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632 Part VI: The Erythrocyte Chapter 43: Iron Deficiency and Overload 633

deficiency decreases the risk and severity of malaria, 80,81 and iron sup- <8 g/dL) and mild iron deficiency anemia (hemoglobin between 8 and
plementation may have the opposite effect, especially when not targeted 12 g/dL) led to decreased work performance, primarily as estimated by
to patients with iron deficiency. 52,82 The mechanism of this effect is of peak oxygen consumption (VO max) measurements, but the evidence
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great interest but not yet well understood. There are some indications that nonanemic iron deficiency had such an effect was less convincing.
that iron deficiency may have a proinflammatory effect. In a mouse However, in athletes with low ferritin levels but normal hemoglobin lev-
model, iron deficiency potentiated the systemic effect of lipopolysac- els, iron-supplemented subjects showed an increased VO max without
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charide in a hepcidin-dependent manner, and in a mouse model of a change in their red cell mass, and in other studies nonanemic subjects
asthma, iron deficiency promoted allergic inflammation. 85 treated with iron showed improved performance and/or VO max. 63
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Infant and Childhood Development It has been proposed that
Growth and Metabolism iron deficiency in infants and children is associated with poor attention
Iron-deficient children have been reported to suffer from growth retar- span, poor response to sensory stimuli, and retarded behavioral and
dation but it is difficult to isolate the effect of iron deficiency from other developmental achievement even in the absence of anemia. The causality
nutritional and environmental causes of stunting. Two comprehensive of these associations is confounded by other coexisting nutritional def-
analyses of randomized controlled trials did not detect an effect on icits and socioeconomic deprivation, so reversibility by iron supple-
growth of iron supplementation alone. 86,87 Decreased thermoregulation mentation would be important in establishing causality. However, in
in response to cold exposure is seen in both humans and laboratory systematic meta-analyses, iron supplementation had weak or no effects
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models. It has been attributed to the conflicting effects on blood flow on these deficits. 86,100–102
of decreased oxygen content of blood and need to minimize heat loss, as Hyperactivity Syndromes It has been speculated that there is a
well as the effect of iron deficiency on thyroid function. relationship between restless legs syndrome, Tourette syndrome, and
attention deficit hyperactivity disorder and that iron deficiency con-
Histologic Findings tributes to their pathophysiology. Restless legs syndrome, a common
Severe iron deficiency may lead to histologic changes in various organs. nocturnal problem, especially in the elderly, is associated with iron
The rapidly proliferating cells of the upper part of the alimentary tract deficiency and is reported to improve on iron therapy, but the bene-
seem particularly susceptible to the effect of iron deficiency. There may ficial effects are inconsistent and not well predicted by blood ferritin
be atrophy of the mucosa of the tongue and esophagus, stomach, and or transferrin saturation. 75,103,104 In children there may be a relationship
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small intestine. The epithelium of the lateral margins of the tongue is between iron deficiency and attention deficit hyperactivity disorder, but
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reduced in thickness despite increase in the progenitor compartment. the association is inconsistent. 105
This thinning presumably reflects accelerated exfoliation of epithelial Other Neurologic Symptoms Breath holding in children, head-
cells. Buccal mucosa has shown thinning and keratinization of epi- aches, and paresthesias have been attributed to iron deficiency but
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thelium and increased mitotic activity. 93,94 However, light microscopic there are no controlled studies to support these impressions. Anecdotal
and electron microscopic examination of exfoliated oral mucosal cells reports of intracranial hypertension with papilledema are buttressed by
showed no aberrations in morphology of nuclei or cytoplasm of the apparent response to iron therapy. 106–109 Stroke in children and in adults,
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cells of patients with iron-deficiency anemia. In iron-deficiency ane- possibly triggered by thrombocytosis, is associated with iron-deficiency
mia resulting from idiopathic pulmonary hemosiderosis, characteristic anemia. 110–114
pathologic changes are found in the lungs, including intense deposition Oral and Nasopharyngeal Symptoms Burning of the tongue has
of iron in the littoral cells of the alveoli and interstitial fibrosis. 45 also been described anecdotally in many accounts of iron deficiency,
Widening of diploic spaces of bones, particularly those of the and although this symptom has been observed to diminish with treat-
skull and hands, 96–98 may be a consequence of chronic iron deficiency ment, no controlled studies have been performed. The tongue symp-
beginning in infancy. In the skull, this is of the same character as in tha- toms could be a result of concurrent pyridoxine deficiency. Although
lassemia, except that in β-thalassemia major there is maxillary hyper- iron deficiency has been proposed as a cause of atrophic rhinitis, the
trophy, whereas in severe iron-deficiency anemia maxillary growth and evidence for this is weak.
pneumatization are normal. Dysphagia In the laryngopharynx, mucosal atrophy may lead to
web formation in the postcricoid region, thereby giving rise to dys-
CLINICAL FEATURES phagia (Paterson-Kelly also known as Plummer-Vinson syndrome).
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Clinical Manifestations of Anemia If these alterations are of long duration, they may lead to pharyngeal
The anemia in iron-deficient patients can be very severe, with blood carcinoma. Although it has been generally thought that these changes
hemoglobin levels as low as less than 4 g/dL being encountered in some are secondary to longstanding iron deficiency, this mechanism is not
patients. Severe iron-deficiency anemia is associated with all of the universally accepted. The frequency of the condition is considered to
various symptoms of anemia, resulting from hypoxia and the body’s have decreased considerably, and it is remarkably rare in many parts of
response to hypoxia, as described in Chap. 32. Thus, tachycardia with the world where iron deficiency is common.
palpitations and pounding in the ears, headache, light-headedness, and Pica The craving to eat unusual substances, for example, dirt, clay,
even angina pectoris, may all occur in patients who are severely anemic. ice, laundry starch, salt, cardboard, and hair, is a well-documented
manifestation of iron deficiency and is usually cured promptly by iron
Clinical Manifestations That May Be Unrelated to Anemia therapy. 116–119
The clinical features of iron deficiency encompass nonhematologic effects Hair Loss Although the association of hair loss with iron defi-
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and symptoms caused by the anemia itself. A number of controlled stud- ciency is controversial, low ferritin levels were a risk factor for hair
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ies show that various manifestations of iron deficiency can occur in indi- loss in a large multivariate analysis. Remarkably, hair loss sparing the
viduals whose hemoglobin is within the accepted normal range. face (“mask mouse”) is a sign of iron deficiency in mice. 122
Decreased Work Performance Objective measurements of work
performance and studies using O consumption as an index of work per- Physical Findings
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formance have given contradictory results, but a comprehensive review The physical findings in iron-deficiency anemia include pallor, glossi-
led to the conclusion that severe iron-deficiency anemia (hemoglobin tis (smooth, red tongue), stomatitis, and angular cheilitis. Koilonychia

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