iron absorbtion

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revised January 11, 2001

Iron Absorption

Overview

Despite the fact that iron is the second most abundant metal in the earth's

crust, iron deficiency is the world's most common cause of anemia. When it comes

to life, iron is more precious than gold. The body hoards the element so

effectively that over millions of years of evolution, humans have developed no

physiological means of iron excretion. Iron absorption is the sole mechanism by

which iron stores are physiologically manipulated.

The average adult stores about 1 to 3 grams of iron in his or her body. An

exquisite balance between dietary uptake and loss maintains this balance. About

1 mg of iron is lost each day through sloughing of cells from skin and mucosal

surfaces, including the lining of the gastrointestinal tract (Cook et al.,

1986). Menstration increases the average daily iron loss to about 2 mg per day

in premenopausal female adults (Bothwell and Charlton, 1982). No physiologic

mechanism of iron excretion exists. Consequently, absorption alone regulates

body iron stores (McCance and Widdowson, 1938). The augmentation of body mass

during neonatal and childhood growth spurts transiently boosts iron requirements

(Gibson et al., 1988).

Iron Absorption

Figure 1. Iron absorption. Iron enters the stomach from the esophagus. Iron is

oxidized to the Fe3+ state no matter its original form when taken in orally.

Gastric acidity as well as solubilizing agents such as ascorbate prevent

precipitation of the normally insoluble Fe3+ . Intestinal mucosal cells in the

duodenum and upper jejunum absorb the iron. The iron is coupled to transferrin

(Tf) in the circulation which delivers it to the cells of the body. Phytates,

tannins and antacids block iron absorption.

Iron absorption occurs predominantly in the duodenum and upper jejunum ( Muir

and Hopfer, 1985) (Figure 1). The mechanism of iron transport from the gut into

the blood stream remains a mystery despite intensive investigation and a few

tantalizing hits (see below). A feedback mechanism exists that enhances iron

absorption in people who are iron deficient. In contrast, people with iron

overload dampen iron absorption.

The physical state of iron entering the duodenum greatly influences its

absorption however. At physiological pH, ferrous iron (Fe2+) is rapidly oxidized

to the insoluble ferric (Fe3+) form. Gastric acid lowers the pH in the proximal

duodenum, enhancing the solubility and uptake of ferric iron (Table 1). When

gastric acid production is impaired (for instance by acid pump inhibitors such

as the drug, prilosec), iron absorption is reduced substantially.

Heme is absorbed by machinery completely different to that of inorganic iron.

The process is more efficient and is independent of duodenal pH . Consequently

meats are excellent nutrient sources of iron. In fact, blockade of heme

catabolism in the intestine by a heme oxygenase inhibitor can produce iron

deficiency (Kappas et al., 1993). The paucity of meats in the diets of many of

the people in the world adds to the burden of iron deficiency.

A number of dietary factors influence iron absorption. Ascorbate and citrate

increase iron uptake in part by acting as weak chelators to help to solubilize

the metal in the duodenum (Table 1) (Conrad and Umbreit, 1993). Iron is readily

transferred from these compounds into the mucosal lining cells. Conversely, iron

absorption is inhibited by plant phytates and tannins. These compounds also

chelate iron, but prevent its uptake by the absorption machinery (see below).

Phytates are prominent in wheat and some other cereals, while tannins are

prevalent in (non-herbal) teas.

Lead is a particularly pernicious element to iron metabolism (Goya, 1993). Lead

is taken up by the iron absorption machinery, and secondarily blocks iron

through competitive inhibition. Further, lead interferes with a number of

important iron-dependent metabolic steps such as heme biosynthesis. This

multifacted attack has particularly dire consequences in children, were lead not

only produces anemia, but can impair cognitive development. Lead exists

naturally at high levels in ground water and soil in some regions, and can

clandestinely attack children's health. For this reason, most pediatricians in

the U.S. routinely test for lead at an early age through a simple blood test.

Immaturity of the gastrointestinal tract can exacerbate iron deficiency in

newborns. The gastrointestinal tract does not achieve competency for iron

absorption for several weeks after birth. The problem is even more severe for

premature infants, who tend to be anemic for a variety of reasons. A substantial

portion of iron stores in newborns are transferred from the mother late in

pregnancy. Prematurity shortcircuits this process. Parenteral iron replacement

is possible, but not often used because of the often delicate health of

premature infants. Transfusion becomes the default option in this circumstance.

