Iron metabolism

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The iron metabolism or metabolism is the absorption, distribution and excretion of iron in the organism . The term is misleading insofar as iron as such is not “ metabolized ”, but is merely bound to various organic molecules in the organism.

iron

The element iron is an important trace element in the human body. Oxygen transport, oxygen uptake, cell functions such as mitochondrial electron transport, cytochrome P450 and ultimately the entire energy metabolism depend on an adequate supply of iron.

A human body contains an average of 4-5 g of iron. It occurs in enzymes ( cytochromes , peroxidases , catalase ), in hemoglobin and myoglobin, and as depot or reserve iron in the form of ferritin and hemosiderin . The depot iron is mainly found in liver cells and macrophages of the reticulohistiocytic system .

Distribution in the body

The following distribution is found in men weighing 70 kg.

hemoglobin 66.1% 2800 mg
Depot iron ( ferritin , hemosiderin ) 18.8% 800 mg
Non-haemzyme iron 10% 420 mg
Myoglobin 4.7% 200 mg
Transport iron ( transferrin ) 0.2% 10 mg
Ferrous enzymes 0.2% 10 mg

Daily need

The daily iron requirement is between 0.5–1.5 mg / day in small children up to 2–5 mg / day in women during pregnancy. With the exception of menstrual bleeding, the daily iron losses, for example due to the exfoliation of skin and mucosal cells and via the urine, are low. The daily iron loss of around 1 mg in a healthy adult man is usually replaced through food. The actual amount of iron consumed should, however, be higher than the daily requirement, since only about 10-15% of the iron consumed is available for the body. The recommended intake is 10 mg / day for men and 15 mg / day for women. In pregnant and breastfeeding women, the amount can increase to up to 30 mg / day.

Loss of blood can significantly reduce the iron content of the body: 1 mg of iron is lost for every 2 ml of blood. The average blood loss during menstruation is 30–60 ml, with hypermenorrhoea up to 800 ml, with uterus myomatosus up to 1200 ml.

metabolism

In contrast to metals such as sodium and calcium, the iron balance can only be regulated through absorption , since normal losses cannot be controlled. The absorption rate of the iron present in food is 6% (men) to 12% (women), in the case of iron deficiency up to 20%.

Absorption (general)

In the common food in Europe, one third of the iron is present as heme , a component of hemoglobin in the blood and myoglobin , which is found in meat . The rest of the dietary iron is mainly in the form of iron (III) complexes, usually bound to cysteine ​​residues of proteins. Really free iron (III) as Fe 3+ never occurs biologically, since it would form insoluble precipitates as hydroxide or phosphate. Both Fe 2+ and, to a greater extent, Fe 3+ form loose complexes with virtually all biomolecules (except fat), which ensure that the iron remains in solution. In heme, 4 of the 6 iron binding sites are already firmly occupied, so that it can no longer form solid or insoluble complexes with other complexing agents (chelators). The uptake (resorption) of heme iron is therefore independent of other food components. Although heme iron makes up only one third of the iron in our diet, it therefore provides around two thirds of the iron absorbed.

Vegetable food contains ligands that facilitate iron absorption on the one hand, and phosphates , polyphenols and phytates on the other hand , which form poorly soluble compounds with iron. So is z. B. the low availability of iron in spinach and similar crops can be attributed to the high content of oxalic acid , which forms complexes with iron that are difficult to dissolve. The absorption of phytate-containing foods can be improved by eating meat at the same time or adding reducing agents such as ascorbic acid (= vitamin C). Ferritin from soybeans can partially compensate for iron deficiency in vegetarians.

The resorption rate of nutritional iron is usually around 6 to 12%. It is increased in iron deficiency and can be up to 20%. The absorption rate is regulated by the organism depending on the iron requirement and the iron storage size, whereby the regulatory mechanisms are still largely unexplored. Genetically caused malfunctions in iron absorption can lead to iron overload over the years, which manifests itself in life-threatening organ damage.

