American Journal of Hematology 78:225–231 (2005)
`
`Iron Deficiency: A Concise Review
`
`Jay Umbreit
`Division of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
`
`Iron deficiency is a major worldwide health problem. There is recent evidence that the
`anemia is only the last manifestation of the syndrome and that symptoms occur before
`the anemia is manifest. Advances in outlining the physiology of iron deficiency have
`been made, gaps remain in the current understanding. While oral iron supplement
`remains the mainstay, some indications for the intravenous administration have devel-
`oped. This review will highlight the epidemiology, physiology, clinical presentation, and
`treatment options. Am. J. Hematol. 78:225–231, 2005. ª 2005 Wiley-Liss, Inc.
`
`Key words: iron deficiency anemia; DMT-1; mobilferrin; hepcidin; hephaestin; ferroportin;
`iron sucrose
`
`INTRODUCTION
`
`The most common nutritional deficiency is the defi-
`ciency of iron. It has the highest prevalence in the US
`among women and young children. Women ages 16–19
`have an iron deficiency incidence as high as 19%. Iron
`deficiency increases in minority populations and is as
`high as 22% in Hispanic women. In children of both
`sexes age 1–2 years, the prevalence is 7%. In infants and
`preschool children, iron deficiency anemia results in
`decreased motor activity,
`social
`inattention, and
`decreased social interaction [1]. These defects are per-
`sistent if not corrected [2]. Among pregnant women,
`iron deficiency anemia during the first two trimesters
`results in increased incidence of preterm labor and
`low-weight births [3]. The prevalence of anemia in
`low-income pregnant females in the 1st, 2nd, and 3rd
`trimesters is 9%, 14%, and 37%, respectively. Iron
`deficiency anemia results
`in (1) decreased work
`productivity (2) increased child mortality, (3) increased
`maternal mortality, (4) slowed child development, and
`(5) mild-to-moderate anemia may increase susceptibil-
`ity to infectious disease [4].
`Iron deficiency without overt anemia can result in
`neuropsychological effects and has been linked to
`delayed cognitive development in children and adoles-
`cents [5]. These delays may respond to iron therapy [6].
`Non-anemia iron deficiency probably does reduce
`work capacity [7]. Tissue iron deficiency without ane-
`mia impairs endurance capacity after aerobic training
`in previously untrained women, which can be corrected
`ª 2005 Wiley-Liss, Inc.
`
`with iron supplementation [8]. Therefore, anemia is
`only part of the overall syndrome of iron deficiency.
`Diet predicts iron status into infancy and early
`childhood. Between 20% and 40% of infants fed
`cow’s milk or nonfortified formula are at risk, as are
`15–20% of breast-fed infants [9]. Breast milk has the
`greatest amount of bioavailable iron. Beyond the age
`of 24 months,
`the incidence of
`iron deficiency
`decreases with the decreased dependence on milk. In
`older children, the risk for deficiency is related to
`limited access to food because of family income,
`low-iron diets, or medical conditions such as bleeding
`or inflammatory disease. Iron requirements increase
`due to growth during adolescence (12–18 years).
`Among females, menstrual blood loss becomes an
`issue, and heavy loss (greater than 80 mL/month) is
`a significant risk factor. Other factors for this popu-
`lation include use of an intrauterine device, high
`parity, and low iron intake [10]. Among pregnant
`women, the expansion of the blood volume, growth
`of the fetus, and other maternal tissues increases
`the demand for iron 3-fold. In the absence of iron
`
`*Correspondence to: Jay Umbreit, M.D., Ph.D., Winship Cancer
`Institute, 1365-C Clifton Road, Atlanta, GA 30322.
`E-mail: jay-umbreit@emoryhealthcare.org
`
`Received for publication 31 March 2004; Accepted 6 July 2004
`
`Published online in Wiley InterScience (www.interscience.wiley.com).
`DOI: 10.1002/ajh.20249
`
`

`

`226
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`
`supplements, many pregnant women are unable to
`maintain iron stores, although prevalence data across
`the entire population are not available. While some
`iron is returned by contraction of the blood volume
`after delivery, the iron deposited in fetal and suppor-
`tive tissues is lost
`from the mother. Data from
`HANES III indicated that 11% of nonpregnant
`women aged 16–49 have iron deficiency and 3–5%
`have iron deficiency anemia. Worldwide, the problem
`of anemia is magnified. As many as 49% of children
`under the age of 5 may be iron deficient, and prob-
`ably 25% of adult females [11].
