Exercise-induced inflammation can influence iron metabolism. Conversely, the effects of vitamin D3, which possesses anti-inflammatory properties, on ultramarathon-induced heart damage and changes in iron metabolism have not been investigated. Thirty-five healthy long-distance semi-amateur runners were divided into two groups: one group received 150,000 IU of vitamin D3 24 h prior to a race (n = 16), while the other group received a placebo (n = 19). Serum iron, hepcidin (HPC), ferritin (FER), erythroferrone (ERFE), erythropoietin (EPO), neopterin (NPT), and cardiac troponin T (cTnT) levels were assessed. A considerable effect of ultramarathon running on all examined biochemical markers was observed, with a significant rise in serum levels of ERFE, EPO, HPC, NPT, and cTnT detected immediately post-race, irrespective of the group factor. Vitamin D3 supplementation showed a notable interaction with the UM, specifically in EPO and cTnT, with no other additional changes in the other analysed markers. In addition to the correlation between baseline FER and post-run ERFE, HPC was modified by vitamin D. The ultramarathon significantly influenced the EPO/ERFE/HPC axis; however, a single substantial dose of vitamin D3 had an effect only on EPO, which was associated with the lower heart damage marker cTnT after the run.
- MeSH
- Running physiology MeSH
- Biomarkers * blood MeSH
- Cholecalciferol * administration & dosage MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Erythropoietin blood administration & dosage MeSH
- Hepcidins blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Marathon Running * MeSH
- Heart Diseases prevention & control etiology MeSH
- Dietary Supplements * MeSH
- Troponin T blood MeSH
- Iron * blood administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.
- MeSH
- Hepcidins genetics MeSH
- Ion Channels genetics MeSH
- Oxygen metabolism MeSH
- Humans MeSH
- Mutation MeSH
- Polycythemia * genetics MeSH
- Receptors, Erythropoietin genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Pri ochoreniach s prejavmi aktivácie zápalu je častým sprievodným stavom anémia, ktorá negatívne ovplyvňuje kvalitu života a výkonnosť pacientov. Táto anémia - anémia zápalu, je spôsobená poruchami metabolizmu železa, ktoré vedú k retencii železa v makrofágoch, cytokínmi sprostredkovanej inhibícii funkcie erytropoetínu a diferenciácii erytroidných progenitorových buniek a zníženým polčasom rozpadu erytrocytov. Anémia je väčšinou mierna až stredne závažná, normocytová a normochrómna. Vyznačuje sa nízkou cirkuláciou železa, ale normálnymi až zvýšenými hladinami zásobného feritínu a hormónu hepcidínu. Primárnym terapeutickým prístupom je liečba základného zápalového ochorenia. V prípade neúspechu možno zvážiť suplementáciu železa a/alebo liečbu liekmi stimulujúcimi erytropoetín. Krvné transfúzie predstavujú len núdzové riešenie život ohrozujúcej anémie. Perspektívne sa objavujú nové modality liečby so stratégiami modifikujúcimi hepcidín a stabilizátormi faktorov indukovateľných hypoxiou. Ich terapeutickú účinnosť je však potrebné overiť a vyhodnotiť v klinických štúdiách.
Anemia, which is a manifestation of the deterioration of patients' health and performance, is a common concomitant condition in diseases with signs of inflammation activation. This anemia - anemia of inflammation, is caused by disturbances of iron metabolism that lead to iron retention within macrophages, cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation, and a reduced erytrocyte half-life. Anemia is usually mild to moderate, normocytic and normochromic. It is characterized by low iron circulation, but normal to increased levels of stored ferritin and the hormone hepcidin. The primary therapeutic approach is the treatment of the underlying inflammatory disease. In case of failure, iron supplementation and / or treatment with erythropoietin stimulating agents may be used. Blood transfusions are just an emergency treatment for life-threatening anemia. A new treatment modalities with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors is emerging. However, their therapeutic efficacy needs to be verified and evaluated in clinical trials.
