Serum Hepcidin Concentrations Research Articles

HeGRI: A Novel Index of Serum Hepcidin Suppression in Relation to the Degree of Renal Dysfunction among β-Thalassemia Major Patients

Background: The progressive renal function inadequacy results in altered hepcidin metabolism due to a shifting of its renal elimination, which consequently affects enteric iron absorption and iron stores’ availability. This study aimed to investigate and correlate renal function, iron status, and hepcidin in patients with β-thalassemia major through a novel index. Methods: In this 1:1 case–control study, serum hepcidin, serum ferritin, iron study, hematological and renal function parameters were compared between 60 β-thalassemia major patients with iron overload and 61 healthy individuals (2–30 years old). Results: The concentrations of serum hepcidin (21.898 vs. 9.941 ng/mL; p < 0.001) and eGFR (179.71 vs. 132.95; p < 0.001) were significantly higher in β-thalassemia major patients compared to the controls. The serum hepcidin levels decreased with increasing levels of total iron-binding capacity (TIBC; β = −0.442; p = 0.024), transferrin saturation (β = −0.343; p = 0.023), serum creatinine (β = −0.625; p = 0.0030), and eGFR (β = −0.496; p = 0.011). The mean hepcidin/ferritin ratio was significantly lower in the β-thalassemia major cases (0.0069 vs. 0.3970; p < 0.001). The novel hepcidin/eGFR ratio index (HeGRI) was significantly higher in the patient group compared to controls (0.12 vs. 0.09; p = 0.031), respectively. Conclusions: These results suggest that HeGRI could be a potential index of the appropriateness of serum hepcidin suppression associated with the degree of renal dysfunction among β-thalassemia major patients.

Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis

Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5.To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2.We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia.Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer.Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis.In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis.1Kautz L et al, Nat Genet, 20142Delaney K et al, Curr Dev Nutr, 20203Coffey R et al, Blood, 2020 DisclosuresGanz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

Exercise and Heat Stress: Inflammation and the Iron Regulatory Response.

This study determined the impact of heat stress on postexercise inflammation and hepcidin levels. Twelve moderately trained males completed three, 60-min treadmill running sessions under different conditions: (a)COOL, 18 °C with speed maintained at 80% maximum heart rate; (b)HOTHR, 35 °C with speed maintained at 80% maximum heart rate; and (c)HOTPACE, 35 °C completed at the average running speed from the COOL trial. Venous blood samples were collected pre-, post-, and 3-hr postexercise and analyzed for serum ferritin, interleukin-6 (IL-6), and hepcidin concentrations. Average HR was highest during HOTPACE compared with HOTHR and COOL (p < .001). Running speed was slowest in HOTHR compared with COOL and HOTPACE (p < .001). The postexercise increase in IL-6 was greatest during HOTPACE (295%; p = .003). No differences in the IL-6 response immediately postexercise between COOL (115%) and HOTHR (116%) were evident (p = .992). No differences in hepcidin concentrations between the three trials were evident at 3hr postexercise (p = .407). Findings from this study suggest the IL-6 response to exercise is greatest in hot compared with cool conditions when the absolute running speed was matched. No differences in IL-6 between hot and cool conditions were evident when HR was matched, suggesting the increased physiological strain induced from training at higher intensities in hot environments, rather than the heat per se, is likely responsible for this elevated response. Environmental temperature had no impact on hepcidin levels, indicating that exercising in hot conditions is unlikely to further impact transient alterations in iron regulation, beyond that expected in temperate conditions.

Hepcidin and Vitamin D Levels: Mutual Effects in Anemia of Chronic Kidney Disease

