Iron metabolism in infants and children
Bo Lönnerdal and Shannon L. Kelleher
Abstract
Meeting the iron requirements of infants and children
is difficult, and supplementation or fortification of food
with iron is often recommended. Although iron supple-
mentation of infants and children with iron deficiency
and iron-deficiency anemia may be beneficial, recent
studies suggest that this may not be the case for those
with adequate iron status, and adverse effects have been
noted. The recent discoveries of proteins and peptides
regulating iron absorption have enhanced our knowledge
of iron metabolism in infants and children. Iron is taken
up in the small intestine by divalent metal transporter-1
and is either stored by ferritin inside the mucosal cell or
transported to the systemic circulation by ferroportin,
while being oxidized by hephaestin to be incorporated
into transferrin. Hepcidin, a small peptide synthesized
by the liver, can sense iron stores and regulates iron
transport by inhibition of ferroportin. However, regula-
tion of iron transporters is immature in infants, possibly
explaining the adverse effects of iron supplementation.
Interactions among iron, vitamin A, zinc, and copper
need to be considered when evaluating the effects of iron
supplementation on infants and children.
Key words: Iron absorption, iron interactions, iron
metabolism, iron requirements
Iron requirements
The healthy infant at term is born with iron stores that
in part can be mobilized and utilized for growth during
The authors are affiliated with the Department of Nutri-
tion and the Program in International Nutrition, University
of California, Davis, California, USA.
Please address queries to the corresponding author: Bo
Lönnerdal, Department of Nutrition, University of California,
1 Shields Ave., Davis, CA 95616, USA: e-mail: bllonnerdal@
ucdavis.edu.
Food and Nutrition Bulletin, vol. 28, no. 4 (supplement) © 2007, The United Nations University.
early infancy. In addition to these stores, the high levels
of hemoglobin at birth will decrease and the iron will
be recycled and also used for growth and blood-volume
expansion. It is therefore frequently assumed that term
infants need no or very little dietary iron to meet their
requirements during early life. That breastmilk con-
tains very little iron and breastfed infants rarely become
iron deficient before 6 months of life are often used as
arguments in support of this notion. However, there
have been several studies in affluent populations show-
ing that iron deficiency is common in this age group
among infants fed formula unfortified with iron, in
spite of the fact that such formula contains three to four
times as much iron as breastmilk. Thus, it is obvious
that infants do need a certain amount of bioavailable
dietary iron during this period of life.
There have been theoretical approaches to estimate
the iron requirements of infants. Total body iron varies
with birthweight and has been estimated to be approxi-
mately 268 mg for an infant with a birthweight of 3.5 kg
and approximately 183 mg for an infant with a birth-
weight of 2.5 kg [1, 2]. At 1 year of age, these values
are 377 and 362 mg, respectively, and the amount of
absorbed iron needed per day in these infants has
been calculated as 0.55 and 0.75 mg, respectively, after
taking iron losses into account [1]. Since the exclu-
sively breastfed infant ingests about 0.16 to 0.24 mg
of iron per day during the first 6 months and absorbs
approximately 0.05 to 0.07 mg, and rarely becomes
iron deficient, it is very obvious that these estimates
have a poor correlation with true needs. It should be
recognized that values for total body iron of infants
must be viewed with caution: they were often derived
from a very limited number of deceased infants quite
some time ago, analytical techniques were of limited
precision, and the cause of death was often uncertain.
Further, it has recently been shown that daily losses
(stool) have been grossly overestimated. This approach
to estimating iron requirements therefore has very
limited validity.
The adequate intake (AI) of iron for 0- to 6-month-
old infants has been estimated as 0.27 mg/day, largely
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based on the iron intake of exclusively breastfed infants.
It should be noted, though, that iron in breastmilk is
well absorbed and infants fed formula absorb consider-
ably less iron [3]. We have used another approach and
“titrated” the iron requirement of formula-fed infants
by feeding cow’s milk formulas with different levels
of iron exclusively from 4 to 6 weeks to 6 months of
age [4, 5]. From these studies it was evident that feed-
ing infant formula with an iron content of 1.6 mg/L
resulted in similar iron status as feeding formulas with
2, 4, 7, or 12 mg/L. Thus, an iron intake of 1.3 to 1.6
mg/day appears to meet the iron requirement of 0- to
6-month-old, term, healthy, formula-fed infants. Ear-
lier studies on infants fed unfortified formula, which
at that time contained 0.8 to 1.0 mg of iron/L, showed
iron deficiency, suggesting that iron intakes of 0.8 to 1.0
mg/day are inadequate for infants not being breastfed.