`In the developing world, the effect of parasite infes-
`tation should never be underestimated [12]. Anemia
`can result from infections of Trichuris (whipworm),
`through intestinal loss [13]. Blood loss in children can
`be estimated to be about 0.005 mL/day/worm [14].
`Because infestations of several thousand worms are
`not unusual, this can result in iron deficiency anemia.
`Even more significant is the chronic intestinal blood
`loss due to the feeding habits of hookworms. ‘‘Hook-
`worm disease’’ is a synonym for iron deficiency anemia
`in much of the world [15]. In the developing world,
`56% of pregnant women are likely anemic as are an
`amazing 74% of pregnant women in Southeast Asia. A
`large percent of these anemias are thought to be sec-
`ondary to hookworm [16]. Current estimates indicate
`that from 30 to 44 million pregnant women also harbor
`hookworms (usually Necator americanus) and that per-
`haps over 7.5 million infected pregnant women live
`in sub-Saharan Africa. An average woman in sub-
`Saharan African 18–43 years of age spends as much
`as 28% of her time pregnant and 65% lactating. In
`India 20% of maternal deaths are due to anemia. In
`the Ivory Coast [17], Sri Lanka, and Sierra Leone,
`treatment for hookworm improved hemoglobin levels
`significantly [18,19]. A study involving 3595 children
`attributed 35% of cases of iron deficiency anemia and
`73% of cases of severe iron deficiency anemia to hook-
`worm infection [20]. Workers in the developing world
`doing physical labor (such as rubber, road, and sugar
`cane workers) become more productive if they are
`treated for hookworms and other infections, given
`iron supplements, and increased energy intakes [21,22].
`Productivity loss in South Asia due to iron deficiency
`may amount to $5 billion dollars per year [23].
`Dietary iron is present in two forms, as inorganic
`iron and heme iron. In meat, 50% of the iron is heme
`and 15–35% is bioavailable [24]. While most iron in
`the diet is inorganic iron, its absorption ranges from
`2% to 20%, so that a large source of iron is from
`organic sources. In developed countries, perhaps two-
`thirds of the iron is derived from heme [25]. Nonheme
`iron absorption is facilitated by meat, ascorbic acid,
`but inhibited by phytates, some dietary fibers and
`
`lignins, phenolic polymers, and calcium. Unusual
`dietary habits resulting in the ingestion of chelators
`such as starch or clay are still found in clinical prac-
`tice. Gastric acid is required in order to maintain the
`common ferric form of inorganic iron soluble, and
`achlorhydria may be a significant cause of iron defi-
`ciency in the elderly. Perhaps 30% of the elderly have
`achlorhydria [26]. Gastric atrophy and Helicobacter
`pylori gastric infestation may result in altered pH and
`iron deficiency [27]. Pharmacological iron is ferrous
`iron, and its absorption is not dependent on gastric
`pH so that treatment in achlorhydric individuals with
`oral supplements is effective.
`Bleeding is the most common cause of iron defi-
`ciency, often associated with inadequate iron intake.
`True inability to absorb iron is extremely rare. Bleeding
`into the hip joint space or intra-abdominally may be
`initially undetected. Menstrual
`loss may not be
`reported as bleeding. A 1-mL loss of blood would
`translate to a loss of 0.5 mg of iron. Occult bleeding
`may be due to GI loss, but a loss of 20 mL/day is
`needed for the usual stool test to become positive for
`occult blood. Rarely may hemosiderinuria cause iron
`deficiency. Failure to absorb iron can occur in gastro-
`intestinal disease with extremely high transient time,
`such as is seen in celiac disease. A recent cause of iron
`deficiency is the use of erythropoietin to treat chemo-
`therapy induced a renal
`failure related anemia
`when iron was not administered concomitantly [28].
`Anemia is common in intensive care units and is occa-
`sionally attributed to bleeding and blood draws for
`laboratory tests [29]. However, in most instances the
`ICU anemia is a form of ‘‘anemia of chronic disease’’
`with diminished erythropoietin production, impaired
`proliferation, and altered iron metabolism, largely due
`to the systemic inflammatory response syndrome [30].
