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1.
Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?
German, KR, Comstock, BA, Parikh, P, Whittington, D, Mayock, DE, Heagerty, PJ, Bahr, TM, Juul, SE
The Journal of pediatrics. 2022;:62-67.e1
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Abstract
OBJECTIVES To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.
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Erythroferrone structure, function, and physiology: Iron homeostasis and beyond.
Srole, DN, Ganz, T
Journal of cellular physiology. 2021;(7):4888-4901
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Abstract
Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.
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Effect of β-hydroxybutyrate monoester on markers of iron metabolism in new-onset prediabetes: findings from a randomised placebo-controlled trial.
Kimita, W, Bharmal, SH, Ko, J, Cho, J, Petrov, MS
Food & function. 2021;(19):9229-9237
Abstract
Background: People with prediabetes often have altered iron metabolism and may benefit from mild exogenous ketosis, which can now be successfully achieved thanks to recent developments in chemistry of food components. Objective: The objective was to investigate the effect of acute exogenous ketone monoester (β-hydroxybutyrate) on plasma levels of markers of iron metabolism in people with prediabetes. Methods: Eighteen participants with new-onset prediabetes after acute pancreatitis aged 18 years or above took part in randomised controlled cross-over trial in Auckland, New Zealand. After an overnight fast, participants consumed the exogenous ketone supplement or placebo. Blood samples were collected in the fasted state (0 minutes) and then serially every 30 minutes for 150 minutes. Both participants and study personnel were blinded to the intervention/placebo allocation. Repeated measures analysis of variance was performed using total area under the curve to determine the change in hepcidin and ferritin over time after consumption of the exogenous ketone supplement and placebo. Results: Consumption of the exogenous ketone supplement significantly elevated blood levels of β-hydroxybutyrate from 0.20 mmol L-1 at baseline to 3.50 mmol L-1 at 30 minutes (p < 0.05) and remained significantly elevated for the duration of the trial. The total area under the curve of hepcidin was 340.5 ± 121.1 ng mL-1 after the exogenous ketone supplementation as compared with 343.2 ± 119.6 ng mL-1 min-1 after the use of placebo (p = 0.91). The total area under the curve of ferritin was 786.7 ± 129.1 ng mL-1 min-1 after the exogenous ketone supplementation as compared with 776.9 ± 131.4 ng mL-1 min-1 after the use of placebo (p = 0.10). Conclusion: Acute supplementation of β-hydroxybutyrate did not significantly affect the circulating levels of hepcidin or ferritin in people with prediabetes. Long-term effects of β-hydroxybutyrate warrant investigations in the future.
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Energy deficit increases hepcidin and exacerbates declines in dietary iron absorption following strenuous physical activity: a randomized-controlled cross-over trial.
Hennigar, SR, McClung, JP, Hatch-McChesney, A, Allen, JT, Wilson, MA, Carrigan, CT, Murphy, NE, Teien, HK, Martini, S, Gwin, JA, et al
The American journal of clinical nutrition. 2021;(2):359-369
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Abstract
BACKGROUND Strenuous physical activity promotes inflammation and depletes muscle glycogen, which may increase the iron regulatory hormone hepcidin. Hepcidin reduces dietary iron absorption and may contribute to declines in iron status frequently observed following strenuous physical activity. OBJECTIVES To determine the effects of strenuous physical activity on hepcidin and dietary iron absorption and whether energy deficit compared with energy balance modifies those effects. METHODS This was a randomized, cross-over, controlled-feeding trial in healthy male subjects (n = 10, mean ± SD age: 22.4 ± 5.4 y, weight: 87.3 ± 10.9 kg) with sufficient iron status (serum ferritin 77.0 ± 36.7 ng/mL). Rest measurements were collected before participants began a 72-h simulated sustained military operation (SUSOPS), designed to elicit high energy expenditure, glycogen depletion, and inflammation, followed by a 7-d recovery period. Two 72-h SUSOPS trials were performed where participants were randomly assigned to consume either energy matched (±10%) to their individual estimated total daily energy expenditure (BAL) or energy at 45% of total daily energy expenditure to induce energy deficit (DEF). On the rest day and at the completion of BAL and DEF, participants consumed a beverage containing 3.8 mg of a stable iron isotope, and plasma isotope appearance was measured over 6 h. RESULTS Muscle glycogen declined during DEF and was preserved during BAL (-188 ± 179 mmol/kg, P-adjusted < 0.01). Despite similar increases in interleukin-6, plasma hepcidin increased during DEF but not BAL, such that hepcidin was 108% greater during DEF compared with BAL (7.8 ± 12.2 ng/mL, P-adjusted < 0.0001). Peak plasma isotope appearance at 120 min was 74% lower with DEF (59 ± 38% change from 0 min) and 49% lower with BAL (117 ± 81%) compared with rest (230 ± 97%, P-adjusted < 0.01 for all comparisons). CONCLUSIONS Strenuous physical activity decreases dietary iron absorption compared with rest. Energy deficit exacerbates both the hepcidin response to physical activity and declines in dietary iron absorption compared with energy balance. This trial was registered at clinicaltrials.gov as NCT03524690.
