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X-linked sideroblastic anaemia (XLSA) arises from pathogenic variants in the 5-aminolevulinate synthase 2 (ALAS2) gene, encoding ALAS2. Although dysregulation of the EPO-ERFE-hepcidin axis has been shown for different iron-loading anaemias,[[6], [10]] our findings for the various iron biomarkers suggest ineffective erythropoiesis in well-treated XLSA patients is less obvious. Iron parameters differed among patients, with some patients showing levels outside the reference interval: median ferritin was 154 g/L (IQR 101-317), transferrin saturation (TSAT) 46% (IQR 41-55), and hepcidin/ferritin-ratio was 14.9 pmol/ g (IQR 9.1-27.6). [Extracted from the article]

We present a p.C282Y homozygous patient with high hepcidin levels and normal iron parameters during systemic inflammation. This suggests that in the absence of a proper functioning HFE, resulting in blockage of the BMP/SMAD pathway, the innate low hepcidin concentration can be upregulated by inflammation, probably via the JAK/STAT3 pathway. [ABSTRACT FROM AUTHOR]

The use of oral contraceptives (OCs) by female athletes may lead to improved iron status, possibly through the regulation of hepcidin by sex hormones. The present work investigates the response of hepcidin and interleukin‐6 (IL‐6) to an interval exercise in both phases of the OC cycle. Sixteen endurance‐trained OC users (age 25.3 ± 4.7 years; height 162.4 ± 5.7 cm; body mass 56.0 ± 5.7 kg; body fat percentage 24.8 ± 6.0%; peak oxygen consumption [VO2peak]: 47.4 ± 5.5 mL min−1 kg−1) followed an identical interval running protocol during the withdrawal and active pill phases of the OC cycle. This protocol consisted of 8 × 3 minutes bouts at 85% VO2peak speed with 90 seconds recovery intervals. Blood samples were collected pre‐exercise, and at 0 hour, 3 hours, and 24 hours post‐exercise. Pre‐exercise 17β‐estradiol was lower (P =.001) during the active pill than the withdrawal phase (7.91 ± 1.81 vs 29.36 ± 6.45 pg/mL [mean ± SEM]). No differences were seen between the OC phases with respect to hepcidin or IL‐6 concentrations, whether taking all time points together or separately. However, within the withdrawal phase, hepcidin concentrations were higher at 3 hours post‐exercise (3.33 ± 0.95 nmol/L) than at pre‐exercise (1.04 ± 0.20 nmol/L; P =.005) and 0 hour post‐exercise (1.41 ± 0.38 nmol/L; P =.045). Within both OC phases, IL‐6 was higher at 0 hour post‐exercise than at any other time point (P <.05). Similar trends in hepcidin and IL‐6 concentrations were seen at the different time points during both OC phases. OC use led to low 17β‐estradiol concentrations during the active pill phase but did not affect hepcidin. This does not, however, rule out estradiol affecting hepcidin levels. [ABSTRACT FROM AUTHOR]

Aims: Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes.Methods and Results: Human embryonic stem cell-derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron-deficient cardiomyocytes, in particular ATP-linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin-bound iron recovered functional and morphological abnormalities within 3 days.Conclusion: Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Anaemia of chronic disease (ACD) has been linked to iron-restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. Here, we report the engineering of the human lipocalin-derived, small protein-based anticalin PRS-080 hepcidin antagonist with high affinity and selectivity.Experimental Approach: Anticalin- and hepcidin-specific pharmacokinetic (PK)/pharmacodynamic modelling (PD) was used to design and select the suitable drug candidate based on t1/2 extension and duration of hepcidin suppression. The development of a novel free hepcidin assay enabled accurate analysis of bioactive hepcidin suppression and elucidation of the observed plasma iron levels after PRS-080-PEG30 administration in vivo.Key Results: PRS-080 had a hepcidin-binding affinity of 0.07 nM and, after coupling to 30 kD PEG (PRS-080-PEG30), a t1/2 of 43 h in cynomolgus monkeys. Dose-dependent iron mobilization and hepcidin suppression were observed after a single i.v. dose of PRS-080-PEG30 in cynomolgus monkeys. Importantly, in these animals, suppression of free hepcidin and subsequent plasma iron elevation were sustained during repeated s.c. dosing. After repeated dosing and followed by a treatment-free interval, all iron parameters returned to pre-dose values.Conclusions and Implications: In conclusion, we developed a dose-dependent and safe approach for the direct suppression of hepcidin, resulting in prolonged iron mobilization to alleviate iron-restricted erythropoiesis that can address the root cause of ACD. PRS-080-PEG30 is currently in early clinical development. [ABSTRACT FROM AUTHOR]