`
`PHYSIOLOGY OF IRON
`
`Iron is transported in the plasma bound to transfer-
`rin as diferric transferrin. There is a specific receptor on
`the cell surface, the transferrin receptor (TfR), with
`high affinity (10
`9 M dissociation constant), and the
`complex is internalized via a clathrin-coated pit. The pit
`fuses with an endosome that is then acidified, decreas-
`ing the affinity of transferrin for the iron and releasing
`it. The transferrin–TfR complex is then recycled to the
`cell surface, where it is externalized, and the apotrans-
`ferrin is released. What happens to the iron within the
`cell is unknown. It may cross the endosome membrane
`by either of the pathways used in intestinal plasma
`membrane iron transport, but transport through the
`cytoplasm is not understood. There may be a direct
`contact between the endosome and the mitochondrion
`to transmit the iron [31].
`
`

`

`During intrauterine life a fetus accumulates about
`250 mg of iron from maternal sources. A newborn
`infant has about 80 mg/kg, which decreases in the first
`year of life to about 60 mg/kg. A growing child main-
`tains this by absorbing about 0.5 mg of iron in excess of
`body losses to ultimately achieving 4,000 mg (70-kg
`man). The majority (two-thirds) is contained in hemo-
`globin, and about 1,000 mg is in ferritin or hemosiderin.
`A woman has a smaller body store of iron (about 3,000
`mg) due to menstrual losses and childbirth. Men absorb
`and excrete about 1 mg of iron daily, and during their
`child-bearing years women must absorb twice as much.
`Iron is absorbed through the intestine. At least three
`pathways have been described. Two pathways utilize
`iron as inorganic iron in the ferric valence (the mobil-
`ferrin,
`integrin, paraferritin [MIP]) or the ferrous
`valence (DMT-1) iron, and the third pathway uses
`organic iron from heme. Almost nothing is known
`about the mechanism of heme iron absorption, except
`that the porphyrin is cleaved by endogenous hemoxy-
`genase. The DMT-1 protein is a classic transmembrane
`pump, increased in iron deficiency, and decreased in the
`Belgrade rat and mk mouse, both noted for microcytic
`anemia and systemic iron deficiency. It was assumed
`that this mutation was ‘‘leaky’’ because the animals
`were alive, but the nonleaky equivalent mutation in
`zebrafish is also alive, which implies that the DMT-1
`pathway cannot be the sole pathway [32]. There are
`data to suggest that the Belgrade rat defect is not at
`the intestinal membrane but further into the iron trans-
`port sequence, perhaps at the endosomal stage [33]. The
`DMT-1 protein transports a number of divalent metals
`in model systems, including ferrous, but not ferric, iron.
`Because the duodenal iron is likely ferric, the ferric iron
`in the diet would need reduction to ferrous iron prior to
`transport by DMT-1, and this may be accomplished by
`a membrane cytochrome containing ferrireductase
`(converting ferric iron, Fe(III), to ferrous iron, Fe(II)).
`This enzyme is increased in iron deficiency, but it has
`not been shown to have a direct role in transport. The
`reduction would require a source of reducing power,
`which has not been identified but could be ascorbic acid
`in rodents (but presumably not in scorbutic animals like
`man). It is not known if the reductant needs to be on the
`lumenal side of the plasma membrane or if only the
`electron crosses the membrane. The MIP pathway
`involves a complex series of nonclassical proteins,
`including a protein mobilferrin, which is highly homo-
`logous to a chaperone protein calreticulin [34]. Muta-
`tions in this protein are lethal, but this may not be due
`to the iron transport function, because calreticulin is
`involved in a variety of cellular processes. In tissue
`culture, these two pathways are independent. Ferric
`iron would not require reduction to be transported
`but would require reduction to ferrous iron to serve as
`
`Concise Review: Iron Deficiency
`
`227
`
`a substrate for ferrochelatase. This may be accom-
`plished by a ferrireductase found in a large protein
`complex called paraferritin.