Objective: Hepcidin is a peptide with anti-microbial properties that is largely synthesized in the liver and has important roles in iron homeostasis, with serum levels elevated in chronic inflammatory conditions, including chronic kidney disease (CKD). Our aim was to discuss on the role of vitamin D in regulation of hepcidin and anemia of CKD. Methods: The study group included 103 patients with CKD and 59 healthy individuals. The serum concentration of hepcidin was measured using ELISA, and the association to the following factors was evaluated: age, sex, body mass index, renal functions (estimated glomerular filtration rate, eGFR), drug history, serum biochemistry, complete blood count, iron and total iron binding capacity, ferritin, vitamin D, high sensitive C-reactive protein, C-reactive protein, and the erythrocyte sedimentation rate. Results: The mean age of the CKD group was 58.63 ± 11.8 years (with 16, 26, 27, 19, and 15 patients; respectively in each chronic kidney disease stage, from I through V and nine on haemodialysis, six on peritoneal dialysis). The mean hepcidin concentration was higher in the chronic kidney disease (30.3±24.7 ng/ml) than control (17.8 ± 8.4ng/ml) group (p&amp;lt;0.05). There was a positive association between hepcidin and CRP, ESR and the following serum factors (urea, creatinine, ferritin, phosphate, pH, parathyroid hormone and alkaline phosphatase), with a negative association with eGFR, haemoglobin, haematocrit, calcium, magnesium, 25-OH vitamin D and bicarbonate levels. Conclusion: Hepcidin levels were found negatively correlated with 25-OH vitamin D levels which was related with the inflammatory effects of vitamin D and hepcidin.

Diagnostic and prognostic value of serum hepcidin concentration in patients with acute spontaneous supratentorial intracerebral hemorrhage

The aim of the study was to evaluate the diagnostic and prognostic value of serum hepcidin concentration in patients with acute spontaneous supratentorial intracerebral hemorrhage (SSICH). Materials and methods. Prospective cohort study of 88 patients with acute SSICH receiving the conservative therapy was conducted. Level of neurological deficit was evaluated using the Full Outline of UnResponsiveness Scale, the Glasgow Coma Scale and the National Institute of Health Stroke Scale. Computed tomography was performed to detect an intracerebral hemorrhage volume (ICHV), secondary intraventricular hemorrhage volume (SIVHV) and total volume of intracranial hemorrhage (TVICH). Laboratory blood samples were taken within 24 hours of hospitalization. Hepcidin levels, serum iron concentrations and total iron-binding capacity were determined, followed by calculations of transferrin saturation coefficient. Early neurological deterioration (END) and unfavorable variants of the acute period of SSICH (lethal outcome, modified Rankin score 4-5 on the 21st day of the disease) were considered as endpoints. Statistical processing of the obtained results included a correlation analysis, logistic regression analysis and ROC-analysis. Results. It was identified, that serum hepcidin level in the patients with SSICH was correlated with ICHV (R = 0.44, P ˂ 0.01), SIVHV (R = 0.45, P ˂ 0.01) and TVICH (R = 0.57, P ˂ 0.01). Hepcidin serum concentrations in the patients with ICHV &gt;30 ml exceeded the value of those in cases of ICHV ≤30 ml by 69.0 % (P ˂ 0.0001). Serum levels of hepcidin were significantly higher in the patients with an unfavorable course and outcome of the disease in the acute period on the 1st day of admission (P ˂ 0.0001). Informative multipredictor models were developed via multiple logistic regression analysis, which include hepcidin values coupled with clinical and neurovisualization findings and are predictive of lethal and unfavorable acute period functional outcomes (AUC = 0,93, P ˂ 0.0001). Conclusions. The level of serum hepcidin in patients with acute SSICH is associated with the severity of cerebral lesions. The integration of serum hepcidin concentration with clinical and neuroimaging findings in the structure of multipredictor logistic regression models allows to determine the vital and functional prognosis of the acute period of SSICH with an accuracy of &gt;85 %

Mortality and serum hepcidin are associated with persistent and transient acute kidney injury in septic patients.

