++
Despite being the most abundant metal on earth, iron is the most
prevalent single nutrient deficiency worldwide. The term newborn
possesses about 75 mg of elemental iron/kg (0.25–0.5
g of total body iron) and must absorb about 4.5 g of iron during
childhood, or about 1 mg/d, to achieve the nearly 5.0 g
of body iron in the average adult. An additional 0.2 to 0.5 mg/day of
absorbed iron is required to balance physiologic losses (eg, desquamation
of epithelial cells in the gastrointestinal tract). During periods
of maximal growth—infancy and adolescence—the
iron requirements for expanding blood volume and muscle mass may
exceed the rate of dietary iron accrual.
++
Iron deficiency is the most common global nutritional deficiency with
an estimated 2 billion affected persons.1 Iron
deficiency affects all age groups, but is particularly common in
infants, young children, and women of childbearing age. Iron-deficiency
anemia is the most common hematologic disease of infancy and childhood.2
++
In industrialized nations, the most common etiology of iron deficiency
is insufficient dietary iron. The availability of iron-fortified
formula, in conjunction with initiatives such as the US federal Special
Supplemental Nutrition Program for Women, Infants and Children (WIC)
and the American Academy of Pediatrics’ promotion of formula
in place of cow’s milk, have greatly reduced the prevalence
of iron deficiency in developed countries. According to the Fourth
National Health and Nutrition Examination Survey (NHANES-IV), iron
deficiency without anemia exists in 7% of toddlers ages
1 to 2 years, 9% of adolescent girls, and 16% of
women of childbearing age.3 Low income, minority
ethnicity, and poor maternal iron status are recognized socioeconomic
risk factors for iron-deficiency anemia.4-7 In
developing countries, the higher prevalence of iron-deficiency anemia
related to nutritional deficiency is compounded by the contribution
of chronic blood loss related to parasitic infections.
+++
Pathophysiology
and Genetics
++
The majority of body iron is incorporated into the hemoglobin
of circulating erythrocytes and their marrow precursors. Only a
small fraction of the average daily requirement to support erythropoiesis
is absorbed from the diet. The majority of the daily erythroid iron requirement
is supplied by recovery of heme iron through the phagocytosis of
senescent erythrocytes by reticuloendothelial macrophages and degradation of
hemoglobin. This recycled iron is then made available to the developing
erythroid precursors in the bone marrow.
++
Because only about 10% of dietary iron is absorbed,
the child’s diet must contain 10 to 15 mg of iron to maintain
a positive iron balance. During infancy, when only small amounts
of iron-rich foods may be consumed, this level of iron intake is
difficult to attain unless iron-fortified foods are provided. Infants
and children from low-income families continue to have iron deficiency,
despite a decline in the incidence of the condition over the past
30 years.
++
Nonheme dietary iron, primarily in the ferric (Fe3+)
state, is reduced to the ferrous (Fe2+)
state in the acidic environment of the proximal duodenum by a brush border
ferrireductase. Gastric acidity may assist conversion to the absorbable
ferrous (Fe2+) form, and the use of histamine H2
blockers or proton pump inhibitors to treat peptic gastroesophageal
reflux can impair iron absorption (see Chapter 394). In addition, many plant products contain iron, but absorption
is limited both by low solubility and by dietary chelators, such
as phytates, that bind ambient iron. Fe2+ iron
is then cotransported with protons through the apical membrane of
the enterocyte by divalent metal transporter 1 (DMT1),8,9 whose
expression is significantly increased in iron deficiency. DMT1 is
also capable of transporting other divalent metals such as Cu2+ and
Zn2+.8 Heme or organic
iron present in animal food products is the most readily absorbed
form of iron, and its absorption occurs by a different mechanism
that is independent of gastric pH and incompletely understood. Some
imported iron remains stored within the enterocyte cytoplasm as
ferritin; the remainder is exported through the enterocyte basolateral
membrane by another transporter protein, ferroportin.10-12 This
basolateral transport of iron is believed to be facilitated by the ferrioxidase
activity of hephaestin or ceruloplasmin,13 which
returns the iron to its Fe3+ state and
allows binding to transferrin, the predominant iron-binding protein
in plasma.