`The cellular localization of the transmembrane trans-
`port proteins is not straightforward. This is due in part
`to their involvement in the transport of iron out of the
`endosome, and endosomal location is evident. Under
`normal conditions DMT-1 is largely found in the cyto-
`plasm and lamina propria, but is brought to the lume-
`nal surface in iron deficiency. The mutation in the mk
`mouse results in defective transport to the apical mem-
`brane [35]. In iron deficiency, DMT-1 is localized in the
`apical membrane, but on refeeding with iron, it inter-
`nalizes as vesicles. Whether this is due to a regulation by
`internalizing the transporter [36] or a mechanism for
`transport itself is not completely clear, but co-localiza-
`tion of apotransferrin and DMT-1 was observed in
`endosomes in cultured cells, suggesting a ‘‘transcytosis’’
`[37]. Mobilferrin is likewise found in the cytoplasm and
`the cell surface. During iron deficiency, mobilferrin
`does not quantitatively increase but becomes localized
`at the cell membrane. In the case of both DMT-1 and
`mobilferrin, electron microscopy revealed that the
`majority of the apical surface increase in the amount
`of these proteins was due to increased binding of the
`proteins to mucin in vesicles near the lumenal surface.
`Significant amounts of the proteins were found outside
`the cell in the lumen, attached to mucin, and only trace
`amounts were found on the membrane itself. This sug-
`gested that the transport proteins might scavenge
`metals in the lumenal space and return to the mem-
`brane along a mucin track [38]. Vesicular uptake
`by DMT-1, or a large molecular weight complex
`for mobilferrin, would appear to be a more reason-
`able part of this mechanism than a simple ion pump
`function.
`Once across the lumenal membrane of the duode-
`num, the iron must exit as transferrin. The iron needs to
`transit the cytoplasm, and this probably involves a
`carrier protein. If the intracellular form is ferrous, the
`likelihood of generating free radical damage and cell
`death is sufficiently high to make it likely that the iron
`must be confined in some manner. If the iron is in the
`ferric form, the risk of free radical damage is decreased,
`but it must be chelated to be soluble. Once at the
`basolateral membrane, the iron will be incorporated
`into transferrin in order to be released to the plasma.
`There must be an independent apo-transferrin receptor
`on the basal–lateral side of the intestinal cell, although
`this has not been shown. The usual transferrin receptor,
`which is present on the basolateral membrane, will be
`saturated with diferric transferrin and unavailable for
`apo-transferrin.
`Hephaestin, a ceruloplasm-like ferro-oxidase, and a
`transport protein ferroportin appear involved in the
`
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`

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`
`iron from the intestinal mucosa [39].
`exodus of
`Hephastin is a multicopper enzyme that can oxidize
`ferrous(II) to ferric(III) for incorporation into trans-
`ferrin that binds only the ferric form. In mice, a
`mutation in hephastin (the sex-linked anemia) cannot
`release
`iron across
`the basolateral membrane.
`Another protein, ferroportin [40], appears to be the
`actual transmembrane transporter. Hephaestin and
`ferroportin appear to respond to systemic rather
`than local (i.e., duodenal) iron levels and may exercise
`control of iron uptake at that stage [41].
`The mechanism by which the cell detects the body
`stores of iron is not known. Because the concentra-
`tion of diferric transferrin in the blood is about
`3 micromolar, and severe iron deficiency drops this
`by two-thirds, the remaining levels are sufficient to
`completely saturate the transferrin receptor. Some
`alternative method of sensing the plasma iron con-
`centration must occur, but it is not known [42].
`Hepcidin may be a major communicator between
`iron stores [43] and the intestinal absorption mechan-
`ism [44]. Hepcidin is increased in the liver of iron-over-
`loaded mice [45]. The liver may detect changes in the
`diferric levels by the ratio of transferrin to receptors,
`and as these decrease, hepcidin levels are also reduced.
`Circulating hepcidin alters ferroportin levels in the villi,
`controlling intestinal iron uptake [46]. Hepcidin reduces
`the expression of the iron transporter DMT-1 [47].
