Iron metabolism is the process by which the body manages the uptake, distribution, and storage of iron. This mineral is necessary for life, but it is highly toxic when present in excess, requiring tight control to maintain health. Since the body has no regulated mechanism for actively excreting iron, the control of its entry into the bloodstream is the primary point of regulation. This system ensures that iron levels remain within a narrow, safe range.
How Iron Enters the Body
The absorption of dietary iron takes place primarily in the duodenum, the first part of the small intestine. Iron from food exists in two main forms: heme iron, derived from animal sources like meat, and non-heme iron, found in plants and supplements. Heme iron is highly bioavailable and is absorbed directly by intestinal cells through a separate pathway, likely involving the transporter Hemoglobin Carrier Protein 1 (HCP1).
Non-heme iron, in the ferric (Fe³⁺) state, first requires reduction to the ferrous (Fe²⁺) state before absorption. This reduction is facilitated by the enzyme duodenal cytochrome b (Dcytb) on the surface of the intestinal cells. The ferrous iron then enters the enterocyte through the specialized transporter Divalent Metal Transporter 1 (DMT1).
Once inside the intestinal cell, the iron is either stored temporarily as ferritin or transported across the basal membrane into circulation. The iron exporter Ferroportin (FPN) moves iron from the cell into the bloodstream. Before iron can bind to its transport protein, it must be oxidized back to the ferric (Fe³⁺) state, a step carried out by a protein like hephaestin.
Transport and Cellular Storage
After leaving the intestinal cells, iron immediately binds to Transferrin (Tf), the primary transport protein in the blood. Transferrin is a glycoprotein synthesized by the liver that carries iron throughout the body.
The Total Iron Binding Capacity (TIBC) reflects the total amount of Transferrin available to bind iron. Under normal conditions, Transferrin is only about one-third saturated with iron, leaving a large reserve capacity. This ensures that all circulating iron is safely sequestered.
For storage, iron is sequestered within Ferritin, the main iron storage protein located primarily in the liver, spleen, and bone marrow. Ferritin can hold up to several thousand iron atoms. A small amount of iron is also stored long-term as Hemosiderin, a less soluble form that accumulates when iron levels are high.
Iron’s Functional Roles
Iron is required for several biological functions. Its most recognized role is in oxygen transport, where it forms the core of the heme component in hemoglobin. Hemoglobin in red blood cells binds and delivers oxygen to tissues throughout the body.
In muscle tissue, iron is found within the protein Myoglobin, which stores and releases oxygen for muscle activity. Iron also acts as a co-factor for numerous enzymes involved in metabolic processes. For instance, it is a component of cytochromes, proteins central to the electron transport chain that generates energy (ATP). Iron is also required for enzymes involved in DNA synthesis, supporting cell proliferation and repair.
The Master Regulator: Hepcidin
The peptide hormone Hepcidin, produced mainly by the liver, controls iron balance. Hepcidin acts as a negative feedback regulator, adjusting iron absorption and release according to the body’s needs. When iron stores are high, the liver increases Hepcidin production.
Hepcidin targets the iron exporter Ferroportin. When Hepcidin binds to Ferroportin on the surface of intestinal cells, macrophages, and liver cells, it triggers the degradation of the exporter. This process blocks iron from leaving the cells.
By regulating Ferroportin, Hepcidin controls three major sources of plasma iron: dietary absorption in the intestine, recycled iron from old red blood cells in macrophages, and stored iron release from the liver. When iron stores are low, Hepcidin levels drop, allowing more Ferroportin to remain active and increase iron flow into the bloodstream.
When Metabolism Goes Wrong
Dysregulated iron metabolism results in two main pathological states: iron deficiency and iron overload. Iron deficiency leads to Iron-Deficiency Anemia. When iron stores are depleted, there is insufficient iron available for hemoglobin synthesis, resulting in the production of small, pale red blood cells.
Iron overload, known as Hereditary Hemochromatosis (HH), is caused by genetic mutations that impair Hepcidin production or activity. A defect in the HFE gene is the most common cause, leading to abnormally low Hepcidin levels. This deficiency results in unrestrained iron absorption and release from storage, causing iron to accumulate in organs like the liver, heart, and pancreas.
Accumulation causes tissue damage when the binding capacity of Transferrin becomes saturated, leading to non-transferrin bound iron (NTBI) in the blood. This free iron generates oxidative stress. The resulting damage can lead to liver cirrhosis, heart failure, and joint disease.