The human organism absorbs both bivalent (Fe 2+ ) and trivalent (Fe 3+ ) iron ions. Since Fe 3+ and Fe 2+ are basically firmly bound to food proteins, the breakdown of the proteins by special digestive enzymes such as pepsin is a prerequisite for iron absorption. If there is sufficient HCl production in the stomach, this breakdown is ensured. Heat denaturation (by boiling, frying, baking) facilitates the breakdown of the iron binding proteins in the stomach, since the natural stable folding of the proteins is at least partially destroyed and therefore there are more points of attack for the digestive enzymes. After the iron binding proteins are broken down in the stomach, most of the iron in the small intestine is found as Fe 3+ in loose complexes with other molecules. All food molecules that contain an acid group as well as other OH , NH or SH groups can form loose complexes with Fe 3+ and Fe 2+ and at the same time ensure solubility (via the additional groups). These are, for example, ascorbic acid , citric acid , glycine , cysteine and many other amino acids .

Enteral absorption, hepatic regulation

Hypothetical regulation of the enteral iron absorption with the different transport proteins for the different iron uptake and storage.

The glycoprotein gastroferrin , an iron-binding protein in gastric juice, is likely to be of little importance for increasing iron absorption.

Enterocyte, schematic representation, the apical side with the brush border membrane

In the intestine, the iron is then in decreasing amounts in loose Fe 3+ complexes, as Fe 2+ in heme, and in loose Fe 2+ complexes. The solubilities of Fe 3+ and Fe 2+ from inorganic chemistry relate to the formation of hydroxide precipitates and are irrelevant in this context, since the loose complexes ensure that even Fe 3+ remains in solution even at the pH of the small intestine. It is therefore not surprising that, despite the insolubility of Fe 3+ in (pure) water at pH 9, the most important route of iron absorption in the body corresponds to the largest amount of iron in food. There are currently three known routes of exposure:

  • MIP route: Fe 3+ is absorbed via mobilferrin, integrin and paraferritin. The Mobilferrin dissolves Fe3 + from loose complexes and binds it firmly. This is not possible if the Fe 3+ has previously formed very solid or even insoluble complexes.
  • Heme path: The iron is absorbed together with the heme, that is, it passes through the enterocyte cell membrane . Usually the iron in heme is Fe 2+ . A heme oxygenase then follows in the intestinal cell , which releases the Fe 2+ contained in the heme and transfers it to the intestinal cell's labile iron pool. Since iron is firmly bound in the heme, it can always be absorbed independently of other food components in the intestine. This is done by the Hem Carrier Protein 1 (HCP1).
  • [DMT1] route: Fe 2+ is absorbed directly. In contrast to the others, this path is not specific for iron, but other divalent metal ions are also transported with it (divalent metal ion transporter). The transport proteins are able to dissolve Fe 2+ from loose complexes. Fe 2+ is also not available for transport if it has formed solid or insoluble complexes. Trivalent nonheme iron can also initially be reduced to Fe 2+ for absorption . This is done either by reducing agents such as ascorbic acid or by a ferric reductase (membrane-based, duodenal cytochrome b ) in the intestinal cell membrane .

Iron is absorbed as Fe 2+ on the apical side of the enterocytes (brush border membrane) in the upper sections of the small intestine, the duodenum and in the upper jejunum . Here, Fe 3+ by reduction by a Membranreduktase, one of the cytochrome b -like duodenal ferrireductase ( duodenal cytochrome B , Dcytb) to its two valent form Fe 2+ converted and the membrane protein, the divalent metal transporter ( divalent metal transporter 1 , DMT 1 ) transported through the apical enterocyte membrane. Intracellular, i.e. in the intestinal cell, the Fe 2+ is either stored in the form of intracellular ferritin or transported to the basolateral cell membrane. On the basolateral enterocyte membrane, the iron that is not stored in ferritin is bound to ferroportin 1 ( iron regulated protein , IREG) in the form of Fe 2+ . Ferroportin as a cellular iron transport protein is also located in the membrane of monocytes and hepatocytes and its function is regulated by the interaction with hepcidin . In its function, ferroportin cooperates with the ferrooxidase Hephaestin , which oxidizes the Fe 2+ into Fe 3+ .

Diagram shows schematically the cellular iron homeostasis in a mammalian cell.

Iron can be imported via the endocytosis of the transferrin receptor 1 or via the iron importers DMT1 and ZIP14, which increase the activity of iron reductases such as STEAP2 ( six transmembrane epithelial antigen of the prostate 2 , metalloreductase), SDR-2 ( stromal cell-derived receptor 2 ) and Dcytb ( duodenal cytochrome B ) require.