`Hepcidin administered to mice significantly reduced
`mucosal iron uptake and transfer, and carcass exam-
`ination showed that at least 10 mg/mouse/day had been
`transferred [48]. Hepcidin is downregulated in hypoxia
`and may explain the increase in iron absorption under
`hypoxia and the increased iron release from reticulo-
`endothelial cells. Chronic inflammatory models (tur-
`pentine injection) in mice result in a pattern similar to
`anemia of chronic disease [49], and increased urinary
`excretion of hepcidin is observed in humans with ane-
`mia of chronic disease [50]. These data have suggested
`that hepcidin is the regulator in anemia of chronic
`disease [51]. This response to inflammation may be
`mediated by interleukin-6.
`How iron deficiency directly affects the cell is lar-
`gely unknown. In iron deficiency there is an increase
`in red cell free porphyrin, so presumably the enzyme
`that places the iron in the heme, ferrochelatase, is
`inhibited. Hemoglobin protein synthesis is probably
`also inhibited, but possibly there is some residue
`chain initiation [52]. Ribonucleotide reductase (RR)
`is a non-heme iron protein that is commonly stated to
`be the enzyme most sensitive to iron deficiency, and
`inhibition by lack of iron is reported to stop DNA
`synthesis [53]. The inhibition of RR by hydroxyurea
`results in macrocytic (DNA synthesis inhibition), not
`microcytic (iron deficiency), anemia. Loss of RR by
`
`iron chelation occurs within 4 hr in culture, which
`qualifies it as an ‘‘early’’ event [54]. In a transferrin
`transport defective cell line, presumably intracellu-
`larly iron deficient, there was a decrease in RR activ-
`ity, but not protein synthesis, as its major defect [55].
`Other essential heme proteins might be involved, in
`particular those of the respiratory chain in the genesis
`of loss of energy and CNS function. Severely anemic
`rats with 50% decrease in hemoglobin have an almost
`50% reduction in myoglobin and cytochrome c [56]
`and decreases in iron–sulfur content, pyruvate dehy-
`drogenase, and other tricarboxylic acid (TCA) cycle
`enzymes. Perinatal iron deficiency in rats decreases
`cytochrome c oxidase activity in the neonatal brain
`[57]. In contrast, in milder anemia, with hemoglobin
`levels in the range of 6–12 g/dL,
`there was an
`increased platelet count, increased serum transami-
`nase consistent with cell damage but no decrease in
`the activities of TCA enzymes or cytochrome oxidase
`activity [58]. The naı¨ ve explanation for the lack of
`energy does not appear to be correct. Abnormalities
`in lipid composition were observed, consistent with
`effects on lipid desaturase activities [59]. The physiol-
`ogy of iron deficiency is still under-explored.
`A variety of genes are increased in iron deficiency as
`observed in limited DNA microarray data, including
`Rb, p21, cdk2, cyclins A, D3, E1, myc, iNOS, FasL,
`none of which is intuitively related to iron metabolism
`but which may help account for the signs and symp-
`toms. Many of the proteins involved in iron homeosta-
`sis may be regulated at the translational (rather than
`transcriptional) level. The mRNAs of ferritin, transfer-
`rin receptor, aminolevulinic acid synthetase, ferropor-
`tin, m-aconitase, and DMT-1 are regulated by an iron-
`responsive element (IRE) on the mRNA, which binds
`either of two binding proteins to regulate translation.
`
`SIGNS AND SYMPTOMS
`
`Individuals with iron deficiency may experience
`no symptoms. Findings common to all anemias may
`be present, or those rather specific to iron effects
`on rapidly turning over epithelial cells resulting in
`glossitis, gastric atrophy, stomatitis, ice eating (pago-
`phagia), and leg cramping. The esophageal web
`syndrome
`(Plummer-Vinson syndrome)
`is
`still
`reported to be related to iron deficiency, and at least
`some cases appear to respond to iron therapy [60].
`Koilonychia or spoon nails may more commonly be
`due to fungal infections or hereditary variations [61].
`Definitive diagnosis requires laboratory tests [62].
`A bone marrow smear containing no stainable iron is
`definitive. Elevated total iron-binding capacity, low
`serum iron level, and a low serum ferritin concentra-
`tion are considered diagnostic for iron deficiency.
