Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study

Contains fulltext : 98009.pdf (publisher's version ) (Open Access)INTRODUCTION: Anemia is a frequently encountered problem during inflammation. Hepcidin is an interleukin-6 (IL-6)-induced key modulator of inflammation-associated anemia. Human sepsis is a prototypical inflammatory syndrome, often complicated by the development of anemia. However, the association between inflammation, hepcidin release and anemia has not been demonstrated in this group of patients. Therefore, we explored the association between hepcidin and sepsis-associated anemia. METHODS: 92 consecutive patients were enrolled after presentation on the emergency ward of a university hospital with sepsis, indicated by the presence of a proven or suspected infection and >/= 2 extended systemic inflammatory response syndrome (SIRS) criteria. Blood was drawn at day 1, 2 and 3 after admission for the measurement of IL-6 and hepcidin-25. IL-6 levels were correlated with hepcidin concentrations. Hemoglobin levels and data of blood transfusions during 14 days after hospitalisation were retrieved and the rate of hemoglobin decrease was correlated to hepcidin levels. RESULTS: 53 men and 39 women with a mean age of 53.3 +/- 1.8 yrs were included. Hepcidin levels were highest at admission (median[IQR]): 17.9[10.1 to 28.4]nmol/l and decreased to normal levels in most patients within 3 days (9.5[3.4 to 17.9]nmol/l). Hepcidin levels increased with the number of extended SIRS criteria (P = 0.0005). Highest IL-6 levels were measured at admission (125.0[46.3 to 330.0]pg/ml) and log-transformed IL-6 levels significantly correlated with hepcidin levels at admission (r = 0.28, P = 0.015), day 2 (r = 0.51, P < 0.0001) and day 3 (r = 0.46, P < 0.0001). Twelve patients received one or more blood transfusions during the first 2 weeks of admission, not related to active bleeding. These patients had borderline significant higher hepcidin level at admission compared to non-transfused patients (26.9[17.2 to 53.9] vs 17.9[9.9 to 28.8]nmol/l, P = 0.052). IL-6 concentrations did not differ between both groups. Correlation analyses showed significant associations between hepcidin levels on day 2 and 3 and the rate of decrease in hemoglobin (Spearman's r ranging from -0.32, P = 0.03 to -0.37, P = 0.016, respectively). CONCLUSIONS: These data suggest that hepcidin-25 may be an important modulator of anemia in septic patients with systemic inflammation

Iron status and the acute post-exercise hepcidin response in athletes

This study explored the relationship between serum ferritin and hepcidin in athletes. Baseline serum ferritin levels of 54 athletes from the control trial of five investigations conducted in our laboratory were considered; athletes were grouped according to values 100 mg/L (SF\u3e100). Data pooling resulted in each athlete completing one of five running sessions: (1) 8x3 min at 85% vVO2peak; (2) 5x4 min at 90% vVO2peak; (3) 90 min continuous at 75% vVO2peak; (4) 40 min continuous at 75% vVO 2peak; (5) 40 min continuous at 65% vVO2peak. Athletes from each running session were represented amongst all four groups; hence, the mean exercise duration and intensity were not different (p\u3e0.05). Venous blood samples were collected pre-, post- and 3 h post-exercise, and were analysed for serum ferritin, iron, interleukin-6 (IL-6) and hepcidin-25. Baseline and post-exercise serum ferritin levels were different between groups (p0.05). Post-exercise IL-6 was significantly elevated compared to baseline within each group (p100;

Iron homeostasis during anemia of inflammation: a prospective study in patients with tuberculosis.

Anemia of inflammation is a hallmark of tuberculosis. Factors controlling iron metabolism during anemia of inflammation and its resolution are uncertain. Whether iron supplements should be given during anti-tuberculosis treatment to support Hb recovery is unclear. Before and during treatment of tuberculosis, we assessed iron kinetics, and changes in inflammation and iron metabolism indices. In a 26-wk prospective study, Tanzanian adults with tuberculosis (n=18) were studied before treatment and then every two weeks during treatment; oral and intravenous iron tracers were administered before treatment, after intensive phase (8/12 wk) and complete treatment (24 wk); no iron supplements were given. Before treatment, hepcidin and erythroferrone (ERFE) were greatly elevated, erythrocyte iron utilization was high (~80%) and iron absorption was negligible (<1%). During treatment, hepcidin and IL-6 decreased ~70% after only 2 wk (p<0.001); in contrast, ERFE did not significantly decrease until 8 wk (p<0.01). ERFE and IL-6 were the main opposing determinants of hepcidin (p<0.05) and greater ERFE was associated with reticulocytosis and hemoglobin (Hb) repletion (p<0.01). Dilution of baseline tracer concentration was 2.6-fold higher during intensive phase treatment (p<0.01) indicating enhanced erythropoiesis. After treatment completion, iron absorption increased ~20-fold (p<0.001); Hb increased ~25% (p<0.001). In tuberculosis-associated anemia of inflammation, our findings suggest elevated ERFE is unable to suppress hepcidin and iron absorption is negligible. During treatment, as inflammation resolves, ERFE may remain elevated, contributing to hepcidin suppression and Hb repletion. Iron is well-absorbed only after tuberculosis treatment and supplementation should be reserved for patients remaining anemic after treatment. (ClinicalTrials.gov Identifier:NCT02176772)

