revised May 15, 2003
Magnitude of the problem
Iron deficiency is a leading cause of anemia, affecting over one-half
billion people world wide. Blood loss nearly invariably is the culprit
producing iron deficiency in adults. The high demand for iron created by
neonatal and adolescent growth spurts occasionally produces iron deficiency
in children. Nonetheless, blood loss is the most frequent cause of iron
deficiency in this group as well. Body iron stores for women normally vary
between one and two grams while men average three to four grams. The liver
is the site of most storage iron. Depletion of iron stores precedes impaired
production of iron-containing proteins, the most prominent of which is
hemoglobin. The two key stages of iron deficiency, are (1) depletion of
iron stores without anemia, and (2) depletion of iron stores with anemia.
Iron replacement therapy cannot be comfortably undertaken until the cause
of the iron deficit is ascertained.
Abnormal iron uptake from the gastrointestinal tract
All iron in the universe is produced in the cores of stars and
by supernovae in a process called nucleosynthesis (Ferris, 1997). Although
the element is the second most abundant metal in the earth's crust, iron's low solubility makes its acquisition for metabolic use a major challenge.
Most environmental iron exists as insoluble salts. Gastric acidity assists
conversion to absorbable forms, but the efficiency of this process is limited.
Many plants produce powerful chelators, such as the phytates (organic polyphosphates)
found in wheat products, that further impair iron absorption (Gillooly
et al., 1984). The challenge of acquiring sufficient iron from the environment
possibly the fueled the spread of the gene for hereditary
Table 1. Factors that modifiy iron absorption
|Physical State (bioavailibility)
||heme > Fe2+> Fe3+
|High Gastric pH
||hemigastrectomy, vagotomy, pernicious anemia
histamine H2 receptor blockers, calcium-based antacids
|Disruption of Intestinal Structure
||Crohn's disease, celiac disease (non-tropical sprue)
||phylates, tannins, soil clay, laundry starch, iron overload
||cobalt, lead, strontium
||ascorbate, citrate, amino acids, iron deficiency
High gastric pH reduces the solubility of inorganic iron, impeding absorption.
Surgical interventions, such as vagotomy or hemigastrectomy for peptic
ulcer disease, formerly were the major causes of impaired gastric acidification
with secondary iron deficiency (Baird et al., 1974; Magnusson, et al.,
1979). Calcium carbonate based antacid compounds are more likely
to produce iron deficiency than are those that contain magnium hydroxide
or aluminum hydroxide (Wienk, et al, 1996), (O'Neil-Cutting, et al, 1986).
Large doses of histamine H-2 blockers can reduce iron absorption (Skine,
et al., 1981). Rountine use of these agents produce iron deficiency only
occasionaly, and then often with other confounding issues such as phytate
ingetion with bran cereals. Despite markedly reducing gatric acidity, the
more recently introduced acid pump blockers appear to cause iron deficiency
infrequently (Koop, et al., 1992; Stewart, et al., 1998). These apparent
paradoxes highlight the substantial deficits that exist in our understanding
of the mechanics of iron absorption.
The impaired function of the gastric parietal cells associated with
pernicious anemia not only reduces the production of intrinsic factor,
but also lessens gastric acidity. Impaired iron absorption can result.
In addition, the megaloblastic enterocytes absorb iron poorly. Frank iron
deficiency can accompany the anemia produced by cobalamin deficiency. The
serum iron level and transferrin saturation often are artifactually high
in patients with pernicious anemia (Demiroglu, et al., 1997). Pernicious
anemia slows hematopoiesis significantly. Since 80% of circulating iron
is destined for the the erythron and red cell production, the iron
accumulates on plasma transferrin awaiting use. Correction of pernicious
anemia dramatically increases hematopoiesis, with a consequent drop in plasma tranferrin
iron levels. A recheck of plasma transferrin saturation
should be performed within a week or two of the start of treatment for
pernicious anemia to ensure that iron stores can support the higher rate of erythropoiesis.
