Effects of Hypoxia and Inflammation on Hepcidin Concentration in Non-Anaemic COVID-19 Patients

Abstract

Background/Objectives: This study aimed to explore the influence of hypoxia, inflammation, and erythropoiesis on hepcidin and other iron status parameters in non-anaemic COVID-19 patients admitted to the emergency unit before the introduction of therapeutic interventions. Methods: Ninety-six COVID-19 patients and 47 healthy subjects were recruited. Patients were subdivided into hypoxic or normoxic groups and, after follow-up, into mild and moderate, severe or critical disease severity groups. Iron, unsaturated iron-binding capacity (UIBC), ferritin, C-reactive protein (CRP), and interleukin 6 (IL-6) were measured on automatic analysers. ELISA kits were used for hepcidin and erythropoietin (EPO) determination. We calculated total iron-binding capacity (TIBC) and ratios of hepcidin with parameters of iron metabolism (ferritin/hepcidin, hepcidin/iron), inflammation (hepcidin/CRP, hepcidin/IL-6), and erythropoietic activity (hepcidin/EPO). Results: Hepcidin, ferritin, EPO, CRP, IL-6, ferritin/hepcidin, and hepcidin/iron were increased, while UIBC, TIBC, hepcidin/CRP, and hepcidin/IL-6 were decreased in hypoxic compared to normoxic patients as well as in patients with severe or critical disease compared to those with mild and moderate COVID-19. Regarding predictive parameters of critical COVID-19 occurrence, in multivariable logistic regression analysis, a combination of EPO and ferritin/hepcidin showed very good diagnostic performances and correctly classified 88% of cases, with an AUC of 0.838 (0.749-0.906). Conclusions: The hypoxic signal in our group of patients was not strong enough to overcome the stimulating effect of inflammation on hepcidin expression. EPO and ferritin/hepcidin might help to identify on-admission COVID-19 patients at risk of developing a critical form of the disease.

Keywords: COVID-19; erythropoietin; ferritin; hepcidin; hypoxia; inflammation; interleukin 6; iron.

Figure 1

Hepcidin (a), ferritin (b), EPO (c), and IL-6 (d) plasma concentrations in healthy subjects and in normoxic and hypoxic COVID-19 patients. Results are shown as the median with Q1–Q3 range. The difference between groups was tested using the Kruskal–Wallis test with post hoc analysis (Conover). Connectors on the graphs show between which groups a statistically significant difference was observed in post hoc analysis with p < 0.05. EPO, erythropoietin; IL-6, interleukin 6.

Figure 1

Hepcidin (a), ferritin (b), EPO (c), and IL-6 (d) plasma concentrations in healthy subjects and in normoxic and hypoxic COVID-19 patients. Results are shown as the median with Q1–Q3 range. The difference between groups was tested using the Kruskal–Wallis test with post hoc analysis (Conover). Connectors on the graphs show between which groups a statistically significant difference was observed in post hoc analysis with p < 0.05. EPO, erythropoietin; IL-6, interleukin 6.

Figure 2

Hepcidin (a), ferritin (b), EPO (c), and IL-6 (d) plasma concentrations in healthy subjects and in COVID-19 patients subdivided by disease severity by prospective follow-up. Results are shown as the median with Q1–Q3 range. The difference between groups was tested using the Kruskal–Wallis test with post hoc analysis (Conover). Connectors on the graphs show between which groups a statistically significant difference was observed in post hoc analysis with p < 0.05. EPO, erythropoietin; IL-6, interleukin 6.

Figure 2

Hepcidin (a), ferritin (b), EPO (c), and IL-6 (d) plasma concentrations in healthy subjects and in COVID-19 patients subdivided by disease severity by prospective follow-up. Results are shown as the median with Q1–Q3 range. The difference between groups was tested using the Kruskal–Wallis test with post hoc analysis (Conover). Connectors on the graphs show between which groups a statistically significant difference was observed in post hoc analysis with p < 0.05. EPO, erythropoietin; IL-6, interleukin 6.