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521-534, 2004
Copyright Taylor X: Fninci.s Inc.
ISSN: 0888-0018 prim / I521-0C69 online
DOI: 10.1080/08880010490477310
^ TaylorStFrancis
TP healthsciences
Iron is an essential nutrient well known to the ancient Greeks, and it was
recognized as a blood component more than 200 years ago [1]. Iron deficiency is the single most common nutritional disorder worldwide and the
leading cause of anemia during infancy and childhood [2]. Its appearance
in early childhood, especially if severe and prolonged, can adversely affect
behavior and psychomotor development, side effects that may not always be
fully reversible even with complete correction of iron deficiency [3].
This article reviews the epidemiology, etiology, clinical manifestations,
laboratory findings, diagnosis, treatment, and prevention strategies of irondeficiency anemia during the whole childhood.
DEFINITION OE IRON DEEICIENCY ANEMIA (IDA)
Anemia is a relatively common finding and correct diagnosis can usually
be established with relatively little discomfort for patient and little laboratory
cost. Finding the cause is always important.
Received 21 October 2003; accepted 27 April 2004.
Address correspondence to John P. Panagiototi, MD, Gennadioti 1, 184 52 Nikea, Athens, Greece.
E-mail: costasdouros@freemail.gr
521
522
Gord blood
2wk
3 mo
6 mo-6 yr
7-12 yr
Ht 1(%)
MGV
Mean
Range
Mean
Range
lowest
RtG (%)
16.8
16.5
12.0
12.0
13.0
13.7-20.1
13.0-20.0
9.5-14.5
10.5-14.0
11.0-16.0
55
50
36
37
38
45-65
42-66
31-41
33-42
34-40
110
5.0
1.0
1.0
1.0
1.0
70-74
76-80
During infancy and childhood the normal ranges for hemoglobin and
hematocrit levels vary significantly and for this reason diagnosis of anemia
depends on normal values for each examined age (Table 1). A characteristic
example is that of normal neonates who show an increased hemoglobin level
after birth (15-22 g/dL), whereas, during infancy, under normal circumstances, have hemoglobin level as low as 10 g/dL, while premature infants
can reach a nadir hemoglobin level of 7-8 g/dL in the 8th-10th postnatal
week [4]. Thereafter, the normal values gradually increase until adult values
are reached after puberty.
Iron deficiency represents a total-body iron deficit, resulting from imbalance between iron requirements and iron supply. This deficit initially
is compensated by the mobilization of iron stores, which are represented
by ferritin levels. Three successive stages of iron deficiency may be distinguished [46]. Initially, storage iron deficiency is recognized by a decreased
serum ferritin (SF) concentration without any biochemical evidence of iron
deficiency. Later on, iron deficiency results in low serum ferritin (below
12 Mg/L) and iron concentration, progressive rise in the concentration of
serum-transferring receptor (TfR), increase in free erythrocyte protoporphyrin (FEP), and low serum transferrin saturation. During this period,
erythropoiesis becomes affected, although hemoglobin levels remain within
normal limits. Finally, anemia occurs when the supply of iron to the bone
marrow is sufficiently impaired presenting with a decrease in Hb concentration below of the 5th percentile of the reference range for age and sex. At
the same time, there is a decrease in the synthesis of iron metalloenzymes,
which are vital components of many metabolic pathways.
EPIDEMIOLOGY OE IDA AND IRON METABOLISM
523
Normal-term infants are born with sufficient iron stores, having approximately 75 mg of elemental iron per kilogram of body weight [8], Totalbody iron changes vary little for the first 4 months of life so there are no
increased requirements during this period. In addition, the reduction of Hb
levels from 18 g/dL at birtb to 14 g/dL during the first 2 weeks of life releases iron, which is stored and gradually reused. Good absorption of human
milk and the increased use of iron-fortified formula, especially in developed
countries, fulfill the iron requirements in these ages, resulting in reduction
of cases with IDA during the first 4 months [9, 10], However, infants who
continue to receive only breast milk after the first 6 months of life are at increased risk. Also at risk are infants who, despite current policy, switch from
an infant formula to whole cow's milk before the age of 1 year [11], Between 4 and 12 months total-body iron increases by about 130 mg and an
external source of iron is necessary. If this is not met, iron deficiency and
subsequently IDA develop after the age of 1 year [12],
The highest prevalence of IDA occurs in toddlers and adolescents because the increment in hemoglobin iron per unit of body weight is greatest
at these ages [7, 12], The prevalence drops among school-age children but
increases again during adolescence [5], Factors that are implicated in this increase are mainly the dietary characteristics of adolescents. Many girls try to
control their weight and inadvertently limit iron intake, while many adolescents pass through a temporary period of vegetarianism because of concerns
with animal welfare. Moreover, athletic performance may lead to blood loss
from the gut and urinary tract, so athletic girls who have passed menarcbe
and are trying to slim may be at particular risk of iron deficiency [13],
IRON METABOLISM
Tbe human body contains about 3-4 g of iron [14], Iron is absorbed
mainly in tbe duodenum and upper jejunum, is transported in blood by
transferrin, and it is found either biologically active (70-90%) or stored
(10-30%), Tbe former is found mainly incorporated in hemoglobin, and
the latter in the reticuloendothelial cells (bone marrow, liver, spleen) as ferritin, a labile and readily accessible source of iron, or in an insoluble form
as bemosiderin [15],
The amount of iron absorption increases when iron deficiency exists,
while when stores are high, much of the iron absorbed by the mucosal cells
is returned into the intestinal lumen by desquamation [16], Although the
entire process of the regulation of iron absorption is still poorly understood, three ways are being considered [17], Tbe first is by dietary iron.
