demonstrated that the higher hepcidin level in diabetic patients may be due to that higher ferritin, the elevated hepcidin might have adaptive value through down-regulated iron absorb and play an important role in pathogenesis of T2 DM.

Serum Hepcidin and GDF-15 levels as prognostic markers in urothelial carcinoma of the upper urinary tract and renal cell carcinoma

BackgroundCancer is a life-threatening disease that causes every fourth death. It is often hard to determine the time point of progression. Therefore, biomarkers for cancer entities that indicate disease progression or aggressiveness and thereby guide therapeutic decisions are required. Unfortunately, reliable biomarkers are rare. In this study, the potential of serum hepcidin and serum GDF-15 as biomarkers that correlate with patient’s survival in the two entities upper urinary tract urothelial carcinomas (UUTUC) and renal cell carcinoma (RCC) were analyzed.MethodsIn this retrospective study n = 38 patients suffering from UUTUC, n = 94 patients suffering from RCC and n = 21 patients without infections or cancer, all hospitalized at the University Hospital Muenster, were included. Serum samples of patients were retrospectively analyzed. Serum hepcidin and GDF-15 levels were measured and correlated to aggressiveness and progression of the disease as well as patient’s outcome.ResultsFor both entities, UUTUC and RCC, serum hepcidin levels as well as serum GDF-15 levels were increased compared to sera of controls. High serum hepcidin and GDF-15 levels were associated with metastases and cancer relapse. Also, in both entities, the overall survival was decreased in patients with increased serum hepcidin and GDF-15 levels. Hence, high serum hepcidin and GDF-15 levels correlated with patient’s outcome.ConclusionTo conclude, the data of this study show a correlation of high serum hepcidin and GDF-15 levels with aggressiveness and progression of the disease and demonstrate potential prognostic properties of serum hepcidin and GDF-15 levels. The data support the further assessment of serum hepcidin and GDF-15 as prognostic markers in RCC and UUTUC.

The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women.

Hepatic hepcidin synthesis is stimulated by inflammation but inhibited during iron deficiency anemia (IDA). In humans, the relative strength of these opposing signals on serum hepcidin and the net effect on iron absorption and systemic iron recycling is uncertain. In this prospective, 45-day study, in young women (n=46; age 18-49 years) with or without IDA, we compared iron and inflammation markers, serum hepcidin and erythrocyte iron incorporation from 57Fe-labeled test meals, before and 8, 24 and 36 hours (h) after influenza/DPT vaccination as an acute inflammatory stimulus. Compared to baseline, at 24-36 h after vaccination: 1) interleukin-6 increased 2-3-fold in both groups (P<0.001); 2) serum hepcidin increased >2-fold in the non-anemic group (P<0.001), but did not significantly change in the IDA group; 3) serum iron decreased in the non-anemic group (P<0.05) but did not change in the IDA group; and 4) erythrocyte iron incorporation did not change in either of the two groups, but was approximately 2-fold higher in the IDA group both before and after vaccination (P<0.001). In this study, mild acute inflammation did not increase serum hepcidin in women with IDA, suggesting low iron status and erythropoietic drive offset the inflammatory stimulus on hepcidin expression. In non-anemic women, inflammation increased serum hepcidin and produced mild hypoferremia, but did not reduce dietary iron absorption, suggesting iron-recycling macrophages are more sensitive than the enterocyte to high serum hepcidin during inflammation. The study was registered as a prospective observational trial at clinicaltrials.gov identifier: 02175888. The study was funded by the International Atomic Energy Agency.

Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in haemodialysis patients.

Anaemia and resistance to erythropoiesis-stimulating agents (ESAs) are common complications in haemodialysis (HD) patients. We investigated the role of hepcidin in the development of anaemia and ESA resistance/hyporesponsiveness and its relation to the plasma levels of the inflammatory markers interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP). This study included 60 maintenance HD patients attending Ain Shams University Hospital and 30 age- and sex-matched healthy subjects as a control group. Serum hepcidin, IL-6, hsCRP and haemoglobin (Hb) levels were measured in all subjects. The erythropoietin resistance index (ERI) was calculated in the patient group only. There was a significant difference between the patients and controls; the patients had higher hepcidin, IL-6, and hsCRP levels and a lower Hb level. Patients were classified according to their response to ESAs into responder and non-responder groups. Those in the non-responder group had higher hepcidin, IL-6, and hsCRP levels, a higher ERI, and a lower Hb level. Hepcidin showed a positive correlation with IL-6 and hsCRP but a negative correlation with Hb. Upon performing a ROC curve analysis, a cut-off of ≥ 280ng/ml for hepcidin and ≥ 7.5 for ERI was able to discriminate the responder and non-responder groups with a prognostic accuracy of 83% and 77.3%, respectively. In addition, upon classifying the patients into tertiles according to the ERI, hepcidin significantly increased with increasing ERI. Our findings demonstrate an association between the hepcidin level, anaemia and ESA resistance/hyporesponsiveness in HD patients, suggesting its possible role as a candidate marker for ESA resistance.

Hepcidin and the BMP-SMAD pathway: An unexpected liaison.

Hepcidin, the main regulator of iron metabolism, is synthesized and released by hepatocytes in response to increased body iron concentration and inflammation. Deregulation of hepcidin expression is a common feature of genetic and acquired iron disorders: in Hereditary Hemochromatosis (HH) and iron-loading anemias low hepcidin causes iron overload, while in Iron Refractory Iron Deficiency Anemia (IRIDA) and anemia of inflammation (AI), high hepcidin levels induce iron-restricted erythropoiesis. Hepcidin expression in the liver is mainly controlled by the BMP-SMAD pathway, activated in a paracrine manner by BMP2 and BMP6 produced by liver sinusoidal endothelial cells. The BMP type I receptors ALK2 and ALK3 are responsible for iron-dependent hepcidin upregulation and basal hepcidin expression, respectively. Characterization of animal models with genetic inactivation of the key components of the pathway has suggested the existence of two BMP/SMAD pathway branches: the first ALK3 and HH proteins dependent, responsive to BMP2 for basal hepcidin activation, and the second ALK2 dependent, activated by BMP6 in response to increased tissue iron. The erythroid inhibitor of hepcidin Erythroferrone also impacts on the liver BMP-SMAD pathway although its effect is blunted by pathway hyper-activation. The liver BMP-SMAD pathway is required also in inflammation to cooperate with JAK2/STAT3 signaling for full hepcidin activation. Pharmacologic targeting of BMP-SMAD pathway components or regulators may improve the outcome of both genetic and acquired disorders of iron overload and deficiency by increasing or inhibiting hepcidin expression.