Hemin, the most readily absorbed form of iron, is taken up independently
of gastric pH. The molecule is, of course, derived primarily from animal
tissue. The scarcity of dietary meat for much of the world's population
increases the risk of iron deficiency. The fact that cultivated grasses,
such as rice, are dietary staples for many people exacerbates the problem
since these plants are very poor sources of iron. The consequences of iron
deficiency can be quite severe.
Inhibition of Iron
A number of environmental factors can produce dietary iron deficiency,
including metals that share the iron absorption machinery, such as lead,
cobalt, and strontium (Table 1). Of these only lead is a significant problem.
For children, the threat is particularly marked. Iron deficiency increases
the rate of uptake both of iron and lead from the gastrointestinal tract.
Iron deficiency and lead intoxication, consequently, are common companions
(Nicholls and McLachlan, 1990).
Disruption of the Enteric
Some disorders disrupt the integrity of the enteric mucosa, thereby
hampering iron absorption. Inflammatory bowel disease, particularly Crohn's
disease, can injure extensive segments of the small intestine, occasionally
extenting to the jejunum and even the duodenum. Invasion of the submucosa
by inflammatory cells and disruption of the tissue architecture of the
intestine impair iron absorption and uptake of dietary nutrients (Beeken,
1973). Occult gastrointestinal bleeding can accompany these condtions and exacerbate the problem of iron
balance. The resulting iron deficiency anemia is further complicated by the anemia
of chronic inflammation. Also, Crohn's disease frequently involves the
terminal ileum, producing concurrent cobalamin deficiency.
Sprue, both of the tropical and non-tropical variety (celiac
disease), can also interfere with iron absorption. Degeneration of the
intestinal lining cells along with chronic inflammation causes profound
malabsorption. The anemia due to chronic inflammation and iron deficiency
often is complicated further by nutritional deficiency. Celiac disease
frequently improves dramatically with a gluten-free diet. Some patients
with deranged iron absorption lack gross or even histologic changes in
the structure of the bowel mucosa. The disease can be mild to the point
that it produces few or no symptoms (Corazza et al., 1995). A gluten-free
diet improves bowel function in many such patients, with secondary correction
of the anemia.
Loss of Functional
Substantial segments of bowel are sometimes removed surgically,
disrupting iron absorption. Intractable inflammatory bowel disease occasionally
is treated by surgical excision. Traumatic abdominal injury, as occurs
with motor vehicle accidents, also requires extensive bowel resection
at times. Structural complications, such as intestinal volvulus or intusseception,
sometimes necessitate removal of significant stretches of bowel in children.
Iron deficiency usually develops slowly, and may not become evident for
several years after the surgical procedure.
Dysfunction of the gastrointestinal absorption machinery is a
very rare cause of iron deficiency. The prototype of this genre of problem
is the mk/mk mouse. These animals fail both to absorb iron from the gastrointestinal
tract and to incorporate transferrin-bound iron into developing normoblasts
in the bone marrow. The result is animals with a severe iron-deficiency
anemia. Deficient synthesis of the recently cloned iron transport protein,
NRAMP2 (now designated, DMT1), causes the problem (Fleming, et al., 1997).
Impaired gastrointestinal iron absorption and defective erythrocyte production
in at least one family appears to result from a deficit in the human analogue
Blood loss is the world's leading cause of iron deficiency. The gastrointestinal
tract is both the site of iron uptake and the most common site of blood
loss. The gastrointestinal tract is unrivalled as a potential site of occult
Gastrointestinal Blood Loss
Other sources of blood loss
Blood loss due to gastrointestinal structural faults commonly
causes iron deficiency. The most frequent congenital defect in the gastrointestinal
tract is Meckel's diverticulum, a persistent omphalomesenteric duct. The
flaw can produce abdominal pain and, occasionally, intestinal obstruction
in young children. Occult blood loss with secondary iron deficiency occurs
in some adolescents with Meckel's diverticulum.