++
Only a small fraction of dietary iron is imported by the enterocyte, and
only a fraction again is exported from the enterocyte into the plasma.
Iron remaining within enterocytes is lost from the body through
the physiologic sloughing of these cells into the gut lumen.
++
The regulation of intestinal iron absorption is the primary mechanism
for determining overall iron status in the body. This intestinal control
is mediated primarily through hepcidin (discussed later in this
chapter).
++
Some disorders disrupt the integrity of the enteric mucosa and
hinder iron absorption. Inflammatory bowel disease, particularly Crohn disease
and celiac sprue, can damage the duodenum, where most iron absorption
occurs, and gastrointestinal bleeding may exacerbate the problem.
An oral iron challenge can assess iron absorption
by obtaining a serum iron level immediately prior to and 1 to 2
hours after an oral dose of 1 to 2 mg/kg of elemental iron.
Failure to observe a significant increase over baseline level is
consistent with iron malabsorption. Rarely, malabsorption of iron
without a structurally defective intestine occurs as an autosomally
recessive inherited syndrome related to the inappropriate expression
of hepcidin.14
++
Virtually all plasma iron exists bound to the abundant, circulating, glycoprotein transferrin
(Tf). In the normal physiologic state, Tf iron-binding sites are
approximately 30% saturated. Each Tf molecule binds two
atoms of Fe3+ iron with high affinity,
serving three major functions. First, transferrin allows Fe3+ to
remain soluble in the aqueous and pH-neutral plasma environment.
Second, it renders iron nonreactive, thus allowing it to circulate
in a safe form. Third, Tf facilitates the cellular import of iron
through the transferrin cycle. The transferrin cycle commences with
iron-loaded plasma Tf (holotransferrin) binding with high affinity to
transferrin receptors (TfR) on the cell surface (reviewed in ref.
15). The Tf/TfR receptor complex is endocytosed. Proton
pumps then acidify the resultant endosome,16 prompting
iron release from transferrin.17 The unbound iron
is reduced and is transported out of the endosome into the cytoplasm
in a proton-dependent process involving DMT1.18 Empty
Tf (apotransferrin) and TfR return to the cell surface, where they
dissociate at neutral pH and become available to repeat the importation
process.
++
In the macrophage, phagocytosed erythrocytes are lysed, hemoglobin
is degraded, and iron is liberated from heme within the phagolysosome
with the aid of heme oxygenase. Macrophages store some iron in
ferritin and hemosiderin, and similar to enterocytes, export the
remainder through ferroportin.19
+++
Regulation of
Iron Homeostasis
++
Iron homeostasis requires carefully coordinated regulation of
intestinal iron absorption, cellular iron import/export,
and iron storage. Humans have no physiologic iron excretion mechanism; therefore,
the control of iron balance must occur at the level of intestinal
absorption. More recent discoveries of molecular modulators of these processes
are allowing greater understanding of the molecular regulation of
these processes.
++
Hepcidin is a small peptide hormone that plays a central role
in the regulation of iron homeostasis as a negative regulator of
intestinal iron absorption and macrophage iron release. Hepcidin
is synthesized by the liver, secreted into the serum, and excreted
into the urine.20 Hepcidin acts as a negative regulator
of iron export from cells21-23 by acting directly
on ferroportin, causing its internalization and degradation, and
thus limiting iron availability to the plasma. As a negative molecular
regulator, decreased hepcidin leads to increased ferroportin-mediated cellular iron
export and to elevated plasma iron levels.
++
Intestinal iron absorption appears to be mediated by at least
five physiologic “regulators”—dietary iron
load, body iron stores, erythropoietic demand, hypoxia, and inflammation.
