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Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia of inflammation. We conducted a first-in-human, double-blind, placebo-controlled, single-ascending dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of DISC-0974 in healthy participants. Overall, 42 participants were enrolled and received a single dose of placebo or DISC-0974 at escalating dose levels (7-56 mg), administered intravenously (IV) or subcutaneously (SC). DISC-0974 was well tolerated, with a safety profile comparable to that of placebo. Pharmacokinetic data was dose and route related, with a terminal half-life of approximately 7 days. The bioavailability of SC dosing was ∼50%. Pharmacodynamic data showed dose-dependent decreases in serum hepcidin, with reductions of nearly 75% relative to baseline at the highest dose level tested, and corresponding increases in serum iron in response to DISC-0974 administration. Dose-dependent changes in serum ferritin and hematology parameters were also observed, indicating mobilization of iron stores and downstream effects of enhanced hemoglobinization and production of RBCs. Altogether, these data are consistent with the mechanism of action of DISC-0974 and support the selection of a biologically active dose range for evaluation in clinical trials for individuals with anemia of inflammation.

UNASSIGNED: Iron overload cardiomyopathy (IOC) is a major co-morbidity of genetic hemochromatosis and secondary iron overload with limited therapeutic options. We aim to investigate mechanisms of rescue action of amlodipine in the murine model of iron overload, characterize changes in human cardiac tissue due to IOC, and compare them to the changes in the animal model of IOC.
UNASSIGNED: As an animal model, we used male hemojuvelin knockout (HJVKO) mice, which lacked hemojuvelin (a co-receptor protein for hepcidin expression). The mice were fed a high-iron diet from 4 weeks to 1 year of age. As a rescue, iron-fed mice received the Ca2+ channel blocker, amlodipine, from 9 to 12 months. Iron overload resulted in systolic and diastolic dysfunctions and changes in the cardiac tissue similar to the changes in the explanted human heart with IOC. An IOC patient (β-thalassemia) with left-ventricular ejection fraction (LVEF) 25% underwent heart transplantation. The murine model and the explanted heart showed intra-myocyte iron deposition, fibrosis, hypertrophy, oxidative stress, remodeling of Ca2+ cycling proteins, and metabolic kinases typical of heart failure. Single-myocyte contractility and Ca2+ release were diminished in the murine model. The amlodipine-treated group exhibited normalization of cellular function and reversed fibrosis, hypertrophy, oxidative stress, and metabolic remodeling. We also report a clinical case of primary hemochromatosis successfully treated with amlodipine.
UNASSIGNED: The aged HJVKO murine model on the iron-rich diet reproduced many features of the human case of IOC. The use of amlodipine in the murine model and clinical case reversed IOC remodeling, demonstrating that amlodipine is effective adjuvant therapy for IOC.

Hepcidin is a liver-derived hormone that controls systemic iron traffic. It is also expressed in the heart, where it acts locally. We utilized cell and mouse models to study the regulation, expression, and function of cardiac hepcidin. Hepcidin-encoding Hamp mRNA was induced upon differentiation of C2C12 cells to a cardiomyocyte-like phenotype and was not further stimulated by BMP6, BMP2, or IL-6, the major inducers of hepatic hepcidin. The mRNAs encoding hepcidin and its upstream regulator hemojuvelin (Hjv) are primarily expressed in the atria of the heart, with ~20-fold higher Hamp mRNA levels in the right vs. left atrium and negligible expression in the ventricles and apex. Hjv-/- mice, a model of hemochromatosis due to suppression of liver hepcidin, exhibit only modest cardiac Hamp deficiency and minor cardiac dysfunction. Dietary iron manipulations did not significantly affect cardiac Hamp mRNA in the atria of wild-type or Hjv-/- mice. Two weeks following myocardial infarction, Hamp was robustly induced in the liver and heart apex but not atria, possibly in response to inflammation. We conclude that cardiac Hamp is predominantly expressed in the right atrium and is partially regulated by Hjv; however, it does not respond to iron and other inducers of hepatic hepcidin.

OBJECTIVE: Iron overload (IO) is a common and life-threatening complication resulting from the therapy of AL and HCT patients. This study aimed to evaluate the prognostic value of 12 serum biomarkers of iron metabolism in pediatric patients treated for AL or undergoing HCT.
METHODS: Overall, 50 patients with AL after intensive treatment and 32 patients after HCT were prospectively included in the study. AL patients at diagnosis and healthy controls served as reference groups.
METHODS: The impact of the following 12 serum iron metabolism parameters on the outcome of AL/HCT patients was analyzed: iron, transferrin (Tf), total iron-binding capacity (TIBC), ferritin, ferritin heavy chains (FTH1), ferritin light chains (FTL), hepcidin, soluble hemojuvelin (sHJV), soluble ferroportin-1 (sFPN1), erythroferrone (ERFE), erythropoietin (EPO), and soluble transferrin receptor (sTfR).
RESULTS: With a median follow-up of 2.2 years, high levels of ferritin and low levels of sHJV had an adverse prognostic impact on OS and EFS in children after HCT. If these patients were combined with those with AL after intensive chemotherapy, the results were confirmed for OS and EFS both for ferritin and sHJV.
CONCLUSIONS: Among the 12 analyzed serum parameters of iron metabolism, increased levels of ferritin and decreased levels of sHJV had an adverse prognostic impact on survival in children after HCT. More data are needed to clarify the relationship between ferritin, sHJV, and mortality of AL children after intensive chemotherapy, and more extensive prospective studies are required to prove sHJV predictivity.