Acute kidney injury (AKI) is a common complication of sepsis and has high mortality. The 2017 Acute Disease Quality Initiative (AQDI) workgroup proposed new definitions for AKI - transient AKI and persistent AKI; however, very little is known about the effect of transient and persistent septic AKI on short-term mortality among critically ill patients with sepsis. The purpose of this study was to assess the impact of persistent AKI on mortality and to evaluate whether serum hepcidin can predict the occurrence of persistent AKI in critically ill patients with sepsis. This prospective observational study was performed in a general hospital mixed surgical-medical ICU in Pudong, China. Consecutive adults with sepsis admitted to the ICU with absence of chronic kidney disease, renal transplant, and AKI were included. AKI was defined according to the KDIGO criteria and classified as transient (&lt; 48-hour duration) or persistent (48-hour duration). Blood samples were obtained within 6 hours from when AKI was diagnosed. A total of 90 patients with sepsis or septic shock were included in the analysis. 44 (48.89%) patients developed AKI during ICU stay: 20 (45.45%) had transient and 24 (54.55%) had persistent AKI. Persistent AKI has a higher mortality than transient AKI (66.7 vs. 30.0%, p = 0.002). Persistent AKI and sequential organ failure assessment (SOFA) scores were an independent predictor of 60-day mortality. Patients with persistent AKI had higher concentrations of serum creatinine (SCr) and hepcidin than transient AKI patients when AKI was diagnosed. Logistic regression indicated that serum hepcidin was an independent predictor of persistent AKI in septic patients, with a fairly predictive value (AUC 0.71, 95% CI: 0.47 - 0.87; p = 0.02). Persistent AKI was associated with increased 60-day mortality compared with transient AKI in septic patients. The serum hepcidin levels measured when AKI was diagnosed have a fair predictive value to predict the occurrence of persistent AKI in septic patients.

DIAGNOSTIC AND PROGNOSTIC VALUE OF IRON METABOLISM PARAMETERS IN PATIENTS WITH SPONTANEOUS SUPRATENTORIAL INTRACEREBRAL HAEMORRHAGE IN ACUTE PERIOD

The aim of the study is to investigate the diagnostic and prognostic value of integrated assessment of iron metabolism parameters in patients with spontaneous supratentorial intracerebral haemorrhage in acute period. Materials and methods. This prospective cohort study included 88 patients with spontaneous supratentorial intracerebral haemorrhage during the course of conservative treatment. Diagnosis was made based on the findings of clinical and neuro-imaging investigations. On the 1st day of the hospital admission fasting blood samples were taken. Levels of ferritin, hepcidin, iron, total iron binding capacity, unsaturated iron binding capacity and transferrin saturation were detected. Early neurological deterioration and unfavourable outcome of acute period of spontaneous supratentorial intracerebral haemorrhage as grading 4-6 scores by modified Rankin scale on the 21st day of the disease were chosen as clinical endpoints. Lethal outcome and unfavourable functional outcome were also recorded. Results. Three profile types of evaluated iron metabolism parameters were identified based on the cluster analysis in the patients with intracerebral haemorrhage. It has been found out the profile types with initial higher levels of serum hepcidin and ferritin in blood together with lower serum iron concentration (type II and particularly type III) are associated with more severe cerebral structures damage and increased risk of early clinical deterioration (relative risk (95% confidence interval) = 6,01 (1,54–24,86), р=0,0120) and unfavourable functional outcome of the disease (relative risk (95% confidence interval) = 4,45 (2,25–8,80), р˂0,0001). Conclusion. Profile type of serum hepcidin, ferritin and iron concentrations together with transferrin saturation in the patients with spontaneous supratentorial intracerebral haemorrhage on the 1st day of hospital admission is the informative integrated marker for short-term prognosis during the course of conservative treatment.

Pro‐inflammatory cytokine interleukin‐6‐induced hepcidin, a key mediator of periodontitis‐related anemia of inflammation

To investigate whether anemia of inflammation (AI) occurs in periodontitis patients and to further explore underlying pathogenesis of periodontitis-related AI by an experimental periodontitis model. Previous studies have reported periodontitis patients could show a tendency toward AI. However, the relationship between periodontitis and AI remains unclear, and the related pathological mechanisms have not been identified. Periodontal clinical parameters, inflammatory markers, and anemia-related indicators were compared between 98 aggressive periodontitis (AgP) patients and 103 healthy subjects. An experimental periodontitis model was induced by ligature placement in mice. The changes in mice inflammatory markers, anemia indicators, hepcidin mRNA expression, and serum hepcidin concentrations were measured. Human and mouse liver cells were treated with interleukin-6 (IL-6) for analyzing the changes in hepcidin expression based on mRNA and protein levels. AgP patients exhibited higher white blood cell counts, IL-6, and C-reactive protein. Adjusted linear regression analyses showed correlations between AgP and decreased hemoglobin (HGB) and hematocrit (HCT). The ligature-induced periodontitis caused systemic inflammation and elevated IL-6 levels. Lower red blood cell counts, HGB, and HCT were detected, whereas the levels of hepcidin mRNA expression and serum hepcidin concentrations increased. The treatment of hepatocytes with IL-6 induced both hepcidin mRNA expression and hepcidin secretion. Systemic inflammation induced by periodontitis leads to an increased risk for AI. IL-6-induced hepcidin could play a central mediator role and act as a key pathologic mechanism. Our results demonstrate periodontitis may be considered as an additional inflammatory disease contributing to the development of AI.