It is obvious that low-birthweight infants, infants with
frequent infections, and infants fed solid foods at a very
young age would have a substantially higher daily need
for iron, but their requirements are difficult to assess.
Such infants, though, frequently become iron deficient
and anemic by 6 months of age.
The recommended daily allowance (RDA) for infants
7 to 12 months of age is set at 11 mg/day. This is sub-
stantially higher than the estimates for younger infants
and is based on the facts that iron stores are depleted
by this age, growth is rapid, and the bioavailability of
iron from most foods consumed at this age is low. The
precise requirements for absorbed iron are difficult to
estimate, but it is obvious that infants in this age group
frequently become iron deficient and anemic [6]. Thus,
there is a need for improved complementary foods, in
most cases including iron fortification, and iron sup-
plementation is often advocated (see below).
Absorption of iron
Iron homeostasis is primarily controlled through
tightly regulated changes in iron absorption in adults.
Three “regulators” of iron homeostasis mechanisms
have been identified that are referred to as the “erythro-
poietic regulator,” the “stores regulator,” and the “dietary
regulator” [7]. Regulation of these compartments
is integrated to control iron absorption, protecting
against both iron deficiency and overload, and may
reflect a hierarchical response in the maintenance of
iron homeostasis such that the erythropoietic regula-
tor may be of primary importance only in response
to chronic iron-deficiency anemia, while the stores
regulator may play the predominant role in maintain-
ing iron homeostasis in response to endogenous iron
stores, and the dietary regulator may functionally
respond to acute changes in iron intake, primarily to
prevent iron overload. Although there is a large body
of evidence concerning the integration of these three
B. Lönnerdal and S. L. Kelleher
regulators in adults, we are just beginning to under-
stand the integration of these mechanisms during
infancy and childhood.
As mentioned previously, hemoglobin levels at birth
are normally quite high and primarily consist of fetal
hemoglobin (hemoglobin F or α2γ2), which comprises
80% to 90% of the total hemoglobin synthesized,
gradually decreasing to < 1% by 10 months of age in
normal infants [8]. The switch from hemoglobin F
to adult hemoglobin (hemoglobin A or α2β2) begins
around 12 weeks of gestation, although production
of hemoglobin A occurs in the bone marrow where
it remains throughout life [9]. Erythropoiesis almost
ceases shortly after birth, resulting in a progressive fall
in hemoglobin level that continues during the first 1 to
2 months of life [10] and providing an endogenous iron
source for the growing neonate, during which time iron
absorption is relatively low [11]. As the main compo-
nent of the “erythropoietic regulator,” erythropoietin
secretion from the kidney increases the erythropoietic
drive [12] and results in increased iron absorption,
facilitating the transition from “physiological anemia”
toward considerable expansion of hemoglobin mass
to meet the demands for rapid infant growth. During
this transition, which occurs during mid-infancy, iron
absorption increases from approximately 21% at 1 to 3
months to approximately 37% at 4 to 6 months [11, 13]
as iron stores become depleted.
Although it would be expected that iron absorption
is primarily regulated by and inversely related to iron
stores, as it is in adults, many studies have shown that
this may not be the case during infancy. For example,
premature infants are born with lower endogenous
iron stores in the liver and in hemoglobin than term
infants [14]; however, mean iron retention is similar
(approximately 30%) [11, 13], illustrating the inability
of infants to appropriately compensate for low iron
stores, and perhaps being more reflective of the high
erythropoietic drive that normally occurs during
this time. Moreover, Domellöf et al. [7] conducted a
randomized, double-blind, placebo-controlled study
in healthy, term infants who were iron supplemented
(1 mg/kg/day) from 4 to 9 months of age (early initia-
tion) or from 6 to 9 months of age (late initiation) and
compared them with infants receiving placebo. At 6
months of age, iron absorption was independent of
iron intake and iron status [7], unlike observations in
adults. By 9 months of age, though, iron absorption was
correlated with recent dietary iron intake, as has been
observed in adults, which is speculated to result from
so-called mucosal block reflecting “dietary regulation”
[15]. However, iron absorption was not yet correlated
with iron status. Furthermore, in young infants (4 to
6 months), but not older infants (6 to 9 months), iron
supplementation increased hemoglobin concentration
regardless of iron status, suggesting that changes in the
normal erythropoietic drive that occur during this time
Iron metabolism in infants and children
play a major role in iron metabolism during early but
not late infancy [16]. Similarly, a study on Peruvian
infants between 6 and 9 months of age showed that
iron absorption was similar in anemic and nonanemic
infants [17]; however, in this population iron absorp-
tion was significantly inversely correlated with iron
stores (serum ferritin). Although the discrepancy
between these two studies is currently not understood,
taken together these observations suggest that unlike
in adults, iron absorption during early infancy may
be primarily regulated by developmental changes in
erythropoietic drive, secondarily by dietary intake, and
least sensitively by endogenous iron stores and suggest
that infants may develop the ability to regulate iron
absorption postnatally; however, the question remains
as to how and when this developmental switch from
endogenous iron mobilization to dietary iron absorp-
tion occurs.