Colonic arteriovenous malformations commonly cause occult blood
loss in older people. These lesions often are extremely difficult to detect,
even while producing major blood loss. Arteriographic imaging of the arteries
that supply the colon frequently is the only way to detect these defects.
Arteriovenous malformations involving the superficial blood vessels along
the gastrointestinal tract also occur with the rare disorder, hereditary
hemorrhagic telangectasia (the Osler-Weber-Rendu syndrome.) These defective
vessels frequently bleed to a degree that engenders iron deficiency. Although
the disorder displays autosomal dominant transmission, the pathognomonic
lesions rarely attain clinical significance prior to early adulthood. The
condition is not a diagnostic enigma, since the mucosal lining of the oropharynx
and nasal cavity exhibit characteristic telangectasia.
Peptic ulcer disease, another condition that produces gastrointestinal
bleeding and iron deficiency, most often affects the stomach and duodenum.
Inflammation and erosion of the gastrointestinal surface are prominent
at affected sites. The recent discovery that many cases of peptic ulcer
disease are associated with Helicobacter pyloriinfection has prompted
the use of antibiotics as part of the treatment regimen (Margnani, et al.,
1997). While some people experience post prandial pain and stomach bloating,
others are asymptomatic. Another common cause of gastrointestinal blood
loss is gastric hiatal hernia. This conditional can also produce a painful
Whole cow's milk contains proteins that often irritate the lining of
the gastrointestinal tract in infants. Low grade hemorrhage sometimes produces
iron deficiency. Although cow's milk contains iron at about the same concentration
as does that from humans, the bioavailability of iron in human milk is
much greater. In addition, the prodigious neonatal growth spurt demands
a tremendous quantity of iron. The intersection of blood loss and decreased
iron intake (due to the immaturity of the gastrointestinal tract) with
a high demand, makes iron-deficiency a significant problem for children
nourished with whole cow's milk. Although the processing that goes into
the manufacture of evaporated cow's milk apparently reduces the irritating
nature of the proteins, avoiding this source of nutrition is probably the
wisest course of action (American Academy of Pediatrics, Committee on Nutrition,
The world's leading cause of gastrointestinal blood loss is parasitic
infestation. Hookworm infection, caused primarily by Necator americanus
or Ancylostoma duodenale, is endemic to much of the world and often
is asymptomatic. Microscopic blood loss leads to significant iron deficiency,
most commonly in children (Hopkins et al., 1997). Over one billion people,
most in tropical or subtropical areas, are infested with gastrointestinal
parasites. Daily blood losses exceed 11 million litres. The larvae spawn
in moist soil and penetrate the skin of unprotected feet. Hookworm infection,
once prevalent in the southeastern United States, declined precipitously
with better sanitation and the routine use of footwear out-of-doors (Stoltzfus,
et al., 1997).
Trichuris trichiura, the culprit in trichuriasis or whipworm
infection, is believed to infest the colon of 600 to 700 million people.
Only about 10 to 15 percent of these people have worm burdens sufficiently
great to produce clinical disease. Most are children between the ages of
2 and 10 years, however. Growth retardation, in addition to iron deficiency,
occurs with heavy infestations. Trichuriasis is the most common helmuthic
infection encountered in Westerners returning from visits to tropical or
subtropical regions of the world.
Occasionally, blood loss into the urinary tract outstrips iron
absorption. Urinary blood loss usually is sufficiently alarming that patients
seek medical attention before substantial iron deficiency develops, however.
Iron deficiency resulting from hematuria due to renal or bladder disease
is relatively uncommon.
The one of the best characterized causes of substantial renal
blood loss is Berger's disease, which produces relapsing episodes of gross
or microscopic hematuria. The disorder occurs most commonly in older children
and young adults. Diffuse mesangial proliferation or focal and segmental
glomerulonephritis are the most common renal pathologies. Diffuse mesangial
deposits of IgA are the hallmark of the disorder. Although the disease
spontaneously remits in some children, progression to end-stage renal disease
occurs in a substantial minority. Occasionally, Goodpasture's syndrome
produces substantial urinary blood loss. Immunofluorescent staining of
biopsy specimens reveals the characteristic antibodies to basement membrane
lining the glomeruli. Blood loss into the urinary bladder occurs most commonly
in association with infections. Hematuria to the point of iron deficiency
is extremely uncommon, however.