Hepcidin response to three consecutive days of endurance training in hypoxia.

The purpose of this study was to determine the effects of 3 consecutive days of endurance training in hypoxia on hepcidin responses. 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 90min session of endurance training per day, consisting of high-intensity endurance interval exercise [10 × 4min of pedaling at 80% of maximal oxygen uptake ([Formula: see text]O2max) with 2min of active rest at 30% of [Formula: see text]O2max] followed by 30min 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. 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. 3 consecutive days of endurance training in hypoxia did not affect hepcidin concentrations compared with endurance training in normoxia.

Hepcidin and Erythroferrone Levels in Child-Bearing Women with Iron Deficiency Anemia

To detect serum hepcidin and erythroferrone levels in child-bearing women with iron deficiency anemia (IDA), and to investigate the association between them and iron status parameters. The study consisted of 65 child-bearing women (35 with iron deficiency anemia and 30 age-matched healthy women). The levels of serum iron were detected by using automated chemistry analyzer, the contents of serum ferritin were detected by electrochemiluminescence immunoassay, and the levels of serum erythroferrone and hepcidin were detected by specific enzyme-linked immunosorbent assay (ELISA) kit. The quantitative variables between two groups were compared and analyzed by SPSS22.0 software. Spearman correlation was used to detect correlation between the parameters. The levels of Hb, serum iron, ferritin and transferrin saturation were significantly decreased in IDA patients as compared with in control group (P<0.001). Serum hepcidin levels in IDA patients were significant lower than those in control group (P<0.001). Serum erythroferrone levels slightly increased in IDA group (P>0.05). In IDA patients, serum hepcidin concentrations were positively correlated with hemoglobin concentration, serum iron, serum ferritin and transferrin saturation (r=0.448, r=0.496, r=0.754, r=0.491). But, serum erythroferrone concentrations showed no correlation with hemoglobin concentration, serum iron, serum ferritin, transferrin saturation and hepcidin (P>0.05). Serum hepcidin levels were significantly decreased in child-bearing women with IDA, but the serum erythroferrone levels were not obviously different between two groups, suggesting that serum erythroferrone may be not involved in the regulation of iron metabolism in child-bearing women with mild and moderate IDA.

Inflammatory Markers and Hepcidin are Elevated but Serum Iron is Lower in Obese Women of Reproductive Age.

Limited evidence suggests that serum iron and hepcidin concentrations are dysregulated in obesity and inflammation. The objective of the present study was to compare C-reactive protein, interleukin-6, circulating levels of hepcidin, serum lipids, and iron status in obese vs. normal-weight women of childbearing age. Healthy women aged 18–30 years were recruited for the study (n = 47: 25 obese and 22 normal weight). Fasting blood samples were obtained to measure serum lipids (total cholesterol, HDL, LDL cholesterol, triglycerides, non-HDL cholesterol), complete blood count, serum iron, total iron-binding capacity, transferrin saturation, serum ferritin, hepcidin, C-reactive protein, and interleukin-6. Obese women had significantly higher mean serum C-reactive protein (p < 0.001), interleukin-6 (p < 0.001), hepcidin (p = 0.024), triglycerides (p < 0.001) and total cholesterol/HDL ratio (p < 0.001) but lower HDL (p = 0.001) and serum iron/hepcidin ratio (p = 0.011) compared with normal-weight women. BMI correlated positively with inflammatory markers, triglycerides, LDL and total cholesterol/HDL ratio, and negatively with HDL and serum iron/hepcidin ratio. Serum iron correlated negatively with ferritin in the obese group (p = 0.030) but positively in normal weight women (p = 0.002). BMI and ferritin were the only predictors of serum iron/hepcidin ratio accounting for 23% of the variation among subjects. Studies are needed to examine anti-inflammatory dietary approaches that can improve iron biomarkers in obese women.