Mechanisms regulating iron absorption
Iron homeostasis is regulated at the level of intesti-
nal absorption, and as more contributors to the iron
transport process are identified and characterized,
the complexity of iron homeostasis becomes increas-
ingly evident. A number of proteins must coordinate
the transfer of iron across the enterocyte and into the
systemic circulation. Dietary iron generally occurs in
the ferric (Fe+3) state and thus must be reduced to the
ferrous form (Fe+2) prior to uptake into the enterocyte,
presumably by an apical membrane-associated ferric
reductase, probably duodenal cytochrome b (Dcytb)
[18], facilitating ferrous iron uptake across the apical
membrane into the enterocyte via divalent metal
transporter-1 (DMT1) [19]. Once inside the cell, iron
may partition into specific cellular pools or may be
transported across the basolateral membrane into the
systemic circulation via ferroportin-1 (FPN1)/iron-
regulated transporter 1 (IREG1)/metal transporter
protein-1 (MTP1)/SLC40A1 [20]. Iron transfer from
the enterocyte into the systemic circulation requires
the oxidation of Fe+2 to Fe+3, which is facilitated by he-
phaestin, a copper-containing ferroxidase homologous
to ceruloplasmin that is associated with the basolateral
membrane [21], thus allowing ferric iron to be incor-
porated into apo-transferrin in the circulation. As in
most mammalian cells, transferrin receptor is localized
to the basolateral membrane of the enterocyte, and in
combination with the hemochromatosis protein (HFE)
permits the successful binding of transferrin–bound
iron and reuptake back into the intestinal cell [22].
However, the role enterocytic transferrin receptor/HFE
plays in the regulation of intestinal iron absorption is
not well understood. Recently, hepcidin, an antimicro-
bial peptide produced by the liver, has been shown to
modulate enterocyte iron transport, and it is believed
to be the communication link or “stores regulator”
S493
between endogenous liver iron stores and intestinal
iron uptake, facilitating increased iron absorption
during iron deficiency and decreased iron absorp-
tion during iron repletion [23] in adults (see below).
Hepcidin levels parallel liver iron stores in adults, and
recent evidence indicates that hepcidin binds to FPN1,
stimulates FPN1 internalization and degradation, and
thus reduces iron absorption when liver iron stores are
high [24]. However, the regulation of this process in
infants is not understood.
Ontogeny of iron transport mechanisms in the small
intestine
The maturation of iron homeostasis f rom
erythropoietic→dietary→stores regulation in infants
to stores→dietary→erythropoietic regulation in adults
suggests the existence of postnatal ontogenic changes.
Iron homeostasis is primarily regulated at the level
of intestinal absorption in adults; thus, the ontogeny
of this homeostatic system has developmental con-
sequences. Similar to observations in human infants
[11, 13], we have detected an age-related increase in
iron absorption using a suckling rat pup model (day 5,
41 ± 13%; day 10, 60 ± 8%; day 20, 79 ± 8%), which is
associated with a concurrent decline in iron retention
in the small intestine (day 5, 25 ± 7%; day 10, 19 ± 2%;
day 20, 6 ± 2%) (unpublished data). This observation
has led us to speculate that the increase in iron absorp-
tion that occurs during infancy reflects the maturation
of small intestine iron absorption mechanisms to
facilitate iron transfer into the systemic circulation.
