Iron absorption

Iron Absorption 7/27/08 1:23 PM


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
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

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.

Table 1. Factors That Influence Iron Absorption
Physical State (bioavailability) heme > Fe2+ > Fe3+
Inhibitors phytates, tannins, soil clay, laundry starch, iron overload, antacids
Competitors lead, cobalt, strontium, manganese, zinc
Facilitators ascorbate, citrate, amino acids, iron deficiency
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.

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).


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).

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
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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 (Andrews, 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.

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