Iron Metabolism: Transferrin, Iron Storage and Iron Overload

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Iron is a critical element required for the normal functioning of all body cells, and is necessary for basic metabolic processes such as oxygen transport, DNA synthesis, cytochrome P450 enzyme oxidative metabolism, and electron transport. Electron transfer is the process by which an electron moves from one atom or molecule to another. Iron can cycle between ferric (Fe³⁺) and ferrous (Fe²⁺) forms through the donation or acceptance of an electron.

Fe³⁺ + O₂^- --> Fe²⁺ + O₂

This ability allows unbound iron to catalyze reactions that generate highly reactive free radicals, such as O² and OH^-, which can cause tissue damage.

Fe²⁺ + H₂O₂ --> Fe³⁺ + OH^- + HO (Fenton reaction)

As such, the properties that make iron an essential for life also mean it is potentially highly toxic.

Unlike other nutritional metals, iron is highly conserved, with no active mechanism of excretion. Body iron stores are roughly maintained at steady state because dietary iron intake is balanced by normal, gradual iron loss (about 1 mg/day in men and 1.5 mg/day in menstruating women), for example via cell shedding from the skin and gastrointestinal tract, or through blood loss.

Iron metabolism Mechanisms of iron homeostasis

The body maintains normal iron homeostasis by regulating the absorption of iron from the diet as well as its distribution within the body [1]. The distribution of iron through the blood is normally accomplished by means of transferrin. When iron is present in excess, it overwhelms the transferrin binding capacity and therefore becomes bound to smaller, low molecular weight molecules in the form of non-transferrin-bound iron (NTBI). Labile plasma iron (LPI), a directly chelatable component of NTBI, is highly toxic as it can catalyze the formation of harmful free hydroxyl radicals. LPI is thought to be the iron that loads cells via an unregulated mechanism other than the transferrin receptor. This is in contrast to the uptake of transferrin-bound iron, which takes place through transferrin receptors in a regulated manner.

Normal iron storage and distribution

Adapted with permission [2].

In a normal balanced state, 1-2 mg of iron enters and leaves the body every day. Dietary iron is absorbed in the duodenum by enterocytes and circulates in the plasma. There it is bound by transferrin, and becomes available for uptake throughout the body by any tissue with transferrin receptors. Liver parenchymal tissue is especially rich in transferrin receptors, and stores large quantities of iron. Most of the circulating iron is used by the bone marrow to generate hemoglobin for red blood cells, while around 10-15% is utilized by muscle fibers to generate myoglobin. Circulating red blood cells normally comprise the largest iron storage pool. When they become senescent, red blood cells are engulfed by reticuloendothelial macrophages, which make their iron available for redistribution to other tissues using transferrin. Traces of iron are lost each day by sloughing of mucosal cells, loss of epithelial cells, and blood loss. Since the human body has not evolved a mechanism to clear excess iron, disorders of iron balance, such as iron overload and iron deficiency, are among the most common diseases in humans.

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