Background: Deferral for low hemoglobin (Hb) increases the likelihood that donors do not return for future donations. Zinc protoporphyrin (ZPP) has been described as a sensitive marker of iron-deficient erythropoiesis, before Hb decreases. It is a relatively cheap, rapid, and easy-to-perform measurement in a drop of whole blood. To assess the utility of ZPP measurement in donor management we examined whether ZPP and Hb levels among first-time donors differ from repeat donors. We further explored whether ZPP increases over subsequent donations at a donor population level and whether increasing ZPP levels coincide with decreasing Hb levels and donor deferral.Study Design and Methods: We included first-time (n = 4983) and repeat (n = 3533) whole blood donors from the ZPP and Iron in the Netherlands Cohort (ZINC) study. ZPP and Hb were measured at each subsequent donation during a 4-year period after inclusion in the study.Results: Median ZPP levels were higher in repeat than in first-time donors. In first-time donors, especially women, ZPP levels were increased with a corresponding decline in Hb levels over subsequent donations. ZPP levels were increased among first-time donors deferred for low Hb.Conclusion: Our results suggest that adding ZPP to Hb measurements in the daily blood collection setting, especially for first-time donors and first-time female donors may add to the identification of a donor subpopulation with low functional iron stores. [ABSTRACT FROM AUTHOR]

Ferric pyrophosphate citrate (Triferic) is a water-soluble iron salt that is administered via dialysate to maintain iron balance and hemoglobin in hemodialysis patients. This double-blind, randomized, placebo-controlled, single-, ascending-dose study was conducted to evaluate the pharmacokinetics and safety of intravenous ferric pyrophosphate citrate in 48 healthy iron-replete subjects (drug, n = 36; placebo, n = 12). Single doses of 2.5, 5.0, 7.5, or 10 mg of ferric pyrophosphate citrate or placebo were administered over 4 hours, and single doses of 15 or 20 mg of ferric pyrophosphate citrate or placebo were administered over 12 hours via intravenous infusion. Serum total iron (sFetot), transferrin-bound iron (TBI), hepcidin-25, and biomarkers of oxidative stress and inflammation were determined using validated assays. Marked diurnal variation in sFetot was observed in placebo-treated subjects. Concentrations of sFetot and TBI increased rapidly after drug administration, with maximum serum concentrations (Cmax) reached at the end of infusion. Increases in baseline-corrected Cmax and area under the concentration-time curve from 0 to the time of the last quantifiable concentration (AUC0-t) were dose proportional up to 100% transferrin saturation. Iron was rapidly cleared (apparent terminal phase half-life 1.2-2 hours). No significant changes from baseline in serum hepcidin-25 concentration were observed at end of infusion for any dose. Biomarkers of oxidative stress and inflammation were unaffected. Intravenous doses of ferric pyrophosphate citrate were well tolerated. These results demonstrate that intravenous ferric pyrophosphate citrate is rapidly bound to transferrin and cleared from the circulation without increasing serum hepcidin levels or biomarkers of oxidative stress or inflammation. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population.Methods and Results: In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1 ± 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex.Conclusions: Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community. [ABSTRACT FROM AUTHOR]

Current treatment for newly diagnosed patients with hereditary hemochromatosis (HH) and iron overload consist of weekly phlebotomy or less frequent and more personalized erythrocytapheresis. Previous observations during phlebotomy suggest an increase in intestinal iron uptake caused by lowering of hepcidin as a result of intensive bloodletting. It is not known whether such an effect is present or even more pronounced using erythrocytapheresis since a larger amount of iron is extracted per procedure. In this study we aimed to assess the effect of erythrocytapheresis on the course of iron parameters, with special focus on serum hepcidin. We performed a retrospective proof-of-principle observational study, comparing serum iron parameters in 12 males during the depletion phase using either phlebotomy ( n = 6) or erythrocytapheresis ( n = 6). Decreases in serum ferritin over time were similar for both treatments but more pronounced using erythrocytapheresis when expressed per treatment procedure. Hemoglobin did not change during erythrocytapheresis, whereas during phlebotomy decreased with 10%. Increase of erythropoietin and soluble transferrin receptor and decrease in transferrin saturation were similar for both treatments. Reduction in serum hepcidin was higher (50% versus 25% of initial value) and occurred more early using phlebotomy (10 versus 20 weeks after start). In aggregate, compared to phlebotomy, the less frequent and more personalized erythrocytapheresis leads to a more pronounced decrease in serum ferritin per treatment procedure, without a larger decrease in serum hepcidin. This may be clinically relevant and may prevent an increase in intestinal iron uptake and an ensuing vicious circle of more frequent treatment procedures. J. Clin. Apheresis 31:564-570, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition. [ABSTRACT FROM AUTHOR]