Iron metabolism parameters and inflammatory status in patients with diabetes mellitus and dyslipidemia

Background:Investigating the inflammatory status and iron metabolism in patients with impaired carbohydrate metabolism seems quite relevant, while only few studies are devoted to the relationship between metabolic parameters, including lipid profile, inflammatory status indicators and the state of ferrokinetics in diabetes mellitus types 1 and 2 in a comparative aspect.Aims: To establish the direction of changes in the inflammatory status and the state of ferrokinetics in patients with type 1 and type 2 diabetes mellitus depending on lipid metabolism disorders.Materials and methods: The study included 48 patients with type 1 diabetes, 81 patients with type 2 diabetes; 11 people with obesity without impaired carbohydrate metabolism made up the comparison group, 17 healthy volunteers - the control group. Low-grade inflammation was assessed by the levels of high-sensitive C-reactive protein (CRP), tumor necrosisfactor-а (TNF-а), ferritin, and erythrocyte sedimentation rate (ESR). The state of iron metabolism was evaluated by the main hematological parameters (hemoglobin, red blood cell count, hematocrit), serum iron concentrations, transferrin, ferritin and hepcidin concentrations. In all patients lipid metabolism parameters, glycated hemoglobin, and microalbuminuria were measured.Results:Patients with type 1 and type 2 diabetes mellitus had significantly higher inflammatory markers concentrations-TNF-а, ESR, and CRP - in relation to obese patients without impaired carbohydrate metabolism and those in the control group. The highest production of TNF-а was observed in patients with type 1 diabetes mellitus (15.28 [12.41-24.41] pg/ml), whereas CRP (7.00 [3.00-11.85] ng/ml) and ESR (18.00 [9.00-27.00] mm/h) were higher in patients with type 2 diabetes. In the structure of the examined individuals with diabetes mellitus (regardless of its type), dyslipidemia type IIb in comparison with less atherogenic type IIa dyslipidemia was characterized by a higher production of CRP (6.9 [3.00-12.35] and 3.00 [1.80-8.70] ng/ml, respectively), ESR (20.00 [10.00-30.00] and 15.00 [5.00-24.50] mm/h, respectively) and ferritin (114.80 [48.90-196.45] and 50.90 [19.58-114.10] ng/ml, respectively). Compared to iron deficiency anemia, anemia of chronic diseases in diabetes mellitus patients was more often accompanied by dyslipidemia llb (χ2=2.743; p=0.098) and was characterized by a higher content of atherogenic fractions of cholesterol.Conclusions: Patients with type 2 diabetes mellitus and a more atherogenic dyslipidemia profile (type IIb) have a phenotype of the local inflammatory mesenchymal reaction of the liver with an increase in acute-phase proteins predominantly of hepatic origin (CRP, ferritin), whereas individuals suffering from type 1 diabetes and less atherogenic lipid profile (type IIa) have a phenotype of an autoimmune, genetically determined inflammatory response. It has been established that anemia of chronic diseases developing in the background of diabetes mellitus is associated with a more atherogenic lipid profile, compared with iron deficiency anemia.

Iron Regulation in Elderly Asian Elephants (Elephas maximus) Chronically Infected With Mycobacterium tuberculosis.

