BACKGROUND: The effect of plasma hepcidin concentrations on the long-term risk of developing adverse cardiovascular outcomes in people with type 2 diabetes mellitus (T2DM) is unclear.
METHODS: We followed for a median of 55.6 months 213 outpatients with established T2DM (45.5% women, mean age 69 ± 10 years; BMI 28.7 ± 4.7 kg/m2; median diabetes duration 11 years). Baseline plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. The primary study outcome was a composite of all-cause mortality or incident nonfatal cardiovascular events (inclusive of myocardial infarction, permanent atrial fibrillation, ischemic stroke, or new hospitalization for heart failure).
RESULTS: 42 patients developed the primary composite outcome over a median follow-up of 55.6 months. After stratifying patients by baseline hepcidin tertiles [1st tertile: median hepcidin 1.04 (IQR 0.50-1.95) nmol/L, 2nd tertile: 3.81 (IQR 3.01-4-42) nmol/L and 3rd tertile: 7.72 (IQR 6.37-10.4) nmol/L], the risk of developing the primary composite outcome in patients in the 3rd tertile was double that of patients in the 1st and 2nd tertile combined (unadjusted hazard ratio [HR] 2.32, 95%CI 1.27-4.26; p = 0.007). This risk was not attenuated after adjustment for age, sex, adiposity measures, smoking, hypertension, statin use, antiplatelet medication use, plasma hs-C-reactive protein and ferritin concentrations (adjusted HR 2.53, 95%CI 1.27-5.03; p = 0.008).
CONCLUSIONS: In outpatients with T2DM, higher baseline hepcidin concentrations were strongly associated with an increased long-term risk of overall mortality or nonfatal cardiovascular events, even after adjustment for established cardiovascular risk factors, plasma ferritin concentrations, medication use, and other potential confounders.

Iron is essential for numerous physiological processes and its deficiency often leads to anemia. Iron deficiency (ID) is a global problem, primarily affecting reproductive-age women and children, especially in developing countries. Diagnosis uses classical biomarkers like ferritin or transferrin saturation. Recent advancements include using soluble transferrin receptor (sTfR) or hepcidin for improved detection and classification of absolute and functional iron deficiencies, though mostly used in research. ID without anemia may present symptoms like asthenia and fatigue, even without relevant clinical consequences. ID impacts not only red-blood cells but also immune system cells, highlighting its importance in global health and immune-related comorbidities. Managing ID, requires addressing its cause and selecting appropriate iron supplementation. Various improved oral and intravenous products are available, but further research is needed to refine treatment strategies. This review updates on absolute and functional iron deficiencies, their relationships with the immune system and advancements in diagnosis and therapies.

Iron deposition and myelin loss are observed in the brain with aging, and iron accumulation is suggested to be involved in myelin damage. However, the exact mechanism of iron deposition with aging remains unclear. This study was aimed to determine whether expanded visceral adipose tissue contributes to iron deposition and myelin loss by inducing hepcidin in the brains of aged male mice. Compared with young adult mice, levels of hepcidin in the brain, epididymal adipose tissue, and circulation were increased in aged mice, which had expanded visceral adipose tissue with inflammation. An increase in expressions of ferritin, an indicator of intracellular iron status, was accompanied by decreased levels of proteins related to myelin sheath in the brains of aged mice. These age-related changes in the brain were improved by visceral fat removal. In addition, IL-6 level, activation of microglia/macrophages, and nuclear translocation of phosphorylated Smad1/5 (pSmad1/5) inducing hepcidin expression were reduced in the brains of aged mice after visceral fat removal, accompanied by decreases of pSmad1/5- and ferritin-positive microglia/macrophages and mature oligodendrocytes. These findings indicate that visceral adiposity contributes to hepcidin-mediated iron deposition and myelin loss with inflammation in the aged brain. Our results support the importance of preventing visceral adiposity for maintaining brain health in older individuals.

Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression. Compared with control mice, mice subjected to SDS (SDS mice) had lower social interaction (SI) behavior. The SDS mice also showed impaired hematopoiesis, as evidenced by reduced circulating red blood cell counts, elevated reticulocyte counts, and decreased plasma iron levels. In the SDS mice, the iron contents in the bone marrow decreased, whereas those in the spleen increased, suggesting dysregulation in systemic iron metabolism. The concentrations of plasma hepcidin, an important regulator of systemic iron homeostasis, increased in the SDS mice. Meanwhile, the concentrations of ferroportin, an iron transport protein negatively regulated by hepcidin, were lower in the spleen and duodenum of the SDS mice than in those of the control mice. Treatment with dalteparin, a hepcidin inhibitor, prevented the decrease in plasma iron levels in the SDS mice. The gene expression and enzyme activity of furin, which converts the precursor hepcidin to active hepcidin, were high and positively correlated with plasma hepcidin concentration. Thus, furin activation might be responsible for the increased plasma hepcidin concentration. This study is the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin-ferroportin axis. Consideration of psychological stressors might be beneficial in the treatment of diseases with iron-refractory anemia.

Anemia is frequently observed in patients with cancer owing to anticancer chemotherapy, radiation therapy, and inflammatory responses. This often leads to functional iron deficiency, characterized by adequate iron stores but impaired use of iron for red blood cell production. This condition, termed functional iron deficiency anemia (IDA), is identified by a ferritin level of 30-500 µg/dL and a transferrin saturation < 50%. Functional iron deficiency often develops with the prolonged use of erythropoiesis-stimulating agents, leading to a diminished response to anemia treatment. Although oral iron supplementation is common, intravenous iron is more effective and recommended in such cases. Recent studies have shown that ferric carboxymaltose (FCM) is effective in treating functional IDA in patients with cancer. However, because of its potential to induce asymptomatic severe phosphate deficiency, it is important to closely monitor phosphate levels in patients receiving FCM.

Objectives: To investigate the diagnostic value of hepcidin for sepsis diagnosis. Methods: The relevant literature on hepcidin for sepsis diagnosis published up to October 20, 2023, was systematically searched in the Web of Science, PubMed, Embase, and China Knowledge Network databases. Two researchers screened the literature and extracted relevant data according to the inclusion and exclusion criteria. Study quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis and calculation of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were performed using State16 and Review Manager 5.3 software. Furthermore, receiver operating characteristic curve (ROC) was plotted, and the respective area under the curve (AUC) was calculated to assess the accuracy of hepcidin. Publication bias was evaluated using Deeks\' funnel plot asymmetry test. Results: Overall, 1047 patients from 8 studies were included (625 patients with sepsis and 422 controls). The quality of the literature was relatively moderate. Meta-analysis demonstrated the presence of heterogeneity in the data (I2 > 50%, P < .05), and a randomized model was employed to combine the diagnostic indicators. Regarding its accuracy for sepsis diagnosis, hepcidin demonstrated a pooled sensitivity of 0.88 (95% confidence interval [CI]: 0.76-0.94) and specificity of 0.91 (95% CI: 0.76-0.97). The diagnostic odds ratio was 69.00 (95% CI: 19.00-253.00), and the ROC curve revealed an AUC of 0.95. Additionally, Deeks\' funnel plot asymmetry test demonstrated absence of publication bias. Conclusions: Our meta-analysis suggested that hepcidin has a high diagnostic value in sepsis and may be a valuable diagnostic tool.

UNASSIGNED: Iron deficiency leads to health problems. Conversely, iron overload induces the generation of reactive oxygen species and health problems. Body iron status contributes to the development of various diseases, including aortic disease. Indeed, several clinical studies have reported that iron status can be linked to the pathogenesis of aortic disease. At the cellular level, iron uptake is regulated by the cellular iron transporter, transferrin receptor 1, while systemic iron homeostasis is regulated by hepcidin. As body iron status is regulated to maintain cellular and systemic iron homeostasis, iron metabolism in aortic disease is puzzling and not well understood.
UNASSIGNED: Perspective and short communication.
UNASSIGNED: This review provides an overview of the relevant research investigating the association between cellular iron metabolism and aortic disease.

