Ensures transport of oxygen and functinality of a number of enzymes.
An important component of more than 200 enzyme systems needed for normal cellular function.
Key role in oxygen uptake, transport, storage and oxidative metabolism in skeletal muscle and erythropoiesis.
Utilized in mitochondria for heme synthesis, and iron sulfur cluster biogenesis.
Iron sulfur cluster are prosthetic groups for key enzymes of DNA duplication and repair.
Potentially toxic as it can react with oxygen to catalyze the synthesis of oxygen species.
Potentially deleterious because of ability to generate free oxygen radicals.
Metabolism closely regulated so that sufficient iron present to meet body’s needs without excessive supplies.
Iron balance maintained by by limiting its intestinal uptake and by continuously recycling and reusing cellular iron.
Regulation occurs at two different levels: duodenal absortion by enterocytes and recycling after red blood cell degradation by macrophages.
The four major cell types that determine body iron content and its distribution are: duodenal enterocytes, erythroid precursors, reticuloendothelial macrophages and hepatocytes.
Mechanisms to protect cells from iron toxicity include: binding to chaperone proteins, ferritin storage, and export through ferroportin.
Iron is obtained primarily from macrophage mediated catabolic activity of hemoglobin from dying RBCs.
Iron hemostasis is composed of a close loop from plasma transferrin to RBCs, from RBCs to macrophages, after macrophages to plasma transferrin.
Duodenal enterocytes affect dietary iron absorption.
Dietary iron is available in two forms: heme and nonheme iron.
Iron is complex as Fe2+, ferrous iron in hemoglobin in the heme form, which is present in animal food sources such as meat, poultry, and seafood.
Non-heme iron, Fe3+ or ferric iron is present in the vegetarian diet that includes black tea, cacoa, cereals, and dry fruit.
Heme iron is estimated to contribute 10-15% of total iron intake in meat eating populations, but because it is generally better absorbed then non-heme iron, it accounts for more than 40% of total absorbed iron.
Following iron absorption in duodenal enterocytes it is reduced at the apical membrane and taken into the cell through divalent metal transporter 1 (DMT1).
Iron export from enterocytes to plasma occurs through the basolateral transporter ferroportin.
Intestinal cells and macrophages bind and internalize extracellular iron using the membrane protein ferroportin.
Much of the iron absorbed from the duodenum is stored in the form ferritin or is lost on sloughing of senescent enterocyte cells.
Iron reduction, absorption, storage, transfer are mediated by signals reflecting oxygen tension in enterocytes, intracellular iron levels and systemic iron requirements.
Dietary iron absorption is influenced by iron reserves, bone marrow erythropoietic activity, and hemoglobin concentration, blood O2 content, and inflammatory cytokines which regulates liver production of the hormone hepcidin.
The production of heme requires transferring bound iron, and non-transferrin bound iron (NTBI) cannot be used.
Iron release from enterocytes binds to free sites on the plasma iron transport protein transferrin.
Transferrin binding capacity normally exceeds plasma iron concentrations, with a normal transferrin saturation of approximately 30%.
Plasma iron is bound to the transport proteins transferrin and is mostly destined to deliver to bone marrow erythroblasts that consume iron to synthesize heme and hemoglobin, with smaller iron flow to meet the requirements of other organs and tissues.
With the exception of most reticuloendothelial macrophages transferrin bound iron is the only physiologic source available in most cells.
Cells regulate the intake of transferrin bound iron by altering surface transferrin receptor 1 (TfR1)1 expression.
Enterocytes regulate iron absorption via its effects on transcription factor hypoxia-inducible factor 2alpha and changes in transcription DMT1 and ferroportin.
Enterocyte iron content regulates iron absorption through its effect on Iron regulatory proteins (IRP) types 1 and 2 and their effects on messenger RNA encoding DMT1, ferrooportin, ferritin, and HIF-2alpha.
When transferrin becomes highly saturated, iron released into circulation is bound to low molecular weight compounds such as citrate.
Non-transferrin bound iron (NTB1) is readily up taken by hepatocytes and cardiomyocytes.
Excess iron uptake as non-transferrin bound iron (NTBI) contributes to oxidant-mediated cellular injury.
A small fraction of non-transferrin bound iron is redox-active and labeled as labile plasma iron.
Erythroid precursors affect iron utilization.
Reticuloendothelial macrophages affect iron storage and recycling.
Hepatocytes affect iron storage and endocrine regulation.