However, the precise mechanisms that are responsible
for the postnatal ontogeny of iron absorption are not
well understood. Since mechanistic studies cannot be
conducted in human infants because of ethical con-
siderations, we have validated the use of the suckling
rat pup as a model of ontogenic changes that occur
postnatally. Observations from these studies indicate
that the postnatal increase in iron absorption results
from multifactorial regulation that includes increased
expression of DMT1, FPN1, and hephaestin and
changes in the localization of these transport proteins
within the enterocyte itself [25]. For example, during
mid-infancy, both DMT1 and FPN1 are localized
within the enterocyte, whereas during weaning, DMT1
and FPN1 are localized appropriately at the apical and
basolateral membranes, respectively. This indicates that
at least several of the main regulators of intestinal iron
absorption may not be localized appropriately until late
infancy, which would limit the ability to homeostati-
cally control iron absorption until this age.
Iron metabolism
In adults, absorbed iron is transported to the liver by
S494
transferrin, where it is taken up into hepatocytes by
transferrin receptors and stored sequestered in ferritin
until needed. During times of high iron demand, iron
is released from ferritin and mobilized into the hepatic
circulation for further distribution to the tissues. The
regulation of this process is just beginning to be elu-
cidated, and our understanding has been aided by the
identification of several genes expressed in the liver
that when mutated cause hereditary hemochromatosis,
resulting in iron overload. These genes include those
for hepcidin, HFE, transferrin receptor 2 (TfR2), and
hemojuvelin.
Hepcidin is a small peptide (25 amino acids) that was
first identified as an antimicrobial peptide in urine and
plasma [26]. It was subsequently discovered to have a
profound role in the regulation of iron metabolism,
since mice with dietary iron overload were found to
have substantially increased hepcidin mRNA expres-
sion and decreased iron absorption [23], providing
evidence that hepcidin is involved in iron homeostasis.
Hepcidin knockout mice showed a hemochromatosis-
like phenotype, further establishing hepcidin as a
negative regulator of iron absorption. Several factors
regulating iron absorption, such as iron stores, eryth-
ropoiesis, inflammation, and hypoxia, have also been
found to regulate liver expression of hepcidin. Thus,
intestinal iron absorption is inversely correlated with
hepcidin expression.
The discovery of hepcidin also provided evidence
against the hypothesis that signals from the body
to alter iron metabolism were detected by intestinal
crypt cells and programmed them to absorb more or
less iron when they matured. Recent results in animals
show that injection of hepcidin reduces serum iron
within 4 hours, demonstrating that hepcidin modu-
lates iron absorption very quickly [27]. It is evident
that liver hepcidin expression is a key regulator of iron
metabolism. The most common form of hereditary
hemochromatosis involves mutations in HFE, a protein
highly expressed in liver, which leads to inappropriately
low levels of hepcidin [28], inappropriately high iron
absorption, and hepatic iron overload. TfR2 is also
highly expressed in liver, and mutations in this protein
cause iron loading disease with symptoms very similar
to those observed in hemochromatosis due to defec-
tive HFE [29]. Hepcidin levels are very low in these
patients, suggesting that HFE and TfR2 are part of the
same regulatory pathway. Recently, hemojuvelin, a
third member of this regulatory network, was identi-
fied [30]. This protein is expressed in hepatocytes and
is mutated in most cases of juvenile hemochromatosis.
These patients suffer from rapid iron overload, which
is much more severe than in patients with defective
HFE or TfR2, and they have undetectable levels of
hepcidin. How these three molecules sense body iron
requirements and regulate hepcidin expression is not
yet known. However, this mechanism must be able
B. Lönnerdal and S. L. Kelleher
to sense events occurring at distant sites in the body,
such as changes in iron requirements of developing
erythroid cells in the marrow. Recent studies show a
close correlation between levels of diferric transfer-
rin and liver hepcidin expression, suggesting that the
iron saturation of transferrin, which is affected by iron
needs, may be the key messenger from the tissues and
the marrow to the hepatocyte [31]. This is corroborated
by the observation that hemoglobin-deficit (hbd) mice,
which have an inherited anemia, have inordinately high
levels of hepcidin, whereas anemic control mice have
very low levels of hepcidin [32]. The hbd mice have
very high levels of diferric transferrin (because their
hemoglobin production is defective), which would
up-regulate hepcidin expression. Further studies on
the role of transferrin saturation in the regulation of
iron metabolism are now needed.
