Iron

Iron is one of the most important elements in the human body. The adult body contains more than 70 mmol (4.0-4.5 g) of iron. In women, this amount is lower than in men, which is attributed to blood loss during menstruation.

Distribution of iron in the body

Metabolism of iron
The presence of iron is essential for cell function. As a part of heme, it participates in the transport of oxygen and as a part of cytochromes it allows the transfer of electrons in the respiratory chain. However, the undesirable effect of iron is its involvement as a transient and highly reactive element of radical reactions, in which so-called reactive oxygen species (ROS) are formed. ROS can damage cell membranes, proteins and DNA.

Iron is absorbed in the Fe2+ form by active transport in the duodenum and upper jejunum by two mechanisms:


 * 1) Porphyrin-bound iron in the form of a stable lipophilic complex;
 * 2) Fe2+ water soluble chelates.

Only a small portion of the iron is absorbed in the ionized form.

The average diet provides approximately 10-50 mg of iron per day, but only 10-15% is absorbed. Iron in heme from meat products are absorbed by the human body better than non-heme iron from plant sources. In addition, plants contain oxalates, phytates, tannins and other phenolic compounds, which form insoluble or chelated complexes with iron that are difficult to be absorbed. On the other hand, ascorbic acid improves iron absorption.


 * After uptake by the intestinal mucosa, part of the iron is incorporated into the storage form - with the protein ferritin in intestinal cells.
 * Other portions of the absorbed iron passes into the plasma as well, where it is transported bound to transferrin.
 * The protein ferroportin (it is also found in the membrane of macrophages and hepatocytes) plays an important role in the transfer of iron across the basolateral membrane of enterocytes. It is the main site of regulation of iron homeostasis in the body.
 * A key regulatory factor is the hepcidin protein, which is synthesized in the liver. By binding to ferroportin, it inhibits the transport of iron from cells and thus contributes to its sequestration in them. Hepcidin levels increase with inflammation. Hepcidin is also partly responsible for anemia of chronic diseases. Mutations in the hepcidin gene lead to juvenile hemochromatosis type 2B.

Plasma iron is captured by target tissue cells via the transferrin receptor and is either incorporated into heme or stored in ferritin. The use of the specific transport protein transferrin and the ferritin storage protein for iron storage represents protective mechanisms to prevent the toxic effects of redox active iron.

Examination of iron metabolism
In medical practice, it is common to encounter diseases associated with changes in iron metabolism and utilization. Laboratory tests of iron metabolism include the following tests:


 * Iron in serum
 * Serum transferrin and iron binding capacity
 * Serum ferritin
 * Transferrin receptor

These parameters are important diagnostic indicators for demonstrating a decrease or increase in iron stores even in stages that are not accompanied by significant clinical manifestations.

Determination of iron in serum
Colorimetric methods, atomic absorption spectrophotometry and other special techniques are used to determine serum iron. The most used are photometric methods based on the reaction of iron with a complexing agent. All procedures include the following steps:


 * 1) Release of Fe3+ from transferrin binding using acids or surfactants (eg HCl).
 * 2) Reduction of Fe3+ to Fe2+, which is necessary for the reaction with the complexing agent. Ascorbic acid, for instance, is used for the reduction.
 * 3) Reaction of Fe2+ with a complexing agent containing reactive groups –N = C – C = N– is used to form a color complex. Metal ions form chelates with two nitrogen atoms. Currently, mainly two complexing agents are used - bathofenentroline and ferrozine (3- (2-pyridyl) -5,6-bis (4-sulfophenyl) -1,2,4-triazine - PST, protected name FerroZine®, which has higher absorption coefficient and is more soluble in water.
 * Evaluation


 * Serum iron concentrations are subject to circadian rhythm and are influenced by other factors. This limits the diagnostic significance of this parameter. It is a poor indicator of tissue iron stores and should always be considered in combination with serum transferrin and iron binding capacity.
 * Decreased concentrations are accompanied by iron deficiency, caused for example, by large or repeated blood loss, insufficient dietary iron intake or impaired absorption. The finding is not specific, as reduced levels are also encountered in acute infection or chronic inflammatory diseases (iron transfer to tissues).
 * High iron levels occur in hemochromatosis (see below), in iron overdose or intoxication, in increased erythrocyte breakdown, and in some liver diseases.
 * Reference values
 * Men: 9–29 μmol/L
 * Women: 7–28 μmol/L

Serum transferrin and iron binding capacity
Iron is transported by the blood bound to a specific protein with β1-electrophoretic mobility, transferrin, which is synthesized in the liver.