`
`

`

`Transferrin saturation should be less than 10%. How-
`ever, serum iron is subject to diurnal variations, with
`higher concentrations late in the day, and may be
`increased after meat ingestion. Oral contraceptives
`increase serum transferrin and result in low transfer-
`rin saturation. The serum ferritin reflects body stores
`and is not affected by recent iron ingestion. Ferritin is
`an ‘‘acute phase reactant’’ and in the presence of
`infection or inflammation the ferritin may be high
`and the serum iron and transferrin low. Perhaps a
`better estimate of body stores is obtained by the ratio
`of serum transferrin receptor (sTfR) to serum ferritin
`(R/F ratio) [63,64]. Studies of the R/F ratio shows age
`dependence [65]; in males there is a Gaussian distri-
`bution, but in females there is a bimodal distribution.
`The R/F ratio can also be affected by inflammation.
`However, at least in the elderly, the R/F ratio may be
`more sensitive than the classic blood tests [66] and
`may be more sensitive in distinguishing iron defi-
`ciency anemia from the anemia of chronic disease
`[67]. A major problem is the lack of standardization
`of the sTfR assay. There has been interest in using
`erythrocyte zinc porphyrin as an assay [68]. This may
`be useful in primary screening tests for assessing iron
`status. It is likely due to the increase transport of Zn
`across the intestine by the upregulation of the DMT-1
`in iron deficiency.
`In individuals treated with recombinant erythro-
`poietin, the increased production of RBCs exhausts
`iron stores rapidly, resulting in serum iron being
`reduced and transferrin becoming desaturated. In
`healthy individuals iron stores determine the response
`to erythropoietin, and baseline ferritin values <1,000
`mg/L have been associated with a ‘‘functional’’ iron
`deficiency. Ferritin concentrations are not correlated
`to body stores in the setting of hyperthyroidism,
`malignancy,
`inflammation, hepatocellular disease,
`alcohol consumption, and oral contraception use.
`The percentage of hypochromic RBC and hypochro-
`mic reticulocytes may or may not be useful in identi-
`fying functional
`iron deficiency and in predicting
`response to erythropoietin and i.v. iron treatments.
`This percentage is not useful in the settings of thalas-
`semia or chemotherapy patients [69].
`
`TREATMENT
`
`The preferred treatment, besides identification of
`the source of iron loss, is oral iron. Ferrous iron salts
`are preferred because of their increased solubility and
`availability at the pH of the duodenum and jejunum.
`Standard therapy for iron deficiency anemia in adults
`is oral administration of a 300-mg tablet of ferrous
`sulfate (60 mg of elemental iron) three or four times
`daily. While absorption is enhanced by administration
`
`Concise Review: Iron Deficiency
`
`229
`
`of the iron on an empty stomach, epigastric pain
`develops in some patients if iron is administered in
`the fasted state, so it must be taken with meals. In
`addition, heartburn, nausea, vomiting, and diarrhea
`may occur. These symptoms can be reduced by
`administering the tablets with meals, decreasing the
`dose of
`iron, by switching from ferrous sulfate
`tablets to other preparations containing less iron,
`such as ferrous gluconate tablets (320 mg with 36 mg
`of elemental
`iron), or by the oral administration
`of carbonyl
`iron (Ircon). Pediatric liquid prepara-
`tions of iron (Fer-In-Sol) can be used with dose
`modifications to avoid side effects. In order to
`ensure a response to treatment, the anemia should
`be monitored. The usual cause of failure to respond
`is noncompliance, but
`failure to absorb enteric-
`coated iron tablets or malabsorption of iron due to
`high transit times may occur. True malabsorption of
`ferrous sulfate is extremely rare, but it may be diag-
`nosed by administering an oral dose of liquid ferrous
`sulfate (50–60 mg of iron) in a fasted state and
`obtaining a serum iron level before administration
`and 1 and 2 hr later. An increase in the serum iron
`concentration of 100 mg/100 mL should be observed.
`Reticulocytosis may be observed as early as 4 days
`after treatment and will reach a maximum at 7–10
`days. An increase in the hematocrit and hemoglobin
`concentration will follow. Therapy needs to continue
`for 2–3 months after correction of the anemia in
`order to replenish the body stores of iron.