The anemia of chronic disease is commonly associ-
ated with infections and inflammatory conditions. In
this anemia, macrophages retain iron, and iron absorp-
tion is decreased, resulting in hypoferremia. It has
recently been shown that interleukin-6 and lipopoly-
saccharide increase hepcidin expression [29], providing
a mechanistic explanation for these observations.
Iron supplementation
Iron supplementation has been shown to be effective
in treating and preventing iron deficiency. The iron is
provided in ferrous form with ascorbic acid, usually
at a dose of 1 mg/kg/day. The current recommenda-
tion is to start the supplements after 6 months of age,
on the assumption that the iron endowment at birth,
combined with iron from breastmilk or alternative
food sources, will be sufficient to meet iron require-
ments up to this age. It is apparent, however, that
many infants in less-developed countries become iron
deficient before 6 months of age. This could be due to
lower than normal iron stores at birth, which may be
caused by maternal iron deficiency during pregnancy,
low birthweight or prematurity, frequent infections, or
early introduction of solid foods with low iron content
and/or low iron bioavailability. Introduction of iron at
an earlier age than 6 months might therefore be con-
sidered. As mentioned previously, this hypothesis was
tested in a double-blind, randomized, controlled trial
performed at two study sites (Sweden and Honduras)
representing infants with very varying iron status at
the start of the study [16]. Breastfed infants were given
either iron supplements (1 mg/kg/day) or placebo
from 4 or 6 months until 9 months of age. The infants
were exclusively breastfed until 6 months of age and
predominantly breastfed until 9 months of age. Iron
intake from complementary foods was assessed by
dietary records and food-composition tables. Iron sup-
plementation between 4 and 6 months of age increased
Iron metabolism in infants and children
hemoglobin and serum ferritin to a similar extent in
both Honduran and Swedish infants, regardless of the
fact that the Swedish infants had adequate iron status at
4 months of age. Between 6 and 9 months, the effect of
iron supplementation was similar in both populations,
except for hemoglobin, which increased only in the
Honduran infants, and reduced anemia from 29% to
9%. There were no significant differences in iron status
indicators between groups that received iron from 4 or
6 months of age. The unexpected increase in hemo-
globin between 4 and 6 months of age in an iron-replete
population suggested that homeostatic regulation of
iron metabolism is immature at this age.
Iron absorption studies at 6 and 9 months of age
using stable isotopes showed that there was no signifi-
cant difference in iron absorption at 6 months between
Swedish infants who had received iron supplements
and those given placebo [7]. At 9 months, however,
infants who had been supplemented with iron absorbed
17% of iron from breastmilk, whereas unsupplemented
infants absorbed 37% of the dose. Thus, homeostatic
regulation of iron absorption occurred at 9 months,
but not at 6 months of age, suggesting that regulatory
mechanisms are immature at a young age. Studies in
rat pups support these observations and provide a
potential mechanistic explanation. Nursing rat pups
were supplemented daily with iron (at a dose propor-
tional to that given to human infants) or placebo from
birth to weaning. At day 10 (“young infants”) and day
20 (“older infants”), iron absorption was assessed with
the use of radioisotopes [33]. The animals were killed
at day 10 or 20, and tissue levels of iron and the expres-
sion of iron transporters were assessed. In a parallel
study, dams were fed an iron-deficient diet during
pregnancy and the iron-deficient rat pups were sup-
plemented with iron or placebo from birth to weaning
[34]. At day 10, there was no difference between the
groups in iron absorption, whereas at day 20, iron-
deficient pups absorbed more iron than those fed
placebo, and those supplemented with iron absorbed
less iron. Thus, these findings are in agreement with
the observations in human infants at 6 and 9 months.
At day 10, there was no effect of iron status on the iron
transporters DMT1 and FPN1. At day 20, however,
iron-supplemented pups had significantly lower levels
and iron-deficient pups had significantly higher levels
of the iron transporters than pups given placebo. Thus,
it appears that homeostatic up- and down-regulation of
the intestinal iron transporters is immature at a young
age. Hepcidin expression responded to body iron stores
even during early infancy, when DMT1 and FPN1 were
unresponsive, suggesting that it is not the signal from
iron stores (“stores regulator”) that is immature [35]. At
birth, hepcidin expression was exceptionally high and
then declined to very low levels by day 10, which may
explain the low iron absorption of young infants.
