Search Results (25)

Background/Objectives: Ineffective erythropoiesis (IE) is a hallmark of β-thalassemia and contributes to major clinical complications, including severe anemia, extramedullary hematopoiesis, and progressive iron overload. Despite its central role in disease pathophysiology, there is no established biomarker for the reliable identification and monitoring of IE. This systematic review was conducted to evaluate potential serum markers that reflect IE in β-thalassemia. Methods: Across seven databases (PubMed, ScienceDirect, Web of Science, SpringerLink, Taylor & Francis, ProQuest, and SAGE), thirteen studies met the eligibility criteria and were analyzed to identify circulating biomarkers associated with IE in β-thalassemia. Results: The most consistently reported markers were growth differentiation factor-15 (GDF-15), soluble transferrin receptor (sTfR), erythropoietin (EPO), and erythroferrone (ERFE), all of which demonstrated strong correlations with the degree of IE and erythroid expansion. Additional markers, including circulating cell-free DNA (cfDNA), CA15.3, hepcidin, ferritin, and phosphatidylserine (PS)-exposed red blood cells, were also found to be elevated, reflecting increased erythroid turnover, apoptosis, and secondary iron dysregulation. These findings suggest that while individual markers capture different aspects of IE, their combined evaluation may provide a more comprehensive picture of disease burden. Conclusions: IE represents the central pathophysiological driver of β-thalassemia and is closely linked to disease complications. Early detection through circulating biomarkers offers the potential for timely identification of high-risk patients, monitoring of therapeutic responses, and prognostication. Although current evidence highlights GDF-15, sTfR, ERFE, and EPO as the most promising candidates, further validation in larger, longitudinal cohorts is required before clinical implementation. Full article

Background/Objectives: Chronic kidney disease (CKD) is commonly complicated by anemia resulting from impaired erythropoietin (EPO) production, iron dysregulation, and chronic inflammation. Erythroferrone (ERFE) and hepcidin are key regulators of erythropoiesis and iron metabolism, but their interaction in CKD remains incompletely understood. This study aimed to examine the associations among ERFE, hepcidin, EPO, and hemoglobin, and to determine whether these markers independently relate to anemia severity in CKD. Methods: This cross-sectional case–control study included 126 patients with CKD (stages 2–5) and 33 age- and sex-matched healthy controls. Laboratory parameters, including hemoglobin, ferritin, transferrin saturation (TSAT), EPO, ERFE, hepcidin, and renal indices (eGFR, BUN, creatinine), were analyzed. Group differences were assessed using ANOVA or Kruskal–Wallis tests with post hoc analyses, and trends were evaluated using the Jonckheere–Terpstra test. Age- and sex-adjusted correlations and multivariable linear regression identified independent associations with hemoglobin. Results: Patients with CKD were older (61.2 ± 14.8 vs. 33.4 ± 10.7 years, p < 0.001) and had lower hemoglobin (11.8 ± 1.9 vs. 13.5 ± 1.4 g/dL, p < 0.001) and higher ferritin levels (245 (110–470) vs. 105 (40–240) ng/mL, p = 0.002) compared with controls. eGFR declined progressively across CKD stages (median (IQR): 73 (64–86) to 12 (7–17) mL/min/1.73 m², p-trend < 0.001). ERFE and hepcidin showed increasing trends with advancing CKD (p-trend = 0.031 and 0.047, respectively). Hemoglobin correlated negatively with ERFE (r = −0.40, 95% CI: −0.53 to −0.26, p < 0.001) and positively with eGFR (r = 0.42, 95% CI: 0.28–0.54, p < 0.001). In adjusted regression analysis, ERFE (β = −0.29, 95% CI: −0.41 to −0.18, p < 0.001) and eGFR (β = 0.25, 95% CI: 0.13–0.37, p < 0.001) remained independently associated variables of hemoglobin (adjusted R² = 0.47). Conclusions: Anemia severity in CKD is independently associated with both renal dysfunction and higher ERFE concentrations, suggesting a disrupted ERFE–hepcidin regulatory balance. These findings provide hypothesis-generating insights into the complex interplay between iron metabolism and erythropoiesis in CKD. Validation in larger, multi-center longitudinal studies that include inflammatory markers is warranted. Full article