`Iron for intramuscular or intravenous administra-
`tion was available in the form of
`iron dextran
`(INnFeD), but it had a high toxicity rate and is now
`rarely indicated. In contrast,
`iron sucrose appears
`safer. The iron is delivered to endogenous iron-bind-
`ing proteins with a half-life of 90 min. It becomes
`rapidly available for erythropoiesis. Some formula-
`tions such as VenoferÒ can cause anaphylactoid reac-
`tions. Other parenteral preparations, such as ferric
`gluconate and ferric citrate, deliver iron to many
`proteins other than iron-binding proteins and can be
`deposited in the parenchyma of the liver, resulting in
`necrosis [70]. Oral iron products have been largely
`abandoned in patients with end-stage renal disease,
`most of whom are being treated with erythropoietin.
`Parenteral iron can be administered by slow intrave-
`nous injection, intravenous drip infusion, or injection
`into the dialyzer. The most frequent adverse effects
`reported during treatment in hemodialysis patients
`are hypotension, cramps, and nausea. Some dialysis
`centers have tried oral heme iron [71]. Some author-
`ities are recommending the combination of erythro-
`poietin and intravenous iron (iron sucrose 200 mg i.v.
`and rhEPO 300 U/kg twice a week) for rapid reversal
`of anemia in pregnant patients [72].
`
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`REFERENCES
`
`1. Pollitt E. Iron deficiency and cognitive function. Annu Rev Nutr
`1993;13:521–537.
`2. Idjradinata P, Pollitt E. Reversal of developmental delays in iron-
`deficient anaemic infants treated with iron. Lancet 1993;341:1–4.
`3. Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron
`deficiency:
`increased risk of preterm delivery in a prospective
`study. Am J Clin Nutr 1992;55:985–988.
`4. Stoltzfus R. Summary: implications for research and programs.
`J Nutr 2001;131:697S–701S.
`5. Grantham-McGregor S, Ani C. A review of studies on the effect of
`iron deficiency on cognitive development in children. J Nutr 2001;
`131:649S–668S.
`6. Sandstead HH. Causes of iron and zinc deficiencies and their
`effects on the brain. J Nutr 2000;130:347–349.
`7. Hass JD, Brownlie T. Iron deficiency and reduced work capacity:
`a critical review of the research to determine a causal relationship.
`J Nutr 2001;131:676S–690S.
`8. Brownlie T 4th, Utermohlen V, Hinton PS, Haas JD. Tissue iron
`deficiency without anemia impairs adaptation in endurance capa-
`city after aerobic training in previously untrained women. Am J
`Clin Nutr 2004;79:437–443.
`9. Pizarro F, Yip R, Dallman PR, Olivares M, Hertrampf E, Walter
`T. Iron status with different infant feeding regimens: relevance to
`screening and preventive iron deficiency. J Pediatr 1991;118:
`687–692.
`10. Lookler AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL.
`Prevalence of iron deficiency in the United States. J Am Med
`Assoc 1997;277:973–976.
`11. DeMaeyer E, Adiels-Tegman M. The prevalence of anaemia in the
`world. World Health Stat Q 1985;38:302–316.
`12. Crompton DWT, Nesheim MC. Nutritional impact of intestinal hel-
`minthiasis during the human life cycle. Annu Rev Nutr 2002;22:35–99.
`13. Cooper ES, Bundy DAP. Trichuriasis. Ballieres Clin Trop Med
`Commun Dis 1987;3:629–643.
`14. Layrisse M, Aparcedo L, Martinez-Torres C, Roche M. Blood
`loss due to infection with Trichuris trichiura. Am J Clin Nutr
`1967;16:613–619.
`15. Pawlowski ZS, Schad GA, Stott GJ. 1991. Hookworm infection
`and anaemia. Geneva: WHO.
`16. WHO. 1996. Report of the WHO Informal Consultation on hook-
`worm infection and anaemia in girls and women. WHO/CTD/SIP/
`96.1. Geneva: WHO.
`17. Welffens-Ekra CH, Kibora M, Koume P, et al. Efficacite et toler-
`ance de l’Helmintox chez la femme enceinte en Cote d’Ivoire. Med
`Afr Noire 1990;37:800–803.
`18. Atukorala TMS, de Silva LD, Dechering WH, Dassenaeike TS,
`Perera RS. Evaluation of effectiveness of iron-folate supplementa-
`tion and anthelmintic therapy against anaemia in pregnancy—a
`study in the plantation sector of Sri Lanka. Am J Clin Nutr
`1994;60:286–292.
