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Effect of cholecalciferol on serum hepcidin and parameters of anaemia and CKD-MBD among haemodialysis patients: a randomized clinical trial.
Obi, Y, Yamaguchi, S, Hamano, T, Sakaguchi, Y, Shimomura, A, Namba-Hamano, T, Mikami, S, Nishi, O, Tanaka, M, Kamoto, A, et al
Scientific reports. 2020;(1):15500
Abstract
In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563 . UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E .
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Vitamin D status is associated with hepcidin and hemoglobin concentrations in patients with severe traumatic injury.
Apple, CG, Miller, ES, Kannan, KB, Stortz, JA, Cox, M, Loftus, TJ, Parvataneni, HK, Patrick, M, Hagen, JE, Brakenridge, S, et al
The journal of trauma and acute care surgery. 2020;(6):1124-1130
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Abstract
BACKGROUND Severe traumatic injury leads to persistent injury-associated anemia that is associated with hypercatecholaminemia, systemic inflammation, increased hepcidin, and a functional iron deficiency. Vitamin D has been shown to reduce proinflammatory cytokines and hepcidin concentrations. This study aimed to investigate the association of vitamin D status with inflammation, iron biomarkers, and anemia following blunt trauma. METHODS A prospective observational cohort study comparing blunt trauma patients (n = 45) with elective hip replacement patients (n = 22) and healthy controls (n = 8) was performed. Bone marrow ferroportin, transferrin receptor, and erythroferrone expression was measured using quantitative polymerase chain reaction (qPCR). Plasma was assessed for systemic inflammation, erythropoietin (EPO), iron regulation, and vitamin D (25-OH) concentrations using enzyme-linked immunosorbent assay. Hemoglobin was measured on the day of discharge. RESULTS Compared with hip replacement, trauma patients had higher plasma interleukin-6 (90.1 vs. 3.8 pg/mL), C-reactive protein (6,223 vs. 2,612 ng/mL), and hepcidin (79.3 vs. 21.2 ng/mL) concentrations. Trauma patients had lower vitamin D (25-OH) (12.8 vs. 18.1 ng/mL) and iron (23.5 vs. 59.9 μg/mL) levels compared with hip replacement patients. Despite the higher hepcidin EPO levels, bone marrow erythroferrone expression was increased 69% following trauma. CONCLUSION Following elective hip replacement, patients did have anemia and impaired iron homeostasis without a significant change in inflammatory biomarkers, EPO, and vitamin D status. Vitamin D status did correlate with systemic inflammation, iron dysfunction, and persistent injury-associated anemia following severe blunt trauma. Further research is needed to determine whether supplementation with vitamin D in the trauma population could improve the persistent injury-associated anemia. LEVEL OF EVIDENCE Prospective study, prognostic, level III.
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Hepcidin and iron: novel findings for elite female rugby Sevens players.
Smith, S, Sims, ST, Thorpe, H, Baker, D, Haszard, J, Badenhorst, C, Black, KE
The Journal of sports medicine and physical fitness. 2020;(2):289-293
Abstract
BACKGROUND Iron deficiency is a common deficiency disease worldwide with athletes at increased risk. METHODS 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. RESULTS 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). CONCLUSIONS Some elite female rugby Sevens players have sub-optimal iron stores over the course of a season.
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Testosterone Administration During Energy Deficit Suppresses Hepcidin and Increases Iron Availability for Erythropoiesis.
Hennigar, SR, Berryman, CE, Harris, MN, Karl, JP, Lieberman, HR, McClung, JP, Rood, JC, Pasiakos, SM
The Journal of clinical endocrinology and metabolism. 2020;(4)
Abstract
CONTEXT Severe energy deprivation markedly inhibits erythropoiesis by restricting iron availability for hemoglobin synthesis. OBJECTIVE The objective of this study was to determine whether testosterone supplementation during energy deficit increased indicators of iron turnover and attenuated the decline in erythropoiesis compared to placebo. DESIGN This was a 3-phase, randomized, double-blind, placebo-controlled trial. SETTING The study was conducted at the Pennington Biomedical Research Center. PATIENTS OR OTHER PARTICIPANTS Fifty healthy young males. INTERVENTION(S): Phase 1 was a 14-day free-living eucaloric controlled-feeding phase; phase 2 was a 28-day inpatient phase where participants were randomized to 200 mg testosterone enanthate/week or an isovolumetric placebo/week during an energy deficit of 55% of total daily energy expenditure; phase 3 was a 14-day free-living, ad libitum recovery period. MAIN OUTCOME MEASURE(S): Indices of erythropoiesis, iron status, and hepcidin and erythroferrone were determined. RESULTS Hepcidin declined by 41%, indicators of iron turnover increased, and functional iron stores were reduced with testosterone administration during energy deficit compared to placebo. Testosterone administration during energy deficit increased circulating concentrations of erythropoietin and maintained erythropoiesis, as indicated by an attenuation in the decline in hemoglobin and hematocrit with placebo. Erythroferrone did not differ between groups, suggesting that the reduction in hepcidin with testosterone occurs through an erythroferrone-independent mechanism. CONCLUSION These findings indicate that testosterone suppresses hepcidin, through either direct or indirect mechanisms, to increase iron turnover and maintain erythropoiesis during severe energy deficit. This trial was registered at www.clinicaltrials.gov as #NCT02734238.