Systemic iron homeostasis maintains plasma iron levels in the range of 10-30 µm and whole body iron stores in the range of 0.3-1 gm with the lower end of the range is typical for women of reproductive age.
Total body iron in a normal adult is around 4 gm in males and 2.5 gm in females.
Circulating red blood cells have about 2.5 gm of iron.
Average human body assay 7 g storage capacity of iron.
Hemoglobin containing red blood cells hold 60% of the iron, with a rest stored in ferritin, myoglobin, heme enzymes, catalases, peroxidases, and nonheme enzymes (25%).
Average daily need in women of reproductive age is about 1.4 to 2 mg owing to the monthly loss of 30 to 80 mL of menstrual blood.
Baseline absorption is 1 mg per day.
Iron absorption takes place in the duodenum.
Normal diet contains 10-20 mg of iron and 1-2 mg absorbed each day to compensate for daily losses.
Typical Western diet contains approximately 6 mg of iron per 1000 kcal.
Caloric restriction of food or food fadism can reduce dietary iron content leading to iron depletion, and this is enhanced with menstration, rapid grwoth rates and pregnancy.
For adequate iron intake an individual may require more than 2000 kcal/d.
Dietary absorption is primarily by duodenal enterocytes
Diets rich in meat and ascorbid acid assocated with less iron deficiency as these are facilitators of iron absorption.
Diets rich in phytates and polyphenols are inhibitors of iron absorption and lead to iron deficiency.
Diets rich in calcium or high in fiber have a negative effect on iron absorption, but to a lesser degree than diets high in phytates, and polyphenols.
Low calcium diets do not have an inhibitory effects on non-heme or heme iron absorption copared to diets with high calcium.
Daily need for iron is about 25-30 mg of iron, which is supplied through the recycling of iron by macrophages following catabolism of senescent red blood cells.
The daily production of new RBCs comprises about 80% of the iron demand requiring about 20-24 mg of iron.
Circulates bound to transferrin which has two high affinity binding sites for iron.
Daily iron need in the third trimester of pregnancy averages 5.6 mg/day.
Total iron requirement for a singleton, uncomplicated pregnancy is about 1 gram.
If a woman is moderately anemic with a hemoglobin concentration of 10 grams at the start of pregnancy, the iron requirement would be 400 mg greater, or about 1400 mg.
Each 250 ml of transfused blood adds about 250 mg of elemental iron to the body.
Absorbed in the duodenum where specific carrier molecules are expressed by the villus enterocyte.
Most of the body’s cells import transferrin bound iron from the circulation via specific membrane bound transferrin receptors (TfR).
Transferrin receptors exist as two different isoforms, encoded by two different genes: TFR1 and TFR2.
When iron overload exists non transferrin bound iron can penetrate tissues.
Hepatic iron concentration via liver biopsy is the most accurate and sensitive method to determine the body iron level.
The liver is the dominant iron storage organ and liver iron concentration correlates closely with total iron balance.
Hepatocytes acquire iron in varying forms: transferrin bound iron, non-transferrin bound iron, heme and hemoglobin.
Within hepatocytes iron is stored assocated to ferritin or hemosiderin and is easliy mobilized when erythopoiesis is required.
Non transferrin bound iron is a likely contributor to iron loading in hepatocytes under conditions of elevated transferrin saturation.
Hepatocytes have a central role in iron homeostasis as the site of hepcidin hormone production.
Macrophages phagocytose senescent erythrocytes and can acquire iron in a number of forms, and can ensure iron storage within ferritin and hemosiderin.
An essential element and must be tightly regulated to prevent toxicity.
Intestinal absorption and mobilization controlled by 2 regulators: the stores regulator and the erythroid regulator.
The stores regulator controls intestinal absorption and is responsible for meeting the body’s normal iron requirement and for accumulating and controlling iron stores.
Iron plasma concentration remains relativley constant, despite varying iron demands.
The erythroid regulator maintains production of erythrocytes by increasing iron absorption and depletion of iron stores in the presence of gastrointestinal bleeding.
In anemias of ineffective erythropoiesis, the erythroid regulator increases iron absorption resulting in its accumulation and iron overload.
The erythroid regulator facilitates the absorption of iron up to 40 mg/day with oral iron supplementation compared to 2 mg/day absorption permitted by the stores regulator.
Erythroid precursors of the major sites of iron utilization, with expression of high levels TfR1 , which mediates the entry of iron bound transparent into recycling endosomes.