Table 1. Factors That Influence Iron AbsorptionPhysical State

(bioavailability)heme > Fe2+ > Fe3+

Inhibitorsphytates, tannins, soil clay, laundry starch, iron overload, antacids

Competitorslead, cobalt, strontium, manganese, zinc

Facilitatorsascorbate, citrate, amino acids, iron deficiency

Ý

The mechanism by which iron enters the mucosal cells lining the upper

gastrointestinal tract is unknown. Most cells in the rest of the body are

believed to acquire iron from plasma transferrin (an iron-protein chelate), via

specific transferrin receptors and receptor-mediated endocytosis (Klausner, et

al, 1983). The hypothesis that apotransferrin (or an equivalent molecule)

secreted by intestinal cells or present in bile chelates intestinal iron and

facilitates its absorption(Huebers et al., 1983) is unsubstantiated. The

transferrin gene is not expressed in intestinal cells. Later work indicated that

transferrin found in the intestinal lumen is derived from plasma (Idzerda et

al., 1986). Plasma transferrin entering bile is fully saturated with iron,

obviating any intraluminal chelating function (Schumann et al., 1986).

Furthermore, hypoxia, which greatly increases iron absorption, has no effect on

intestinal transferrin levels (Simpson et al., 1986).

Exogenous transferrin cannot donate iron to intestinal mucosal cells (Bezwoda

et al., 1986), and the brush boarder membrance lacks transferrin receptors

(Parmley et al., 1985) (although they are present on the basolateral surface of

intestinal epithelial cells (Levin et al., 1984); (Banerjee et al., 1986).

Lastly and perhaps most compellingly, humans and mice with hypotransferrinemia

paradoxically absorb more dietary iron than normal. Although the erythron is

iron deficient, these individuals develop hepatic iron overload (Heilmeyer et

al., 1961); (Craven et al., 1987).

Ý

Mechanism of Iron Absorption

In searching for molecules involved in intestinal iron transport, Conrad and

co-workers took the approach of characterizing proteins that bind iron

[summarized in (Conrad and Umbreit, 1993)]. Their hypothesis of iron transport

is based on identification of iron binding proteins at several key sites. They

propose that mucins bind iron in the acid environment of the stomach, thereby

maintaining it in solution for later uptake in the alkaline duodenum. According

to their model, mucin-bound iron subsequently crosses the mucosal cell membrane

in association with integrins. Once inside the cell, a cytoplasmic iron-binding

protein, dubbed " mobilferrin " , accepts the element, and shuttles it to the

basolateral surface of the cell, where it is delivered to plasma. In this model

mobilferrin could serve as a rheostat sensitive to plasma iron concentrations.

Fully occupied mobilferrin would dampen mucosal iron uptake, and while the

process would be enhanced by

unsaturated mobilferrin (Conrad and Umbreit, 1993). This model has not gained

universal acceptance however.

A very different scheme of iron uptake has been proposed by investigators

studying iron transport in yeast. Yeast face the problem of taking in iron from

the environment, a process similar to that of intestinal mucosal cells. Dancis

et al. used genetic selection to isolate Sacchromyces cerevisiae mutants with

defective iron transport (Dancis et al., 1994); (Stearman et al., 1996). They

constructed an expression plasmid in which an enzyme necessary for histidine

biosynthesis was under the control of an iron-repressible promoter. The plasmid

was introduced into a yeast histidine auxotroph (i.e. a strain of yeast that

requires histidine to survive). Mutants were selected in the absence of

histidine, in the presence of high levels of iron. Among the mutats they

isolated, were cells with defective iron uptake. They discovered that membrane

iron transport depends absolutely upon copper transport. In this model, ferric

iron in yeast culture medium is reduced to

its ferrous form by an externally oriented reductase (FRE1). The element is

shuttled rapidly into the cell by a ferrous transporter, which appears to be

coupled to an externally oriented copper-dependent oxidase (FET3) embedded in

the cell membrane (De Silva et al., 1995); (Stearman et al., 1996). FET3 is

strikingly homologous to the mammalian copper oxidase ceruloplasmin. The

re-oxidation of ferrous to ferric iron is apparently an obligatory step in the

transport mechanism, although the coupling mechanism of oxidation and membrane

transport is unclear. (De Silva et al., 1995); (Stearman et al., 1996); (Yuan et

al., 1995). Although the genetic evidence for this scheme is compelling, the

central component, the ferrous transporter itself, remains elusive. These

investigators speculate that mammalian intestinal iron transport is analogous to

the yeast iron uptake process (Harford et al., 1994). This assertion is

supported by studies of copper-deficient

swine, which show co-existing iron deficiency unresponsive to iron therapy

(Lahey et al., 1952); (Gubler et al., 1952); (Cartwright et al., 1956).