BACKGROUND: Despite great scientific efforts, understanding the role of COVID-19 clinical biomarkers remains a challenge.
METHODS: A cross-sectional descriptive study in two Peruvian cities at different altitudes for comparison: Lima and Huaraz. In each place, three groups were formed, made up of 25 patients with COVID-19 in the ICU, 25 hospitalized patients with COVID-19 who did not require the ICU, and 25 healthy subjects as a control group. Five biomarkers were measured: IL-6, hepcidin, ferritin, C-reactive protein, and zinc using ELISA assays.
RESULTS: Ferritin, C-reactive protein, and IL-6 levels were significantly higher in the ICU and non-ICU groups at both study sites. In the case of hepcidin, the levels were significantly higher in the ICU group at both study sites compared to the non-ICU group. Among the groups within each study site, the highest altitude area presented statistically significant differences between its groups in all the markers evaluated. In the lower altitude area, differences were only observed between the groups for the zinc biomarker.
CONCLUSIONS: COVID-19 patients residing at high altitudes tend to have higher levels of zinc and IL-6 in all groups studied compared to their lower altitude counterparts.

Hepcidin has a crucial role in iron homeostasis upon inflammatory conditions such as inflammatory bowel disease (IBD). Thus, we conducted a systematic review and meta-analysis to determine the overall association between serum hepcidin concentrations and IBD. Based on the preferred reporting items for systematic review and meta-analysis (PRISMA) protocols, an electronic literature search was conducted on PubMed/MEDLINE, Scopus, and Web of Science until June 2020. Studies were deemed eligible for inclusion if they met the following criteria: (1) diagnosis of IBD, (2) observational design, and (3) measured serum hepcidin and prohepcidin concentrations in IBD patients and control group. Overall, 10 studies including 1184 participants were evaluated. Random-effects meta-analysis revealed that subjects with IBD had 7.22 ng/mL (95% CI: 2.10, 12.34; p = .006) higher serum hepcidin concentrations compared to control groups. A nonsignificantly lower serum prohepcidin concentration (0.522 ng/mL, 95% CI: -1.983 to 0.939; p = .484) was found for IBD patients compared to healthy subjects. However, there was significant heterogeneity among the studies regarding both hepcidin (I 2 = 98%, p < .001) and prohepcidin levels (I 2 = 96%, p < .001), respectively. In an age-based subgroup analysis, patients aged ≥18 years with IBD displayed higher serum hepcidin levels when compared to healthy individuals (22.36 ng/mL, 95% CI, 2.12-42.61; p = .030). Hepcidin concentrations are elevated in subjects with IBD; however, the clinical relevance of this finding requires further evaluation in future investigations as the increase is relatively small compared to the wide range of normal hepcidin values.

The regulation of iron (Fe) levels is essential to maintain an adequate supply for erythropoiesis, among other processes, and to avoid possible toxicity. The liver-produced peptide hepcidin is regarded as the main regulator of Fe absorption in enterocytes and release from hepatocytes and macrophages, as it impairs Fe export through ferroportin. The glycoprotein erythropoietin (Epo) drives erythroid progenitor survival and differentiation in the bone marrow, and has been linked to the mobilization of Fe reserves necessary for hemoglobin production. Herein we show that Epo inhibits hepcidin expression directly in the HepG2 hepatic cell line, thus leading to a decrease in intracellular Fe levels. Such inhibition was dependent on the Epo receptor-associated kinase JAK2, as well as on the PI3K/AKT/mTOR pathway, which regulates nutrient homeostasis. Epo was also found to decrease binding of the C/EBP-α transcription factor to the hepcidin promoter, which could be attributed to an increased expression of its inhibitor CHOP. Epo did not only hinder the stimulating effect of C/EBP-α on hepcidin transcription, but also favored hepcidin inhibition by HIF-1α, by increasing is nuclear translocation as well as its protein levels. Moreover, in assays with the inhibitor genistein, this transcription factor was found necessary for Epo-induced hepcidin suppression. Our findings support the involvement of the PI3K/AKT/mTOR pathway in the regulation of Fe levels by Epo, and highlight the contrasting roles of the C/EBP-α and HIF-1α transcription factors as downstream effectors of the cytokine in this process.