Background Blood donors that meet the hemoglobin ( Hb) criteria for donation may have undetected subclinical iron deficiency. The aim of this study was to assess the prevalence of subclinical iron deficiency in whole blood donors with Hb levels above cutoff levels for donation by measuring zinc protoporphyrin ( ZPP) levels. In addition, prevalence rates based on other iron variables were assessed for comparison. Study Design and Methods The study population comprised 5280 Dutch whole blood donors, who passed the Hb criteria for donation. During donor screening, Hb levels were measured in capillary samples (finger prick), and venous blood samples were taken for measurements of ZPP and other iron variables. These variables included ferritin, transferrin saturation, soluble transferrin receptor ( sTfR), hepcidin, red blood cell mean corpuscular volume ( MCV), and mean cell Hb ( MCH). Results With a ZPP cutoff level of at least 100 μmol/mol heme, subclinical iron deficiency was present in 6.9% of male donors and in 9.8% of female donors. Based on other iron variables, iron deficiency was also observed. Prevalence rates ranged from 4.8% (based on transferrin saturation) to 27.4% (based on hepcidin concentration) in men and from 5.6% (based on sTfR concentration) to 24.7% (based on hepcidin concentration) in women. Conclusion Results from this study showed that subclinical iron deficiency is prevalent among blood donors that meet the Hb criteria for blood donation, based on ZPP levels and on other iron variables. This finding needs attention because these donors are at increased risk of developing iron deficiency affecting Hb formation and other cellular processes. [ABSTRACT FROM AUTHOR]

Background Iron catalyzes the formation of free radicals, which could lead to damaged vascular walls and subsequent atherosclerosis. Blood donation decreases iron stores and can thus decrease cardiovascular risk. Even within blood donors, differences in stored iron are observed. This study investigates whether increasing lifetime number of donations decreases the extent of subclinical atherosclerosis within blood donors. Study design and methods Subclinical atherosclerosis was evaluated in 269 blood donors by measuring intima-media thickness (IMT), pulse-wave velocity (PWV), and ankle-brachial index (ABI). Lifetime number of whole blood donations was categorized into sex-specific donation tertiles. Results Ferritin and hepcidin were lower in high-frequency donors compared to low-frequency donors. Donors in the third sex-specific donation tertile had on average a 0.3% (95% confidence interval [CI], −3.6 to +3.0%) lower IMT, a 2.1% (95% CI, −3.9 to +8.0%) higher PWV, and a 1.5% (95% CI, −1.4 to +4.5%) higher ABI compared to donors in the first sex-specific donation tertile. Conclusion With such small differences and no consistent trend across donation groups, it cannot be concluded that blood donation has a beneficial effect on the extent of subclinical atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective Congenital dyserythropoietic anemia ( CDA) is a rare group of red blood cell disorders with ineffective erythropoiesis and secondary hemochromatosis. Inappropriate suppression of hepcidin and high levels of growth differentiation factor 15 ( GDF15) have been described in CDA I and II patients, probably contributing to secondary hemochromatosis. Hemojuvelin ( HJV) is an important regulator of serum hepcidin, while soluble form of HJV (s- HJV) competitively down-regulates hepcidin. Methods We determined the soluble hemojuvelin (s- HJV) levels in 17 patients with CDA I and in 17 healthy volunteers ( HV) and looked for correlations with other parameters of iron overload and erythropoiesis. Results Significantly higher levels of s- HJV were found in patients (2.32 ± 1.40 mg/L) compared with healthy volunteers (0. 69 ± 0.44 mg/L) ( P = 0.001). Western blot analysis confirmed the presence of high levels of s- HJV in CDA I patients. s- HJV positively correlated with serum ferritin, erythropoietin, soluble transferrin receptor, and GDF15 and negatively correlated with hepcidin to ferritin ratios. Conclusions We for the first time documented high levels of serum s- HJV in CDA I patients, suggesting that it may contribute to iron loading pathology in CDA I and eventually in other anemias with ineffective erythropoiesis. [ABSTRACT FROM AUTHOR]