 * The rate of its formation is inversely proportional to the body's iron stores; it increases with iron deficiency and decreases with excess.
 * The biological function of transferrin is the ability to easily form non-toxic iron complexes and transfer iron absorbed by the small intestinal mucosa to the bone marrow or storage forms (ferritin or hemosiderin).
 * Each transferrin molecule binds two Fe3+ atoms (1 g transferrin binds 25.2 μmol iron).
 * Transferrin can be determined directly by immunochemical methods or indirectly as the ability of transferrin to bind iron - the so-called iron binding capacity.
 * Total iron binding capacity (TIBC ) is the amount of iron that transferrin is able to bind when all binding sites are occupied. Usually only 1/3 of transferrin-bound capacity is saturated with iron. Free transferrin without bound iron represents the free binding capacity (2/3 of transferrin) that is available for iron transport in increased demands.

Conversion between transferrin concentration and total binding capacity:


 * Total binding capacity (μmol/L) = Transferrin (g/L) x 25.2

The reference range for serum transferrin concentration (S-transferrin) is 2.0–3.6 g/L and for a total binding capacity is 50–70 μmol/L.

Transferrin saturation
From the values ​​of iron and transferrin concentration, we can calculate transferrin saturation (TfS), which is defined as the ratio of serum iron concentration to total iron transfer capacity for transferrin. This is a sensitive parameter for detecting latent iron deficiency.


 * Evaluation of transferrin saturation
 * Physiological values: 25-50%
 * Iron deficiency saturation reduction: <15%
 * Increase in saturation with excess iron: > 50%

Feritin a hemosiderin
thumb |300px|Schema struktury feritinu Feritin je nejdůležitější zásobní protein pro železo. Molekula feritinu je přizpůsobena vázat velké množství Fe3+ v rozpustné a netoxické formě pro organismus. Feritin je tvořen vnějším proteinovým obalem z 24 podjednotek – apoferitinem (Mr 440 000), ohraničujícím dutinu, ve které může být soustředěno až 4500 atomů železa ve formě oxyhydroxidu železitého (FeO·OH)n v mikrokrystalické podobě s fosfáty (FeO·OPO3H2). Vstup a výstup atomů železa umožňují póry mezi jednotlivými podjednotkami obalu molekuly feritinu. Normálně je jeho kapacita využita asi z 20 %. Ukládá se do buněk v játrech, slezině a střevní sliznici. V krevním séru se feritin nachází ve velmi nízké koncentraci. Sérové koncentrace feritinu jsou měřítkem zásob železa v organismu. Nízké koncentrace indikují vyčerpání celkové tělesné rezervy železa a slouží k časnému odhalení anémie z nedostatku železa ještě v prelatentní fázi. Zvýšené koncentrace feritinu jsou doprovodným jevem vysokých tkáňových zásob železa. Dále se s nimi setkáváme u mnohých pacientů s onemocněním jater, některými maligními nádory (nádorový marker) nebo zánětlivými onemocněními (pozitivní reaktant akutní fáze).

Referenční rozmezí pro koncentraci feritinu v séru (S-feritin) je pro muže 30–300 &mu;g/l a pro ženy 20–120 &mu;g/l.

Hemosiderin je dalším zásobním proteinem pro železo. Vzniká agregací denaturovaného feritinu s dalšími komponentami. Vytváří partikule o velikosti 1 až 2 μm, které jsou při použití barvení na železo viditelné ve světelném mikroskopu. Hemosiderin obsahuje větší množství železa než feritin, ale vzhledem ke špatné rozpustnosti ve vodě je obtížně dostupné. Tvoří se za situace, kdy množství železa v organismu převýší skladovací kapacitu feritinu.

Transferinový receptor
thumb |300px|Transferinový receptor Železo transportované krví transferinem je zachycováno buňkami prostřednictvím specifického transferinového receptoru (TfR). V určitém stádiu vývoje se nachází na povrchu všech buněk, nejvíce je však exprimován na povrchu prekursorů buněk červené řady v kostní dřeni. TfR je transmembránový protein, který je tvořen dvěma identickými podjednotkami, spojenými disulfidovou vazbou. Oddělením extracelulárních domén receptoru se do cirkulace uvolňuje tzv. solubilní (rozpustná) frakce transferinového receptoru (sTfR), který může být v podobě dimeru nebo monomeru. Buňky reagují na snížení zásob železa syntézou zvýšeného množství transferinových receptorů.

Zvýšení sTfR je spolehlivým ukazatelem nedostatku železa pro krvetvorbu. Se zvýšenými hladinami sTfR se setkáváme u anemií z nedostatku železa nebo u hemolytických anemií. Cenné je stanovení sTfR u anemických pacientů, u nichž je zvýšen feritin z důvodů reakce akutní fáze. Stanovení koncentrace sTfR je možno využít i u pacientů s transplantovanou kostní dření pro sledování průběhu erytropoézy.

Ke stanovení se používají imunochemické metody.

Související články

 * Stopové prvky
 * Hemoglobin
 * Erytropoeza
 * Onemocnění z nedostatku živin

Použitá literatura

 * Human iron metabolism
 * Hepcidin
 * Ferroportin
 * Iron overload