COVID-19 compromises iron homeostasis: Transferrin as a target of investigation

Abstract

Importance: Since the beginning of the COVID-19 pandemic, numerous metabolic alterations have been observed in individuals with this disease. It is known that SARS-CoV-2 can mimic the action of hepcidin, altering intracellular iron metabolism, but gaps remain in the understanding of possible outcomes in other pathways involved in the iron cycle.

Objective: To profile iron, ferritin and hepcidin levels and transferrin receptor gene expression in patients diagnosed with COVID-19 between June 2020 and September 2020.

Design, setting and participants: Cross-sectional study that evaluated iron metabolism markers in 427 participants, 218 with COVID-19 and 209 without the disease.

Exposures: The primary exposure was positive diagnose to COVID-19 in general population of Santo André and São Bernardo cities. The positive and negative diagnose were determinate through RT-qPCR.

Main outcomes and measures: Devido a evidências de alterações do ciclo do ferro em pacientes diagnosticados com COVID-19 e devido a corregulação entre hepcidina e receptor de transferrina, uma análise da expressão gênica deste último, poderia trazer insights sobre o estado de ferro celular. A hipótese foi confirmada, mostrando aumento da expressão de receptor de transferrina concomitante com redução do nível de hepcidina circulante.

Results: Serum iron presented lower values in individuals diagnosed with COVID-19, whereas serum ferritin presented much higher values in infected patients. Elderly subjects had lower serum iron levels and higher ferritin levels, and men with COVID-19 had higher ferritin values than women. Serum hepcidin was lower in the COVID-19 patient group and transferrin receptor gene expression was higher in the infected patient group compared to controls.

Conclusions and relevance: COVID-19 causes changes in several iron cycle pathways, with iron and ferritin levels being markers that reflect the state and evolution of infection, as well as the prognosis of the disease. The increased expression of the transferrin receptor gene suggests increased iron internalization and the mimicry of hepcidin action by SARS-CoV-2, reduces iron export via ferroportin, which would explain the low circulating levels of iron by intracellular trapping.

Keywords: Coronavirus; Ferritin; Hepcidin and transferrin receptor; Iron.

Fig. 1

Serum iron and ferritin quantification. Graphic representation of blood iron (A) and ferritin (B) quantification data from control patients and patients with a confirmed diagnosis of COVID-19. Mann-Whitney test versus CTL group.

Fig. 2

Relation between age and iron and ferritin levels. Graphic representation of Pearson's coefficient test between age of the individuals with COVID-19 and quantifications of Iron (A) and Ferritin (B). Pearson's coefficient test.

Fig. 3

Quantification of hepcidin. Hepcidin quantification values in serum samples from control patients and patients with a confirmed diagnosis of COVID-19. Mann-Whitney test versus CTL group.

Fig. 4

TFRC gene expression. Graphic representation of the evaluation of transferrin receptor gene expression TFRC in the blood of control patients and patients with a confirmed diagnosis of COVID-19. Mann-Whitney test versus CTL group.