- MeSH
- Anemia * diagnosis etiology drug therapy MeSH
- Erythropoiesis drug effects MeSH
- Hepcidins metabolism MeSH
- Humans MeSH
- Inflammation * complications pathology MeSH
- Iron metabolism therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
The use of herbal medicinal products and supplements in amateur and professional sports has increased in the last decades. This is because most of these products and supplements contain bioactive compounds with a variety of biological properties that exert a physiological effect on the human body. The aim of this study was to analyze the effect of dietary supplementation with lyophilized black chokeberry extract on the levels of pro-inflammatory cytokines, hepcidin, and selected markers of iron metabolism in a group of young football players. This double-blind study included 22 male football players (mean = 19.96 ± 0.56), divided into two groups: supplemented and placebo. Before and after a 90-day period of training combined with supplementation (6 g of lyophilized black chokeberry extract), participants performed maximal multistage 20-m shuttle run tests at the beginning and at the end of the supplementation period, with blood sampled for analysis at different times before and after exercise. The levels of IL-6, IL-10, ferritin, myoglobin, hepcidin, 8-OHdG, albumin, and TAC were analyzed. The analysis of variance revealed a significant effect of 90-day supplementation with the lyophilized extract on changes in the IL-6 and IL-10 levels, and TAC induced by maximal aerobic effort. In conclusion, supplementation with lyophilized black chokeberry extract improves the performance and antioxidant status of serum in humans and induces protective changes in inflammatory markers.
- MeSH
- Double-Blind Method MeSH
- Soccer MeSH
- Hepcidins MeSH
- Interleukin-10 MeSH
- Interleukin-6 MeSH
- Humans MeSH
- Young Adult MeSH
- Photinia * MeSH
- Dietary Supplements * MeSH
- Plant Extracts * pharmacology MeSH
- Athletes MeSH
- Inflammation MeSH
- Iron * metabolism MeSH
- Check Tag
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
INTRODUCTION: Major clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity. COHORTS: To investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses - in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other. RESULTS: We showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation - in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and P = 0.03. DISCUSSION: Our findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19.
- MeSH
- Biomarkers MeSH
- COVID-19 * MeSH
- Ferritins MeSH
- Hepcidins metabolism MeSH
- Humans MeSH
- Shock, Septic * MeSH
- Inflammation MeSH
- Iron metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Anemia is the most common extraintestinal systemic complication of inflammatory bowel disease. Iron deficiency anemia and anemia of chronic disease are among the most frequent types. Intestinal iron absorption is controlled by the activity of ferroportin. Cells with high expression of ferroportin include enterocytes, and also macrophages and hepatocytes. Iron homeostasis is controlled by the hepcidin-ferroportin axis. Hepcidin is a central regulator of iron metabolism and can also serve as a marker of systemic inflammation. During systemic inflammatory response, the synthesis of hepcidin increases, and hepcidin binds to ferroportin and inhibits its activity. Thus, iron is not absorbed from the bowel into the circulation and also remains sequestered in macrophages. Conversely, hepcidin synthesis is suppressed during conditions requiring increased iron intake for enhanced erythropoiesis, such as iron deficiency anemia or hypoxia. Here, ferroportin is not blocked, and iron is actively absorbed into the bloodstream and also released from the stores. Production of hepcidin is influenced by the status of total body iron stores, systemic inflammatory activity and erythropoietic activity. Oral iron therapy is limited in inflammatory bowel diseases due to ongoing gastrointestinal inflammation. It is less effective and may worsen the underlying disease. Therefore, the choice between oral and parenteral iron therapy must be made with caution. Oral iron would be ineffective at high hepcidin levels due to concurrent ferroportin blockage. Contrarily, low levels of hepcidin indicate that oral iron therapy should be successful. An understanding of hepcidin can help in understanding the body's reaction to iron depletion during the inflammatory process.
- MeSH
- Anemia etiology therapy MeSH
- Hepcidins metabolism MeSH
- Inflammatory Bowel Diseases complications MeSH
- Humans MeSH
- Cation Transport Proteins metabolism MeSH
- Gene Expression Regulation MeSH
- Iron administration & dosage metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Anémie, zejména sideropenická anémie a anémie chronických chorob, jsou nejčastější extraintestinální systémovou komplikací nespecifických střevních zánětů. U těchto pacientů se často kombinuje relativní deficit železa a chronická zánětlivá aktivita, kdy i přes dostatečné celkové zásoby železa v organismu není železo dostupné pro erytropoézu (tzv. "funkční" deficit železa). Klíčovým regulátorem metabolismu železa je hepcidin a jeho interakce s transmembránovým přenašečem železa feroportinem. Diagnostika a léčba anémie se řídí platnými doporučeními. A aktuální sérová hladina hepcidinu může, vedle ostatních markerů, přispět k rozhodnutí o správné strategii léčby železem (parenterální versus perorální forma).