People who have sickle
cell trait occacionally develop gross hematuria (McInnes, 1980). Renal
papillary necrosis secondary to sickling in the high osmolar, relatively
acidic condition in renal medulla is believed to contribute significantly
to the problem. Bleeding is nearly always from the left kidney and can
presist for weeks or even months. Conservative management with bedrest,
urinary alkalination, and possibly DDAVP are tbe best approaches. Surgical
interventions tend not to provide definitive treatment, and risks further
Although pulmonary blood loss sufficiently severe to produce iron deficiency
occurs, the phenomenon is distinctly rare. Pulmonary blood loss includes
not only hemoptysis, but also bleeding into the lung airways where the
blood and debris are ingested by macrophages and stored as hemosiderin.
Since these macrophages are distinct from the normal iron recycling circuit,
iron that is trapped within these cells is effectively lost to body metabolism.
Chronic pulmonary infection with bronchiectasis, once a frequent cause
of this problem, now is quite rare.
Idiopathic pulmonary hemosiderosis, a condition characterized
by recurrent pulmonary hemorrhage along with pulmonary fibrosis and right
heart strain, leads to iron deficiency in some patients. A few patients
have been described with diffuse pulmonary hemosiderosis in association
with immunologically mediated disorders such as Goodpasture's syndrome
or celiac disease. Most often the etiology is unknown. Treatment of the
associated disorder has been associated with remission of the pulmonary
process, suggesting an immunologic mechanism to the lung injury. A variety
of treatments have been tried, such as immunosuppression, generally with
only modest success. Iron deficiency is a relatively minor issue in the
clinical course of these often severely ill patients.
Consequences of iron deficiency
Although anemia is most prominently linked to iron deficiency, the
condition produces a wide range of abnormalities, depending on its severity
and duration. Some of these abnormalities, such as cognitive dysfunction
in young children, have been recognized only recently.
Since most iron is directed to hemoglobin synthesis, erythrocyte
production is among the first casualties of iron deficiency:
prelatent iron deficiency occurs when stores are depleted without a change
in hematocrit or serum iron levels.
This stage of iron deficiency is rarely detected.
latent iron deficiency occurs when the serum iron drops and the TIBC increases
without a change in the hematocrit. This stage is occasionally detected
by a routine check of the transferrin saturation.
frank iron deficiency anemia is associated with erythrocyte microcytosis
and hypochromia. Iron deficiency attracts medical attention most commonly
at this stage.
Figure 1. Photomicrograph of blood cells from a patient with
iron deficiency anemia.
The microcytic, hypochromic anemia impairs tissue oxygen delivery,
producing weakness, fatigue, palpitations, and light-headedness (Figure
1). Thalassemia trait is sometimes
confused with iron deficiency, since the condition is characterized by
microcytosis and sometimes mild anemia. Iron deficiency alters red cell
size unevenly as shown in Figure 1. Electronic blood analysers determine
the mean red cell volume (MCV) as well as the range of variation in red
cell size (expressed as the RDW or red cell distribution width). The RDW
(determined with every electronically processed complete blood count) is
normal in patients with thalassemia trait but is high with iron deficiency
(Lin et al., 1992). Other common features of thalassemia trait are basophilic
stippling and target cells. These characteristics are not sufficiently
unique to distinguish between thalassemia trait and iron deficiency, however.
The plasma membranes of iron deficient red cells are abnormally
rigid (Tillman, et al., 1980). This rigidity could contribute to poikilocytic
changes, seen particularly with severe iron deficiency. These small, stiff,
misshapen cells are cleared by the reticuloendothelial system, contributing
to the low-grade hemolysis that often accompanies iron deficiency. The
cause of this alteration in erythrocyte membrane fluidity is unknown.
