Human iron metabolism

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.
A 2024 review examined iron metabolism and its interactions with calcium, magnesium, and selected trace elements, as well as their roles in certain diseases.

Importance of iron regulation

Iron is an essential element for most forms of life, from bacteria to mammals. Its importance lies in its ability to mediate electron transfer. In the ferrous state, iron acts as an electron donor, while in the ferric state it acts as an acceptor. Thus, iron plays a vital role in the catalysis of enzymatic reactions that involve electron transfer. Proteins can contain iron as part of different cofactors, such as iron–sulfur clusters and heme groups, both of which are assembled in mitochondria.

Cellular respiration

Human cells require iron in order to obtain energy as ATP from a multi-step process known as cellular respiration, more specifically from oxidative phosphorylation at the mitochondrial cristae. Iron is present in the iron–sulfur cluster and heme groups of the electron transport chain proteins that generate a proton gradient that allows ATP synthase to synthesize ATP.
Heme groups are part of hemoglobin, a protein found in red blood cells that serves to transport oxygen from the lungs to other tissues. Heme groups are also present in myoglobin to store and diffuse oxygen in muscle cells.

Oxygen transport

The human body needs iron for oxygen transport. Oxygen is required for the functioning and survival of nearly all cell types. Oxygen is transported from the lungs to the rest of the body bound to the heme group of hemoglobin in red blood cells. In muscle cells, iron binds oxygen to myoglobin, which regulates its release.

Toxicity

Iron is also potentially toxic. Its ability to donate and accept electrons means that it can catalyze the conversion of hydrogen peroxide into free radicals. Free radicals can cause damage to a wide variety of cellular structures, and ultimately kill the cell.
Iron bound to proteins or cofactors such as heme is safe. Also, there are virtually no truly free iron ions in the cell, since they readily form complexes with organic molecules. However, some of the intracellular iron is bound to low-affinity complexes, and is termed labile iron or "free" iron. Iron in such complexes can cause damage as described above.
To prevent that kind of damage, all life forms that use iron bind the iron atoms to proteins. This binding allows cells to benefit from iron while also limiting its ability to do harm. Typical intracellular labile iron concentrations in bacteria are 10-20 micromolar, though they can be 10-fold higher in anaerobic environment, where free radicals and reactive oxygen species are scarcer. In mammalian cells, intracellular labile iron concentrations are typically smaller than 1 micromolar, less than 5 percent of total cellular iron.

Bacterial protection

In response to a systemic bacterial infection, the immune system initiates a process known as "iron withholding". If bacteria are to survive, then they must obtain iron from their environment. Disease-causing bacteria do this in many ways, including releasing iron-binding molecules called siderophores and then reabsorbing them to recover iron, or scavenging iron from hemoglobin and transferrin. The harder the bacteria have to work to get iron, the greater a metabolic price they must pay. That means that iron-deprived bacteria reproduce more slowly. So, control of iron levels appears to be an important defense against many bacterial infections. Certain bacteria species have developed strategies to circumvent that defense, TB causing bacteria can reside within macrophages, which present an iron rich environment and Borrelia burgdorferi uses manganese in place of iron. People with increased amounts of iron, as, for example, in hemochromatosis, are more susceptible to some bacterial infections.
Although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when it goes on so long that the body is deprived of needed iron for red cell production. Inflammatory cytokines stimulate the liver to produce the iron metabolism regulator protein hepcidin, that reduces available iron. If hepcidin levels increase because of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or other chronic diseases, then the anemia of chronic disease may result. In this case, iron withholding actually impairs health by preventing the manufacture of enough hemoglobin-containing red blood cells.

