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Abstract: Iron deficiency is the single most prevalent nutritional deficiency worldwide.
It accounts for anemia in 5% of American women and 2% of American men. The goal of this
review article is to assist practitioners in understanding the physiology of iron metabolism and
to aid in accurately diagnosing iron deficiency anemia. The current first line of therapy for
patients with iron deficiency anemia is oral iron supplementation. Oral supplementation is
cheap, safe, and effective at correcting iron deficiency anemia; however, it is not tolerated by
some patients and in a subset of patients it is insufficient. Patients in whom the gastrointestinal
blood loss exceeds the intestinal ability to absorb iron (e.g. intestinal angiodysplasia) may
develop iron deficiency anemia refractory to oral iron supplementation. This population of
patients proves to be the most challenging to manage. Historically, these patients have
required numerous and frequent blood transfusions and suffer end-organ damage resultant
from their refractory anemia. Intravenous iron supplementation fell out of favor secondary to
the presence of infrequent but serious side effects. Newer and safer intravenous iron prepa-
rations are now available and are likely currently underutilized. This article discusses the
possible use of intravenous iron supplementation in the management of patients with severe
iron deficiency anemia and those who have failed oral iron supplementation.
Introduction normally absorbed each day. The human diet Correspondence to:
Anemia (from the ancient Greek 0nai0a, anai- contains two forms of iron: heme iron and non- David Y. Graham, MD
Michael E. DeBakey VA
mia, meaning lack of blood) is defined by a heme iron. Heme iron is derived from meat and is Medical Center, Room
3A-320 (111D), 2002
decrease in the total amount of hemoglobin or well absorbed. Pancreatic enzymes digest heme Holcombe Boulevard,
the number of red blood cells. Iron deficiency to free it from the globin molecule in the intesti- Houston, TX 77030, USA
dgraham@bcm.tmc.edu
anemia is a form of anemia due to the lack of nal lumen. Iron is then absorbed into the enter-
Terri D. Johnson-
sufficient iron to form normal red blood cells. ocytes as metalloporphyrin and degraded by Wimbley, MD
Iron deficiency anemia is typically caused by heme oxygenase-1 to release nonheme iron. Baylor College of
Medicine, Houston, Texas,
inadequate intake of iron, chronic blood loss, or Subsequently, iron is exported by ferroportin USA
a combination of both. Iron deficiency anemia is located on the basolateral aspect of the entero-
the most common cause of anemia in the world. cyte. Nonheme dietary iron, which is found in
Approximately 5% and 2% of American women cereals, beans, and some vegetables, is less well
and men, respectively, have iron deficiency absorbed. Nonheme iron is present as either
anemia [Clark, 2009; Looker et al. 1997]. ferric (Fe2) or ferrous (Fe3) iron. The acidic
environment of the stomach and certain foods are
Iron metabolism known to increase the bioavailability of dietary
Iron is a trace element that is required for numer- iron [Zhang and Enns, 2009; Schmaier and
ous cellular metabolic functions. As iron is toxic Petruzzelli, 2003; Conrad and Umbreit, 1993].
when present in abundance, tight regulation is Vitamin C, for example, functions to prevent pre-
required to avoid iron deficiency or iron overload cipitation of ferric iron in the duodenum. Other
[Anderson et al. 2009; Byrnes et al. 2002]. The foods containing plant phytates (grains) and tan-
adult body contains 34 g of iron. The usual nins (nonherbal tea) are known to decrease the
Western diet contains approximately 7 mg of absorption of nonheme iron [Schmaier and
iron per 1000 kcal; however, only 12 mg is Petruzzelli, 2003; Conrad and Umbreit, 1993].
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Therapeutic Advances in Gastroenterology 4 (3)
After entry of ferric iron into the duodenum it released into the plasma. Haptoglobin is a protein
must first be reduced to the ferrous form by duo- synthesized primarily in the liver and functions to
denal cytochrome b prior to absorption. bind free hemoglobin. The hemoglobinhapto-
Duodenal cytochrome b is a reductase located globin complex is then removed by the reticulo-
in the brush border of the duodenum and prox- endothelial system and the iron salvaged. The
imal jejunum. Once reduced, the divalent metal binding potential of haptoglobin is limited by
transporter 1, the only currently known intestinal the amount of circulating molecules and quickly
iron importer, transports ferrous iron from the becomes saturated in moderate to severe hemo-
proximal small intestinal lumen into the apical lytic states.