Restriction of nutrients to pathogens (nutritional immunity) is a critical innate immune response mechanism that operates when pathogens such as Mycobacterium tuberculosis have the potential to evade humoral immunity. Tuberculosis is of growing concern for zoological collections worldwide and is well-illustrated by infections of Asian and African elephants, where tuberculosis is difficult to diagnose. Here, we investigated hematological parameters and iron deposition in liver, lung, and spleen of three Asian elephants (Elephas maximus) infected with Mycobacterium tuberculosis. For reference purposes, we analyzed tissue samples from control M. tuberculosis-negative elephants with and without evidence of inflammation and/or chronic disease. Molecular analyses of bacterial lesions of post mortally collected tissues confirmed M. tuberculosis infection in three elephants. DNA sequencing of the bacterial cultures demonstrated a single source of infection, most likely of human origin. In these elephants, we observed moderate microcytic anemia as well as liver (mild), lung (moderate) and spleen (severe) iron accumulation, the latter mainly occurring in macrophages. Macrophage iron sequestration in response to infection and inflammation is caused by inhibition of iron export via hepcidin-dependent and independent mechanisms. The hepatic mRNA levels of the iron-regulating hormone hepcidin were increased in only one control elephant suffering from chronic inflammation without mycobacterial infection. By contrast, all three tuberculosis-infected elephants showed low hepcidin mRNA levels in the liver and low serum hepcidin concentrations. In addition, hepatic ferroportin mRNA expression was high. This suggests that the hepcidin/ferroportin regulatory system aims to counteract iron restriction in splenic macrophages in M. tuberculosis infected elephants to provide iron for erythropoiesis and to limit iron availability for a pathogen that predominantly proliferates in macrophages. Tuberculosis infections appear to have lingered for more than 30 years in the three infected elephants, and decreased iron availability for mycobacterial proliferation may have forced the bacteria into a persistent, non-proliferative state. As a result, therapeutic iron substitution may not have been beneficial in these elephants, as this therapy may have enhanced progression of the infection.

Serum hepcidin concentrations in relation to iron status in children with type 1 diabetes

Chronic low-grade inflammation in type 1 diabetes (T1D) might increase hepcidin synthesis, possibly resulting in functional iron deficiency (FID). We hypothesized that in T1D children with FID, hepcidin concentrations are increased compared to those with normal iron status and those with absolute iron deficiency (AID). We evaluated hepcidin concentrations in T1D children in relation to iron status, and investigated whether hepcidin is useful in assessing FID. A cross-sectional study was conducted. FID was defined as elevated zinc protoporphyrin/heme ratio and/or red blood cell distribution width, and AID as low serum ferritin concentration. Post-hoc analyses with different definitions of FID were performed, using transferrin saturation and reticulocyte hemoglobin content. Serum hepcidin concentrations were measured using mass-spectrometry. The IRODIAB-study is registered at www.trialregister.nl (NTR4642). This study included 215 T1D children with a median age of 13.7 years (Q1–Q3: 10.1–16.3). The median (Q1–Q3) hepcidin concentration in patients with normal iron status was 1.8 nmol/l (0.9–3.3), in AID-patients, 0.4 nmol/l (0.4–0.4) and in FID-patients, 1.6 nmol/l (0.7–3.5). Hepcidin concentrations in FID-patients were significantly higher than in AID-patients (p < 0.001). Irrespective of FID-definition used, hepcidin concentrations did not differ between FID-patients and patients with normal iron status. This might be explained by the influence of various factors on hepcidin concentrations, and/or by differences in response of iron parameters over time. Single hepcidin measurements do not seem useful in assessing FID in T1D children. Multiple hepcidin measurements over time in future studies, however, might prove to be more useful in assessing FID in children with T1D.

The Impact Of Three Consecutive Days Of Endurance Training In Hypoxia On Hepcidin Responses.

Endurance exercise in hypoxia resulted in similar hepcidin elevation compared with exercise in normoxia (Govus et al. 2014; Goto et al. 2017). However, how consecutive days of endurance training in hypoxia affects hepcidin elevation remains unclear. PURPOSE: The purpose of the present study was to determine the effect of three consecutive days of endurance training in hypoxia on hepcidin response. METHODS: Nine active healthy males completed two trials on different days, consisting of either three consecutive days of endurance training in hypoxia (FiO2: 14.5%) or normoxia (FiO2: 20.9%). They performed 90-min sessions of endurance training consisting of high-intensity endurance interval exercise (10 × 4 min pedaling at 80% of VO2max with 2 min of active rest at 30% of VO2max) followed by 30 min continuous pedaling at 60% of VO2max during three consecutive days (days 1-3). Venous blood samples were collected after an overnight fast during experimental periods (days 1-4) to determine the serum hepcidin, iron, ferritin and haptoglobin concentrations. RESULTS: Pedaling workload during endurance training were significantly lower in the HYP (interval exercise: 166 ± 4.3 W) than in the NOR (194 ± 7.6 W, P < 0.0001). Serum iron (P < 0.0001) and ferritin (P = 0.005) concentrations on days 2-4 significantly increased in both trials, whereas there was no significant difference between the two trials. Serum haptoglobin concentrations did not significantly change throughout the experimental periods in either trial. Moreover, NOR showed significantly greater serum hepcidin elevation on the days 2-4 compared with day 1 (day1: 13.9 ± 8.6 ng/mL, day2: 30.4 ± 9.9 ng/mL, P = 0.004). However, no significant difference was observed in serum hepcidin concentrations between the NOR and HYP. CONCLUSION: Three consecutive days of endurance training in hypoxia did not affect further hepcidin elevation compared with endurance training in normoxia.

