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Regulation of iron homeostasis through the erythroferrone-hepcidin axis in sickle cell disease.
Mangaonkar, AA, Thawer, F, Son, J, Ajebo, G, Xu, H, Barrett, NJ, Wells, LG, Bowman, L, Clair, B, Patel, N, et al
British journal of haematology. 2020;(6):1204-1209
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Abstract
Sickle cell disease (SCD) has a distinct pattern of transfusional iron overload (IO) when compared to transfusion-dependent β-thalassaemia major (TDT). We conducted a single institution prospective study to evaluate plasma biomarkers of iron regulation and inflammation in patients with SCD with IO (SCD IO cases, n = 22) and without IO (SCD non-IO cases, n = 11), and non-SCD controls (n = 13). Hepcidin was found to be inappropriately low, as evidenced by a significantly higher median hepcidin/ferritin ratio in non-SCD controls compared to SCD IO cases (0·3 vs. 0·02, P < 0·0001) and SCD non-IO cases (0·3 vs. 0·02, P < 0·0001), suggesting that certain inhibitory mechanism (s) work to suppress hepcidin in SCD. As opposed to the SCD non-IO state, where hepcidin shows a strong significant positive correlation with ferritin (Spearman ρ = 0·7, P = 0·02), this correlation was lost when IO occurs (Spearman ρ = -0·2, P = 0·4). Although a direct non-linear correlation between erythroferrone (ERFE) and hepcidin did not reach statistical significance both in the IO (Spearman ρ = -0·4, P = 0·08) and non-IO state (Spearman ρ = -0·6, P = 0·07), patients with highest ERFE had low hepcidin levels, suggesting that ERFE contributes to hepcidin regulation in some patients. Our results suggest a multifactorial mechanism of hepcidin regulation in SCD.
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Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation.
Barcellini, W, Zaninoni, A, Gregorini, AI, Soverini, G, Duca, L, Fattizzo, B, Giannotta, JA, Pedrotti, P, Vercellati, C, Marcello, AP, et al
British journal of haematology. 2019;(3):523-531
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Abstract
Iron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non-transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 μg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis-associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ-interferon (IFN-γ) was increased, and both interleukin 6 and IFN-γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.
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Changes in the Serum Hepcidin-to-ferritin Ratio with Erythroferrone after Hepatitis C Virus Eradication Using Direct-acting Antiviral Agents.
Inomata, S, Anan, A, Yamauchi, E, Yamauchi, R, Kunimoto, H, Takata, K, Tanaka, T, Yokoyama, K, Morihara, D, Takeyama, Y, et al
Internal medicine (Tokyo, Japan). 2019;(20):2915-2922
Abstract
Objective Hepcidin is a master iron regulator hormone produced by the liver, but precise mechanism underlying its involvement in iron overload in hepatitis C virus (HCV) infection remains unclear. We investigated the serum hepcidin levels against iron overload before and after HCV eradication. Methods We prospectively investigated the iron metabolism characteristics in 24 patients with HCV genotype 1b infection before and after treatment. We also assessed the serum erythroferrone (ERFE) levels to investigate its association with iron metabolism changes. Patients were treated with Ledipasvir 90 mg and Sofosbuvir 400 mg once daily for 12 weeks and observed for 12 more weeks in order to evaluate their sustained virological response. Results Serum hepcidin levels at baseline were in the normal range, although serum ferritin levels were increased. After HCV eradication, both serum ferritin and hepcidin levels were significantly decreased at 24 weeks from baseline (p<0.001, p=0.006, respectively). However, the serum hepcidin-to-ferritin ratios were significantly increased (p<0.001). In addition, the serum ERFE levels were significantly decreased (p<0.001). Increases in the serum hepcidin-to-ferritin ratios were correlated with decreases in the serum ERFE levels (ρ=-0.422, p=0.039). Conclusion Serum hepcidin levels were relatively low against ferritin levels in HCV infection. However, after HCV eradication, the serum hepcidin-to-ferritin ratios were increased. These results indicate the improvement of inadequate hepcidin secretion against iron overload after HCV eradication. Downregulation of ERFE may have affected the improvement of iron metabolism.
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Serum hepcidin potentially identifies iron deficiency in survivors of critical illness at the time of hospital discharge.
Shah, A, Wray, K, James, T, Shine, B, Morovat, R, Stanworth, S, McKechnie, S, Kirkbride, R, Griffith, DM, Walsh, TS, et al
British journal of haematology. 2019;(2):279-281
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Hepcidin and arterial stiffness in children with systemic lupus erythematosus and lupus nephritis: A cross-sectional study.