Growth and developmental retardation
Iron deficiency, with or without concomitant anemia, commonly impairs
growth and intellectual development in children. Studies of cognitive development
in the setting of iron deficiency produced disparate results for a time.
In some investigations, dietary iron supplementation for infants reversed
cognitive dysfunction, while others failed to show improvement. Some of
the disparities may have resulted from differences in the instruments used
in the analyses, and differences in the populations examined.
The Bayles Scales of Infant Development, uncovers abnormalities
in children as young as 9 to 12 months of age. Developmental abnormalities
occur with or without anemia. In one study, iron replacement increased
the Mental Development Index scores substantially in only seven days. Iron
deficiency does not impair motor development even in infants with low scores
on the tests of cognitive development. Concomitant lead exposure can further
hamper the psychological development of these children.
Information on the long-term effects of iron deficiency during
infancy highlights the importance of early intervention. One group of children
with iron deficiency anemia (hemoglobin less than 10 g/dl) was treated
during infancy and tested for cognitive development at five years of age
(Lozoff et al., 1991). This cohort scored lower in tests of mental and
motor functioning than did their counterparts, despite correction of the
deficiency during infancy. The disparity persisted despite adjustments
for differences in socioeconomic background. The investigators soberly
concluded that children who are iron deficient during infancy are at risk
of long-lasting developmental disadvantage relative to peers with better
iron status. Other investigations concur. Correction of iron deficiency
during infancy clearly improves scores in short-term tests, such as the
Bayles Scales of Infant Development, without preventing longer-term, and
possibly more serious, impairment in cognitive function. Health care providers,
therefore, must strive to prevent iron deficiency during infancy (Oski,
The mechanism by which iron deficiency impairs neurologic function
is unknown. Many enzymes in neural tissue require iron for normal function.
The cytochromes involved in energy production, for example, predominantly
are heme proteins. In rats,
weanlings maintained on iron deficient diets develop severe behavioural
anomalies, motor incoordination, and seizures. The abnormalities seen in
iron deficient children and adults are much less pronounced, but are a
source of serious concern nonetheless.
The effect of iron deficiency on childhood growth is often difficult
to separate from overall nutritional deficiency. The high prevalence of
childhood iron deficiency among less affluent people has yoked deficiencies
of iron and general nutrients. When the two factors have been separated,
correction of iron deficiency improves growth independently of nutritional
Iron deficiency produces significant gastrointestinal tract abnormalities,
reflecting the enormous proliferative capacity of this organ. Some patients
develop angular stomatitis and glossitis with painful swelling of the tongue.
The flattened, atrophic lingual papillae makes the tongue smooth and shiny.
A rare complication of iron deficiency is the Plummer-Vinson syndrome with
the formation of a postcrycoid oesophageal web. Long-standing, severe iron
deficiency affects the cells that generate the finger nails producing koilonychia.
The nail substance is soft, so that ordinary pressure on the fingertips,
as occurs with writing for instance, produces a concave deformity. The
"spoon-shaped" changes featured in many text books are rare. Koilonychia
usually is much more subtle. Often, a transverse depression or depressions
across the thumb nail is the only manifestation. The alteration most commonly
affects the right thumb nail, reflecting the right-handedness of most people.
Pica occurs variably in patients with iron deficiency. The precise
pathophysiology of the syndrome is unknown. Patients consume unusual items,
such as laundry starch, ice, and soil clay. Both clay and starch can bind
iron in the gastrointestinal tract, exacerbating the deficiency (Roselle,
1970). A dramatic example of the problems produced with clay consumption
occurred in the 1960s with reports of iron deficiency in children along
the border between Iran and Turkey (Say, et al., 1969). These youngsters
had other, peculiar abnormalities including massive hepatosplenomegaly,
poor wound-healing, and a bleeding diathesis. Presumably, the children
initially had simple iron deficiency associated with pica, including geophagia.
