Absorption Excretion Transport and Storage

Absorption Both heme and non-heme (inorganic) iron are absorbed in an inverse proportion to body iron stores (indicated by serum ferritin; Figure 2). Heme iron is absorbed more efficiently than the non-heme form. Non-heme iron absorption can vary from 0.1 to >35% and that of heme iron from 20 to 50%, depending on body iron status (stores, erythropoiesis, and hypoxia) and dietary bioavailability. These ranges indicate greater control of non-heme compared to heme iron absorption. When iron stores are high, absorption of non-heme iron can be minimized more completely, and when iron stores are low, non-heme iron is absorbed nearly as efficiently as heme iron. Because there is considerably more non-heme iron in the diet (~85-100%), this form accounts for most of the physiological control of iron absorption in relation to iron needs.

The upper portion of the duodenum, with its low pH luminal conditions, is the primary site for both heme and non-heme iron absorption (Figure 3). Non-heme iron absorption is better understood

Serum Ferritin, ug/L

Figure 2 Heme and non-heme iron absorption as influenced by body iron stores and dietary bioavailability. HBV and LBV indicate high and low dietary bioavailability, respectively.

Serum Ferritin, ug/L

Figure 2 Heme and non-heme iron absorption as influenced by body iron stores and dietary bioavailability. HBV and LBV indicate high and low dietary bioavailability, respectively.

than heme iron absorption, and only receptors for mucosal uptake of non-heme iron have been identified. The globin proteins of hemoglobin are proteolytically digested in the intestinal lumen, producing peptide remnants that may enhance the absorption of the heme molecule by preventing heme polymerization. The heme molecule is absorbed as an intact porphyrin structure, possibly involving endocytosis. In the mucosal cell, heme iron is split into ferrous iron and bilirubin by heme oxygenase, adding to a common pool of cellular iron for transport into plasma or intracellular storage and exfoliation.

Non-heme iron is best absorbed if presented to the intestinal villi as soluble ions (preferably reduced, ferrous ions) or as low-affinity, low-molecular-weight iron ligands. Stomach acid facilitates these conditions. Ascorbic acid concurrently ingested with iron helps to maintain the iron in a soluble, reduced, low-molecular ligand form in the intestinal lumen. Mucin, an intraluminal protein, has been proposed to bind iron and facilitate duodenal uptake.

Proteins involved in mucosal uptake and transfer of non-heme iron as well as possible regulatory molecules have been identified (Figures 3 and 4). These include duodenyl cytochrome b (Dcytb), which converts ferric to ferrous iron at the apical mucosal surface. A divalent metal transporter (DMT-1) transfers ferrous iron into the mucosal cell. Mutations in DMT-1 impair iron absorption and produce microcytic anemia in rodents. Ferrous iron has the highest affinity for DMT-1, but it will also transport other divalent ions, such as manganese, lead, cadmium, zinc, and copper. This may contribute to competitive inhibition observed in the absorption of these metals. Ferric iron is transported into the mucosal cell by mobilferrin, followed by ferroreduction with the protein paraferritin. Iron transported into the enterocyte may be further transported to the body at the basolateral membrane, completing absorption, or may be held and returned to the intestinal lumen with cellular desquamation. Ireg-1, or ferroportin, is involved in efflux of iron from the mucosal cell at the basolateral membrane. A mutation in Ireg-1 results in an uncommon form of hemochromatosis, an iron storage disorder. The mRNA for both DMT-1 and Ireg-1 contain an IRE, enabling regulation of mRNA translation by intra-cellular iron concentrations. Dcytb, DMT-1, and Ireg-1 are all upregulated in iron deficiency. Intestinal transfer of iron to the circulation also involves hephaestin, an intestinal ferroxidase with a protein sequence similar to that of ceruloplasmin (a copper-containing ferroxidase in serum). A defective hephaestin gene in mice results in anemia and

Duodenal lumen

Hemoglobin & Myoglobin

Globins + Heme

Hemoglobin & Myoglobin

Globins + Heme

Iron Absorption

Mucosal villi cells

Plasma

Vesicular? dMT1?

Heme Heme Heme oxygenase

Fe3+ Fe

Mucin

Paraferritin Fe2+ 3+.

Vit C

Mobilferrin

Fe3+ Fe

Mobilferrin

DMT1

Hephestin \

Hephestin \

DMT1

Ireg1

Figure 3 Absorption of iron in the intestinal mucosa.

Duodenal lumen

Regulation of Iron Absorption

Differentiating mucosal crypt cells

Plasma

Cellular Fe status influences IRP-IRE system, regulating DNA expression of DMT-1, ferritin, Tfr1 Dcytb(?) IREG(?)

Plasma

Cellular Fe status influences IRP-IRE system, regulating DNA expression of DMT-1, ferritin, Tfr1 Dcytb(?) IREG(?)

Fe C

^ Hepcidin?

Fe C

^ Hepcidin?

Figure 4 Regulation of iron absorption in the mucosal crypt cells before differentiation and development into actively absorbing intestinal villi cells.

accumulation of iron in intestinal cells. However, unlike Dcytb, DMT-1, or Ireg-1, hephaestin is not preferentially expressed in the duodenum, the main site of iron absorption.