Atkinson, MA, Joo, S, Sule, S
PloS one. 2019;(3):e0214248
Abstract
BACKGROUND Cardiovascular disease is common in patients with systemic lupus erythematosis (SLE) and lupus nephritis (LN). Up to 80% of children with SLE develop kidney disease, which is also associated with increased risk for cardiovascular disease and death compared to those without renal involvement. Hepcidin is an iron-regulatory protein which may contribute to atherosclerosis and is elevated in autoimmune disease. Pulse wave velocity (PWV) is a validated indicator of arterial stiffness, an early marker of cardiovascular risk, and is increased in children with SLE versus healthy controls. Our objective was to quantify hepcidin and PWV in children with SLE and investigate if those with biopsy-proven LN have higher hepcidin levels and higher PWV compared to those without kidney disease. METHODS Cross-sectional analysis with hepcidin was measured via ELISA assay in 16 children aged 10-21 years with SLE recruited from a single center. Subjects were classified as having LN if histologic evidence of the disease was documented on a clinical renal biopsy. Serum hepcidin was quantified using a validated competitive enzyme-linked immunoassay. Carotid-femoral PWV was measured using applanation tonometry. Wilcoxon rank sum testing was used to compare median levels of hepcidin, PWV, and other continuous variables by nephritis status. RESULTS The cohort (n = 16) was 93.8% female and 68.8% African-American with mean (SD) 16 (3.6) years. 37.5% (n = 6) had LN. Overall median (IQR) hepcidin was 34.4 (18.9, 91.9) ng/ml, and PWV 4.4 (4, 4.6) meters/second. Although significance was limited by small sample size, both hepcidin and PWV were higher in the subjects with LN. Median (IQR) hepcidin in subjects with LN was 71.5 (26.4, 116.4) ng/ml compared to 27.9 (18.7, 59.7) ng/ml in those with SLE(p = 0.19). Similarly, median (IQR) PWV in those with LN was 4.4 (4.4, 4.9) meters/second compared to 3 (3.75, 4.55) meters/second in those with without kidney involvement (p = 0.10). CONCLUSION PWV and serum hepcidin were higher in subjects with LN compared to those with SLE alone, suggesting that elevated hepcidin levels may be associated with morbid CV changes in children with LN. This association, along with identification of additional predictors of arterial stiffness in patients with LN, warrants further investigation.
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First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.
Renders, L, Budde, K, Rosenberger, C, van Swelm, R, Swinkels, D, Dellanna, F, Feuerer, W, Wen, M, Erley, C, Bader, B, et al
PloS one. 2019;(3):e0212023
Abstract
In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.
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Plasma hepcidin is associated with future risk of venous thromboembolism.
Ellingsen, TS, Lappegård, J, Ueland, T, Aukrust, P, Brækkan, SK, Hansen, JB
Blood advances. 2018;(11):1191-1197
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Abstract
Red cell distribution width (RDW) is associated with venous thromboembolism (VTE), but the underlying mechanism(s) is unclear. Iron deficiency is associated with high RDW, and studies suggest an association between iron deficiency and VTE. To assess whether iron deficiency is a risk factor for VTE that explains the association between RDW and VTE, we conducted a nested case-control study of 390 patients with VTE and 802 age- and sex-matched controls selected from the population-based cohort of the Tromsø Study. Physical measurements and blood samples were collected from 1994 to 1995. Logistic regression models were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE by RDW, hepcidin, and ferritin light chain (FtL). RDW was inversely associated with hepcidin, FtL, and hemoglobin. The risk of VTE increased linearly across categories of higher plasma hepcidin levels. Participants with hepcidin in the highest quartile had an OR for VTE of 1.32 (95% CI, 1.00-2.42), and those in the >90% percentile had an OR for VTE of 1.66 (95% CI, 1.14-2.42) compared with the reference group (quartiles 2 and 3). The risk estimates remained similar after adjustment for C-reactive protein. The risk of VTE increased by categories of higher RDW and was strengthened after inclusion of hepcidin and FtL in the multivariable model. Our findings reject the hypothesis that iron deficiency explains the association between RDW and VTE and suggest, in contrast, that high body iron levels might increase the risk of VTE.
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A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia.