Ý

Genetic Insights into Mammalian Iron Absorption

Mouse genetics provides a different perspective on mammalian intestinal iron

transport. Mouse breeders readily recognize pale animals, and have developed

anemic stocks with various mutations. Intestinal mucosal iron transport is

defective in two mutant strains. Microcytic (mk) mice and sex-linked anemia

(sla) mice have severe iron deficiency due apparently to defects in iron uptake

and release, respectively, from the intestinal cell (reviewed in [bannerman,

1976].) Mice with the homozygous autosomal recessive mk mutation absorb iron

poorly, have low serum iron levels, and lack stainable iron in intestinal

mucosal cells. These findings are consistent with a defect in an apical iron

transport molecule. Intriguingly, mk/mk mice are not rescued by parenteral iron

replacement. Anemia develops in normal mice tranplanted with mk bone marrow,

indicating that mk erythroid precursor cells also have a defect in red cell iron

uptake. A common component to iron

transport may therefore exist in intestinal cells and red cell precursors

(s, et al, 2000).

ÝMice that are homozygous or heterozygous for the sla mutation (sla/sla or

sla/y) also have low serum iron levels. In contrast to mk mice, they have

abnormal iron deposits within intestinal mucosal cells, suggesting that this

X-linked defect impairs intracellular iron trafficking or basolateral export of

iron to the plasma. The sla animals differ further from the mk mice by

correction of anemia by parenteral iron. Based on studies of these mutants,

distinct apical and basolateral iron transport systems possibly exist that

function coordinately to transfer iron from intestinal lumen to plasma.

ÝWhatever the mechanism of iron uptake, normally only about 10% of the elemental

iron entering the duodenum is absorbed. However, this value increases markedly

with iron deficiency (Finch, 1994). In contrast, iron overload reduces but does

not eliminate absorption, reaffirming the fact that absorption is regulated by

body iron stores. In addition, both anemia and hypoxia boost iron absorption. A

portion of the iron that enters the mucosal cells is retained sequestered within

ferritin. Intracellular intestinal iron is lost when epithelial cells are

sloughed from the lining of the gastrointestinal tract. The remaining iron

traverses the mucosal cells, to be coupled to transferrin for transport through

the circulation.

Erythropoiesis and Iron Absorption

ÝApproximately 80% of total body iron is ultimately incorporated into red cell

hemoglobin. An average adult produces 2 x 1011 red cells daily, for a red cell

renewal rate of 0.8 percent per day. Each red cell contains more than a billion

atoms of iron, and each ml of red cells contains 1 mg of iron. To meet this

daily need for 2 x 1020 atoms (or 20 mg) of elemental iron, the body has

developed regulatory mechanisms whereby erythropoiesis profoundly influences

iron absorption. Plasma iron turnover (PIT) represents the mass turnover of

transferrin-bound iron in the circulation, expressed as mg/kg/day (Huff et al.,

1950). Accelerated erythropoiesis increases plasma iron turnover, which is

associated with enhanced iron uptake from the gastrointestinal tract (Weintraub

et al., 1965). The mechanism by which PIT alters iron absorption is unknown.

ÝA circulating factor related to erythropoiesis that modulates iron absorption

has been hypothesized, but not identified (Beutler and Buttenweiser, 1960);

(Finch, 1994). Several candidate factors have been excluded, including

transferrin (Aron et al., 1985) and erythropoietin (Raja et al., 1986). Clinical

manifestations of this apparent communication between the marrow and the

intestine includes iron overload that develops in patients with severe

thalassemia in the absence of transfusion. The accelerated (but ineffective)

erythropoiesis in this condition substantially boosts iron absorption. In some

cases, the coupling of increased PIT and increased gastrointestinal iron

absorption is beneficial. In pregnancy, placental removal of iron raises the

PIT. This process enhances gastrointestinal iron absorption thereby increasing

the availability of the element to meet the needs of the growing and developing

fetus.

ÝCompetition studies suggest that several other heavy metals share the iron

intestinal absorption pathway. These include lead, manganese, cobalt and zinc

(Table 1). Enhanced iron absorption induced by iron deficiency also augments the

uptake of these elements. As iron deficiency often coexists with lead

intoxication, this interaction can produce particularly serious medical

complications in children (Piomelli et al., 1987). Interestingly, copper

absorption and metabolism appear to be handled mechanisms different to those of

iron.

ÝÝÝ