Obesity and bariatric surgery are both associated with disrupted iron homeostasis. These alterations may be mediated by newly identified iron metabolism regulators. The aim of this study was to conduct a short-term, detailed analysis of hepcidin, soluble hemojuvelin, ferroportin, and erythroferrone—as well as whole-body composition—before and five months after sleeve gastrectomy. This approach may help elucidate the potential impact of bariatric surgery on iron metabolism and the timing of these changes. The study included 40 obese patients aged 26–64 eligible for laparoscopic sleeve gastrectomy. Iron parameters were assessed with immunoenzymatic methods. We found significantly increased iron levels (79 µg/dL vs. 95 µg/dL, p = 0.0016) as well as reduced hepcidin concentrations five months after bariatric surgery (54.46 ng/mL vs. 33.88 ng/mL, p = 0.0177). The change in the reduction in mean body fat (delta MBF) and body fat percentage (delta BPF) was positively associated with delta hepcidin levels with correlation coefficients of R = 0.36 (p = 0.0228) for MBF and R = 0.42 (p = 0.0070) for BPF. Moreover, significant correlations were observed between the reduction in body fat and soluble hemojuvelin (R = 0.31 p = 0.0489 for MBF) (R = 0.45 p = 0.0032 for PBF). No patient showed laboratory signs of iron deficiency. Decreased serum hepcidin levels observed five months after sleeve gastrectomy are associated with improved iron status, as indicated by increased serum iron and red blood cell indices. Positive correlations between body fat reduction and both hepcidin and soluble hemojuvelin levels suggest that the resolution of adipose tissue-related inflammation may contribute to improved iron bioavailability. Full article

Background: Recent studies suggest that erythroferrone (ERFE), an iron-regulating protein whose primary role is to inhibit hepcidin synthesis, may affect glucose and lipid metabolism, and its serum concentration is reduced in obese and diabetic individuals. The aim of this study was to evaluate the association of ERFE concentration with selected cardiometabolic risk factors in apparently healthy young adults. Methods: This preliminary study consisted of 122 (63 females, 59 males) normoglycemic, non-smoking subjects aged 25–40 years. In all participants, anthropometric measurements and the following laboratory tests were performed: fasting plasma glucose, glycated hemoglobin (HbA1c) and serum iron, lipid profile, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), C-reactive protein (CRP), ERFE and hepcidin. Results: The serum ERFE concentration was significantly lower in men compared to women (p = 0.009) and in subjects who were overweight (p < 0.001) and had abdominal obesity (p < 0.001). ERFE showed significant negative correlations with body mass index, waist–hip ratio, HbA1c, CRP, insulin, HOMA-IR and triglycerides. In the logistic regression analysis, ERFE was significantly associated with being overweight (OR = 0.051; p = 0.004), abdominal obesity (OR = 0.372; p < 0.001), HOMA-IR ≥ 2.0 (OR = 0.584; p = 0.013), CRP > 1 mg/L (OR = 0.648; p = 0.020) and triglycerides (OR = 0.521; p = 0.033). A relevant predominance in the prevalence of cardiometabolic risk factors was observed in subjects with ERFE levels in the first tertile (<1.35 ng/mL), compared to the third tertile (>2.19 ng/mL). Conclusions: Serum ERFE is inversely associated with being overweight, increased waist circumference, CRP, and markers of insulin resistance and lipid abnormalities, suggesting its potential relevance as a marker of early cardiometabolic risk in apparently healthy young adults. Full article

Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory disease that can range in presentation from mild symptoms to severe conditions such as pneumonia and acute respiratory distress syndrome. SARS-CoV-2, a single-stranded RNA virus, spreads through aerosols and respiratory droplets. It enters human cells by binding to the angiotensin-converting enzyme 2 receptor, leading to various complications, including significant alterations in red blood cells and potential disruptions in haemoglobin function and oxygen transport. During infection, the interaction between hypoxia, inflammation, and haematopoiesis affects erythropoiesis at multiple levels. Hypoxia and inflammation, resulting from lung complications and a reduced red blood cell count, influence the regulation of hepcidin, a key regulator of iron levels in the blood. Elevated hepcidin levels are associated with hypoxia and the suppression of erythroferrone, a hormone that normally inhibits hepcidin production. Despite high levels of inflammation, patients in intensive care units often exhibit elevated ferritin levels, which, rather than indicating low hepcidin, suggest disrupted iron metabolism and the development of severe anaemia. Iron is kept in stores, likely due to paradoxically high hepcidin levels, which explains the elevated ferritin measurements. An increase in immature blood cells and a decrease in CD71+ erythroid cells are observed. The elevated levels of CD71+ erythroid cells highlight their dual role in modulating hyper-inflammation and immune response during disease progression. This review examines the pathway by which SARS-CoV-2 affects red blood cell production and the haematopoietic system and how it triggers cytokine storms through interleukins, immature blood cells, and CD71+ erythroid cells. Understanding these processes provides novel pathways for managing haematological manifestations and immune responses in patients with COVID-19. Full article

