Human iron metabolism



Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease. Hematologists have been especially interested in the system of iron metabolism because iron is essential to red blood cells. Most of the human body's iron is contained in red blood cells. Iron deficiency anemia is the most common type of anemia.

Understanding this system is also important for understanding diseases of iron overload, like hemochromatosis.

Importance of iron regulation
Iron is an absolute requirement for most forms of life, including humans and most bacterial species, because plants and animals all use iron; hence, iron can be found in a wide variety of food sources.

Iron is essential to life because of its unusual flexibility to serve as both an electron donor and acceptor.

Iron can also be potentially toxic. Its ability to donate and accept electrons means that if iron is free within the cell, 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. To prevent that kind of damage, all life forms that use iron bind the iron atoms to proteins. That allows the cells to use the benefits of iron, but also limit its ability to do harm.

The most important group of iron-binding proteins contain the heme molecules, all of which contain iron at their centers. Humans and most bacteria use variants of heme to carry out redox reactions and electron transport processes. These reactions and processes are required for oxidative phosphorylation. That process is the principal source of energy for human cells; without it, most types of cells would die.

The iron-sulfur proteins are another important group of iron-containing proteins. Some of these proteins are also essential parts of oxidative phosphorylation.

Humans also use iron in the hemoglobin of red blood cells, in order to transport oxygen from the lungs to the tissues and to transport carbon dioxide back to the lungs. Iron is also an essential component of myoglobin to store and diffuse oxygen in muscle cells.

The human body needs iron for oxygen transport. That oxygen is required for the production and survival of all cells in our bodies. Human bodies tightly regulate iron absorption and recycling. Iron is such an essential element of human life, in fact, that humans have no physiologic regulatory mechanism for excreting iron. Most humans prevent iron overload solely by regulating iron absorption. Those who cannot regulate absorption well enough get disorders of iron overload. In these diseases, the toxicity of iron starts overwhelming the body's ability to bind and store it.

Bacterial protection
In response to a systemic bacterial infection, the immune system initiates a process known as iron withholding. In iron withholding, the free iron in the plasma binds to transferrin, making it harder for bacteria to obtain it. The body cells, however, can easily get iron from transferrin. 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 they have to work to get iron, the greater a metabolic price they must pay. That means that iron-deprived bacteria reproduce more slowly. So our control of iron levels appears to be an important defense against bacterial infection. People with increased amounts of iron, like people with hemochromatosis, are more susceptible to bacterial infection.

Although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when inflammation goes on for longer. Since the liver produces hepcidin in response to inflammatory cytokines, hepcidin levels can increase as the result of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or other chronic diseases. When this occurs, the sequestration of iron appears to be the major cause of the syndrome of anemia of chronic disease, in which not enough iron is available to produce 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 2.5 g is contained in the hemoglobin needed to carry oxygen through the blood, and most of the rest (approximately 2 grams in adult men, and somewhat less in women of childbearing age) is contained in ferritin complexes that are present in all cells, but most common in bone marrow, liver, and spleen. The liver's stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in adults 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 body stores, which may consist of 500 mg or even less.

Of the body's total iron content, about 400 mg is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin), or performing energy-producing redox reactions (cytochromes). A relatively small amount (3-4 mg) circulates through the plasma, bound to transferrin. . Because of its toxicity, free soluble iron (soluble ferrous ions Fe(II)) is kept in low concentration in the body.

Iron deficiency first attacks the storage iron in the body, and depletion of these stores is thought to be relatively non-symptomatic, although some vague and non-specific symptoms have been assocated with it. Since so much iron is required for hemoglobin, iron deficiency anemia is the primary clinical manifestation of iron deficiency. Oxygen transport is so important to human life that severe anemia harms or kills people by depriving their organs of enough oxygen. Iron-deficient people will suffer or die from organ damage well before 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 in an apparently pathologic process. This molecule appears to be mainly the result of cell damage. It is often found engulfed by macrophages that are scavenging regions of damage. It can also be found among people with iron overload due to frequent blood cell destruction and transfusions.

How the body gets its iron
Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. However, people lose a small but steady amount by sweating and by shedding cells of the skin and the mucosal lining of the gastrointestinal tract. The total amount of loss for healthy people in the developed world amounts to an estimated average of 1 mg a day for men, and 1.5–2 mg a day for women with regular menstrual periods. People with gastrointestinal parasitic infections, more commonly found in developing countries, often lose more.

This steady loss means that people must continue to absorb iron. They do so via a tightly regulated process that under normal circumstances protects against iron overload.

Absorbing iron from the diet
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 (as in most supplements) 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 effcient, 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 must be in its ferrous Fe2+ form. A ferric reductase enzyme on the enterocytes' brush border, Dcytb, reduces ferric Fe3+ to Fe2+. A protein called divalent metal transporter 1 DMT1, which transports all kinds of divalent metals into the body, then transports the iron across the enterocyte's cell membrane and into the cell.