Objective To explore the utility of the novel iron indices hepcidin, reticulocyte hemoglobin content (Ret-Hgb), and erythrocyte (red blood cell) hemoglobin content (RBC-Hgb) for detection of iron deficiency in rheumatoid arthritis (RA) patients with anemia and active inflammation and to compare these indices with conventional parameters of iron deficiency. Methods Blood samples from 106 outpatients with RA were analyzed in a cross-sectional exploratory study. Forty patients were classified as having either iron deficiency anemia (IDA), anemia of chronic disease (ACD), their combination (IDA/ACD), or 'other anemia' based on biochemical parameters for inflammation and iron deficiency. The ability of serum and urine hepcidin, Ret-Hgb, and RBC-Hgb measurement to discriminate among these states was evaluated. Results Hepcidin content in serum from patients in the IDA group as well as that from patients in the combined IDA/ACD group differed significantly from that in serum from patients in the ACD group. This difference was also observed with hepcidin in urine, Ret-Hgb, and RBC-Hgb, although with less significance. The area under the receiver operating characteristic curve for serum hepcidin was 0.88 for the comparison of IDA/ACD patients with ACD patients and 0.92 for the comparison of the combined IDA group and IDA/ACD group to all other patients with anemia. Hepcidin at <2.4 nmoles/liter had a sensitivity of 89% and a specificity of 88% to distinguish IDA/ACD from ACD. Both Ret-Hgb and RBC-Hgb measurements also allowed differentiation between these latter groups, with a sensitivity of 67% and 89%, respectively, and a specificity of 100% and 75%, respectively. Conclusion Serum hepcidin and, to a lesser extent, urine hepcidin, Ret-Hgb, and RBC-Hgb, are potential useful indicators for detecting iron deficiency in RA patients with anemia and active inflammation. [ABSTRACT FROM AUTHOR]

Background We applied a diagnostic algorithm using apolipoprotein B (apoB) in combination with triglycerides (TG) and total cholesterol to determine the prevalence of dyslipoproteinemias in the general population. We also characterized the overall cardiovascular (CV) risk profiles, including arterial structure and function as measured with a panel of noninvasive parameters. Design Clinical and biochemical characteristics and noninvasive measurements of atherosclerosis (NIMA) were determined in 1517 individuals, aged 50-70 years. Results In general, all dyslipoproteinemias were characterized by a worse CV risk profile and deteriorated outcomes of NIMA compared to those with normal apolipoprotein B (< 1.2 g L-1) and TG (< 1.5 mM) levels. The prevalence of hyperapoB-hyperTG was 15.1%, and these individuals showed the most abnormal atheroma-related parameters: reduced ankle-brachial-index at rest (-3.5%) and after exercise (-9.8%), increased intima-media thickness (+5.5%) and more carotid plaques (+39.1%). The prevalence of normoapoB-hyperTG because of increased VLDL was 18.1% and 2.3% because of increased chylomicrons and VLDL, and in these groups, the parameters related to stiffness (e.g. pulse-wave-velocity +7.6% and +5.2%, respectively) were most abnormal. Adjustment for apolipoprotein B (apoB) reduced differences in NIMA in the hyperapoB-hyperTG group, whereas adjustment for TG reduced differences in NIMA in the normoapoB-hyperTG group. Conclusions The overall prevalence of dyslipoproteinemias according to the algorithm was approximately 40% in the Dutch population. The different dyslipoproteinemias showed a less favourable CV risk profile and deteriorated NIMA parameters, reflecting increased subclinical atherosclerosis. Furthermore, different effects on different NIMA parameters were observed in the different dyslipoproteinemias. [ABSTRACT FROM AUTHOR]