membrane of the enterocyte [Zhang and Enns,
2009]. After entry into the cell, ferrous iron No physiologic mechanism for iron excretion
may either be stored as ferritin or transverses exists and only 12 mg of iron is lost each day
the cell to the basolateral aspect of the enterocyte as a result of sloughing of cells (i.e. from the
where the ferroportin is located. Ferroportin is mucosal lining of the gastrointestinal tract, skin,
present in the mucosa of the proximal small intes- and renal tubules). In women, approximately
tine, macrophages, hepatocytes, and syncytiotro- 0.006 mg iron/kg/day is lost during normal men-
phoblasts of the placenta. Ferroportin, along with struation [Schmaier and Petruzzelli, 2003].
ceruloplasmin and hephaestin, facilitates the Thus, normally iron loss and gain is in balance
reoxidation of ferrous iron to ferric iron, which with the amount lost daily being equal to the
must occur prior to exportation. Transferrin has amount absorbed daily. The body has the ability
a high affinity for ferric iron and binds it so to increase intestinal iron absorption dependent
quickly that there is essentially no free iron circu- on the body iron needs. When the pendulum
lating in the plasma. Binding of iron to transfer- swings towards more iron being lost than is
rin occurs via the apotransferrin receptor absorbed, iron stores become depleted and the
pathway [Conrad, 2009; Zhang and Enns, 2009]. patient develops iron deficiency. If the process
continues the patient develops iron deficiency
Once in the plasma the iron is transported by anemia. Iron deficiency is associated with upre-
transferrin to the bone marrow for synthesis of gulation of iron absorption from the gut by way of
hemoglobin and incorporation into the erythro- an increase in the production of key proteins,
cytes. Normal erythrocytes circulate for roughly such as duodenal cytochrome b, divalent metal
120 days before being degraded. Senescent red transporter 1, and ferroportin. Hypoxia-induci-
blood cells are engulfed by macrophages in the ble, factor-mediated signaling and iron regulatory
reticuloendothelial system, primarily in the proteins also play critical roles in the local regu-
spleen and liver where they are degraded and lation of iron absorption. Hypoxia-inducible
catabolized by the cytosolic hemeoxygenase-1 to factor-signaling upregulates the expression of
release the bound iron. Recycling of heme iron duodenal cytochrome b and divalent metal trans-
from senescent red blood cells is the primary porter 1; iron regulatory proteins upregulate the
source of iron for erythropoiesis and accounts expression of divalent metal transporter 1 and
for delivery of 4060 mg iron/day to the bone ferroportin. These two pathways are vital for
marrow [Hillman and Henderson, 1969]. Some the enhancement of iron absorption associated
of the iron from senescent red blood cells is also with iron deficiency [Zhang and Enns, 2009].
stored in macrophages as ferritin (the major stor- Within limits, iron absorption enhancement is
age form of iron) or hemosiderin (the water-solu- proportional to the degree of iron deficiency
ble form of iron), and the majority of it is released (i.e. the synthesis of key proteins, such as
via ferroportin into the plasma bound to transfer- transferrin receptor, divalent metal transporter
rin for recycling. Around 70% of the total body 1, ferritin, and ferroportin, is regulated in an
iron is in heme compounds (e.g. hemoglobin and iron-dependent manner) [Byrnes et al. 2002].