These intestinal lining cells can then either store the iron as ferritin, which is accomplished by Fe3+ binding to apoferritin(in which case the iron will leave the body when the cell dies and is sloughed off into feces) or the cell can move it into the body, using a protein called ferroportin. The body regulates iron levels by regulating each of these steps. For instance, cells produce more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia.

Our bodies' rates of iron absorption appear 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. We also absorb less iron during times of inflammation. Recent discoveries demonstrate that hepcidin regulation of ferroportin (see below) is responsible for the syndrome of anemia of chronic disease.

While Dcytb is unique to iron transport across the duodenum, ferroportin is distributed throughout the body on all cells which store iron. Thus, regulation of ferroportin is the body's main way of regulating the amount of iron in circulation.

Hephaestin, a ferroxidase that which 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.

Iron absorption from diet is enhanced in the presence of vitamin C and diminished in the presence of calcium.

Reasons for iron deficiency
Functional or actual iron deficiency can result from a variety of causes, explained in more detail in the article dedicated to this topic. These causes can be grouped into several categories:
 * Increased demand for iron, which the diet cannot accommodate.
 * Increased loss of iron (usually through loss of blood).
 * Nutritional deficiency. This can result due to a lack of dietary iron or consumption of foods that inhibit iron absorption, including calcium, phytates and tannins. Contrary to popular belief, persons following vegetarian and vegan diets have similar iron status and the same rates of iron deficiency as non-vegetarians.
 * Inability to absorb iron because of damage to the intestinal lining. Examples of causes of this kind of damage include surgery involving the duodenum, or diseases like Crohn's or celiac sprue which severely reduce the surface area available for absorption.
 * Inflammation leading to hepcidin-induced restriction on iron release from enterocytes (see below).

Iron overload
The body is able to substantially reduce the amount of iron it absorbs across the mucosa. It does not seem to be able to entirely shut down the iron transport process. Also, in situations where excess iron damages the intestinal lining itself (for instance, when children eat a large quantity of iron tablets produced for adult consumption), even more iron can enter the bloodstream and cause a potentially deadly syndrome of iron intoxication. Large amounts of free iron in the circulation will cause damage to critical cells in the liver, the heart and other metabolically active organs.

Iron toxicity results when the amount of circulating iron exceeds the amount of transferrin available to bind it, but the body is able to vigorously regulate its iron uptake. Thus, iron toxicity from ingestion is usually the result of extraordinary circumstances like iron tablet overdose rather than variations in diet. The type of acute toxicity from iron ingestion causes severe mucosal damage in the gastrointestinal tract, among other problems.

Chronic iron toxicity is usually the result of more chronic iron overload syndromes associated with genetic diseases, repeated transfusions or other causes. In such cases the iron stores of an adult may reach 50 grams (10 times normal total body iron) or more. Classic examples of genetic iron overload includes hereditary hemochromatosis (HH) and the more severe disease juvenile hemochromatosis (JH) caused by mutations in either the gene RGMc gene, a member of a three gene repulsive guidance molecule family, (also called hemojuvelin (HJV), and HFE2), Hemojuvelin, or the HAMP gene that encodes (an iron regulatory peptide).

How cells get their iron from the body
As discussed above, 60% or more of the iron in the body is located in hemoglobin molecules of red blood cells, and much of the rest is in ferritin storage form in the liver and other places, the amount of this varying widely between persons. When red blood cells reach a certain age, they are degraded and engulfed by specialized scavenging macrophages. These cells internalize the iron-containing hemoglobin, degrade it, put the iron onto transferrin molecules, and then export the transferrin-iron complexes back out into the blood. Most of the iron used for blood cell production comes from this cycle of hemoglobin recycling.

All cells use some iron, and must get it from the circulating blood. Since iron is tightly bound to transferrin, cells throughout the body have receptors for transferrin-iron complexes on their surfaces. These receptors engulf and internalize both the protein and the iron attached to it. Once inside, the cell transfers the iron to ferritin, the internal iron storage molecule which is present in all cells.

Transferrin receptor production will increase, and ferritin production will decrease.

Regulation by location
Regulation of iron levels is a task of the whole body, as well as for individual cells.

When body levels of iron are too low, then hepcidin in the duodenal epithelium is decreased. This causes an increase in ferroportin activity, stimulating iron uptake in the digestive system. The reverse occurs when there is an iron surplus.

In individual cells, an iron deficiency causes responsive element binding protein to iron responsive elements on mRNA for transferrin receptors, resulting in increased production of transferrin receptors. These receptors increase binding of transferrin to cells, and therefore stimulating iron uptake.



Diseases of iron regulation
The exact mechanisms of most of the various forms of adult hemochromatosis, which make up most of the genetic iron overload disorders, remain unsolved. So while researchers have been able to identify genetic mutations causing several adult variants of hemochromatosis, they now must turn their attention to the normal function of these mutated genes.