Sandbox: jss

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

In the human body, iron mainly exists as bound to protein (hemoprotein), as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferring, and ferritin).
The body requires iron for the synthesis of its oxygen transport proteins, (hemoglobin and myoglobin), and for the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and oxidation-reductions.
60% of the body iron is found in the hemoglobin present in circulating erythrocytes, 25% is contained in tranferrin and ferritin, and the remaining 15% is bound to myoglobin in muscle tissue and in a variety of enzymes involved in the oxidative metabolism and many other cell functions.
Iron is bound and transported in the body via transferrin and stored in ferritin molecules.

Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma from intestinal enterocytes or reticuloendothelial macrophages.
The binding of transferrin to the cell-surface transferrin receptor (TfR) 1 results in endocytosis and uptake of iron.
Internalized iron is transported to mitochondria for the synthesis of heme or other iron containing enzymes.
Excess iron is stored in cytosolic ferritin.

Iron absorption occurs by the enterocytes in the duodenum and upper jejunum.
Dietary iron occurs in two forms: heme and nonheme. The primary sources of heme iron are hemoglobin and myoglobin from consumption of meat, poultry, and fish, whereas nonheme iron is obtained from cereals, pulses, legumes, fruits, and vegetables.
In the blood, it is transported by transferrin to the cells or the bone marrow for erythropoiesis.
Iron absorption is controlled by ferroportin which allows or does not allow iron from the mucosal cell into the plasma.
Iron is absorbed in Fe⁺² (ferric) state
The iron is consumed in Fe+3 (ferrous) state and is reduced to Fe+2 state by the acidic gastric pH by enzyme ferric reductase.

Fe+2 is absorbed by the enterocytes and exported across the basolateral membrane into the bloodstream via Fe+2 transporter ferroportin.
The ferroportin-mediated efflux of Fe+2 is coupled by its reoxidation to Fe+3, catalyzed by ferroxidase hephaestin that interacts with ferroportin.
The total iron content of transferrin is dynamic and undergoes changes to sustain erythropoiesis.
Senescent RBCs are cleared by reticuloendothelial macrophages, which metabolize hemoglobin and heme, and release iron into the bloodstream.
The transferrin iron pool is replenished by iron recycled from RBCs and by newly absorbed dietary iron
Macrophages export Fe+2 from their plasma membrane via ferroportin, in a process coupled by reoxidation of Fe+2 to Fe+3 by ceruloplasmin and followed by the loading of Fe+3 to transferrin.

Iron balance is mainly regulated at the point of absorption.
Hepcidin is a circulating peptide hormone secreted by the liver that plays a central role in the regulation of iron homeostasis.
This hormone is produced by hepatocytes and is a negative regulator of iron entry into plasma.
Hepcidin acts by binding to ferroportin.
Binding of hepcidin induces ferroportin degradation.
The loss of ferroportin from the cell surface prevents iron entry into plasma and decreased iron levels in the body.
Decreased expression of hepcidin leads to increased cell surface ferroportin and increased iron absorption.
Plasma hepcidin levels are regulated by cytokines, plasma iron, anemia, and hypoxia.
Overexpression of hepcidin leads to the anemia of chronic disease, while low hepcidin production results in hereditary hemochromatosis (HFE)
with consequent iron accumulation in vital organs [Figure 2]. Most hereditary iron disorders result from inadequate hepcidin production relative to the degree of tissue iron accumulation. Impaired hepcidin expression has been shown to result from mutations in any of 4 different genes: TfR2, HFE, hemochromatosis type 2 (HFE2), and hepcidin antimicrobial peptide (HAMP). Mutations in HAMP, the gene that encodes hepcidin, result in iron overload disease, as the absence of hepcidin permits constitutively high iron absorption. The role for other genes (TFR2, HFE, and HFE2) in the regulation of hepcidin production has been unclear.[27]

Ferritin concentration together with that of hemosiderin reflects the body iron stores.
They store iron in an insoluble form and are present primarily in the liver, spleen, and bone marrow.
Serum ferritin is the most convenient laboratory test to estimate iron stores.

Factors that enhance iron uptake are:
- Ascorbate and citrate increase iron uptake by acting as weak chelators.
- Iron is readily transferred from these compounds into the mucosal lining cells.

Navigation menu