myoglobin), 29% is stored as ferritin and hemo- This system is checked by hepcidin, a hormone
siderin, <1% is incorporated into heme-contain- that is synthesized in the liver, secreted into the
ing enzymes (e.g. cytochromes, catalase, blood, and systemically controls the rate of iron
peroxidase), and <0.2% is found circulating in absorption as well as its mobilization from stores
the plasma bound to transferrin [Zhang and (Figure 1). Hepcidin binds to, and negatively
Enns, 2009; Schmaier and Petruzzelli, 2003]. modulates, the function of ferroportin. Janus
During states of intravascular hemolysis, red kinase 2 is activated upon binding of hepcidin
blood cells are destroyed and hemoglobin is to ferroportin and results in the internalization,
178 http://tag.sagepub.com
TD Johnson-Wimbley and DY Graham
Laboratory diagnosis of iron deficiency anemia Iron studies diagnostic for iron deficiency anemia
The World Health Organization defines anemia consist of a low hemoglobin (<7.7 mmol/l in men
as blood hemoglobin values of less than and 7.4 mmol/l in women), a low serum iron
7.7 mmol/l (13 g/dl) in men and 7.4 mmol/l (<7.1 mg/l), a low serum ferritin (storage form of
(12 g/dl) in women. Typically, the evaluation of iron) (<30 ng/l), a low transferrin saturation
the cause of anemia includes a complete blood (<15%), and a high total iron-binding capacity
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Therapeutic Advances in Gastroenterology 4 (3)
(>13.1 mmol/l) [Bermejo and Garcia-Lopez, acute or chronic. Patients may present with
2009; Clark, 2009]. The ferritin level may be mis- maroon-colored stools or blood in their stools
leading in the presence of acute or chronic inflam- with brisk bleeding but more often the blood
mation as ferritin is also an acute phase reactant loss is unrecognized by the patient as blood loss
and thus one cannot exclude iron deficiency as the up to 100 ml/day from the gastrointestinal tract
cause of anemia when the serum ferritin is normal may be associated with normal-appearing stools
or even elevated in the presence of an inflamma- [Rockey, 2005]. The physiologic response of the
tory process [Bermejo and Garcia-Lopez, 2009; small bowel to bleeding will be to increase iron
Conrad and Umbreit, 1993]. In the presence of absorption by twofold to threefold by upregula-
an underlying infection or inflammation other tion of proteins duodenal cytochrome b, divalent
iron markers may be useful including the reticu- metal transporter 1, ferroportin, and downregula-
locyte hemoglobin content which, because reticu- tion of hepcidin. However, iron loss greater than
locytes are only 12 days old, is reflective of the 5 mg/day over a prolonged period of time exceeds
iron available in the bone marrow for erythropoi- this compensatory response; the patients iron
esis. The alternative, which is likely to be more stores will become depleted and iron deficiency
readily available, is the measurement of soluble anemia ensues [Rockey, 1999]. Chronic gastroin-
transferrin receptor. In the setting of iron defi- testinal bleeding is associated with a variety of
ciency with increased erythroid activity (e.g. fol- lesions and can occur at any location within the
lowing administration of exogenous gastrointestinal tract. Iron deficiency anemia is
erythropoiesis stimulating agents), there is especially prone to occur in those taking aspirin
increased expression of membrane transferrin or nonsteroidal anti-inflammatory drugs chroni-
receptors in the bone marrow and some of these cally. For those with angiodysplasia or other struc-
receptors are detectable in the serum. The limita- tural lesions, the site can often be visualized by
tions are that it is not as reliable as ferritin, it is not endoscopic evaluation (e.g. video capsule endos-
yet widely available, and the clinician must copy) of the gastrointestinal tract. However, in
exclude other causes of elevated erythroid activity 1040% of patients with occult gastrointestinal
[Wish, 2006]. When all else fails and it is impor- bleeding the cause remains obscure [Till and
tant to establish whether iron deficiency is pre- Grundman, 1997; Rockey and Cello, 1993].
sent, demonstration of the absence of stainable
iron via a bone marrow biopsy remains the gold Oral iron therapy and its limitations
standard for diagnosis. Traditionally hemodynamically stable patients
with iron deficiency anemia resultant from
Causes of iron deficiency anemia chronic blood loss from the gut are prescribed
In developing countries, low iron bioavailability oral iron therapy. The two categories of iron sup-
of the diet is the primary cause of iron deficiency plements are those containing the ferrous form of
anemia [Berger and Dillon, 2002; Yip and iron and those containing the ferric form of iron.
Ramakrishnan, 2002]; however, in developed The most widely used iron supplements are those
countries, decreased iron absorption and blood that contain the ferrous form of iron given that it
loss account for the more likely etiologies of is the better absorbed of the two. The three com-
iron deficiency. Decreased iron absorption may monly administered types of ferrous iron supple-
also be the result of atrophic gastritis or malab- ments: ferrous fumarate, ferrous sulfate, and
sorption syndromes especially celiac disease ferrous gluconate, which differ in the amount of
[Bermejo and Garcia-Lopez, 2009]. elemental iron (the form of iron in the supple-
Postsurgical gastrectomy (partial or total) and ment that is available for absorption by the
intestinal resection or bypass may also produce body), and contain 33%, 20%, and 12% iron,
iron deficiency anemia secondary to decreased respectively (NIH, 2010). Recent studies have
iron absorption. Chronic blood loss from genito- suggested that these iron preparations are essen-
urinary, gynecological, or gastrointestinal tracts tially equivalent in terms of bioavailability
accounts for the majority of causes for iron defi- [Harrington et al. 2011; Navas-Carretero et al.