The latter four appear to have hepcidin as their common effector
molecule (reviewed in ref. 15). Large oral iron loads result in an
observed “mucosal block” of subsequent dietary
iron, even in the setting of iron deficiency, by an unclear mechanism.24 Iron
replete or overload states result in increased hepcidin expression,
whereas the converse occurs in iron deficiency.21,25 The “stores
regulator”26 can modulate intestinal absorption severalfold
through an unclear mechanism that may detect the degree of transferrin
saturation. The “erythroid regulator” increases
intestinal absorption in response to increased erythropoietic iron
demand, regardless of the current body iron stores26 and
is associated with depressed hepcidin levels, resulting in increased
intestinal iron absorption and reticuloendothelial iron release.
At times, as seen in diseases of ineffective erythropoiesis such as
thalassemia intermedia and congenital dyserythropoietic anemia, this
may lead to iron overload. The expression of hepcidin is also decreased
in hypoxic states,21 yet the “hypoxia
regulator” appears to be distinct from the erythroid regulator.26 Finally,
an “inflammatory regulator,” likely mediated through
IL-6,27 induces increased hepcidin expression21,28,29 results
in cellular iron sequestration, decreased serum iron, iron-restricted
erythropoiesis, and, if persistent, the development of the anemia
of chronic inflammation. Elevation of hepcidin in response to inflammation
may have evolved as an element of host defense against invading
pathogens and neoplastic cells requiring iron for proliferation.30 Inappropriately
high hepcidin levels can also occur as a paraneoplastic phenomenon,28 or
an inherited disorder14 can lead to an iron-resistant
iron-deficiency anemia (IRIDA) phenotype.
++
The regulation of hepcidin in response to these regulators appears to
be at the level of hepcidin gene transcription; however, the exact molecular
mechanism remains incompletely understood.
++
Chronic blood loss, particularly menstrual and gastrointestinal tract
bleeding, commonly causes iron deficiency. Gastroesophageal reflux,
peptic ulcer disease, or Meckel diverticulum can result in chronic
blood loss that may present as iron-deficiency anemia. Other structural
defects such as hereditary hemorrhagic telangiectasia (the Osler-Weber-Rendu syndrome)
are much less frequent. Cow’s milk contains proteins that can
irritate the lining of the gastrointestinal tract in some infants, resulting
in chronic blood loss and iron deficiency. The leading cause of
gastrointestinal blood loss worldwide is hookworm infection, caused
by Necator americanus or Ancylostoma duodenale,
which is endemic in much of the world. Trichuriasis,
or whipworm infection, and schistosomiasis, very
common in tropical areas, may be associated with chronic blood loss
and iron-deficiency anemia in children.
++
Menorrhagia may lead to iron-deficiency anemia. Anovulatory dysfunctional
uterine bleeding is a relatively common phenomenon that can often
be ameliorated by oral contraceptives. Disorders of hemostasis,
particularly von Willebrand disease, and pelvic anatomic abnormalities
may also contribute to blood loss.
++
Occasionally, bleeding into the urinary tract causes iron deficiency,
but gross urinary blood is usually sufficiently alarming that patients
seek medical attention before iron deficiency develops. Patients
with chronic intravascular hemolysis, such as occurs with intracardiac
prostheses and paroxysmal nocturnal hemoglobinuria, may develop
iron deficiency as consequence of hemoglobinuria. Pulmonary blood
loss sufficiently severe to produce iron deficiency is rare but
can occur in idiopathic pulmonary hemosiderosis (see Chapter 517).
+++
Clinical Features
and Differential Diagnosis
++
Careful inquiry into dietary intake and blood loss must always
be undertaken.
++
The anemia impairs tissue oxygenation, producing the symptoms
of pallor, weakness, fatigue, and lightheadedness. Pica—the
compulsion to eat nonfood substances—occurs variably in
patients with iron-deficiency anemia; the ingested substances may
include soil, laundry starch, and clay, which can bind iron in the
gastrointestinal tract, thereby exacerbating the deficiency. Iron deficiency
increases the gastrointestinal absorption not only of iron, but
also of a number of divalent metals, including lead, that share
the same absorption pathways. Risk factors for chronic lead exposure
should be explored because it can exacerbate iron deficiency by
competitive inhibition of iron absorption.
