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Roles & Homeostasis

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Not only is iron an essential component of the hemoglobin molecule, but it also has multiple roles in DNA and RNA synthesis, production of thyroid hormones, cellular transport, cellular immune responses, and regulation of mitochondrial enzymes.

 
Iron homeostasis involves the interplay between iron absorption from the gastrointestinal tract, recycling of iron from red cells at the end of their lifespan, release of iron form the macrophages, and iron loss.
 

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Heme & Non-Heme Iron

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Iron is derived from the diet as heme-based iron and nonheme-based iron.

Heme iron, which exists as ferrous (Fe2+) iron, is found in animal products such as red meat, poultry, and fish, and is absorbed by a protein called HCP1. The heme carrier protein 1 protein, HCP1, is located at the brush border of the duodenal and jejunal enterocytes, enables the absorption of heme iron.

Nonheme iron is found in plant-based foods, and exists in ferric (Fe3+) form, which has less bioavailability and absorption compared to heme iron. These foods include including green leaf vegetables, lentils, and beans.

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Iron Absorption

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Iron is absorbed by a protein, divalent metal transporter 1 (DMT1), after being reduced from the oxidized ferric form to the ferrous form. Oxidized Ferric iron (Fe3+) is reduced to the ferrous (Fe2+) form by ferrireductase. Ferrous iron is then absorbed by DMT1, which is in the brush border of duodenal enterocytes. The divalent metal ions, such as calcium and magnesium, act as non-competitive inhibitors of this DMT1.

The absorption of iron is predominately at the duodenum and proximal jejunum, with only 1-2mg being absorbed in a healthy diet. In a healthy diet, approximately 5–15 mg of non-heme iron and 1–5 mg of haem iron are ingested daily although only 1–2 mg is ultimately absorbed in the small intestine.

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Factors that Promote Iron Absorption

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Gastric acid and ascorbic acid Both reduce the insoluble ferric iron to the more soluble and well absorbed ferrous iron. Ascorbic acid also forms a chelate with ferric iron at acidic pH, which improves solubility and the absorption of iron.

Cysteine and fructose These chelate iron that helps promote iron absorption in the increased pH of the duodenum.

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Inhibitors of Iron Absorption

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Medications that decrease gastric acid production such as proton pump inhibitors and histamine 2 receptor antagonists.

Medications that bind to iron such as such as cholestyramine, and tetracycline.

Phytates and polyphenols These chelate with non-heme iron, forming insoluble complexes with limited absorption.

Calcium and magnesium This is due to their inhibitory effect on the transporter protein, DMT1, which leads to decreased absorption of both heme and nonheme iron.

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Iron Metabolism

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The main proteins involved in iron metabolism are ferroportin and hepcidin.

Ferroportin transports iron from enterocytes and macrophages into circulation. Ferroportin acts as the iron export protein by transporting absorbed iron from enterocytes into the circulation, and from the maternal circulation to the fetus, and also allows macrophages to recycle senescent and damaged red blood cells back into the circulation.

Hepcidin regulates iron metabolism by inactivating ferroportin, thus reducing iron absorption and release from macrophages. Hepcidin also has antimicrobial activity due to its role in sequestering iron from circulating siderophilic bacteria, such as E. Coli, Klebsiella, Salmonella, Yersinia and Listeria, thus preventing the pathogen from growing in an iron-rich environment.

Hepcidin also increases in high iron states which appropriately decreases absorption and recycling of iron.

Hepcidin regulates iron metabolism by inactivating ferroportin, thus reducing iron absorption and release from macrophages. Hepcidin also has antimicrobial activity due to its role in sequestering iron from circulating siderophilic bacteria, such as E. Coli, Klebsiella, Salmonella, Yersinia and Listeria, thus preventing the pathogen from growing in an iron-rich environment.

Hepcidin is a positive acute phase reactant; therefore, its levels increase in inflammation, and this will result in iron sequestration and functional iron deficiency.

Hepcidin levels decrease in response to hypoxia, anemia, and iron deficiency. In conditions with chronically decreased hepcidin levels, iron overload can occur, such as in certain forms of hereditary hemochromatosis. Interestingly, it is believed that carriers of mutations in the HFE gene, such as C282Y, which are associated with hereditary hemochromatosis, may have had a survival advantage in ancestors given the protection against iron deficiency, owing to the low hepcidin levels and increased iron absorption. This may be the reason why HFE mutations are common in certain populations, found in approximately one in ten individuals of northern European ancestry, especially as carriers were unlikely to experience the effects of iron overload.

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Iron Transfer & Storage

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Iron from enterocytes or macrophages binds to transferrin in the circulation, with only 20-40% of transferrin binding sites being occupied under normal conditions, and most of this iron is supplied to the bone marrow for erythropoiesis.

Excess iron is stored as ferritin or hemosiderin in the liver, spleen, and bone marrow.

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Normal Iron Levels

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The normal body iron content is 3-4 grams, with most of it present in circulating red blood cells. Additional iron is present in myoglobin and certain enzymes, along with iron in transport forms (plasma iron bound to transferrin) and storage forms (ferritin or hemosiderin).

Iron absorption is almost equal to iron loss in a normal physiological state. Iron loss occurs from shedding of skin cells, sweating, gastrointestinal mucosal turnover, and menstruation. This will result in approximately 1mg of iron lost daily in adult males and 1-2mg in females during reproductive ages.

The amount of iron lost is higher in states of increased iron demand, such as pregnancy, growth, excessive bleeding, and increased erythropoiesis from polycythemia or use of erythropoiesis stimulating agents.

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Absolute Iron Deficiency

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Iron deficiency occurs in several stages, starting with absolute iron deficiency, where there is depletion of iron stores, but an adequate level to maintain normal hemoglobin synthesis. In absolute iron deficiency, the decreased iron and increased transferrin suppress hepcidin expression. This leads increased iron absorption from the gut and export from the macrophages and hepatocytes into the circulation. At early stages, the hemoglobin concentration will be normal, but there will be decreased serum ferritin. Iron has multiple other functions besides production of hemoglobin and myoglobin, such as regulation of mitochondrial enzymes and generation of ATP, therefore iron deficiency without anemia will have negative consequences. It is therefore important to note that iron deficiency without anemia is not a normal physiological state and requires management including iron supplementation and identifying the underlying cause.

This is then followed by decreased iron available for hemoglobin synthesis, anemia and with chronic iron deficiency iron-deficient red blood cells develop. The anemia is initially normocytic with normal reticulocyte count, but will eventually result in microcytic hypochromic anemia with a reticulocyte count that is inappropriately low. The normal physiologic response to iron deficiency results in increased erythropoietin and decreased hepcidin, provided there is normal renal function and absence of an inflammatory condition interfering with iron homeostasis.

Chronic anemia may cause end-organ damage to the heart, kidney, and brain.

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Functional Iron Deficiency

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Functional iron deficiency occurs when there is an imbalance between iron demand and serum iron availability, despite adequate iron stores, secondary to inflammation and  increased hepcidin levels.

This is the predominant mechanism of anemia of inflammation or anemia of chronic disease. This is most frequently observed in the setting of infections or systemic inflammation, such as inflammatory bowel disease, cancer, chronic kidney disease, and heart failure, where the release of inflammatory cytokines, such as IL-6, result in increased hepcidin expression and reduced ferroportin transcription. This results in iron sequestration where there is impaired iron absorption and decreased iron mobilization from the macrophages and hepatocytes into the circulation. This decreased iron bioavailability results in iron-deficient erythropoiesis.

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