The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania\'s host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv-/- mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv-/- mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv-/- peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv-/- and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.

The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, to approximately 200% of control values. This increase in heart ferroportin protein is very probably caused by a decrease in systemic hepcidin expression, in accordance with the classical regulation of ferroportin by hepcidin. However, the control of heart ferroportin protein by systemic hepcidin could apparently be overridden by changes in heart non-heme iron content since injection of ferric carboxymaltose to mice at 300 mg Fe/kg resulted in an increase in liver hepcidin expression, heart non-heme iron content, and also a threefold increase in heart ferroportin protein content. In a separate experiment, feeding an iron-deficient diet to young Wistar rats dramatically decreased liver hepcidin expression, while heart non-heme iron content and heart ferroportin protein content decreased to 50% of controls. It is, therefore, suggested that heart ferroportin protein is regulated primarily by the iron regulatory protein/iron-responsive element system and that the regulation of heart ferroportin by the hepcidin-ferroportin axis plays a secondary role.

Patients with non-transfusion dependent thalassemia (NTDT) develop variable degrees of iron overload. Possible genes which may be implicated in causing iron overload are hepcidin (HAMP) and hemojuvelin (HFE). There is variable data assessing the role of c.-582Y A > G HAMP gene and H63D hotspot in HFE-1 gene in causing iron overload, while role of HFE-2 gene is undetermined. Twenty-five patients with NTDT (≥ 10 years) were assessed for iron overload. Genetic analysis for β-globin, α-globin, HAMP, HFE-2 and C282Y and H63D hotspots in HFE-1 genes was performed. T2*MRI demonstrated elevated LIC in 48% patients. No mutations were detected in HAMP gene or HFE-1 hotspots. Four single nucleotide variations (SNV) were detected in HFE-2 gene in 4 (20%) patients, including a novel SNV, p.Gln315Arg in 2 patients in heterozygous state. This is a likely pathogenic mutation; however, in heterozygous state, it did not lead to iron overload. HAMP and HFE-2 gene variations were infrequently seen in this pilot study, with no significant impact on iron overload. Presence of SNV p.Gln315Argin HFE-2 gene needs to be evaluated in larger sample sizes in our population to determine the incidence in homozygous state and its association with iron overload.
BACKGROUND: The online version contains supplementary material available at 10.1007/s12288-021-01442-9.

OBJECTIVE: There is clear evidence that lifestyle factors affect iron bioavailability. However, information regarding the effect of alcohol and caffeine consumption on iron metabolism is limited. The aim of the current study was to evaluate the effect of caffeine and alcohol consumption on iron metabolism in healthy men, regarding their everyday physical activity level.
METHODS: The study enrolled 83 men (59 physically active and 24 sedentary men) aged 18-32 years. Fasting blood samples were collected. ELISA kits were used to determine levels of ferritin, soluble transferrin receptor, hepcidin, hemojuvelin, and C-reactive protein (hsCRP). Level of physical activity was assessed using the International Physical Activity Questionnaire (IPAQ). Caffeine and alcohol intake was assessed using a food frequency questionnaire. A general linear model was performed to evaluate the relationship between caffeine intake and levels of serum ferritin, ferritin, soluble transferrin receptor, hepcidin, hemojuvelin, and hsCRP.
RESULTS: Physically active men (but not sedentary men) who consumed alcohol in excess presented higher ferritin levels when compared to moderate drinkers and abstainers (R2 = 0.35, p = 0.0001). Heavy drinkers presented the highest hepcidin levels when compared to both abstainers and moderate drinkers (p < 0.0001 for physically active, and p = 0.0267 for sedentary men). However, moderate drinkers showed significantly lower hsCRP levels when compared to heavy drinkers and abstainers drinkers (p < 0.0001 for physically active, and p = 0.0116 for sedentary men). Greater caffeine intake was generally associated with greater serum hepcidin levels, with the strongest effect on moderate drinkers. A significant influence of caffeine intake on hsCRP was shown for physically active men but not for sedentary men - greater caffeine intake was connected with higher hsCRP levels for participants who drank alcohol.
CONCLUSIONS: Based on the presented results it can be assumed that high caffeine consumption may lead to suppression of iron bioavailability through increased inflammation. Furthermore, physical activity and moderate alcohol consumption seemed to benefit reduction of inflammatory response, at least as represented by hsCRP levels.

BACKGROUND: Several inherited diseases cause hyperferritinemia with or without iron overload. Differential diagnosis is complex and requires an extensive work-up. Currently, a clinical-guided approach to genetic tests is performed based on gene-by-gene sequencing. Although reasonable, this approach is expensive and time-consuming and Next Generation Sequencing (NGS) technology may provide cheaper and quicker large-scale DNA sequencing.
METHODS: We analysed 36 patients with non-HFE-related hyperferritinemia. Liver iron concentration was measured in 33 by magnetic resonance. A panel of 25 iron related genes was designed using SureDesign software. Custom libraries were generated and then sequenced using Ion Torrent PGM.
RESULTS: We identified six novel mutations in SLC40A1, three novel and one known mutation in TFR2, one known mutation and a de-novo deletion in HJV, and a novel mutation in HAMP in ten patients. In silico analyses supported the pathogenic role of the mutations.
CONCLUSIONS: Our results support the use of an NGS-based panel in selected patients with hyperferritinemia in a tertiary center for iron metabolism disorders. However, 26 out of 36 patients did not show genetic variants that can individually explain hyperferritinemia and/or iron overload suggesting the existence of other genetic defects or gene-gene and gene-environment interactions needing further studies.