Effectiveness of low-dose iron treatment in non-anaemic iron-deficient women: a prospective open-label single-arm trial

BACKGROUND: Iron deficiency without anaemia is highly prevalent and is particularly associated with fatigue, cognitive impairment, or poor physical endurance. Standard oral iron therapy often results in intestinal irritation with associated side effects and premature discontinuation of therapy, therefore, optimal oral iron therapy with sufficient iron absorption and minimal side effects is desirable. METHODS: Thirty-six iron-deficient non-anaemic premenopausal women (serum ferritin ≤30 ng/ml, haemoglobin ≥117 g/l) with normal body mass index (BMI) and no hypermenorrhea received 6 mg of elemental oral iron (corresponding to 18.6 mg ferrous sulphate) twice daily for 8 weeks. RESULTS: Participants treated with low-dose iron had an average age of 28 years and a BMI of 21 kg/m2. Their serum ferritin and haemoglobin increased significantly from 18 ng/ml to 33 ng/ml (p <0.001) and from 135 g/l to 138 g/l (p = 0.014), respectively. Systolic blood pressure increased from 114 mmHg to 120 mmHg (p = 0.003). Self-reported health status improved after 8 weeks (p <0.001) and only one woman reported gastrointestinal side effects (3%). CONCLUSION: This prospective open-label single-arm trial shows that oral iron treatment of 6 mg of elemental iron twice daily over 8 weeks is effective in iron-deficient non-anaemic women. Due to the negligible side effects, low-dose iron treatment is a valuable therapeutic option for iron-deficient non-anaemic women with normal BMI and menstruation. Further placebo-controlled studies with a larger number of participants are needed to confirm these results. ClinicalTrials.gov NCT0463606

Urinary hepcidin levels in iron-deficient and iron-supplemented piglets correlate with hepcidin hepatic mRNA and serum levels and with body iron status

Among livestock, domestic pig (Sus scrofa) is a species, in which iron metabolism has been most intensively examined during last decade. The obvious reason for studying the regulation of iron homeostasis especially in young pigs is neonatal iron deficiency anemia commonly occurring in these animals. Moreover, supplementation of essentially all commercially reared piglets with iron entails a need for monitoring the efficacy of this routine practice followed in the swine industry for several decades. Since the discovery of hepcidin many studies confirmed its role as key regulator of iron metabolism and pointed out the assessment of its concentrations in biological fluids as diagnostic tool for iron-related disorder. Here we demonstrate that urine hepcidin-25 levels measured by a combination of weak cation exchange chromatography and time-of-flight mass spectrometry (WCX-TOF MS) are highly correlated with mRNA hepcidin expression in the liver and plasma hepcidin-25 concentrations in anemic and iron-supplemented 28-day old piglets. We also found a high correlation between urine hepcidin level and hepatic non-heme iron content. Our results show that similarly to previously described transgenic mouse models of iron disorders, young pigs constitute a convenient animal model to explore accuracy and relationship between indicators for assessing systemic iron status

Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?

BACKGROUND: Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. RESULTS: Analyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [-0.27 (SE 0.34) and -0.22 (SE 0.35), respectively] and ABI after exercise [-0.29 (SE 0.34) and -0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations. CONCLUSIONS: Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women

Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who participated in a 3-year randomized, placebo-controlled double-blind trial examining the effects of folic acid on carotid intima-media thickness. All participants had slightly elevated homocysteine levels and were vitamin B12 replete. Cognitive functioning was assessed at baseline and after 3 years by means of a neuropsychological test battery. At baseline, increased serum ferritin was associated with decreased sensorimotor speed, complex speed, and information-processing speed and increased serum iron was associated with decreased sensorimotor speed. Cognitive performance over 3 years was not associated with HFE C282Y genotype or iron parameters. In conclusion, serum iron parameters do not show a straightforward relationship with cognitive functioning, although elevated iron levels may decrease cognitive speed in older individuals susceptible to cognitive impairmen

Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function

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