The soil contained compounds that bound both iron and zinc. The secondary
zinc deficiency caused the hepatomegaly and other unusual abnormalities.
Unexplained thrombocytosis occurs frequently with platelet counts
in the range of 500,000 to 700,000 cells /fl. Megakaryocytes and normoblasts
are derived from a common committed progenitor cell, the CFU-GEMM (colony-forming
unit, granulocytic, erythroid, myelomonocytic). Thrombopoietin, the molecule
that stimulates the growth of megakaryocytes and the production of platelets,
is structurally similar to erythropoietin; the molecule that promotes red
cell development. Some investigators speculated that the elevated levels
of erythropoietin in patients with iron deficiency anemia might modestly
increase platelet production by cross-reacting with the thrombopoietic
receptor. Investigations with recombinant human erythropoietin and thrombopoietin
indicate that cross-reactivity does not occur. The etiology of the thrombocytosis
in iron deficiency remains a mystery.
Diagnosis of iron deficiency anemia
The Effect of Iron Deficiency on Serum Levels of Transferrin,
Iron and Ferritin
Iron deficiency anemia lowers the number of circulating red cells
(a feature of all anemias). The red cells are microcytic (usually less
than 80 fl in size) and hypochromic. The quantity of the iron-carrying
protein, transferrin, in the circulation increases over baseline by 50%
to 100%. The quantity of iron on transferrin can fall by as much as 90%.
Consequently the transferrin saturation frequently declines from its usual
30% to under 10%. Figure 2 schematically illustrates these changes.
|Figure 2. Changes in Serum Levels of Transferrin, Iron, and Ferritin
Produced by Iron Deficiency. The panel on the left shows the normal
serum levels of transferrin, iron, and ferritin, in arbitrary units. The
panel on the right shows the effect of iron deficiency on these values.
The increase in serum transferrin level along with a fall in serum iron
level lowers the transferrin saturation (serum iron level divided by the
serum transferrin level.) The best laboratory indicator of body iron stores
is the serum ferritin level, which drops substantially in people with iron
The most useful single laboratory value for the diagnosis of
iron deficiency may be the plasma ferritin. Ferritin is the cellular storage
protein for iron. Plasma ferritin differs from its cellular counterpart
in several respects, and appears to be a secreted protein of a different
origin (Arosio, et al., 1977). The plasma ferritin value often falls to
under 10% of its baseline level with significant iron deficiency.
Other phenomena, such as chronic inflammation with rheumatoid
arthritis, perturb the plasma values of iron, transferrin, and ferritin.
Establishing the diagnosis of iron deficiency in these patients can be
difficult. The situation is further complicated by the fact that chronic
per se can produce anemia (Sears, 1992). Newer tests,
such as assay of circulating transferring receptors, can help with the
diagnosis of iron deficiency in many instances (Shih, et al., 1993). If
all else fails, a bone marrow biopsy with Prussian blue staining for iron
is the touchstone for the diagnosis.
Treatment of iron deficiency
The most important steps in the evaluation and treatment of iron
deficiency are determining the cause of the deficiency, and correcting
the abnormality. Malignancy of the gastrointestinal is the haunting spectre
in adults with iron deficiency. In children, iron deficiency due to growth
spurts, poor dietary patterns, or benign gastrointestinal bleeding sources
are much more common. After the cause of the iron deficiency has been ascertained,
oral iron supplementation replaces stores most efficiently.
Oral iron supplementation
Oral iron supplementation is the ideal way to replace iron stores
as it uses the body's normal mechanisms. The shortcoming is the gastrointestinal
tract's limited capacity for iron absorption. Only about 2 to 3 mg of elemental
iron are absorbed, even when 50 or 100 mg are presented to the gut lumen.
Most orally consumed iron flows untouched through the alimentary tract.
Replenishing a 2,000 mg iron deficit can take most of a year. With ongoing
blood loss, replacement of stores with oral iron becomes a herculean task.
Many, if not most, patients fail to comply with such a prolonged medical
regimen. Therapeutic failures are common with oral iron replacement.
