New Perspectives on Circulating Ferritin: Its Role in Health and Disease

Abstract

The diagnosis of iron disturbances usually includes the evaluation of serum parameters. Serum iron is assumed to be entirely bound to transferrin, and transferrin saturation-the ratio between the serum iron concentration and serum transferrin-usually reflects iron availability. Additionally, serum ferritin is commonly used as a surrogate of tissue iron levels. Low serum ferritin values are interpreted as a sign of iron deficiency, and high values are the main indicator of pathological iron overload. However, in situations of inflammation, serum ferritin levels may be very high, independently of tissue iron levels. This presents a particularly puzzling challenge for the clinician evaluating the overall iron status of the patient in the presence of an inflammatory condition. The increase in serum ferritin during inflammation is one of the enigmas regarding iron metabolism. Neither the origin, the mechanism of release, nor the effects of serum ferritin are known. The use of serum ferritin as a biomarker of disease has been rising, and it has become increasingly diverse, but whether or not it contributes to controlling the disease or host pathology, and how it would do it, are important, open questions. These will be discussed here, where we spotlight circulating ferritin and revise the recent clinical and preclinical data regarding its role in health and disease.

Keywords: biomarker; disease; ferritin; iron metabolism; therapy.

Figure 1

Iron in circulation. In mammalians, iron from the diet is absorbed through enterocytes, and it can be lost through cell desquamation and blood loss. Circulating iron is bound to Tf, used in the erythropoiesis process, and recycled by the macrophages after phagocytosis of old or senescent red blood cells. For storage purposes, iron is kept mostly in the hepatocytes inside the FT nanostructure. Image created with BioRender (www.biorender.com, accessed on 15 September 2023).

Figure 2

Cellular iron metabolism. (A) Dietary iron is absorbed by the enterocytes. (B) Macrophages participate in the process of iron recycling from the erythrocytes. (C) The hepatocytes act as the major cell site for iron storage. Abbreviations: CD163—Cluster of differentiation 163, hemoglobin-haptoglobin receptor; CD91—Cluster of differentiation 91, also known as Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) or α2-macroglobulin receptor; CP—Ceruloplasmin; Dcytb—Duodenal cytochrome B; DMT1—Divalent metal transporter 1; FPN—Ferroportin; FT—Ferritin; Hb—Hemoglobin; HCP1—Heme carrier protein 1; HEPH—Hephaestin; HMOX—Heme oxygenase; HP—Haptoglobin; HPX—Hemopexin; PCBP1—Poly(RC) binding protein 1; Tf—Transferrin; TfR—Transferrin receptor. Image created with BioRender (www.biorender.com, accessed on 15 September 2023).

Figure 3

Scheme of ferritin’s heteropolymer. The 24-meric shell is constituted by L- and H-ferritin subunits formed by 4 alpha-helices and a short helix on top (for simplicity, represented here by one helix each) and lodges iron in its core. The ratio of each peptide varies depending on the cell type. Image created with BioRender (www.biorender.com, accessed on 15 September 2023).

Figure 4

Ferritin in health and disease. Serum ferritin has a role in health and disease. Apart from its fully described role regarding iron storage, FT also responds to inflammatory stimuli, including infection. Its rising serum levels are associated with the development of deleterious conditions, such as ferroptosis or hyperferritinemia, which makes it an attractive target for the development of new host-directed therapies. However, these increased levels also give crucial information regarding the development of certain diseases or even their progression. Additionally, due to its nanocage structure, FT has also been used as a delivery system for drug therapies, such as vaccines. Image created with BioRender (www.biorender.com, accessed on 15 September 2023).