Body iron stores

Most well-nourished people in industrialized countries have 4 to 5 grams of iron in their bodies. Of this, about is contained in the hemoglobin needed to carry oxygen through the blood, and most of the rest is contained in ferritin complexes that are present in all cells, but most common in bone marrow, liver, and spleen. The liver stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in industrialized countries tend to be lower in children and women of child-bearing age than in men and in the elderly. Women who must use their stores to compensate for iron lost through menstruation, pregnancy or lactation have lower non-hemoglobin body stores, which may consist of, or even less.
Of the body's total iron content, about is devoted to cellular proteins that use iron for important cellular processes like storing oxygen or performing energy-producing redox reactions. A relatively small amount circulates through the plasma, bound to transferrin. Because of its toxicity, free soluble iron is kept in low concentration in the body.
Iron deficiency first affects the storage of iron in the body, and depletion of these stores is thought to be relatively asymptomatic, although some vague and non-specific symptoms have been associated with it. Since iron is primarily required for hemoglobin, iron deficiency anemia is the primary clinical manifestation of iron deficiency. Iron-deficient people will suffer or die from organ damage well before their cells run out of the iron needed for intracellular processes like electron transport.
Macrophages of the reticuloendothelial system store iron as part of the process of breaking down and processing hemoglobin from engulfed red blood cells. Iron is also stored as a pigment called hemosiderin, which is an ill-defined deposit of protein and iron, created by macrophages where excess iron is present, either locally or systemically, e.g., among people with iron overload due to frequent blood cell destruction and the necessary transfusions their condition calls for. If systemic iron overload is corrected, over time the hemosiderin is slowly resorbed by the macrophages.

Mechanisms of iron regulation

Human iron homeostasis is regulated at two different levels. Systemic iron levels are balanced by the controlled absorption of dietary iron by enterocytes, the cells that line the interior of the intestines, and the uncontrolled loss of iron from epithelial sloughing, sweat, injuries and blood loss. In addition, systemic iron is continuously recycled. Cellular iron levels are controlled differently by different cell types due to the expression of particular iron regulatory and transport proteins.

Systemic iron regulation

Dietary iron uptake

The absorption of dietary iron is a variable and dynamic process. The amount of iron absorbed compared to the amount ingested is typically low, but may range from 5% to as much as 35% depending on circumstances and type of iron. The efficiency with which iron is absorbed varies depending on the source. Generally, the best-absorbed forms of iron come from animal products. Absorption of dietary iron in iron salt form varies somewhat according to the body's need for iron, and is usually between 10% and 20% of iron intake. Absorption of iron from animal products, and some plant products, is in the form of heme iron, and is more efficient, allowing absorption of from 15% to 35% of intake. Heme iron in animals is from blood and heme-containing proteins in meat and mitochondria, whereas in plants, heme iron is present in mitochondria in all cells that use oxygen for respiration.
Like most mineral nutrients, the majority of the iron absorbed from digested food or supplements is absorbed in the duodenum by enterocytes of the duodenal lining. These cells have special molecules that allow them to move iron into the body. To be absorbed, dietary iron can be absorbed as part of a protein such as heme protein or iron must be in its ferrous Fe²⁺ form. A ferric reductase enzyme on the enterocytes' brush border, duodenal cytochrome B, reduces ferric Fe³⁺ to Fe²⁺. A protein called divalent metal transporter 1, which can transport several divalent metals across the plasma membrane, then transports iron across the enterocyte's cell membrane into the cell. If the iron is bound to heme, it is instead transported across the apical membrane by heme carrier protein 1. Heme is then catabolized by microsomal heme oxygenase into biliverdin, releasing Fe²⁺.
These intestinal lining cells can then either store the iron as ferritin, which is accomplished by Fe²⁺ binding to apoferritin, or the cell can release it into the body via the only known iron exporter in mammals, ferroportin. Hephaestin, a ferroxidase that can oxidize Fe²⁺ to Fe³⁺ and is found mainly in the small intestine, helps ferroportin transfer iron across the basolateral end of the intestine cells. Upon release into the bloodstream, Fe³⁺ binds transferrin and circulates to tissues. In contrast, ferroportin is post-translationally repressed by hepcidin, a 25-amino acid peptide hormone. The body regulates iron levels by regulating each of these steps. For instance, enterocytes synthesize more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia. Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or manganese.
The human body's rate of iron absorption appears to respond to a variety of interdependent factors, including total iron stores, the extent to which the bone marrow is producing new red blood cells, the concentration of hemoglobin in the blood, and the oxygen content of the blood. The body also absorbs less iron during times of inflammation, in order to deprive bacteria of iron. Recent discoveries demonstrate that hepcidin regulation of ferroportin is responsible for the syndrome of anemia of chronic disease.