Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.
Overview of Iron
Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.4 Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.
Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.8 The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.
Overview of Ferritin Structure and Function
Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.6
Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe2+) iron into ferric (Fe3+) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.11 Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe2+ and limit oxidative stress.6
Regulation of Ferritin Synthesis and Secretion
Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.6 In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.12 In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.13 Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.17,18 Pourzand et al18 suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,18 consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.19
Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.10 However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.10 Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.10,18,21