Iron absorption is responsive to recent iron intake, iron stores, erythropoiesis, hypoxia, pregnancy, and inflammation. A newly identified peptide, hepcidin, may be related to several of these stimuli of regulatory control. Hepcidin is an antimicrobial peptide found in human blood and urine that apparently serves as a signal for limiting iron absorption. Control of absorption also likely involves the HFE protein located in the basolateral membrane of intestinal crypt cells. A specific point mutation in the HFE gene is associated with the most common form of hemochromatosis, a disorder involving excessive iron absorption and accumulation. The HFE protein interacts with ,32-microglobin and transferrin receptor, apparently influencing iron uptake from serum transferrin, the primary protein involved in serum iron transport (Figure 4). Knowledge of the control of iron absorption is growing rapidly.

Transport Transferrin transports essentially all of the 3 or 4mg of iron in blood serum, including dietary iron absorbed from the duodenum as well as iron from macrophages after the degradation of hemoglobin. Each transferrin molecule binds two iron atoms; the transferrin in serum is normally approximately one-third saturated with iron. The amount of iron that can be bound by transferrin is measured as the total iron binding capacity (TIBC). In iron deficiency, serum iron is reduced, and TIBC is elevated; expressing serum iron as a fraction of the TIBC defines the transferrin saturation, which is reduced in iron deficiency. As iron deficiency develops, these measures of iron transport signal iron deficiency before the functional pool of circulating hemoglobin is reduced (Figure 5).

Membrane transferrin receptors enable the cellular uptake of iron. Transferrin receptors complex with transferrin, the complex is internalized by endocytosis, and the iron is released to the cell from transferrin upon vesicular acidification (Figure 4). Transferrin receptors are abundant in erythrocyte precursors, placenta, and liver, and the number of receptors changes inversely with cellular iron status. Serum transferrin receptors are a soluble, truncated form of the cellular receptors, present in proportion to the cellular receptors, which serve as a clinical indicator of cellular iron status that is useful in distinguishing between iron deficiency and other causes of anemia.

Other proteins involved in iron transport include lactoferrin, which is structurally similar to transfer-rin and occurs in body fluids such as milk and semen. Haptoglobin and hemopexin proteins clear hemoglobin and heme, respectively, from circulation as they are released from senescent red blood cells.

Storage Iron is primarily stored in liver, spleen, and bone marrow in the form of ferritin or hemo-siderin. Ferritin is a water-soluble protein complex of 24 polypeptide subunits in a spherical cluster with a hollow center that contains up to 25% iron by weight, or 4000 atoms of iron per molecule.

I Iron Excess Iron Depletion

I Iron Excess Iron Depletion

Excessive Body Iron

Adequate Iron

Low Iron Stores

Iron Deficiency

Iron Deficiency Anemia

Serum Ferritin

T

---

i

ii

ii

Transferrin Receptor (sTfR)

-

---

---

T

TT

Index: Log (sTfR/ferritin)

T

---

i

ii

iii

Transferrin Saturation

TT

---

---

i

i

Serum Iron

TT

---

---

i

i

Total Iron Binding Capacity

---

---

---

T

T

Erythrocyte Protoporphyrin

---

---

---

T

TT

Hemoglobin, Hematocrit

---

---

---

---

i

Figure 5 Clinical indicators of body iron status.

Figure 5 Clinical indicators of body iron status.

Hemosiderin is a water-insoluble complex, immuno-logically similar to ferritin, containing up to 35% iron. Ferritin and hemosiderin each account for approximately half of the storage iron in liver.

Excretion The approximately 1 mg of iron lost daily by men and postmenopausal women represents mainly obligatory fecal losses from exfoliated muco-sal cells, bile, and extravasated red cells, with minor additional amounts in desquamated skin cells and sweat. Urine contains minimal amounts of iron.

Adolescent girls and premenopausal women excrete considerable amounts of iron through menstruation. The menstrual losses of individual women vary considerably; half of women lose less than 14 mg of iron per menstrual period, but the distribution is highly skewed, and 5% lose 50 mg or more. Iron deficiencies among women in prosperous countries are commonly attributable to these high iron excretion rates rather that to differences in dietary intakes.

Body iron balance The body contains 2-4 g of total iron, or approximately 50 mg/kg in men and 40 mg/kg in women. Red blood cells contain approximately two-thirds of body iron and have an average life span of 120 days; consequently, approximately 20 mg of iron daily is efficiently recycled from senescent to newly formed erythrocytes through the reticulo-endothelial system.

In contrast to other nutrients, controlled through both absorption and excretion, body iron balance is controlled almost exclusively by absorption. Approximately 10-20 mg iron is consumed daily from food. Average absorption and excretion of iron for adult men or postmenopausal women is approximately 1 mg daily. Menstruation can more than double iron losses in women of child-bearing age, increasing their requirement for absorbed iron. Iron balance is also challenged by the growth demands of pregnancy and early childhood.

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