ciency anemia. The most common etiology of 2007; Lysionek et al. 2003]. The recommended
iron deficiency anemia in premenopausal daily dose of treatment by the Centers for
women is excessive menstruation. Disease Control and Prevention (CDC) ranges
from 150 mg/day to 180 mg/day of elemental
Gastrointestinal bleeding is a common cause of iron administered in divided doses two to three
iron deficiency anemia, whether the bleeding is times a day [CDC, 1998]. The reticulocyte count
180 http://tag.sagepub.com
TD Johnson-Wimbley and DY Graham
begins to increase within the first week of iron erythropoesis [Hillman and Henderson, 1969].
therapy, whereas the hemoglobin usually trails Supplementation with oral iron provides
by 12 weeks [National Institutes of Health, 6080 mg iron/day, whereas intravenous iron or
2010; Provenzano et al. 2009]. Oral iron supple- nonviable red cells provide 80160 mg iron/day.
ments are desirable as first-line therapy as they They found that the maximum red blood cell
are safe, cheap, and effective in restoring iron production achieved by patients with a mean
balance in the average chronic gastrointestinal serum iron less than 70 mg/100 ml was between
bleeder. 2.5 and 3.5 times normal. With oral iron supple-
mentation, patients were able to achieve serum
Therapy with iron supplements may be limited iron values between 70 mg/100 ml and 150 mg/
by gastrointestinal side effects, such as abdominal 100 ml, and red blood cell production was able
discomfort, nausea, vomiting, constipation, and to increase to four to five times normal. Only
dark colored stools. Enteric-coated and delayed- when nonviable red cells or intravenous iron dex-
release iron supplements have been developed to tran was administered was the iron supply suffi-
increase compliance as they are associated with cient to increase the serum iron to values greater
fewer side effects; however, they are not as well than 200 mg/100 ml with a concomitant increase
absorbed as the nonenteric-coated preparations in marrow production to 4.57.8 times normal
[Provenzano et al. 2009]. (Figure 2). It is important to note that this
response was transient lasting only 710 days as
Physicians are often faced with the challenge of the excess iron was subsequently sequestered in
managing iron deficiency anemia with oral iron
the reticuloendothelial system. The physician can
when a patients iron losses exceed the maximum
amount of iron that the gut is able to absorb. It is
this group of patients that generally requires
8 C
repeated transfusions and suffers end-organ
RBC production (times normal)
http://tag.sagepub.com 181
Therapeutic Advances in Gastroenterology 4 (3)
estimate a patients total iron deficit and then one to tailor the dose to maintain red blood cell
decide how much to administer intravenously production at a maximum with limited sequestra-
(Table 1). tion in the reticuloendothelial system. Some of
the additional reported adverse events associated
Iron dextran has since been replaced by newer with each of the iron preparations are hypoten-
safer iron preparations. Available intravenous sion, arthralgias, myalgias, malaise, abdominal
iron preparations in the USA include iron dex- pain, nausea, and vomiting. These nonlife-threa-
tran (INFeD or DexFerrum ), iron sucrose tening adverse reactions are also more commonly
(Venofer ), sodium ferric gluconate associated with iron dextran and less so with iron
(Ferrlecit ), and ferumoxytol (Feraheme ). sucrose or sodium ferric gluconate (50%, 36%,
Iron dextran is the oldest of these and has the 35%, respectively) (Table 2) [Silverstein and
advantage of total dose infusion (ability to Rodgers, 2004]. Ferumoxytol provides 510 mg
infuse the patients total iron requirement in of iron per infusion and thus allows the physician
one administration) and lowest cost. It fell out to give patients large doses of iron with fewer
of favor because of its association with fatalities infusions [De Domenico et al. 2009].
secondary to anaphylactic reactions, with an inci- Intravenous iron formulations are now most
dence of 0.60.7%. Sodium ferric gluconate and commonly used in hemodialysis patients and
iron sucrose are more bioavailable and have a there is a great deal of literature regarding the
lower incidence of life-threatening anaphylaxis use of intravenous iron in patients with endstage
(0.04% and 0.002%, respectively); these prepa- renal disease. Regular infusions of intravenous
rations are significantly more expensive than iron iron may also allow improved management of
dextran and require repeated infusions to replace patients with iron deficiency anemia refractory
the lost iron stores. However, it is important to to oral iron therapy, especially those with
note that the administration of repeated injec- anemia as a result of chronic gastrointestinal
tions has the potential advantage of allowing blood loss. However, there is a scarcity of
*Injection/infusion rates are based on studies in hemodialysis dependent-chronic kidney disease patients. FDA, US Food and Drug Administration.