Anemia is the most common extraintestinal complication of inflammatory bowel disease. Iron deficiency anemia and anemia of chronic disease are the most frequent types. Iron deficiency and chronic inflammation are often combined in patients with inflammatory bowel diseases: total iron body stores are sufficient, but are not available for erytropoiesis (so called "functional" iron deficiency). Hepcidin (interaction of hepcidin-ferroportin) is a key regulator of iron metabolism and also marker of systemic inflammation. Hepcidin binds to ferroportin and blocks its function. The diagnosis and treatment of anemia are guided by available recommendations and the current serum level of hepcidin, in addition to other markers, may contribute to the decision of adequate form of iron supplementation (parenteral versus oral).
Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe-/-/hepatic Alk3fl/fl;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3fl/fl;Alb-Cre mice compared to Alk3fl/fl mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.
- MeSH
- Hepcidins * genetics MeSH
- Liver metabolism MeSH
- Histocompatibility Antigens Class I genetics MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Iron Overload * genetics MeSH
- Hemochromatosis Protein genetics MeSH
- Bone Morphogenetic Protein Receptors, Type I MeSH
- Signal Transduction MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
AIM: The aim of this study was to compare changes in serum hepcidin levels in paediatric patients with inflammatory bowel disease during therapy and correlate them with markers of iron metabolism, inflammation and type of treatment. METHODS: Children with newly diagnosed Crohn's disease (CD) and ulcerative colitis (UC) were included in this longitudinal study. Blood and stool samples were collected to assess levels of serum hepcidin and markers of iron metabolism parameters and inflammation. The parameters were examined before treatment (baseline levels) and compared with levels in the follow-up period during maintenance therapy (mean follow-up of 39 months after diagnosis). RESULTS: Patients with CD (n = 30) had higher serum hepcidin levels (expressed as a median and interquartile range) at diagnosis than subjects with UC (n = 13). These levels significantly decreased during the follow-up (from 36.5 (11.5-79.6) to 2.1 (0.9-6.7) ng/mL). In contrast, no significant serum hepcidin level changes were observed in the UC patients (5.4 (3.4-16.6) vs. 4.8 (0.9-8.1) ng/mL). While hepcidin level changes correlated with disease activity and inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein), in CD patients, they correlated only with serum iron levels in patients with UC. Biological therapy was accompanied by a significant decrease in C-reactive protein and interleukin-6 compared to conventional anti-inflammatory therapy in CD patients. CONCLUSIONS: Children with CD had higher serum hepcidin levels on diagnosis compared to subjects with UC. During an anti-inflammatory therapy, serum hepcidin decreased in the CD group but remained consistently low in children with UC.
- MeSH
- Anti-Inflammatory Agents therapeutic use MeSH
- Biomarkers MeSH
- Child MeSH
- Hepcidins MeSH
- Inflammatory Bowel Diseases * drug therapy MeSH
- Humans MeSH
- Longitudinal Studies MeSH
- Case-Control Studies MeSH
- Colitis, Ulcerative * drug therapy MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
The liver secretes hepcidin (Hepc) into the bloodstream to reduce blood iron levels. Hepc accomplishes this by triggering degradation of the only known cellular iron exporter ferroportin in the gut, macrophages, and liver. We previously demonstrated that systemic Hepc knockout (HepcKO) mice, which have high serum iron, develop retinal iron overload and degeneration. However, it was unclear whether this is caused by high blood iron levels or, alternatively, retinal iron influx that would normally be regulated by retina-produced Hepc. To address this question, retinas of liver-specific and retina-specific HepcKO mice were studied. Liver-specific HepcKO mice had elevated blood and retinal pigment epithelium (RPE) iron levels and increased free (labile) iron levels in the retina, despite an intact blood-retinal barrier. This led to RPE hypertrophy associated with lipofuscin-laden lysosome accumulation. Photoreceptors also degenerated focally. In contrast, there was no change in retinal or RPE iron levels or degeneration in the retina-specific HepcKO mice. These data indicate that high blood iron levels can lead to retinal iron accumulation and degeneration. High blood iron levels can occur in patients with hereditary hemochromatosis or result from use of iron supplements or multiple blood transfusions. Our results suggest that high blood iron levels may cause or exacerbate retinal disease.
- MeSH
- Retinal Degeneration etiology metabolism pathology MeSH
- Blood-Retinal Barrier MeSH
- Hepcidins physiology MeSH
- Liver metabolism pathology MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Iron Overload etiology metabolism pathology MeSH
- Retina metabolism pathology MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