Aims Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response. Methods and results In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin- 25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/ matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r² = 0.18, P = 0.02), and positively with ferritin (r² = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P , 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r² = 0.23, P = 0.03) and sTfR (r² = 0.23, P = 0.03) and also with the Hb response after 6 months (r² = 0.49, P = 0.001). Conclusion In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated humoral immune response to Streptococcus bovis biotype I during the different stages of colorectal cancer. The study included Dutch and Americans who were examined for the presence of serum antibodies against Streptococcus bovis antigen RpL7/L12. It found that immune response against the bacterial antigen is increased in polyp and stage I/II colorectal cancer patients. Study authors concluded that intestinal bacteria is a risk factor for the progression of premalignant lesions into early stage cancer.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem cell malignancies. A subgroup, the so-called sideroblastic MDS, shows ring sideroblasts in the bone marrow aspirate that represent mitochondrial iron accumulation. Patients with sideroblastic MDS also develop systemic iron overload and generally have a low-risk MDS. Therefore it is important to understand the mechanisms responsible for iron accumulation and the associated toxicity in these patients. Recently, low levels of the iron-regulatory peptide hepcidin were found to contribute to body iron overload in β-thalassaemia patients. A similar mechanism may account for systemic iron accumulation in sideroblastic MDS. Mitochondrial iron accumulation is observed in several subtypes of MDS, and predominantly in refractory anaemia with ring sideroblasts. The presence of ring sideroblasts is also the diagnostic hallmark in patients with inherited forms of sideroblastic anaemia. The ever-increasing insights into the affected pathways in inherited sideroblastic anaemia may lead to a better comprehension of the pathogenesis of mitochondrial iron accumulation in MDS patients. Overall, an improved understanding of the mechanisms responsible for iron overload in MDS will lead to novel treatment strategies to reduce both systemic and mitochondrial iron overload, resulting in less tissue damage and more effective erythropoiesis. [ABSTRACT FROM AUTHOR]

The hepatic peptide hormone hepcidin plays a central role in body iron metabolism. Despite its promise as a biomarker, the availability of high-sensitive hepcidin assays is still limited. We developed and validated a RadioImmunoAssay (RIA) to measure hepcidin quantitatively in human serum. This assay exhibited a very low detection limit (0·02 μg/l), low imprecision (coefficient of variation-range 4·4–6·2%) and good linearity and recovery (range: 81–105%). Hepcidin levels of samples of controls and patients with iron deficiency and inflammation showed an excellent correlation with our previously described quantitative time-of-flight mass spectrometry assay (range 2·5–266·8 μg/l, r = 0·92, P < 0·0001). The RIA detected: (i) differences in mean hepcidin levels between men ( n = 29) and women ( n = 35), (ii) differences between individuals of different HFE-genotypes ( n = 60) and (iii) daily increases in hepcidin levels ( n = 64). The assay (i) is easy to perform and many samples can be processed within one assay-run, (ii) shows accurate, reproducible and high-sensitive measurements and (iii) is anticipated to be particularly useful to study the effects of pathological and physiological stimuli on hepcidin levels in the lower range. [ABSTRACT FROM AUTHOR]

The correct selection of individuals who will benefit from iron supplements in malaria-endemic regions requires improved insight in the effects of malaria on host iron homeostasis and innovative biomarkers. We assessed sequential changes in serum hepcidin and in traditional biochemical iron status indicators during an experimental Plasmodium falciparum malaria infection with five adult volunteers. The haemoglobin content of reticulocytes (Ret-He) and of mature red blood cells (RBC-He) represented iron incorporation into haemoglobin. Low-density parasitaemia and its treatment induced a mild increase in interleukin (IL)-6 and serum hepcidin concentrations. Despite this only mild increase, a marked hypoferraemia with a strong increase in serum ferritin concentrations developed, which was associated with a sharp fall in Ret-He, while RBC-He remained unchanged. The ratio of soluble transferrin receptor (sTfR) to log ferritin concentrations decreased to an average nadir of 63% of the baseline value. We concluded that even mild increases in serum hepcidin and IL-6 concentrations result in a disturbed host iron homeostasis. Serum hepcidin, Ret-He and Delta-He (Ret-He minus RBC-He) are promising biomarkers to select those individuals who will benefit from iron supplements in malaria endemic regions, while the sTfR/log ferritin ratio should be used with caution to assess iron status during malaria. [ABSTRACT FROM AUTHOR]