Although iron supplements had beneficial effects, in
S495
that they were shown to reduce anemia in Honduran
infants between 6 and 9 months of age, some adverse
effects were also noted in this study [36]. Among Swed-
ish infants, gains in length and head circumference
were significantly lower in those who received iron than
in those given placebo from 4 to 9 months. The same
effect on length was observed in Honduras, but only
between 4 and 6 months among those with hemoglobin
≥ 110 g/L. Among infants with hemoglobin < 110 g/L
at 4 months, diarrhea was less common in those given
iron than in those given placebo from 4 to 9 months,
whereas the opposite was true among those with
hemoglobin ≥ 110 g/L. Further, we found that infants
supplemented with iron had significantly lower copper
status (assessed by erythrocyte copper/zinc-superoxide
dismutase [CuZn-SOD] activity) at 9 months of age
than those receiving placebo [37]. Thus, routine iron
supplementation of infants may benefit those with
low hemoglobin but may present risks for those with
normal hemoglobin. These findings are consistent with
those of a study by Idjradinata et al. [38], who found
that weight gain in iron-replete Indonesian children (12
to 18 months old) was significantly lower in those given
iron (3 mg/kg/day) for 4 months than in those given
placebo. The growth of iron-deficient, anemic children
was improved by iron supplementation, whereas iron-
deficient, nonanemic children were unaffected. To date,
few studies have reported such adverse effects, but it
should be noted that very few studies on infants and
children have separated their populations into initially
iron-deficient and iron-replete subjects.
It is not yet known why these adverse effects were
observed in iron-replete infants and children. It is pos-
sible that iron itself causes toxic effects when absorbed
in excess, possibly through free radical–mediated
reactions. It is also possible that iron interferes with
zinc metabolism and that the adverse effects are due to
local or systemic suboptimal zinc status, which in turn
can affect growth via the insulin-like growth factor-1/
growth hormone (IGF-1/GH) axis and morbidity via
impaired immune function. Further studies are needed
to resolve this question.
Iron fortification of foods for infants and children has
not been found to have any adverse effects on growth
or morbidity. It is possible that the lower amount of
iron absorbed from each fortified meal is less likely
to cause such effects than the larger amount absorbed
from an iron supplement that is usually given to infants
and children in a “semifasting” state. It is also possible
that iron introduced in “free form” (as a supplement)
affects iron metabolism in a different manner than
iron given as a fortificant. A recent study on Swedish
infants between 6 and 9 months of age showed that
iron given as drops resulted in a significant increase in
iron stores (measured by serum ferritin), whereas the
same amount of iron given in fortified cereal had no
effect [39]. In contrast, iron fortification resulted in a
S496
significant increase in infant hemoglobin at 9 months,
whereas iron supplements did not. Thus, different
forms of iron appear to be metabolized differently, pos-
sibly mediated via hepcidin affecting iron transporters
in the intestine and the reticuloendothelial system.
Interactions between other micronutrients
and iron metabolism
Many iron-supplementation programs targeted at
infants have been implemented throughout the world,
including in developed countries, and it is common
pediatric practice in the United States to prescribe fer-
rous sulfate drops to all infants through the first year
of life. The failure of iron supplementation to cure
anemia, which is commonly observed, is often ascribed
to poor compliance or an inadequate duration of sup-
plementation. However, quite often multiple micro-
nutrient deficiencies coexist [40], and interactions
between iron metabolism and other micronutrients
have been detected, all of which may play a role in
these observations.
Vitamin A
Vitamin A deficiency is associated with secondary
iron-deficiency anemia, and many studies have shown
a positive effect of vitamin A supplementation on iron
status in humans and in animal models [41, 42]. Vita-
min A deficiency reduces the incorporation of iron
into erythrocytes [43], alters red blood cell morphology
[44], produces mild anemia [45], lowers plasma total
iron-binding capacity, increases iron absorption, and
causes accumulation of iron in the spleen and bone
[46]. The relatively high prevalence of marginal vitamin
A status among pregnant and lactating women has
raised concern about its contribution to morbidity and
mortality and its contribution to the etiology of anemia
among women and their infants [41]. Interestingly,
Schmidt et al. observed a positive effect of improved
vitamin A status during pregnancy on maternal and
infant iron status [47] and a trend toward increased
milk iron concentration, which was lower in women
supplemented with iron alone than in women supple-
mented with iron and vitamin A, suggesting a positive
effect of improved vitamin A status on mammary gland
iron metabolism. Using a lactating rat model, we have
previously determined specific effects of a marginal
vitamin A diet on iron transporters in the mammary
gland and liver and found that liver transferrin receptor
expression was higher while mammary gland transfer-
rin receptor expression was lower in rats fed a marginal
vitamin A diet, a result suggesting that vitamin A
deficiency increases iron acquisition in the liver at the
expense of the mammary gland. Furthermore, DMT1
and FPN1 protein levels in the liver and mammary
B. Lönnerdal and S. L. Kelleher
gland were lower in rats fed a marginal vitamin A diet,
indicating that there are tissue-specific responses to
vitamin A deficiency and that a diet marginal in vita-
min A results in specific effects on iron transporters.
