Iron metabolism

Synonyms

Iron metabolism;

First descriptor

In the 18th century, accounts first appeared reporting the presence of iron in the blood. However, it was not until the 1930s that the first reports of iron metabolism at the molecular level became known. The discovery of the plasma iron responder, known as transferrin dates back to 1946. Iron absorption was published in 1958, and the transferrin receptor (TfR) in the 1970s. The long-sought iron-regulating hormone, hepcidin and the iron exporter ferroportin were discovered in the early 2000s.

However, the exact knowledge of iron biology is incomplete even today (Chifman 2014).

Iron plays a crucial role in cellular respiration, oxygen transport, oxygen storage (Gafter- Gvili 2019), energy production and DNA synthesis (Chifman 2014).

A man's body has about 50 mg / kg bw of iron, while a woman's has about 35 mg / kg bw.

Daily iron loss is 1 mg in men, 2 mg in menstruating women, and 3 mg in pregnant women (Herold 2022). Iron loss occurs through exfoliation of epithelia of the internal and external surfaces, in menstruating women through menstruation (Heimpel 2003), and through sweating. To compensate for this loss, the body absorbs approximately 1 - 2 mg of iron per day from food (Chifman 2014).

Iron is toxic to the body at high doses. Since it cannot be excreted in the case of clinically relevant iron overload, bloodletting or therapy with chelating agents is required in this case (Heimpel 2003), see "Iron overload" below.

Iron levels in the human body are differentiated between:

• heme iron:

This makes up the largest proportion with up to 70 %. As divalent iron, it is bound to the hemoglobin of erythrocytes and erythroblasts. Small amounts of iron are bound to myoglobin (about 2 %) and iron-containing cytochromes (less than 0.1 %) (Heimpel 2003).

One gram of hemoglobin contains about 3.4 mg of iron, 1 ml of blood contains 0.5 mg, and 1 red cell concentrate contains 250 mg of iron (Herold 2022).

• Depot iron:

Depote iron-also referred to as storage iron-accounts for approximately 18% (Herold 2022). It is stored intracellularly in the macrophages of liver, spleen and bone marrow as trivalent iron protein, the so-called apoferritin compounds in the form of ferritin and hemosiderin (Heimpel 2003).

• Transfer iron:

This is bound as so-called transferrin and accounts for only 0.1% of the iron stock (Herold 2022). Normally, one third of the binding capacity of transferrin is utilized (Heimpel 2003).

In the body, iron is contained in the following proteins:

• Heme protein as:
  • Hemoglobin
  • Myoglobin
• Iron carboxylate protein as:
  • Ferritin
• iron- sulfur- protein as:
  • Akonitine
• mononuclear protein as:
  • Superoxide dismutase (Kühne 2016)

• 1. homeostasis:

Since iron is essential to the body, during evolution the organism has developed mechanisms to recycle the metal (Kühne 2016).

Intestinal absorption occurs through a divalent metal transporter 1 (DMT 1) that takes up divalent iron into duodenal enterocytes. A brush border enzyme, duodenal cytochrome b (Dcytb) first reduces the iron.

From the enterocytes, the iron entered the blood with the help of ferroportin 1 and a valence change by hephaestin (hephastein) to trivalent iron occurs (Herold 2022).

The released iron is used for hematopoiesis or initially stored for further use (Gafter- Gvili 2019).

On the other hand, however, iron in abundance is toxic (Kühne 2016) because it can accept and transfer electrons, leading to severe oxidative stress and tissue damage (Gafter- Gvili 2019).

Regulation of iron balance occurs through adaptation and absorption. The peptide hormone hepcidin, which is mainly produced in the liver (Percy 2017), plays a crucial role in this process. It effectively represents the "insulin of iron metabolism" (Herold 2022).

Hepcidin prevents iron transport by binding to the iron transporter ferroportin (Gafter- Gvili 2019).

Hepcidin, in turn, is regulated by the hormone erythroferron, which is produced in the bone marrow. When erythropoiesis increases, erythroferron decreases hepcidin levels (Herold 2022).

The ability to excrete iron is negligible in the human body (Gafter- Gvili 2019).

• 2. iron- recovery

Released heme iron or functional iron is recovered by macrophages of the reticulohistiocytic system (RHS) and stored as ferritin or hemosiderin or bound to transferrin (Herold 2022).

