Dietary iron uptake[edit]
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 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 (Dcytb), reduces ferric Fe3+ to Fe2+.[5] A protein called divalent metal transporter 1 (DMT1), which can transport several divalent metals across the plasma membrane, then transports iron across the enterocyte’s cell membrane 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 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. 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.[6] Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or magnesium.[7][citation needed]
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. Recent discoveries demonstrate that hepcidin regulation of ferroportin is responsible for the syndrome of anemia of chronic disease.
Iron recycling and loss[edit]
Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. In contrast to iron uptake and recycling, there is no physiologic regulatory mechanism for excreting iron. People lose a small but steady amount by gastrointestinal blood loss, 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.[2] 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.[8]
Cellular iron regulation[edit]
Iron import[edit]
Most cell types take up iron primarily via receptor-mediated endocytosis by the transferrin receptor 1 (TFR1), transferrin receptor 2 (TFR2) and GAPDH. Transferrin-bound ferric iron is recognized by the transferrin receptor, trigering a conformational change that causes endocytosis. Iron then enters the cytoplasm from the endosome via importer DMT1 after being reduced to its ferrous state by a STEAP family reductase.[9][10][11]
Alternatively, iron can enter the cell directly via plasma membrane divalent cation importers such as DMT1 and ZIP14 (Zrt-Irt-like protein 14). Again, iron enters the cytoplasm in the ferrous state after being reduced in the extracellular space by a reductase such as STEAP2, STEAP3 (in erythrocytes), Dcytb (in enterocytes) and SDR2.[9]
The labile iron pool[edit]
In the cytoplasm, ferrous iron is found in a soluble, chelatable state which constitutes the labile iron pool (~0.001 mM).[12] In this pool, iron is thought to be bound to low-mass compounds such as peptides, carboxylates and phosphates, although some might be in a free, hydrated form (aqua ions).[12] Alternatively, iron ions might be bound to specialized proteins known as metallochaperones.[13] the labile iron pool is potentially toxic due to iron's ability to generate reactive oxygen species. Iron from this pool can be taken up by mitochondria via mitoferrin to synthesize Fe-S clusters and heme groups.[9]
The storage iron pool[edit]
Iron can be stored in ferritin as ferric iron due to the ferroxidase activity of the ferritin heavy chain.[14] Dysfunctional ferritin may accumulate as hemosiderin, which can be problematic in cases of iron overload.[15] The ferritin storage iron pool is much larger than the labile iron pool, ranging in concentration from 0.7 mM to 3.6 mM.[12]
Iron export[edit]
Iron export occurs in a variety of cell types, including neurons, erythrocytes, macrophages and enterocytes. The latter two are especially important since systemic iron levels depend upon them. There is only one known iron exporter, ferroportin.[16] It transports ferrous iron out of the cell, generally aided by ceruloplasmin and/or hephaestin (mostly in enterocytes), which oxidize iron to its ferric state so it can bind ferritin in the extracellular medium.[9] Hepcidin causes the internalization of ferroportin, decreasing iron export. Besides, hepcidin seems to downregulate both TFR1 and DMT1 through an unknown mechanism.[17] Another player assisting ferroportin in effecting cellular iron export is the higher order multifunctional[18] glycolytic enzyme Glyceraldehyde-3-phosphate dehydrogenase (GAPDH). A specific post translationally modified isoform of GAPDH is recruited to the surface of iron loaded cells where it recruits apo-transferrin in close proximity to ferroportin so as to rapidly chelate the iron extruded.[19]
The expression of hepcidin, which only occurs in certain cell types such as hepatocytes, is tightly controlled at the transcriptional level and it represents the link between cellular and systemic iron homeostasis due to hepcidin's role as "gatekeeper" of iron release from enterocytes into the rest of the body.[9] Erythroblasts produce erythroferrone, a hormone which inhibits hepcidin and so increases the availability of iron needed for hemoglobin synthesis.[20]
Translational control of cellular iron[edit]
Although some control exists at the transcriptional level, the regulation of cellular iron levels is ultimately controlled at the translational level by iron-responsive element-binding proteins IRP1 and especially IRP2.[21] When iron levels are low, these proteins are able to bind to iron-responsive elements (IREs). IREs are stem loop structures in the untranslated regions (UTRs) of mRNA.[9]
Both ferritin and ferroportin contain an IRE in their 5' UTRs, so that under iron deficiency their translation is repressed by IRP2, preventing the unnecessary synthesis of storage protein and the detrimental export of iron. In contrast, TFR1 and some DMT1 variants contain 3' UTR IREs, which bind IRP2 under iron deficiency, stabilizing the mRNA, which guarantees the synthesis of iron importers.[9]
Iron-related pathology[edit]
Main article: Iron metabolism disorder
Iron deficiency[edit]
Main article: Iron deficiency
Iron is an important topic in prenatal care because women can sometimes become iron-deficient from the increased iron demands of pregnancy.
Functional or actual iron deficiency can result from a variety of causes. 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. Black tea steeped for long has high tannins.
• Inability to absorb iron: A common cause of iron deficiency is the widespread use of acid reducing medications, the strongest are the proton pump inhibitors (PPIs) such as omeprazole. The use of this class of medication is causing an increase in iron deficiency and is almost an epidemic.
• 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 above).
Iron overload[edit]
Main article: 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 overload. Large amount