Following an oral iron load, the absorption rate diminishes even if there
is a systemic iron deficiency. It is believed that the intracellular accumulation of iron decreases further absorption. The second way depends on the
524
total-body iron stores and is termed the stores regulator. It works with a mechanism still unknown and is capable of increasing iron absorption by only 2-3
times. It has been postulated that the saturation of circulating transferrin
affects the iron "set point" of developing duodenal enterocytes. The third
way is the erylhropoielic regulator. Through this mechanism the iron absorption can be increased greatly in cases of ineffective erythropoiesis, even in
cases where an iron overload exists, Tbalassemia, sideroblastic anemia, and
other congenital disorders of red cell maturation are some examples. It is
worth mentioning that such an increase in iron absorption does not happen
in cases of anemias that are characterized by peripberal destruction, sucb as
sickle cell and autoimmune hemolytic anemias. The mediator of this procedure remains unknown.
Additional factors that influence tbe absorption rate are the composition
of the diet and the efficacy and integrity of the mucosa of the upper small
bowel [18], Tbere are two kinds of iron in the diet with respect to the mechanism of absorption, heme and nonheme, utilizing two different receptors
on the mucosal cells, Heme iron, found in meat, poultry, and fish, constitutes about 5-10% of the daily iron intake in most industrialized countries,
and is highly bioavailable, being 2-3 times more absorbable than nonheme
iron. Its absorption is less influenced by body iron stores, and the only dietary factor that negatively acts on the absorption procedure is calcium [19,
20], Within the mucosal cells, an enzyme splits heme, releasing iron into the
circulation.
The main sources of nonbeme iron are plant-based foods, eggs, and ironfortified foods, primarily in the form of ferric complexes [21], In the process
of digestion, the iron is reduced from tbe ferric to the ferrous form, which is
more readily absorbed. Its absorption is enhanced by ascorbic acid and hydrochloric acid, and inhibited by phytates (in bran), polyphenols (in certain
vegetables and legumes), tannins (in tea), calcium, and pbosphate (in high
concentration in unmodified cow's milk) [16, 22],
After having been absorbed by the enterocytes, the iron must cross the
serosal membrane to enter the circulation. Studies in animals have shown
that a protein similar to ceruloplasmin is probably responsible for this transport [14, 23], Once iron has traversed the serosal membrane it is bound to
transferrin, wbicb is its main vebicle in tbe serum and extracellular fluid.
The transferrin-iron complex beads for the marrow and liver through the
circulation, Transferrin's high affinity for iron protects the body from free
iron, but has the drawback of competing witb iron cbelators. This is the reason why the development of efficient and easy to use chelators is a difficult
task.