Intracellular iron can be stored in ferritin and used for protein biosynthesis, or it can also generate reactive oxygen species ( ROS ) and regulate transcription via iron-binding proteins ( iron regulatory protein , IRP1 / 2). The export is carried out by Ferroportin, often supported by Hephaestin (Hp) and / or Ceruloplasmin (Cp), and is suppressed by Hepcidin. STEAP2, SDR2 and Dcytb: ferric iron reductases; DMT1 and ZIP14: ferrous iron importers, zinc transporters; Tf: transferrin; TfR1: transferrin receptor 1; ROS: reactive oxygen species; IRP1 / 2: iron responsive element binding proteins; FTH: ferritin heavy chain gene; FTL: ferritin light chain gene; Fpn: ferroportin; Hp: hephaestin; Cp: ​​ceruloplasmin.

Hepcidin is an acute phase protein and has a key function in regulating the absorption, tissue distribution and extracellular concentration of iron. If the body's iron level is high, or if there is infection or inflammation (resulting in an increase in interleukins II-6, II-1), the HAMP gene, which codes for hepcidin, is upregulated. This also increases the amount of hepcidin circulating in the blood. The latter binds to ferroportin, which induces its internalization and ubiquitin-mediated degradation. As a result, the iron ions cannot be absorbed from the intestine by the enterocytes. In addition, no iron is released into the circulation from the monocytes or hepatocytes . This causes the serum iron level to drop.

Specialized endothelial cells in the liver sinusoids regulate the formation of the hormone hepcidin, which regulates iron metabolism, through the synthesis of the growth factor Bmp2 ( bone morphogenic protein 2 ).

In the enterocyte, the iron is either stored as depot iron in ferritin or released into the blood by the transport protein ferroportin . This process is inhibited by Hepcidin , which essentially regulates iron absorption. The divalent iron released by ferroportin is transported to the contraluminal cell surface and oxidized by the membrane protein hephestine . In this oxidized trivalent form, it binds to apotransferrin and is then transported to the points of need in the organism.

Onward transport

Ferroportin transfers the iron to the transferrin as an oxidized form Fe 3+ , in this case the transport protein cooperates with the ferroxidase Hephaestin . The transferrin molecule has two binding sites for a trivalent Fe 3+ each . Transferrin (apotransferrin) is a glycoprotein and is synthesized in the liver, releases iron by smuggling iron ions into the cells or tissue to be supplied via the binding with the transferrin receptor ( TfR-1 ) of the cell in the form of a receptor -mediated endocytosis ( clathrin-coated pits ) free. After the clathrin layer has dissolved intracellularly , it fuses with the endosomes . Proton pumps in the endosomal membrane lower the pH value to 5 to 6. The acidification causes a conformational change in the transferrin-TfR complex and leads to the release of the trivalent Fe 3+ . A metalloreductase or ferrireductase ( STEAP3 ) reduces the trivalent iron ion to the bivalent Fe 2+ , which can then be transported into the cytosol of the cell by the -divalent metal transporter ( DMT 1 ), divalent metal transporter 1 .

There are two ways open to the divalent iron ion, so it can be used directly by incorporation into proteins (functional iron) or it is stored in ferritin in the form of trivalent iron . Ferritin storage occurs mainly in cells of the liver , spleen and bone marrow . Only a small proportion is found as serum ferritin. The serum ferritin level shows u. U. a certain correlation to the total iron supply in the organism. First iron-containing enzymes are supplied, then the red bone marrow (formation of hemoglobin ) and the muscles (formation of myoglobin ). The daily exchange of iron between tissues averages around 40 mg.

The expression of the proteins of ferritin, transferrin receptor ( TfR-1 ) and divalent metal transporter 1 ( DMT 1 ) is regulated post-transcriptionally in the cell by the iron response element or iron regulatory protein ( IRE / IRP ) depending on the intracellular iron content .

In the course of heme synthesis in mammals, Fe (II) is stored by ferrochelatase (synonym heme synthase), an enzyme of the mitochondrial inner membrane . The electrons necessary for the reduction are provided by the respiratory chain .