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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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Genetic Variability and Trajectories of DNA Methylation May Support a Role for HAMP in Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.
Heinsberg, LW, Arockiaraj, AI, Crago, EA, Ren, D, Shaffer, JR, Sherwood, PR, Sereika, SM, Weeks, DE, Conley, YP
Neurocritical care. 2020;(2):550-563
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Abstract
BACKGROUND/OBJECTIVE Preclinical evidence suggests that iron homeostasis is an important biological mechanism following aneurysmal subarachnoid hemorrhage (aSAH); however, this concept is underexplored in humans. This study examined the relationship between patient outcomes following aSAH and genetic variants and DNA methylation in the hepcidin gene (HAMP), a key regulator of iron homeostasis. METHODS In this exploratory, longitudinal observational study, participants with verified aSAH were monitored for acute outcomes including cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) and evaluated post-discharge at 3 and 12 months for long-term outcomes of death and functional status using the Modified Rankin Scale (mRS; poor = 3-6) and Glasgow Outcome Scale (GOS; poor = 1-3). Participants were genotyped for two genetic variants, and DNA methylation data were collected from serial cerebrospinal fluid over 14 days post-aSAH at eight methylation sites within HAMP. Participants were grouped based on their site-specific DNA methylation trajectory, with and without correcting for cell-type heterogeneity (CTH), and the associations between genetic variants and inferred DNA methylation trajectory groups and patient outcomes were tested. To correct for multiple testing, an empirical significance threshold was computed using permutation testing. RESULTS Genotype data for rs10421768 and rs7251432 were available for 241 and 371 participants, respectively, and serial DNA methylation data were available for 260 participants. Acute outcome prevalence included CV in 45% and DCI in 37.1% of the overall sample. Long-term outcome prevalence at 3 and 12 months included poor GOS in 23% and 21%, poor mRS in 31.6% and 27.3%, and mortality in 15.1% and 18.2%, respectively, in the overall sample. Being homozygous for the rs7251432 variant allele was significantly associated with death at 3 months (p = 0.003) and was the only association identified that passed adjustment for multiple testing mentioned above. Suggestive associations (defined as trending toward significance, p value < 0.05, but not meeting empirical significance thresholds) were identified between the homozygous variant allele for rs7251432 and poor GOS and mRS at 3 months (both p = 0.04) and death at 12 months (p = 0.02). For methylation trajectory groups, no associations remained significant after correction for multiple testing. However, for methylation trajectory groups not adjusted for CTH, suggestive associations were identified between cg18149657 and poor GOS and mRS at 3 months (p = 0.003 and p = 0.04, respectively) and death at 3 months (p = 0.04), and between cg26283059 and DCI (p = 0.01). For methylation trajectory groups adjusted for CTH, suggestive associations were identified between cg02131995 and good mRS at 12 months (p = 0.02), and between cg26283059 and DCI (p = 0.01). CONCLUSIONS This exploratory pilot study offers preliminary evidence that HAMP may play a role in patient outcomes after aSAH. Replication of this study and mechanistic investigation of the role of HAMP in patient outcomes after aSAH are needed.
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Association of Hepcidin With Anemia Parameters in Incident Dialysis Patients: Differences Between Dialysis Modalities.
Lim, JH, Park, YW, Lee, SH, Do, JY, Kim, SH, Han, S, Jung, HY, Choi, JY, Cho, JH, Kim, CD, et al
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2020;(1):4-16
Abstract
Hepcidin's relationships with other variables are unclear. We evaluated associations of serum hepcidin with clinical parameters in ESRD patients. Ninety-nine incident dialysis patients, including 57 on peritoneal dialysis (PD) and 42 on HD, were prospectively followed for 6 months. Serum hepcidin levels significantly increased during initial 6 months of dialysis. In the multivariate regression model, independent predictors of serum hepcidin levels in ESRD patients before maintenance dialysis were interleukin-6, ferritin, phosphate, iron, and aspartate transaminase. Six months after initiating dialysis, serum hepcidin levels were independently predicted by ferritin, total iron binding capacity (TIBC), and aspartate transaminase in all patients, whereas by ferritin and TIBC in PD patients, and ferritin, TIBC, and 24-h urine volume in HD patients. Serum hepcidin levels are differentially associated with anemia parameters in PD compared with HD patients. Urine volume was an independent predictor of hepcidin levels in early HD patients.
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How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children.
Abuga, KM, Muriuki, JM, Williams, TN, Atkinson, SH
International journal of molecular sciences. 2020;(18)
Abstract
Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.
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The role of iron in viral infections.
Schmidt, SM
Frontiers in bioscience (Landmark edition). 2020;(5):893-911
Abstract
Crucial cellular processes such as DNA synthesis and the generation of ATP require iron. Viruses depend on iron in order to efficiently replicate within living host cells. Some viruses selectively infect iron - acquiring cells or influence the cellular iron metabolism via Human hemochromatosis protein (HFE) or hepcidin. During infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) iron overload is associated with poor prognosis for the patient and enhanced progression of the disease. Recent findings still lack to fully describe the viral interaction with the host iron metabolism during infection. This review summarizes the current knowledge of the viral regulation on the host cell iron metabolism in order to discuss the therapeutic option of iron chelation as a potential and beneficial adjuvant in antiviral therapy.
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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.