Serum Hepcidin In Patients With Chronic Hepatitis C And Its Relation To Treatment With Antiviral Drugs

HCV infection has been implicated in iron accumulation in the liver and iron overload has been shown to be a potential cofactor for HCVassociated hepatocellular carcinoma progression.Hepcidin produced by hepatocytes, is a key regulator of iron metabolism. Alteration of Hepcidin expression levels has been reported in the setting of chronic HCV infection and hepatocellular carcinoma. The aim of the work is to assess the serum concentration of hepcidin in chronic hepatitis C patients and evaluate any possible association with the viral load after therapy. Ourstudy was carried on50 patients with chronic hepatitisC.Hepcidin levels were evaluated for Hepcidin before starting the antiviral therapy treatment (group A) and after 24 weeks course of antiviral therapy(group B)with a commercially available enzyme-linked immunosorbentassay kitin addition to 20 healthy volunteers with matched age and sex as control group.As regard serum Hepcidin level, there was a highly statistical significant differencebetween control and patient group.Hepcidin concentrations in patients with CHC were relatively low compared to HCV negative individuals. Highly statistical significant (p-value > 0.05) positive correlation (r = 0.67) between Hepcidin before and after treatment in patients group. In conclusion Chronic HCV infection is associated with reduced level of hepcidin. The level of hepcidin was fully reversible after antiviral therapy.Initial rise in serum hepcidin concentration might have a potential for being used as one of the indicators of patient response to therapy.

Association between dexamethasone treatment and alterations in serum concentrations of trace metals.

Previously, a significant elevation in the serum levels of iron (Fe) was observed within a few days after the initiation of cisplatin (CDDP)-based chemotherapy. To clarify the underlying mechanisms, the serum concentration of hepcidin, a negative regulator of Fe release, was determined in the clinical samples obtained from six patients with cancer. The result showed that the serum concentration of hepcidin in patients receiving CDDP-based chemotherapy was significantly increased after 4-6 days of treatment, in comparison to the baseline level, suggesting that aforementioned excessive systemic Fe was not explained by the change of serum hepcidin level. All these patients received antiemetic premedication. We next evaluated of the effects of Pt-containing drugs and prophylactic antiemetic dexamethasone medication on the serum concentration of trace metals in mice, and on the hepatic and renal concentration of trace metals. The serum concentrations of Fe, Cu, and Zn in the CDDP-treated and oxaliplatin-treated mice were not significantly altered in comparison to those of the vehicle-treated control group. The serum concentrations of Fe, Cu, and Zn were increased after 24 h of dexamethasone treatment, compared to those of the control group (P < 0.05). The hepatic concentration of Mn was significantly reduced, whereas those of Fe and Cu inclined to diminish. The present findings suggest that dexamethasone can partly contribute to the changes in the serum concentrations of trace metals during anticancer chemotherapy.

Clinical Immunoassay for Human Hepcidin Predicts Iron Deficiency in First-Time Blood Donors.