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Intravenous iron supplementation after liver surgery: Impact on anemia, iron, and hepcidin levels-a randomized controlled trial.
Assouline, B, Benoliel, A, Zamberg, I, Legouis, D, Delhumeau, C, Favre, M, Andrès, A, Toso, C, Samii, K, Schiffer, E
Surgery. 2021;(3):813-821
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Abstract
BACKGROUND Anemia is a recognized risk factor for perioperative related morbidity and mortality and is frequently reported in liver surgeries with an estimated incidence of 32%. We aim to assess the impact of intravenous iron administration in the immediate postoperative period on anemia and iron status as well as to determine the kinetics of hepcidin after liver surgery. METHODS The HepciFer trial, a randomized controlled trial, included 50 patients undergoing liver surgery. In accordance with the randomization process, patients received either ferric carboxymaltose (15 mg/kg, maximum 1 g) or placebo 4 hours after surgery. RESULTS The mean hemoglobin level, 7 days after surgery, did not differ significantly between the intervention and control group (11.1 ± 1.8 g/dL and 10.4 ± 1.6 g/dL, respectively) with a mean difference of +0.7 g/dL ([95% confidence interval, -0.3 to +1.7], P = .173). Within patients receiving intravenous iron supplementation, none presented biological signs of functional iron deficiency. Hepcidin levels remained significantly higher during the observation period in the intervention group. Inflammatory biomarkers, red blood cells transfusion rate and hospital duration of stay were similar between groups. CONCLUSION Intravenous ferric carboxymaltose administration did not result in a significant increase of hemoglobin levels 7 days after surgery. However, this study suggests that intravenous iron supplementation in the immediate postoperative settings prevents functional iron deficiency. Intravenous iron supplementation overcame the hepcidin-mediated blockade of iron absorption and should be considered as the preferred route of administration in the postoperative period.
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Hepcidin and other indicators of iron status, by alpha-1 acid glycoprotein levels, in a cohort of Mexican infants.
Mendoza, E, Duque, X, Moran, S, Martínez-Andrade, G, Reyes-Maldonado, E, Flores-Huerta, S, Martinez, H
Annals of hematology. 2021;(4):879-890
Abstract
The purpose of this study was to describe the changes in iron status indicators at 6 and 12 months of age, controlling by inflammation by measuring alpha-1 acid glycoprotein (AGP). This longitudinal study included 48 healthy-term singleton infants with birth weight ≥ 2500 g, born in hospitals of the Mexican Institute for Social Security. Complete blood count, ferritin, soluble transferrin receptor (sTfR), hepcidin, and AGP were measured in blood at 6 and 12 months of age. sTfR/ferritin ratio and total body iron (TBI) stores were calculated. Hemoglobin and sTfR/ferritin ratio increased with age, while ferritin and TBI decreased. In infants without inflammation, hepcidin, sTfR, and MVC did not show significant changes from 6 to 12 months of age, while ferritin and TBI decreased. In infants with inflammation, hepcidin, TBI, and ferritin levels increased, while hemoglobin and sTfR/ferritin ratio decreased. MVC and sTfR did not change significantly in the presence or absence of inflammation. Hepcidin concentration correlated positively and significantly with ferritin and TBI stores and showed significant negative correlation with sTfR/ferritin ratio. Our study showed that, in absence of inflammation and ID, during the first year of life, physiological changes occur in hemoglobin and ferritin levels as well as in indicators derived from ferritin and sTfR; in contrast, hepcidin and sTfR did not show significant change. However, hepcidin concentration was lower in infants with ID and was higher when inflammation was present, supporting that infants have a functional hepcidin response to changes in iron stores.
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Urinary Neutrophil Gelatinase-Associated Lipocalin/Hepcidin-25 Ratio for Early Identification of Patients at Risk for Renal Replacement Therapy After Cardiac Surgery: A Substudy of the BICARBONATE Trial.