The transferrin-iron complexes attach to transferrin receptors, which
are found on every nucleated cell's surface. Liver, placenta, and developing red cells are equipped with large numbers of sucb receptors. After tbe
525
Though various factors may cause IDA, nutritional factors are the most
frequent causes in infancy and childhood (Table 2), Rapid growth during
the first 2 years of life and again during adolescence under conditions of
either decreased or deficient iron uptake may result in IDA, More vulnerable
are preterm infants and twins, baving botb lower iron stores at birth and a
more rapid growth. Their blood volume expansion may be so rapid that their
iron stores may be depleted by 2-3 months of age. Proportional growth spurt
occurs during adolescence and increased iron requirements are needed to
maintain positive balance [5], Especially for adolescent girls, there is more
need for iron because of menstrual blood loss, which is about 40 mL (20 mg
iron) per period [28],
Poor iron diet is a major etiologic factor to the development of IDA,
Both breast and cow's milk bave low levels of iron, containing less than 0,31 mg/L, The iron content of human is highest in early transitional milk
(0,97 mg/L) [29] but decreases steadily during lactation, reaching a level
of approximately 0,3 mg/L by tbe age of 5 months [30], It is important to
stress the high bioavailability of breast milk, possibly because of tbe lower calcium content and the presence of lactoferrin [22], Nevertheless, prolonged
526
Symptoms and signs of IDA vary with the severity of the deficiency and
are often nonspecific. Mild IDA is usually asymptomatic. In infants with more
severe IDA pallor, irritability, fatigue, and delayed motor development are
common, while in the case of feeding with unfortified cow's milk they may
be fat and flabby with poor muscle tone. In older children pallor is the
527
528
levels greater than 400 /xg/dL suggest iron deficiency, whereas values less
than 200 /ig/dL characterize inflammatory diseases [5]. The role of these
tests in the diagnosis of IDA should be reevaluated because of their unpredictable variability and relative insensitivity [42-44].
Ferritin and serum-transferrin receptor (sTfR) are more sensitive indicators of early iron deficiency. Both undergo a gradual change as iron stores
decrease from normal levels to those found in IDA. The continuous process
of iron depletion passes through 3 stages. The first stage, where a progressive
decrease in serum ferritin takes place, represents the depletion of storage
iron compartments. The sTfR, which reflects the functional iron compartments (i.e., hemoglobin, myoglobin, cytochromes, etc.), remains stable. The
second stage is characterized by the depletion of functional iron compounds
and the beginning of iron-deficient erythropoiesis (IDE). The indicator of
this phase is the elevated concentration of sTfR. Finally, the third stage begins with the fall of Hb below the lower normal limits due to the continuing
IDE, and, as a consequence, IDA ensues.
Ferritin measurements have been used to distinguish normality from
IDA, so the reference limits have been designed for this purpose. Disagreement still remains on the value of ferritin that indicates clinically relevant
storage iron depletion. This is chiefly attributed to the large physiologic
variability occurring between individual patients [46, 47]. Another confusing factor is that ferritin is a well-known acute phase reactant that rises in
inflammatory diseases [46, 48]. In any case, levels ranging between 10 and
20 fA-g/h are considered indicative of depletion of iron stores, while levels
less than 10 fJ.g/h are diagnostic of iron deficiency. In reverse, levels greater
than 50 Mg/L argue against the diagnosis of iron deficiency, even in the
presence of other conditions that may cause an elevation of the ferritin level
[5].
The functional iron status can be estimated better with the measurement of sTfR instead of ferritin. Apart from that, sTfR is not an acute phase
reactant, so its concentrations remain unchanged in inflammatory diseases
[45, 49]. Its day-to-day fluctuation is limited, so it is much more acceptable
than other conventionally used indices, as, for example, transferrin saturation [50]. sTfR concentrations exceeding 2.75 mg/L, but not 3.6 mg/L,
are deemed to define those having depletion of the functional iron compartment leading to IDE, whereas sTfR levels above 3.6 mg/L indicate IDA
[45,49].
As mentioned above, serum ferritin reflects the storage iron compartment, whereas sTfR reflects the functional iron compartment. These two
indices can be combined in the sTfR/log ferritin ratio (TfR-E index), which
is very useful for the estimation of the entire range of body iron stores
[51]. A ratio of 1.8 or greater indicates storage iron depletion, whereas 2.2
or greater indicates IDE. Some evidence suggests that this index might be
529
sensitive enough for the detection of iron-deficient states in cases where ferritin and sTfR are borderline [45].
A hematologic index currently in use for the assessment of functional
iron status is the measurement of hypochromic red cells (HYPO). Since
erythrocytes have a relatively long life span of about 120 days, the HYPO
index provides information over a several-month period, so it is a late indicator of iron-restricted erythropoiesis [52]. Another noteworthy index is the
reticulocyte Hb content (CHr), which can be used as an early marker of functional iron deficiency (ID), since reticulocytes circulate in the bloodstream
for only 1-2 days [53, 54]. Unfortunately, the aforementioned hematologic
indices have two major drawbacks. First, they are available only on analyzers
from a single manufacturer and, second, various cutoff values for functional
ID have been reported in literature, ranging from 2 to 10% for HYPO and
23 ng to 29 ng for CHr [52, 53, 55, 56].
Another investigation, as diagnostic or screening method, is the level of
free erythrocyte (EPP) or zinc (ZPP) protoporphyrin. EPP reflects the adequacy of iron delivery to the erythroid precursors in the bone marrow. Its
level is increased in IDA, and values greater than 3 A'-g/g of Hb are considered abnormal [57].