Serum markers currently used as indicators of iron status have clinical limitations. Hepcidin, a key regulator of iron homeostasis, is reduced in iron deficiency (ID) and increased in iron overload. We describe the first CLIA-validated immunoassay with excellent accuracy and precision to quantify human serum hepcidin. Its diagnostic utility for detecting ID in first-time blood donors was demonstrated. A monoclonal competitive ELISA (C-ELISA) was developed for the quantitation of human hepcidin and validated according to CLIA guidelines. Sera from nonanemic first-time blood donors (n = 292) were analyzed for hepcidin, ferritin, transferrin, and serum iron. Logistic regression served to determine the utility of hepcidin as a predictor of ID. The C-ELISA was specific for human hepcidin and had a low limit of quantitation (4.0 ng/mL). The hepcidin concentration measured with the monoclonal C-ELISA was strongly correlated with a previously established, extensively tested polyclonal C-ELISA (Blood 2008;112:4292-7) (r = 0.95, P < 0.001). The area under the receiver operating characteristic curve for hepcidin as a predictor of ID, defined by 3 ferritin concentration thresholds, was >0.9. For predicting ID defined by ferritin <15 ng/mL, hepcidin <10 ng/mL yielded sensitivity of 93.1% and specificity of 85.5%, whereas the same hepcidin cutoff for ferritin <30 ng/mL yielded sensitivity of 67.6% and specificity of 91.7%. The clinical measurement of serum hepcidin concentrations was shown to be a potentially useful tool for diagnosing ID.

Hepcidin and Erythroferrone Correlate with Hepatic Iron Transporters in Rats Supplemented with Multispecies Probiotics.

The influence of probiotic supplementation on iron metabolism remains poorly investigated. However, a range of studies, especially on Lactobacillus plantarum 299v (Lp229v), have indicated a possible positive impact of probiotics on iron absorption. The aim of the study was to determine the effect of multistrain probiotic supply on iron balance. Thirty Wistar rats were randomized into three groups: placebo (KK group), and multistrain probiotic per os in a daily dose of 2.5 × 109 colony forming units (CFU) (PA group) or 1 × 1010 CFU (PB group). Multistrain probiotic consisted of nine bacterial strains: Bifidobacterium bifidum W23, B. lactis W51, B. lactis W52, Lactobacillus acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, Lactococcus lactis W19, and Lc. lactis W58, in equal proportions. After six weeks, blood and organ samples were collected. No differences were found between the three groups in terms of serum concentrations of hepcidin (HEPC), lactoferrin (LTF), homocysteine (HCY), ferritin (Ft), or erythroferrone (ErFe), or in liver content of divalent metal transporter 1 (DMT1), transferrin receptors 1 and 2 (TfR), or ZRT/IRT-like protein 14 (ZIP14) proteins. In the overall sample, positive correlations were noted between the serum concentrations of hepcidin and lactoferrin, and hepcidin and ferritin; serum concentration of hepcidin and DMT1 and TfR1 in the liver; and serum concentration of erythroferrone and TfR2 in the liver. The correlations of serum hepcidin and erythroferrone with liver DMT1 and TfR represent significant mechanisms of Fe homeostasis. Our study has shown that multistrain probiotic supplementation used in the experiment did not disrupt the biochemical and hepatic regulatory processes of Fe balance and did not demonstrate significant influence on selected parameters of Fe metabolism.

Serum levels of hepcidin and interleukin 6 in Parkinson’s disease

Neurodegeneration in Parkinson's disease (PD) includes processes of chronic inflammation and oxidative stress which are related to dysregulation in the homeostasis of iron metabolism. Hepcidin is a peptide hormone responsible for systemic iron homeostasis and simultaneously the inflammatory response protein, induced in response to interleukin 6 (IL‑6). We assessed the serum concentration of hepcidin and IL‑6 in the groups of patients with PD treated only pharmacologically with optimal individualized therapy (MT) and treated additionally with deep brain stimulation (DBS), compared to the control group. The serum concentrations of hepcidin and IL‑6 in the group of all PD patients were significantly higher than in the control group. In the group of PD patients treated with DBS hepcidin and IL‑6 concentrations were significantly higher compared to the control group. Additionally, the positive correlations between serum hepcidin and IL‑6 were found in the PD (MT and DBS) and PD‑DBS group. The obtained results may indicate the influence of immunological mechanisms on iron metabolism and oxidative stress, in particular when the inflammatory process is more active in the DBS‑treated group. This effect can be protective as well as neurodegenerative.