Regulation of the iron level in the blood

The iron level at the level of the organism is probably regulated primarily by the later discovered peptide hepcidin , which binds to ferroportin in the intestine and causes it to be broken down. If the iron level is too low, the liver slows down its production of hepcidin. As a result, the release of iron from cells into the blood is increased. If the iron level is too high, the liver increases its hepcidin production and iron release decreases (" mucosal block "). That is why hepcidin has also been referred to as the hormone of iron metabolism . The release of iron from the cells of the reticuloendothelial system (RES) and from macrophages is also controlled by hepcidin.

Diseases

Iron deficiency

Main article: Iron deficiency .

Iron deficiency anemia has the greatest practical significance among the anemias that can be traced back to a disturbance in the formation of hemoglobin . It is the most common deficiency disease worldwide . Iron deficiency can lead to anemia, immune deficiency, severe symptoms of fatigue, poor concentration and trophic disorders ( nutritional disorders ), which are summarized under the term Plummer-Vinson syndrome . Failure to thrive can occur in young children.

Iron deficiency symptoms occur more frequently in women than in men because women regularly lose iron from their bodies through menstruation . In underdeveloped areas there is a diet-related iron deficiency, which is attributed to a low protein content in the diet with a high phosphate content.

Iron incorporation disorders in heme biosynthesis can lead to anemia, although the total iron concentration in the body is not reduced, cf. z. B. erythropoietic protoporphyria .

Acute poisoning

Acute iron poisoning is rare in Germany; it mostly affects children who have taken 2 to 10 g of iron orally. The symptoms are circulatory collapse, bleeding in the gastrointestinal tract, decreased blood clotting ability and long-term liver and kidney failure. The therapy consists of preventing the ingested iron from being absorbed ( gastric lavage ) and removing the iron that has already been absorbed from the organism, e.g. B. by intravenous administration of deferoxamine .

Chronic poisoning

Main article: Hemochromatosis (iron overload).

Depending on the organ affected, iron overload can lead to liver cirrhosis , destruction of the pancreas, bronze diabetes and other organ disorders. Examples of such diseases are hemochromatosis and hemosiderosis . Hemochromatosis is the most widespread genetic disease in Northern Europe, about one in two hundred Northern Europeans is homozygous in this regard , in Ireland even about 1% of the population. Heterozygous “carriers” of hereditary hemochromatosis, approx. 10–20% in the white populations mentioned, store slightly more iron than non-carriers of such mutations. Even low iron storage above the low values ​​of healthy children can lead to a. on insulin resistance or insulin resistance syndrome and its consequences, in particular on various dangerous age-related diseases such as type 2 diabetes including complications, atherosclerosis, heart attack, stroke. This provides an indication of why both children and women are (relatively) protected at a younger age.

Donating blood or bloodletting therapy can reduce the amount of iron in the organism. According to studies from Finland, male blood donors (approx. 50 years and older) have a greatly reduced heart attack risk, around 1/10 of the heart attack risk of other men.

How can you check the iron balance of humans?

If iron deficiency is suspected

The determination of iron in the blood is not suitable.

If you suspect hemochromatosis (iron storage disease)

See also

  • For the consequences of the increased uptake of iron-containing compounds in the plant organism, see iron toxicity .

literature

Web links

Individual evidence

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  4. ^ Federal Institute for Risk Assessment, Eisen
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  17. ↑ Schematic representation of the relationships and networks between the liver cells and their interactions with macrophages and enterocytes; Hepcidin is at the center of iron homeostasis and the like. a. Hemojuvelin (HJV) act as a co-receptor and the bone morphogenetic protein (BMP) acts as a ligand for the BMP receptor (BMP-Rs). [3]
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  24. ↑ Lothar Thomas et al .: New parameters for diagnosing iron deficiency states: Conclusion. (PDF; 35 kB) In: Dtsch Arztebl 2005; 102 (42): A-2878. German Medical Association, August 25, 2009, accessed on August 5, 2010 : "Ferritin must always be determined if iron deficiency is suspected"
  25. ↑ Lothar Thomas et al .: New parameters for the diagnosis of iron deficiency conditions: reticulocyte hemoglobin and soluble transferrin receptor. (PDF; 213 kB) In: Dtsch Arztebl 2005; 102 (9): A-580-86. German Medical Association, August 25, 2009, accessed on August 5, 2010 : "In the event of an acute phase reaction or chronic liver disease, ... a normal serum ferritin concentration is measured despite a reduction in total body iron"
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