++
On physical examination, pallor, tachycardia, and systolic murmur are
more prevalent as the microcytic, hypochromic anemia worsens. Epithelial
changes such as atrophy of the papillae of the tongue and spooning
of the fingernails can be seen in adults with iron-deficiency anemia
but are unusual in children.
++
Given that iron is an essential metal in numerous biologic processes
other than oxygen delivery by erythrocytes, it is not surprising
that it can be associated with other significant morbidities. Iron
deficiency, with or without anemia, may affect growth and cause
potentially irreversible mental and psychomotor developmental abnormalities
in children younger than 2 years,31,32 and thus
prevention of iron deficiency during infancy is imperative.
+++
Diagnostic Evaluation
++
The diagnosis of iron-deficiency anemia is not tenable if the
red blood cell (RBC) indices are normal. Iron-deficiency anemia
is associated with microcytic, hypochromic RBCs on peripheral blood smear
(see Fig. 430-1), corresponding to low mean
corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Iron-restricted
erythropoiesis also results in an uneven RBC size (anisocytosis),
which is reflected by an increased RBC distribution width (RDW).
The reticulocyte count may be low or inappropriately “normal” relative
to the degree of anemia. Measurement of reticulocyte hemoglobin
content (CHr) has been suggested for early detection of iron-restricted
erythropoiesis because it measures the amount of hemoglobin in the
most recently produced cells, rather than the entire population
of cells of varying ages. Thrombocytosis is often present with platelet counts
> 450 × 109/L,
but rarely a significant thrombocytopenia may be present. Serum iron
concentration is low, and serum iron-binding capacity is increased,
resulting in low transferrin iron saturation (< 15%).
When serum transferrin saturation is < 15%, iron availability begins
to restrict erythropoiesis. Serum ferritin reflects the iron stores
within both the liver and the reticuloendothelial system. Low ferritin
concentrations (< 10–15 ng/mL) invariably indicate that
iron stores are essentially absent. Greatly elevated ferritin (> 1000
ng/mL) occurs in iron overload states such as transfusional hemosiderosis.
Serum ferritin is also an acute phase reactant that is increased
during infection or inflammation, as well as in hepatocellular disease;
therefore, its diagnostic value can be limited in these circumstances.
++
Another marker of iron status is the serum transferrin receptor (sTfR)
(normal < 8.5 mg/L). A portion of the extracellular
component of the transferrin receptor is cleaved from developing
normoblasts, and the plasma level of sTfR reasonably reflects erythropoietic
activity; sTfR is characteristically increased in iron deficiency
and states of ineffective erythropoiesis and decreased in aplastic
anemia. Although sTfR is not specific for iron deficiency, the ratio
of sTfR to the log of ferritin (sTfR-F index) can help distinguish
iron deficiency from the anemia of chronic inflammation. A sTfR-F
index < 1.5 is characteristic of the anemia of chronic inflammation,
whereas values > 1.5 suggests iron deficiency alone or in combination
with an inflammatory condition.33
++
The ultimate step of heme formation is the insertion of an iron
molecule into the porphyrin ring. If iron is not available to complete this
step, there is an increase in the ratio of zinc protoporphyrins (ZPP)
to heme. A ZPP-to-heme ration of > 80 mmol/mol is biochemical
evidence of relative iron-deficient erythropoiesis attributable
to any etiology, including lead poisoning (see Chapter 120).
++
Progressive iron deficiency has several stages that are defined
by laboratory values (Table 431-1). Prelatent iron deficiency occurs when
tissue iron stores are decreased, as indicated by a low (but still
> 15 ng/mL) serum ferritin level, but normal transferrin
saturation and no anemia. Latent iron deficiency is characterized
by low serum ferritin and transferrin saturation (< 15%),
but without anemia, decrease in MCV, or increased free erythrocyte
protoporphyrin (FEP). In frank iron-deficiency anemia, all measures
of iron status are abnormal, and significant microcytic anemia is present.