• 3. iron transport in the blood

Iron is bound in the blood as 3-valent iron to the transport protein transferrin. Transferrin provides iron exchange between enterocytes located in the intestine, erythroblasts, and storage compartments (Herold 2022). The organism is protected from toxicity by binding the iron (Heimpel 2003).

Normally, approx. 20 - 45 % of the serum transferrin is saturated with iron. By determining the transferrin saturation (TfS or TSAT), statements about the iron supply during erythropoiesis are possible. If the TSAT value is < 20 %, too little iron is available for erythropoiesis (Herold 2022).

Transferrin- receptors can take up plasma iron bound to transferrin across the cell membrane into the erythroblasts of the bone marrow and reticulocytes. If iron deficiency occurs, the number of transferrin receptors becomes highly regulated. The number of transferrin receptors can be measured in blood by determining the "soluble transferrin receptors (sTfR)". Therefore, the concentration of sTfR in serum is an indicator of iron supply during erythropoiesis (Herold 2022).

• 4. storage iron

Storage iron is found intracellularly as water-soluble ferritin and water-insoluble hemosiderin at 1 /3 each in the liver and bone marrow, and in smaller amounts in spleen and various tissues such as muscle (Herold 2022).

• 4. a. Ferritin

Ferritin consists of a protein shell and a core. It is a so-called acute phase protein that stores iron in biological form and protects cells from the toxic effects of ionized iron. Circulating iron in serum correlates well with the body's iron stores.

It can be detected:

- in serum radioimmunologically

- in bone marrow puncture by staining (so-called Berlin blue reaction)

- electron microscopically (Herold 2022)

• 4. b. (Hemo-) Siderin

Electron microscopically, these are siderosomes(lysosomes) formed from denatured ferritin particles. They can be recognized by light microscopy as yellow-brown granules or blue in the Berlin-blue reaction.

If there is an oversupply of iron, siderin granules occur increasingly in parenchymal cells, e.g. in those of the liver or also in macrophages (Herold 2022).

Each cell has a system to coordinate consumption, storage and uptake of iron. This system is regulated by specific RNA structures, the so-called "iron responsive elements (IRE)" and special cytoplasmic proteins, the so-called "iron regulatory proteins (IRP- 1)".

(Herold 2022)

• Iron intake

Iron is supplied with the diet. With a normal Central European diet, this amounts to approx. 10 - 30 mg iron / d. Of this iron, only 10 - 30 % is absorbed in the upper small intestine.

Bivalent iron, which can be utilized immediately, is found in animal food. In plant foods, the iron is present in trivalent form and must first be converted by ferrin reductases of the enterocytes into a readily absorbable divalent form (Heimpel 2003).

The daily iron turnover in healthy individuals is about 30 mg / d. Plasma iron is subject to large daily fluctuations because it is exchanged with a half-life of 60 - 120 minutes (Heimpel 2003).

• Iron overload

If an excess of iron occurs, it is stored in the liver, heart, pancreas and endocrine glands. This results in the formation of proteins that damage cell membranes and can lead to cell death. Diseases that can result from chronic iron overload include:

- carcinomas

- hypogonadism

- arthritis

- retinal degeneration

- cardiac arrhythmias

- cardiac insufficiency

- neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.

- diabetes mellitus

- premature death (Chifman 2014)

• Iron deficiency

s. Iron deficiency and iron deficiency anemia

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2. Gafter- Gvili A, Schechter A, Rozen- Zvi B (2019) Iron deficiency anemia in chronic kidney disease. Acta Haematol. 142 (1) 44 - 50
3. Heimpel H (2003) Physiology of iron metabolism and pathogenesis of iron deficiency. Oncodin Iron Deficiency Anemia ISSN: 2193-6021.
4. Herold G et al (2022) Internal medicine. Herold Publishers 33 - 35
5. Kühne T, Schifferli A (2016) Compendium of pediatric hematology. Springer Verlag Berlin / Heidelberg 13 - 19
6. Percy L, Mansur D, Fraser I (2017) Iron deficiency and iron deficiency anemia in women. Best Pract Res Clin Obstet Gynaecol (40) 55 - 67.