DIFFERENTIAL DIAGNOSIS
Lead poisoning
Vitamin Bg responsive
Copper deficiency
Sideroblastic anemia (some)
530
j8-thalassemia minor, but the value is falsely low if iron deficiency coexists.
Therefore, in cases of clinical suspicion repeated testing is necessary after
iron-replacement therapy [5, 12, 58].
The anemia of chronic inflammation or infection is classically normochromic and normocytic, but in about 20-30% of infected children may
be bypochromic. It is the result of a decreased red blood cell survival, diminished reutilization of iron, impaired iron mobilization from macrophages by
transferrin, and decreased intestinal absorption of iron. Characteristic laboratory findings of this disorder should be considered a decreased TIBC, a
normal RDW, an increased serum ferritin level, and a normal serum transferrin receptor level [5, 12, 59]. An elevated serum transferrin receptor level
is characteristic of iron deficiency irrespective of whether the patient has coexisting anemia of chronic disease [60].
SCREENING AND PREVENTION
531
infants the dosage depends on birth weight and varies between 2 and 4
mg/kg per day. Infants who are not breast-fed should receive iron-fortified
formula up to 12 months of age [57].
Proportional situations may be found among adolescents in whom iron
deficiency is the most common cause of anemia. Surveys reflect an irondeficiency prevalence up to 24% and overt anemia in 10% of high school
students [65]. Also, IDA is a common disorder in the athletes, especially
in girls [66]. Because females, besides having lower Hb levels, tend to have
higher iron losses and, as a consequence, higher prevalence of IDA [67].
TREATMENT PLAN
The goals of treatment of iron deficiency should be twofold: replenishment of body iron stores and correction of underlying diseases. Treatment
is based on oral administration of one of the ferrous salts, among which ferrous sulfate is preferred because of high bioavailability and low cost. It must
be pointed out that ferrous sulfate is 20% elemental iron by weight, and that
optimal response is achieved with a dosage of elemental iron of 6 mg/kg
per day in 2 or 3 divided doses. The medicine must be given between meals
and not with milk. Side effects are uncommon and dose related. The most
frequent are transient staining of teeth, nausea, constipation, diarrhea, and
abdominal pain [67, 68]. Reducing the dosage of the medication or giving
it with food minimizes these side effects.
Apart from oral administration there are parenteral iron preparations
that are alternative solutions in cases of patients noncompliant with oral
therapy or genuine intolerance of oral iron, and in malabsorption situations
compromising gastrointestinal iron absorption. The dosage of iron (mg)
may be calculated by using the following formula: deficient Hb (g/dL) x
body weight (kg) x 0.22. The most severe side effect is anaphylaxis and a
tolerance test must be performed. Other side effects of parenteral administration are nausea, vomiting, abdominal pain, flushing, fever, headache,
malaise, shivering, myalgia, arthralgia, urticaria, lymphadenopathy, pleural
effusion, hypotension, and shock [68]. Intramuscular injection of iron is
painful and may be associated with permanent staining of the skin, muscle necrosis, and sterile abscesses [68]. Iron dextran preparations for intramuscular or intravenous administration have been in use for many years.
Recently, however, there has been concern about their safety since they
have been assosiated with life-threatening reactions [69]. Two new nondextran preparations for intravenous administration are now being tested: iron
sucrose and sodium ferric gluconate complex. Both seem to be associated
with a markedly lower incidence of life-threatening anaphylactoid reactions.
Nonanaphylactoid reactions also seem to be extremely uncommon [70, 71].
532
The regular response of IDA is an important diagnostic and therapeutic feature. Within 72-96 h after administration of iron peripheral reticulocytosis is noted, which is followed by an increase of Hb levels as much as
0.5 g/dL/day [41]. Failure to respond to iron therapy may be caused by
poor compliance, an inadequate iron dose, an ineffective iron preparation,
ongoing blood loss, coexistent disease resulting in nonabsorption or nonutilization of iron, or a misdiagnosis [41]. Iron replacement should continue
for 3 months more after the Hb level is within the normal range for age and
gender [72].
In conclusion, IDA is the most common anemia in infancy and childhood, which must be differentiated from other microcytic anemias. Strategies for prevention are screening, health education, fiscal measures, food
fortification, and supplementation. Iron fortification of formulas and cereals
is the most effective method of prevention and has reduced the prevalence
of this disease. However, pediatricians should be cognizant of its presence,
especially in high-risk children (preterm infants, children of immigrants or
minorities, etc.).
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