++
++
The α- and β-thalassemia traits
are often confused with iron deficiency because both are associated
with microcytosis and hypochromia. The clinician can discern clues
distinguishing these entities from the RBC indices and peripheral
blood smear: The Mentzer Index (MCV/RBC) is usually > 12
in iron deficiency and < 11 in thalassemia. The RDW is usually
normal in thalassemia trait, which produces uniformly small erythrocytes,
but is increased in iron-deficiency anemia, which alters RBC size unevenly.
Basophilic stippling and target cells are seen in thalassemia trait.
Laboratory measures of iron status in thalassemia trait are usually normal,
and the associated mild anemia/microcytosis is unresponsive
to iron therapy.
+++
Prevention and
Treatment
++
To prevent iron deficiency in infancy, the Committee on Nutrition of
the American Academy of Pediatrics has recommended the following:
++
1. Breast milk should be used for at least 6 months,
when possible. Elemental iron supplementation of 1 mg/kg/day
should be provided to infants who are exclusively fed breast milk
beyond 6 months of age.
2. Infants weaned before 12 months of age should not receive
cow’s milk but should receive iron-fortified infant formula.
Whole cow’s milk should be avoided during the first year
of life.
3. Infants who are not breast-fed should receive an iron-supplemented
formula (4–12 mg of elemental iron per liter) for the first
year of life.
4. Complementary foods rich in iron (eg, iron-enriched cereals)
should be introduced gradually beginning around 6 months of age.
++
Premature infants are particularly susceptible to iron deficiency
as a result of a reduced iron endowment at birth because the majority of
iron is transferred during the third trimester. Iron supplementation
or iron-fortified formulas should be started by 1 to 2 months of
age and continued for at least 1 to 2 years.
++
The introduction of whole cow’s milk (prior to 12 months
of age) and consumption of more than 16 ounces of whole cow’s
milk per day in toddlerhood should be avoided because this increases
the risk of iron deficiency. In addition to a poor iron source and
interference with iron absorption, cow’s milk may cause
occult gastrointestinal bleeding in some infants.
++
Treatment of iron deficiency should always be coupled with the
identification and correction of an underlying cause when possible.
Oral iron salts are inexpensive and almost always sufficient to
correct anemia and replete iron stores. The treatment dose of oral
iron is 2 to 6 mg of elemental ferrous iron per kilogram per day,
given as a single or divided dose. The iron should not be mixed
with milk or taken with food. Ascorbic acid supplementation can
enhance iron absorption. Gastrointestinal intolerance and constipation
related to iron therapy are unusual in children. Oral iron may cause
staining of the teeth, but this is temporary and can be avoided
by rinsing the mouth or brushing the teeth after the medication
is given. Response to iron therapy is signaled by a rise in CHr
and reticulocytosis beginning at 3 to 5 days and peaking 7 to 10
days after starting therapy. An increase in hemoglobin of at least
10 to 20 g/L after 1 month is diagnostic of iron deficiency. Lack
of response usually indicates noncompliance with the medication
or another diagnosis. Adequate replacement of storage iron in iron-deficiency
anemia usually requires several months of therapy after the anemia
has been corrected. With ongoing blood losses, oral replacement
of storage iron can be futile. Parenteral iron is rarely indicated
in children with nutritional iron deficiency unless oral iron is
poorly tolerated, duodenal absorption is compromised, or rapid replacement
of iron stores is required. In addition to iron dextran, which can be
administered intravenously or intramuscularly, there are newer intravenous
formulations, including iron gluconate and iron sucrose, that are
primarily used for iron replacement in the setting of hemodialysis.
++
Transfusion of packed red blood cells (PRBCs) for iron-deficiency anemia
is indicated only in the most severe cases (eg, heart failure or
hemoglobin < 5 g/dL) and/or when ongoing losses
are expected to exceed or equal bone marrow production after appropriate
iron therapy. Correction of severe chronically developed iron-deficiency
anemia with transfusion must be performed slowly and requires special
care to prevent fluid overload due to the relatively expanded plasma
volume in such patients.