Vadhan-Raj, S, Abonour, R, Goldman, JW, Smith, DA, Slapak, CA, Ilaria, RL, Tiu, RV, Wang, X, Callies, S, Cox, J, et al
Journal of hematology & oncology. 2017;(1):73
Abstract
BACKGROUND Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia. METHODS Thirty-three patients with hepcidin levels ≥5 ng/mL received LY2787106 either every 3 weeks (19 patients, dose range 0.3-10 mg/kg) (part A) or weekly (14 patients, dose 10 mg/kg) (part B). LY2787106 PK/PD markers of iron and hematology biology were measured. RESULTS LY2787106 clearance (32 mL/h) and volume of distribution (7.7 L) were independent of dose and time, leading to a dose-proportional increase in concentration with dose. Consistent dose-dependent increases in serum iron, and transferrin saturation were seen at the 3 and 10 mg/kg dose levels, typically peaking within 24 h after LY2787106 administration and returning to baseline by day 8. CONCLUSIONS Our findings indicate that LY2787106 was well tolerated in cancer patients with anemia and that targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization, thus supporting the role of hepcidin in iron regulation. TRIAL REGISTRATION ClinicalTrial.gov, NCT01340976.
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Serum Hepcidin and Iron Absorption in Paediatric Inflammatory Bowel Disease.
Martinelli, M, Strisciuglio, C, Alessandrella, A, Rossi, F, Auricchio, R, Campostrini, N, Girelli, D, Nobili, B, Staiano, A, Perrotta, S, et al
Journal of Crohn's & colitis. 2016;(5):566-74
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Abstract
BACKGROUND AND AIMS We sought to correlate hepcidin levels in inflammatory bowel disease [IBD] children with disease activity, inflammatory markers, and iron load test [ILT] and to compare IBD patients with coeliac and healthy patients. METHODS Between December 2012 and June 2013, 145 subjects [50 IBD patients, 45 coeliac patients and 50 healthy controls] were included in the study. All patients underwent the following examinations: blood count, iron status, erythropoiesis parameters, serum hepcidin, C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR]. In order to evaluate the efficacy of iron absorption, ILT was performed in IBD patients. Disease activity indexes and IBD duration, localisation, and therapy were also evaluated, and a faecal sample for calprotectin collected. RESULTS Serum hepcidin was significantly higher in IBD patients with active disease compared with both coeliac and healthy patients [p = 0.005, p = 0.003 respectively]. In a multivariate logistic regression model, having a Paediatric Crohn's Disease Activity Index [PCDAI] / Paediatric Ulcerative Colitis Activity Index [PUCAI] ≥ 30 resulted in the only variable independently associated with a positive serum hepcidin (odds ratio [OR] = 6.87; 95% confidence interval [CI] 1.4-33, p = 0.01]]. Patients with iron malabsorption [IM] showed higher values of ESR, CRP, and hepcidin [p = 0.02, p = 0.001, and p = 0.06, respectively]. Eight out of 12 [66.7%] children with IM showed an active disease compared with 6/31 [19.3%] children with normal ILT [p = 0.01]. Hepcidin levels correlated negatively with ILT [r = -0.451, p = 0.002], and positively with ferritin and CRP [r = 0.442, p = 0.0001; r = 0.243, p = 0.009, respectively] CONCLUSIONS Our study demonstrates that serum hepcidin is increased in IBD children with active disease and it is responsible for IM.
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Correlation of serum hepcidin levels with disease progression in hepatitis B virus-related disease assessed by nanopore film based assay.
Wang, J, Dong, A, Liu, G, Anderson, GJ, Hu, TY, Shi, J, Hu, Y, Nie, G
Scientific reports. 2016;:34252
Abstract
Chronic hepatitis B virus (HBV) infection often develop into cirrhosis, and both are major risk factors of hepatocellular carcinoma. However, effective approaches for the monitoring of HBV-related disease progress are still in need. Increased iron storage has an important role in HBV-related diseases. Hepcidin is a key regulator of iron homeostasis whose expression changes are often indicative of abnormal iron metabolism. There are few reports of hepcidin levels in patients with HBV infections, and the available results are inconsistent. In this study, using a recently validated nanopore silica film based method, we measured serum hepcidin levels in 46 HBV-related patients and 20 healthy controls. Patients were divided into three groups: chronic hepatitis B without cirrhosis; HBV-related cirrhosis; and HBV-related cirrhosis with hepatocellular carcinoma. Compared to healthy controls, the mean serum hepcidin level was significantly higher in CHB patients without cirrhosis, and in those with hepatocellular carcinoma, but not in those with cirrhosis. Iron-loading, viral infection and liver dysfunction are determined to be the major regulators of hepcidin in these patients. These observations suggest correlations between serum hepcidin and progression of chronic HBV infection, and may shed a new light on the development of biomarkers for HBV-related disease surveillance.