Table 2. Poor Response to Oral Iron
|On-going Blood Loss
|Insufficient Duration of Therapy
|High Gastric pH
histamine H-2 blockers
|Inhibitors of Iron Absorption/Utilization
aluminum intoxication (hemodialysis patients)
Although ferrous sulphate is often recommended to treat iron deficiency,
frequent problems with the drug including gastrointestinal discomfort,
bloating and other distress, make it unacceptable to many patients (Table
2). Ferrous gluconate, which is roughly equivalent in cost, produces fewer
problems, and is preferable as the initial treatment of iron deficiency.
Ascorbic acid supplementation enhances iron absorption. Combination tablets
containing iron salts and ascorbic acid are significantly more expensive
than separate tablets for each, however.
Polysaccharide-iron complex, a replacement form of iron that
differs from the iron salts, is a more recent option. The polar oxygen
groups in the polysaccharide form coordination complexes with the iron
atoms. The well-hydrated microspheres of polysaccharide iron remain in
solution over a wide pH range. Most patients tolerate this form of iron
better than the iron salts, even though the 150 mg of elemental iron per
tablet is substantially greater than that provided by iron salts (50 to
70 mg per tablet). No study exists comparing iron uptake from polysaccharide-iron
complex and ferric salts.
Parenteral iron replacement
Parentaral iron is available either as iron dextran or iron saccharide
(commonly ferric polymaltose). Only iron dextran has been licensed for
general use in the U.S. A ferric polymaltose compound, Ferrlicit®,
has been licensed for use in patients on hemodialysis who need parenteral
iron replacement. Similar drugs have been used in Europe and the rest of
the world for decades. The incidence of side effects, particularly the
dreaded though uncommon anaphylaxis, is far less with the iron saccharide
compounds. Current investigations are underway aimed at broadening the
FDA-approved indications. Ferrelicit has been used safely in patients who
have had anaphylactic reactions to iron dextran.
Parenteral iron is indicated when i) oral iron is poorly tolerated,
ii) rapid replacement of iron stores is needed, or iii) gastrointestinal
iron absorption is compromised. Iron-dextran can be administered via intramuscular
or intravenous injection. Intramuscular injection of iron-dextran can be
painful, and leakage into the subcutaneous tissue produces long-standing
skin discoloration. A "Z-track" injection into the muscle minimizes the
chance of subcutaneous leak. Suboptimal muscle mass frequently associated
with nutritional deficiency further complicates this mode of replacement.
Intravenous infusion of iron-dextran circumvents these problems altogether
(Auerbach et al., 1988). Commonly, patients are given total
dose infusion replacement with iron dextran,
with entails the adminstration of up to 3,000 mg at a single sitting (Ahsan,
1998). This is the fastest way to replete iron stores. With either route
of administration, a test dose of 10 mg of iron should be given and the
patient observed by a physician for 30 minutes to rule out an anaphylactic
reaction to the medication (such reactions are infrequent).
About 10% to 15% of patients experience transient mild to moderate
arthralgias the day after intramuscular or intravenous administration of
iron-dextran. Acetaminophen usually effectively relieves the discomfort.
Administration of methylprednisolone at a dose of 1 mg/kg after the test dose and before the repletion dose virtually eliminates
this reaction. Premedication with steroids is particularly helpful for
patients with autoimmune inflammatory disorders such as rheumatoid arthritis.
The treatment strategy largely suppresses the pain flairs of disease that
these patients can otherwise experience. The symptoms possible result from
release of inflammatory cytokines such as interleukin-1 and tumour necrosis
factor. The iron dextran is cleared from the circulation by fixed tissue
macrophages, which probably are activated to release these proinflammatory
Iron saccharide complexes work at least as well as iron-dextran
when administered intravenously. Anaphylaxis occurs extremely infrequently
with these drugs. The other side effects seen with iron dextran, such as
fevers, dyspnea, and myalgias are also very uncommon with the iron saccharides.