`19. Torlesse H, Hodges M. Anthelminthic treatment and haemoglobin
`concentrations during pregnancy. Lancet 2000;35b:1083.
`20. Stoltzfus RJ, Chwaya HM, Tielsch J, et al. Epidemiology of iron
`deficiency anaemia in Zanzibari schoolchildren: the importance of
`hookworms. Am J Clin Nutr 1997;65:153–159.
`21. Brookes RM, Latham MC, Crompton DWT. The relationship of
`nutrition and health to worker productivity in Kenya. East Afr
`Med J 1979;56:413–421.
`22. Wolgemuth JC, Latham MC, Hall A, Chesher A, Crompton
`DWT. Worker Productivity and the nutritional status of Kenyan
`road construction laborers. Am J Clin Nutr 1982;36:68–78.
`23. Stephenson LS, Holland CV, Ottesen EA (editors). Controlling
`intestinal helminths while eliminating lymphatic filariasis. Parasi-
`tology 2000;121(Suppl):S5–S22.
`
`24. Monsen ER. Iron nutrition and absorption: dietary factors which
`impact on bioavailability. J Am Diet Assoc 1988;88:786–790.
`25. Carpenter CE, Mahoney AW. Contribution of heme and non-heme
`iron to human nutrition. Crit Rev Food Sci Nutr 1992;31:333–337.
`26. Champagne ET. Low gastric hydrochloric acid secretion and
`mineral bioavailability. Adv Exp Med Biol 1989;249:173–184.
`27. Annibale B, Capurso G, Lahner E, et al. Concomitant alterations
`in intragastric pH and ascorbic acid concentration in patients with
`Helicobacter pylori gastritis and associated iron deficiency anemia.
`Gut 2003;52:496–501.
`28. Glaspy J, Cavill I. Role of iron in optimizing response of anemic
`cancer patients to erythropoietin. Oncology (Huntingt) 1999;13:
`461–473.
`29. Eckardt KU. Anemia in critical illness. Wien Klin Wochenschr
`2001;113:84–89.
`30. Scharte M, Fink MP. Red blood cell physiology in critical illness.
`Crit Care Med 2003;31(12 Suppl):S651–S657.
`31. Ponka P, Sheftel AD, Zhang AS Iron targeting to mitochondria in
`erythroid cells. Biochem Soc Trans 2000;30:735–738.
`32. Donovan A, Brownlie A, Dorschner MO, et al. The zebrafish
`mutant gene chardonnay (cdy) encodes divalent metal transporter
`1 (DMT1). Blood 2003;100:4655–4659.
`33. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD,
`Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat:
`evidence of a role for Nramp2 in endosomal iron transport. Proc
`Natl Acad Sci USA 1998;95:1148–1153.
`34. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood
`Cells Mol Dis 2002;29:336–355.
`35. Canonne-Hergaux F, Fleming MD, Levy JE, et al. The Nramp2/
`DMT1 iron transporter is induced in the duodenum of microcytic
`anemia mk mice but is not properly targeted to the intestinal brush
`border. Blood 2000;96:3964–3970.
`36. Yeh KY, Yeh M, Watkins JA, Rodriguez-Paris J, Glass J. Dietary
`iron induces rapid changes in rat intestinal divalent metal trans-
`porter expression. Am J Physiol Gastrointest Liver Physiol 2000;
`279:G1070–1079.
`37. Ma Y, Specian RD, Yeh KY, Yeh M, Rodriguez-Paris J, Glass J.
`The transcytosis of divalent metal transporter 1 and apo-transfer-
`rin during iron uptake in intestinal epithelium. Am J Physiol
`Gastrointest Liver Physiol 2002;283:G965–974.
`38. Simovich M, Hainsworth LN, Fields PA, Umbreit JN, Conrad
`ME. Localization of the iron transport proteins Mobilferrin and
`DMT-1 in the duodenum: the surprising role of mucin. Am J
`Hematol 2003;74:32–45.
`39. Aisen P, Enns C, Wessling-Resnick M. Chemistry and biology of
`eukaryotic iron metabolism. Int J Biochem Cell Biol 2001;33:940–959.
`40. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-
`regulated