HFE C282Y-homozygosity has been associated with low hepcidin expression, leading to increased ferritin levels. However, serum hepcidin protein levels have not been documented in humans. In the current study, we compared serum hepcidin levels of newly diagnosed HFE C282Y-homozygotes with ( N = 15) and without ( N = 7) elevated serum ferritin levels to levels of 40 controls (20 heterozygotes and 20 wild types). In addition, hepcidin levels of four C282Y homozygotes were investigated during the course of all phlebotomy treatment phases. Serum hepcidin levels were lower in HFE C282Y-homozygotes (median; 25th–75th percentile: 1·88; 0·78–2·77 nmol/l) compared to controls (2·74; 1·45–5·39). Hepcidin/ferritin ratios were also lower in homozygotes. Homozygotes with an elevated serum ferritin had a higher serum hepcidin but a lower hepcidin/ferritin ratio than those with normal ferritin (2·28; 1·62–3·23 nmol/l hepcidin vs. 0·80; 0·60–1·29 and 3·63; 2·72–7·59 pmol hepcidin/μg ferritin vs. 13·2; 5·15–14·2). Serum hepcidin decreased during the depletion phase of phlebotomy and remained low during maintenance. This study showed that serum hepcidin is innately low in HFE-related haemochromatosis. Elevated ferritin levels were associated with increased hepcidin levels while erythropoiesis lead to lower hepcidin levels. During depletion, therefore, hepcidin levels are decreased, which may exacerbate intestinal iron absorption. [ABSTRACT FROM AUTHOR]

Scrutiny of NOE data available for the protein encoded by gene V of the filamentous phage Ike (Ike GVP), resulted in the elucidation of a &bera;-sheet structure which is partly five stranded. The DNA-binding domain of Ike GVP was investigated using a spin-labeled deoxytrinucleotide. The paramagnetic-relaxation effects observed in the ¹H-NMR spectrum of Ike GVP, upon binding of this DNA fragment, could be visualized using two-dimensional difference spectroscopy. In this way, the residues present in the DNA-binding domain of Ike GVP can be located in the structure of the protein. They exhibit a high degree of identity with residues in the gene V protein encoded by the distantly related phage M13 (M13 GVP), for which similar spectral perturbations are induced by such a spin-labeled oligonucleotide. Binding studies with negatively charged lanthanide-1,4,7,10-tetraazacyclodecanetrayl-1,4,7,10-tetrakis(methylene)tetrakisphosphonic acid (DOTP) complexes, showed that these complexes bind to Ike and M13 GVP at two spatially remote sites whose affinities have different pH dependencies. Above pH 7, there is one high-affinity binding site for Gd(DOTP)8−/M13 GVP monomer, which coincides with the single-stranded DNA-binding domain as mapped with the aid of spin-labeled oligonucleotide fragments. The results show that single-stranded DNA binds to conserved (phosphate binding) electropositive clusters at the surface of M13 and Ike GVP. These positive patches are interspersed with conserved or conservatively replaced hydrophobic residues. At pH 5, a second Gd(DOTP) 5−-binding site becomes apparent. The corresponding pattern of spectral perturbations indicates the accommodation of patches of conserved, or conservatively replaced, hydrophobic residues in the cores of the M13 and Ike dimmers. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "A novel tri-allelic mutation of TMPRSS6 in iron-refractory iron deficiency anaemia with response to glucocorticoid" by N. Nie and others, in a2014 issue of the journal is presented.

A response from the authors of the article "Hepcidin and Hemoglobin Content Parameters in the Diagnosis of Iron Deficiency in Rheumatoid Arthritis Patients with Anemia" in the December 2011 issue is presented.

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Heme oxygenase-1 (HO-1) contribution to iron homeostasis has been postulated, because it facilitates iron recycling by liberating iron mostly from heme catabolism. This enzyme also appears to be responsible for the resolution of inflammatory conditions. In a patient with HO-1 deficiency, inflammation and dysregulation of body iron homeostasis, including anemia and liver and kidney hemosiderosis, are evidenced. Here we postulated that HO-1 is critical in the regulation of ferroportin, the major cellular iron exporter, and hepcidin, the key regulator of iron homeostasis central in the pathogenesis of anemia of inflammation. Our current experiments in human THP-1 monocytic cells indicate a HO-1-induced iron-mediated surface-ferroportin expression, consistent with the role of HO-1 in iron recycling. Surprisingly, we observed low hepcidin levels in the HO-1-deficient patient, despite the presence of inflammation and hemosiderosis, both inducers of hepcidin. Instead, we observed highly increased soluble transferrin receptor levels. This suggests that the decreased hepcidin levels in HO-1 deficiency reflect the increased need for iron in the bone marrow due to the anaemia. Using human hepatoma cells, we demonstrate that HO-activity did not have a direct modulating effect on expression of HAMP, the gene that encodes for hepcidin. Therefore, we argue that the decreased iron recycling may, in part, have contributed to the low hepcidin levels. These findings indicate that dysregulation of iron homeostasis in HO-1 deficiency is the result of both defective iron recycling and erythroid activity-associated inhibition of hepcidin expression. This study therefore shows a crucial role for HO-1 in maintaining body iron balance.