They are the preferred formulation in countries where it is available.
Total dose infusion cannot be used with iron saccharide complexes because significant side-effects occur with doses that exceed about 250 mg. Patients wiht large iron deficits therefore require multiple treatments with these medications.
In uncomplicated cases of iron deficiency, IV replacement produces
subjective improvement in a few days. Peak reticulocytosis occurs after
about 10 days, and complete correction of the anemia can take 3 to 4 weeks.
The hematocrit rises sufficiently in a week or two to provide symptomatic
relief for most patients.
Functional iron deficiency
Human erythropoietin was one of the first agents of widespread clinical
utility produced by recombinant DNA technology (rHepo) (Adamson, et al.,
1990). Used to correct the anemia of end-stage renal disease (ESRD), this
hormone has provided new insight into the kinetic relationship between
iron and erythropoietin in red cell production. Erythropoietin treatment
of anemia in patients with ESRD has also underscored the variable nature
of storage iron. The shifting states of storage iron contribute to the
inconsistency with which erythropoietin corrects the anemia of renal failure.
With steady-state erythropoiesis, iron and erythropoietin flow
to the bone marrow at constant, low rates. In patients with ESRD, recombinant
human erythropoietin (rHepo) is administered in intermittent surges, most
commonly as intravenous boluses. The resulting kinetics of erythropoiesis
are markedly unphysiological and strain the production process (Madore,
et al., 1997). Erythropoietin, the accelerator of erythroid proliferation
is not coordinated with the supply of iron, the fuel for erythroid proliferation.
This imbalance almost never occurs naturally. The rHepo jars previously
quiescent cells to proliferate and produce hemoglobin. The requirement
for iron jumps dramatically, and outstrips its rate of delivery by transferrin
Interplay between iron and erythropoietin
Erythropoietin stimulates proliferation and differentiation of erythroid
precursors, with an upsurge in heme synthesis. Iron is taken into the cells
from ferrotransferrin by cell surface transferrin receptors, is transported
to the mitochondria, and inserted into the protoporphyrin
IX ring by ferrochelatase (Ponka, 1997). The newly synthesized heme
modulates globin synthesis in part through its effect on the translational
factor, eIF-2. Primitive erythroid cells have relatively few transferrin
receptors. The number increases with differentiation, peaking at over 106
per cell in the late pronormoblasts. The number subsequently declines,
to the point that mature erythroid cells lack transferrin receptors altogether.
This variable expression of transferrin receptors means that iron delivery
must be synchronized both with proliferation and stage of erythroid development.
Late normoblasts, for instance, cannot compensate for iron that was not
delivered during the basophilic normoblast stage. These cells have fewer
transferrin receptors, and those receptors are busy supplying iron for
currently produced heme molecules.
Transferrin-bound iron bound is the only important source of
the element for erythroid precursors. Even with normal body iron stores
and normal transferrin saturation, robust proliferation of erythroid precursors
can create a demand that outstrips the capacity of the iron delivery system
(Brugnara et al., 1994). Transferrin iron saturation falls as the available
iron on plasma transferrin is stripped off by voracious erythroid precursors.
Plasma iron turnover (PIT) rises, as does erythron iron turnover (EIT)
and erythron transferrin uptake (ETU) (Hotta, et al, 1991). The late arrival of newly mobilized
storage iron fails to prevent production of hypochromic cells. This is
"functional iron deficiency" or "iron-erythropoietin kinetic imbalance".
The ESRD patients who initially received erythropoietin had substantial
iron stores. More importantly, supraphysiological quantities of iron were
bound to their circulating transferrin (i.e., transferrin saturations of
70 to 90%). As a result, even the bursts of heme production induced by
pharmacological levels of exogenously administered rHepo could be matched
by the available transferrin-bound iron. In these patients, the rate limiting
factor in erythrocyte synthesis was the proliferative capacity of the erythroid
precursors. The number of red cells produced was determined by the number
of precursor cells and the quantity of erythropoietin they encountered.
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