Some of these effects may be a consequence of retinoic
acid decreasing [48] or increasing [49] transferrin
receptor levels and thus altering tissue iron acquisition.
Okano et al. [50] found that retinoic acid up-regulated
erythropoietin production threefold in HepG2 cells
and further found elevated serum erythropoietin con-
centrations in rats intragastrically injected with retinoic
acid. However, a recent study in severely anemic pre-
schoolers [51] indicated that vitamin A supplementa-
tion actually suppressed erythropoietin production but
was associated with increased iron mobilization and
erythropoiesis. Although the authors speculated that
the reduced erythropoietin levels were a consequence
of increased iron mobilization and erythropoiesis,
these results illustrate our lack of understanding of the
role vitamin A plays in regulating iron metabolism.
There is little information regarding the effects of iron
supplementation on vitamin A status; however, in a
randomized, double-blind, placebo-controlled study of
infants aged 4 months, Wieringa et al. [52] found that
iron reduced plasma and increased liver retinol con-
centrations, suggesting a redistribution of retinol from
plasma to the liver. In contrast, Jang et al. [53] showed
that iron deficiency inhibited the mobilization of reti-
nol stores in rats, which may impair the absorption
and utilization of vitamin A in rats. This interaction
warrants further investigation, as it may require cau-
tion when supplementing populations where vitamin A
deficiency and iron deficiency are both common.
Zinc
Although zinc deficiency is estimated to affect approxi-
mately 20% of the world’s population [54], there is little
evidence to suggest that zinc deficiency affects iron
metabolism. In contrast, adverse effects of zinc sup-
plementation on iron metabolism have been demon-
strated, such as decreased iron absorption, hemoglobin,
and serum ferritin levels in adults [55–58]. Although
no direct effect of zinc supplementation on iron status
in infants older than 6 months in developing countries
has been observed [59], we previously determined that
young infant rhesus monkeys supplemented with zinc
(approximately 7.5 mg/day) from birth to 4 months
had reduced iron absorption and impaired iron status
[60]. With that said, several studies have observed a
negative effect of zinc on recovery from anemia [61],
hemoglobin repletion [62], and ferritin concentration
[55]. Using our suckling rat model, we determined that
zinc supplementation negatively affects iron absorption
in an age-dependent manner in such a way that during
early infancy zinc supplementation was associated with
increased small intestine iron retention, decreased
Iron metabolism in infants and children
hephaestin, and increased FPN1 expression in the
small intestine [25]. In contrast, during late infancy,
when DMT1 and FPN1 are appropriately localized
to the apical and basolateral membranes, respec-
tively, the negative effects of zinc supplementation
on iron absorption were absent. Although the precise
mechanisms by which these effects are mediated are
not understood, zinc treatment increases DMT1 and
FPN1 expression in enterocyte-like Caco-2 cells [63],
indicating specific effects of zinc supplementation on
intestinal iron transporters.
Few studies have observed negative effects of iron
supplementation on zinc metabolism. For example, Yip
et al. [64] randomized 1-year-old infants to receive 30
mg of iron/day or placebo and after 3 months of sup-
plementation, found no significant difference in serum
zinc concentration between the groups. Another small
study (N = 11) found no effect on zinc absorption with
the addition of iron (5 mg/serving) to a commercial
vegetable-based weaning food among 9-month old
infants [65]. However, in a study of Honduran children,
we observed an increase in the incidence of morbidity
in infants who received iron supplements, and iron
supplementation also resulted in a negative effect on
growth [36]. An enhancing effect of iron on bacterial
growth has been demonstrated both in vitro and in vivo
[66, 67], whereas the negative effect on infant growth
suggests that iron supplementation may indirectly
affect the IGF-1/GH axis through interference with
zinc absorption in the intestine.
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