Elitok, S, Kuppe, H, Devarajan, P, Bellomo, R, Isermann, B, Westphal, S, Kube, J, Albert, C, Ernst, M, Kropf, S, et al
Anesthesia and analgesia. 2021;(6):1510-1519
Abstract
BACKGROUND Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.
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Biology of the iron efflux transporter, ferroportin.
Rishi, G, Subramaniam, VN
Advances in protein chemistry and structural biology. 2021;:1-16
Abstract
Iron, the most common metal in the earth, is also an essential component for almost all living organisms. While these organisms require iron for many biological processes, too much or too little iron itself poses many issues; this is most easily recognized in human beings. The control of body iron levels is thus an important metabolic process which is regulated essentially by controlling the expression, activity and levels of the iron transporter ferroportin. Ferroportin is the only known iron exporter. The function and activity of ferroportin is influenced by its interaction with the iron-regulatory peptide hepcidin, which itself is regulated by many factors. Here we review the current state of understanding of the mechanisms that regulate ferroportin and its function.
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Importance of Hepcidin in the Etiopathogenesis of Anemia in Inflammatory Bowel Disease.
Karaskova, E, Pospisilova, D, Velganova-Veghova, M, Geryk, M, Volejnikova, J, Holub, D, Hajduch, M
Digestive diseases and sciences. 2021;(10):3263-3269
Abstract
Anemia is the most common extraintestinal systemic complication of inflammatory bowel disease. Iron deficiency anemia and anemia of chronic disease are among the most frequent types. Intestinal iron absorption is controlled by the activity of ferroportin. Cells with high expression of ferroportin include enterocytes, and also macrophages and hepatocytes. Iron homeostasis is controlled by the hepcidin-ferroportin axis. Hepcidin is a central regulator of iron metabolism and can also serve as a marker of systemic inflammation. During systemic inflammatory response, the synthesis of hepcidin increases, and hepcidin binds to ferroportin and inhibits its activity. Thus, iron is not absorbed from the bowel into the circulation and also remains sequestered in macrophages. Conversely, hepcidin synthesis is suppressed during conditions requiring increased iron intake for enhanced erythropoiesis, such as iron deficiency anemia or hypoxia. Here, ferroportin is not blocked, and iron is actively absorbed into the bloodstream and also released from the stores. Production of hepcidin is influenced by the status of total body iron stores, systemic inflammatory activity and erythropoietic activity. Oral iron therapy is limited in inflammatory bowel diseases due to ongoing gastrointestinal inflammation. It is less effective and may worsen the underlying disease. Therefore, the choice between oral and parenteral iron therapy must be made with caution. Oral iron would be ineffective at high hepcidin levels due to concurrent ferroportin blockage. Contrarily, low levels of hepcidin indicate that oral iron therapy should be successful. An understanding of hepcidin can help in understanding the body's reaction to iron depletion during the inflammatory process.
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Hepcidin response to three consecutive days of endurance training in hypoxia.
Sumi, D, Hayashi, N, Yamaguchi, K, Badenhorst, CE, Goto, K
European journal of applied physiology. 2021;(4):1197-1205
Abstract
PURPOSE The purpose of this study was to determine the effects of 3 consecutive days of endurance training in hypoxia on hepcidin responses. METHOD Nine active healthy males completed two trials, consisting of 3 consecutive days of endurance training in either hypoxia [fraction of inspired oxygen (FiO2): 14.5%) or normoxia (FiO2: 20.9%). On days 1-3, participants performed one 90 min session of endurance training per day, consisting of high-intensity endurance interval exercise [10 × 4 min of pedaling at 80% of maximal oxygen uptake ([Formula: see text]O2max) with 2 min of active rest at 30% of [Formula: see text]O2max] followed by 30 min of continuous exercise at 60% of [Formula: see text]O2max. Venous blood samples were collected prior to exercise each day during the experimental period (days 1-4) to determine serum hepcidin, iron, ferritin, haptoglobin, and ketone body concentrations. RESULT Serum iron (p < 0.0001), ferritin (p = 0.005) and ketone body (p < 0.0001) concentrations increased significantly in both trials on days 2-4 compared with day 1, with no significant differences between trials. No significant changes in serum haptoglobin concentrations were observed throughout the experimental period in either trial. Serum hepcidin concentrations also increased significantly on days 2-4 compared with day 1 in both trials (p = 0.004), with no significant differences observed between trials. CONCLUSION 3 consecutive days of endurance training in hypoxia did not affect hepcidin concentrations compared with endurance training in normoxia.