Preterm infants are most at risk of iron deficiency. However, our knowledge of the regulation of iron homeostasis in preterm infants is poor. The main goal of our research was to develop and validate an animal model of human prematurity to assess iron status in preterm infants. We performed a cesarean section on sows on the 109th day of pregnancy, which corresponds to the last trimester of human pregnancy. Preterm piglets showed decreased body weight, red blood cell indices, plasma iron level and transferrin saturation. Interestingly, higher hepatic and splenic non-heme iron content and plasma and hepatic ferritin levels were found in premature piglets compared with term ones. In addition, premature piglets showed higher mRNA levels of iron-regulatory hormone hepcidin in the liver than term animals, which have not been reflected in higher plasma hepcidin-25 levels. We also showed changes in hepcidin regulators, including hepatic bone morphogenetic protein 6, plasma erythroferrone and growth differentiation factor 15 in preterm piglets. Consequently, no difference was observed in iron-exporter ferroportin levels in the spleen and liver. Overall, it seems that premature piglets show a pattern of iron metabolism characteristic of functional iron deficiency and iron accumulation in the tissue. Full article

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. Full article

In recent years, a steady increase in the incidence of inflammatory bowel diseases (IBD) has been observed with anemia as their most common extraintestinal symptom. Erythroferrone and Bone Morphogenetic Protein 6 (BMP-6) are recently identified cytokines involved in the process of increased erythropoiesis in anemia of various pathomechanisms. The aim of this study was to analyze the concentration of erythroferrone and BMP-6 in IBD patients in relation to clinical and laboratory data. The study comprised 148 patients: 118 with IBD, including 73 (61.85%) diagnosed with anemia (42 with Crohn’s disease (CD) (66.7%) and 31 (56.4%) with ulcerative colitis (UC)) and 30 as a control group. The erythroferrone concentration was significantly higher in IBD patients with anemia (p = 0.009) and higher in UC patients both with and without anemia (p = 0.018), compared to the control group. In CD, no similar difference was observed between patients with and without anemia. Regarding BMP-6, higher levels were found in CD patients with anemia compared to the control group (p = 0.021). The positive correlation between BMP-6 and iron concentration in UC was also noticed. In conclusion, we confirm an increase in erythroferrone concentration in the entire group of IBD patients with anemia, while BMP-6 levels were higher only in anemic CD patients. Due to the clinical importance of anemia in IBD, this problem is worth further analysis and research projects. Full article

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders. Full article

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. Patients: 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. Full article

The erythroferrone gene (ERFE), also termed CTRP15, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE in cancer progression is largely unknown. We previously found that ERFE was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the ERFE mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma, ERFE overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of ERFE is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover, ERFE expression influences intratumoral immune cell infiltration. Conclusively, ERFE is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development. Full article

Thalassemia is a disease of erythrocytes that varies largely on its genetic composition and associated clinical presentation. Though some patients may remain asymptomatic, those with a complicated course may experience severe anemia early in childhood, carrying into adulthood and requiring recurrent blood transfusions as a pillar of symptom management. Due to the consequences of ineffective erythropoiesis and frequent transfusions, patients with severe beta thalassemia may be subsequently susceptible to hemochromatosis. In light of the established role of hepcidin and erythroferrone in the pathogenesis of beta thalassemia, this review aims to discuss current clinical trials and studies in the field while presenting clinical implications of the HAMP gene polymorphisms and novel treatments. Research suggested incorporating erythroferrone and serum hepcidin testing as a part of routine workups for beta thalassemia, as they could be a predictive tool for early iron accumulation. Furthermore, ameliorating low hepcidin and high erythroferrone appeared to be crucial in treating beta thalassemia and its complications due to iron overload. Currently, hepcidin-like compounds, such as minihepcidins, LJPC-401, PTG-300, VIT-2763, and agents that promote hepcidin production by inhibiting TMPRSS6 expression or erythroferrone, were shown to be effective in restoring iron homeostasis in preliminary studies. Moreover, the natural bioactives astragalus polysaccharide and icariin have been recently recognized as hepcidin expression inductors. Full article

The treatments available for thalassemia are rapidly evolving, with major advances made in gene therapy and the modulation of erythropoiesis. The latter includes the therapeutic potential of hepcidin tuning. In thalassemia, hepcidin is significantly depressed, and any rise in hepcidin function has a positive effect on both iron metabolism and erythropoiesis. Synthetic hepcidin and hepcidin mimetics have been developed to the stage of clinical trials. However, they have failed to produce an acceptable efficacy/safety profile. It seems difficult to avoid iron over-restricted erythropoiesis when directly using hepcidin as a drug. Indirect approaches, each one with their advantages and disadvantages, are many and in full development. The ideal approach is to target erythroferrone, the main inhibitor of hepcidin expression, the plasma concentrations of which are greatly increased in iron-loading anemias. Potential means of improving hepcidin function in thalassemia also include acting on TMPRSS6, TfR1, TfR2 or ferroportin, the target of hepcidin. Only having a better understanding of the crosslinks between iron metabolism and erythropoiesis will elucidate the best single option. In the meantime, many potential combinations are currently being explored in preclinical studies. Any long-term clinical study on this approach should include the wide monitoring of functions, as the effects of hepcidin and its modulators are not limited to iron metabolism and erythropoiesis. It is likely that some of the aspects of hepcidin tuning described briefly in this review will play a role in the future treatment of thalassemia. Full article

Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis. Full article