182 http://tag.sagepub.com
TD Johnson-Wimbley and DY Graham
literature in support of intravenous iron versus Byrnes, V., Barrett, S., Ryan, E., Kelleher, T.,
oral iron in the medical management of anemia OKeane, C., Coughlan, B. et al. (2002) Increased
duodenal DMT-1 expression and unchanged HFE
associated with chronic intestinal bleeding and mRNA levels in HFE-associated hereditary hemo-
details of administration (doses, interval, factors chromatosis and iron deficiency. Blood Cells Mol Dis
to assess when the next dose is needed, etc.) are 29: 251260.
lacking. Comparative studies of the different Centers for Disease Control and Prevention (CDC).
intravenous iron preparations have not been car- (1998) Recommendations to prevent and control iron
ried out in terms of sustaining the hemoglobin deficiency in the United States. MMWR Recomm Rep
levels among those with chronic blood loss and 47: 129.
are sorely needed to provide physicians with good Clark, S.F. (2009) Iron deficiency anemia: Diagnosis
practice-based guidelines. and management. Curr Opin Gastroenterol
25: 122128.
Research questions include the therapeutic doses Clouse, R.E., Costigan, D.J., Mills, B.A. and
and frequency of iron infusions indicated, as well Zuckerman, G.R. (1985) Angiodysplasia as a cause of
as, which indices are best to guide therapy and upper gastrointestinal bleeding. Arch Intern Med
identify when additional infusions are necessary. 145: 458461.
Many physicians remain hesitant in implement- Conrad, M.E. (2009) Iron deficiency anemia.
ing intravenous iron therapy in patients with emedicine. http://emedicine.medscape.com/article/
chronic blood loss from the gut. Until we are 202333-overview.
able to get answers to these questions, many Conrad, M.E. and Umbreit, J.N. (1993) A concise
patients with chronic gastrointestinal bleeding review: Iron absorption the mucin-mobilferrin-
will continue to receive substandard therapy for integrin pathway. A competitive pathway for metal
iron deficiency anemia and suffer end-organ absorption. Am J Hematol 42: 6773.
damage because of chronic anemia. De Domenico, I., Lo, E., Ward, D.M. and Kaplan, J.
(2009) Hepcidin-induced internalization of ferropor-
Funding tin requires binding and cooperative interaction with
DYG is supported in part by the Office of Jak2. Proc Natl Acad Sci U S A 106: 38003805.
Research and Development Medical Research Harrington, M., Hotz, C., Zeder, C., Polvo, G.O.,
Service Department of Veterans Affairs, Public Villalpando, S., Zimmermann, M.B. et al. (2011) A
Health Service (grant numbers DK56338, comparison of the bioavailability of ferrous fumarate
and ferrous sulfate in non-anemic Mexican women
which funds the Texas Medical Center
and children consuming a sweetened maize and milk
Digestive Diseases Center, and DK067366, drink. Eur J Clin Nutr 65: 2025.
DK067366 and CA116845). The contents are
solely the responsibility of the authors and do Hillman, R.S. and Henderson, P.A. (1969) Control of
marrow production by the level of iron supply. J Clin
not necessarily represent the official views of the Invest 48: 454460.
VA or NIH.
Looker, A.C., Dallman, P.R., Carroll, M.D., Gunter,
E.W. and Johnson, C.L. (1997) Prevalence of iron
Conflict of interest statement deficiency in the United States. JAMA 277: 973976.
The authors have no potential conflicts of interest
with regard to this work. Lysionek, A.E., Zubillaga, M.B., Salgueiro, M.J.,
Caro, R.A., Leonardi, N.M., Ettlin, E. et al. (2003)
Stabilized ferrous gluconate as iron source for food
fortification: Bioavailability and toxicity studies in rats.
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