Acidification of endosomes results in iron release and then exportation by DMT1.
IRE-IRP ( iron responsive elements-iron regulatory proteins) system regulates stability of messenger RNA for TfR1 and translation of messenger RNA or erythroid specific 5- aminolevulinate synthase, the initial enzyme in heme synthesis (Ponka P ).
Hepcidin is the principal iron regulatory hormone which blocks intestinal absorption of iron and the release of iron from stores by inducing the internalization and degradation of cellular iron exporter ferroportin.
Hepcidin controls intestinal iron absorption and macrophage recycling.
Ferroportin is both the Hepcidin receptor and the soul cellular iron exporter through which iron is transferreded to blood plasma.
Hepcidin inhibits the iron exporting activity of ferroportin, controlling the transfer the iron to blood plasma from iron absorbing duodenal enterocytes, from macrophages that recycle the iron of senescent erythrocytes, and from iron storing hepatocytes.
Hepcidin decreases plasma iron concentration body triggering internalization and degradation of ferroportin by intestinal cells and macrophages keeping iron within these cells.
Hepcidin deficiency results in iron overload in the absence of transfusion dependence, as occurs with beta thalassemia.
Hepcidin production disruption can lead to development of transfusion dependent anemia.
Hepcidin hormone mediates systemic regulation of iron absorption.
Hepcidin functions as a hypoferremia hormone by down regulating ferrooportin mediating release of iron into the circulation.
Hepcidin production by liver cells results in iron retention in duodenal enterocytes, decreasing dietary iron absorption, iron retention in reticuloendothelial macrophages all resulting in decreased iron turnover.
Liver production of hepcidin is regulated by inflammatory signals, iron status, erythpoietic activity and oxygen tension.
Hepcidin Is a type II acute phase protein associated with infection, inflammation and hypoferremia.
Hepcidin hormone binds to the iron exporter ferrooportin and degrades it thereby decreasing the transfer of iron from the enterocytes to the circulation.
Hepcidin is regulated by anemia and iron and is the final mediator of the stores and erythroid regulators.
Erythroid regulator exerts its activity to some degree by suppressing hepcidin.
Reticuloendothelial cells serve as a hepcidin regulated iron repository.
Reticuloendothelial cells release approximately 25 mg of iron daily, and represents the most dynamic iron compartment, turning over about 10 times daily.
The pool of circulating transferrin in iron amounts to less than 3 mg daily.
Reticuloendothelial cells obtain most of their iron From phagocytosis of red blood cells.
Iron release from senescent RBCs can be stored as ferritin or exported into the circulation.
Ferritin is and iron storage protein complex composed of 24 ferritin monomers of 2 subtypes: heavy and light chains.
Heavy chain ferritin has ferrooxidase activity, that is needed for oxidation of incoming ferrous ions.
Lght chain ferritin promotes nucleation and mineralization.
Iron acquisition by RBCs mediated by endocytosis of circulating Fe2-Tf through TfR1 which is highly expressed at the cell surface of mature erythroblasts.
Following the internalization of iron in the red blood cells it is released from Tf by acidification of the endosome and reduced to Fe(II) by Steap3, an endosomal reductase, and exported to the cytosol reductase and exported to the cytoplasm by DMT1/Nramp2 (Shaw).
Most iron is targeted to the mitochondria.
Increases in erythropoiesis requires an increase in flow of iron from diet or storage pools to meet needs of red blood cells.
After phlebotomy, erythropoietin administration or hemolysis hepcidin production is reduced allowing increased iron absorption and release of iron from stores.
With postoperative recovery from anemia and use of erythropoietin can increase iron need from 1 mg/d to as much as 30mg/d.
Accumulation of iron in excess of requirements implicated in increased risk of chronic diseases via iron catalyzed free radical mediated oxidative stress.
The body has no active mechanism for eliminating iron.
Contributes to higher risk of atherosclerosis at a relatively early age.
Deficiency affects brain development.
Iron deficiency, with or without anemia, decreases aerobic performance and is accompanied by fatigue and exercise intolerance (Haas JD).
Iron repletion improves cognition, and exercise performance (Davies KJ).
Is required by muscles and the kidney.
Excess related to neurodegeneration.
Intravenous iron improves hemoglobin response when added to erythropoiesis stimulating agents in patients with chemotherapy induced anemia, in both iron deficient and iron replete patients.