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484 Part V Red Blood Cells

Epidemiology
Parenteral Iron Therapy
Parenteral iron preparations that are approved for use in the United The most common form of iron overload in the United States is a
States include low-molecular-weight iron dextran, ferric gluconate, iron genetically determined disorder, the homozygous state for HFE
sucrose, ferumoxytol, and ferric carboxymaltose; iron isomaltoside is hemochromatosis, which occurs in approximately 4 to 5 of every
approved for use only in Europe. Each preparation has been widely 1000 persons of northern European descent. 13–15 In the United States,
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used, often in hemodialysis patients receiving recombinant human other forms of iron overload are less frequent but affect thousands of
erythropoietin, but neither prospective, randomized controlled com- patients with iron-loading or chronically transfused anemias, such as
parisons among these intravenous agents nor long-term safety studies thalassemia major, sickle cell disease, myelodysplasia, and other
have been done. Although infrequent, immediate life-threatening acquired refractory anemias. Globally, HFE hemochromatosis is the
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anaphylactic reactions constitute the most serious risk associated with most common genetic disorder in populations of northern European
use of either intramuscular or intravenous iron preparations, may have 13–15
a fatal outcome, and can occur with all intravenous iron preparations. ancestry. Thalassemia major and other forms of iron-loading
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Delayed but severe serum sickness-like reactions may also develop, anemia are important public health problems in countries bordering
with fever, urticaria, adenopathy, myalgias, and arthralgias. the Mediterranean and in an area extending from Southwest Asia and
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the Indian subcontinent to Southeast Asia. Dietary iron overload
resulting from intake of iron in brewed beverages is a common
problem affecting many populations in sub-Saharan Africa and may
met by oral therapy because of either chronic uncontrollable bleeding have a genetic component. Other inherited types of systemic iron
or other sources of blood loss, such as hemodialysis, or a coexisting overload, the various forms of perinatal iron overload, and the syn-
chronic inflammatory state; (3) malabsorbs iron; or (4) has IRIDA. 6,8 dromes associated with focal sequestration of iron are uncommon or
rare disorders.
Prognosis
Genetic Aspects
The prognosis for iron deficiency itself is excellent, and the response
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to either oral or parenteral iron also is excellent. Frequently, both The varieties of iron overload known to be genetically determined
clinical and subjective indications of constitutional improvement are are listed in Table 36.3, and their cardinal features are summarized
seen within the first few days of treatment, with the patient reporting in Table 36.4. The known forms of hereditary iron overload all
an enhanced sense of well-being and increased vigor and appetite. involve defects in the interaction between hepcidin and ferroportin
Pica may resolve, and soreness and burning of the mouth may abate. (see box on Control of Iron Homeostasis by Hepcidin and Ferropor-
Mild reticulocytosis begins within 3 to 5 days, is maximal by days tin and Chapter 35). 13–15 The autosomal recessive disorders have in
8 to 10, and then declines. The hemoglobin concentration begins to common an inappropriately low hepatic hepcidin production that
increase after the first week and usually returns to normal within 6 leads to parenchymal iron overload. HFE and transferrin receptor
weeks. Complete recovery from microcytosis may take up to 4 2-associated hemochromatosis and hemojuvelin- and hepcidin-
months. With oral iron dosage totaling 200 mg/d or less, the plasma associated juvenile hemochromatosis are the consequence, respec-
ferritin concentration usually remains less than 12 µg/dL until the tively, of mutations in regulatory genes controlling hepcidin expression
anemia is corrected and then gradually rises as storage iron is replaced (HFE, TFR2, HJV) and in the structural gene for hepcidin (HAMP).
over the next several months. Although epithelial abnormalities begin Hepcidin production is also suppressed in three other rare autosomal
to improve promptly with treatment, resolution of glossitis and recessive disorders with distinctive syndromes of iron overload:
koilonychia may take several months. The overall prognosis depends DMT1-associated hemochromatosis, atransferrinemia, and acerulo-
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on the underlying disorder responsible for the iron deficiency. plasminemia. The autosomal dominant disorders have in common
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Failure to obtain a complete and characteristic response to iron mutations in the gene for ferroportin (FPN). In general, these
therapy necessitates a review of findings and reevaluation of the mutations either (1) interfere with iron export, resulting in reticulo-
patient. A common problem is an incorrect diagnosis, with the endothelial macrophage iron accumulations with only minor clinical
anemia of chronic disease (see Chapter 37) mistaken for the anemia manifestations; or (2) produce resistance to the action of hepcidin,
of iron deficiency. Coexisting conditions may impede recovery, such resulting in parenchymal iron loading resembling that in the autoso-
as other nutritional deficiencies; hepatic or renal disease; or infec- mal recessive forms of hereditary iron overload.
tious, inflammatory, or malignant disorders. Occult blood loss may Several of the acquired forms of iron overload involve disorders
be responsible for an incomplete response. With oral iron therapy, with a genetic origin or component. The genetically determined
the adequacy of the form and dose of iron used should be reconsid- iron-loading anemias include the inherited sideroblastic anemias (see
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ered; compliance with the treatment regimen reviewed; and, finally, Chapter 38), some of the hereditary disorders of globin synthesis
the possibilities of malabsorption and of the genetic disorder IRIDA (see Chapter 40), and some chronic hemolytic anemias (see Chapters
considered. 8 41–47). Similarly, some forms of chronic liver disease and porphyria
cutanea tarda (see Chapter 38) are inherited disorders. African dietary
iron overload and, possibly, susceptibility to iron accumulation with
IRON OVERLOAD prolonged medicinal iron ingestion may have genetic components.
Many of the disorders requiring chronic RBC transfusion are heredi-
Iron overload is an increase in the amount of body iron resulting from tary, including thalassemia major (see Chapter 40), sickle cell disease
a sustained expansion of iron supply beyond iron requirements. (see Chapters 41 and 42), and other chronic refractory anemias.
Because requirements are limited and humans lack a physiologic Although the exact etiology of some of these conditions is unknown,
means of excreting excess iron, any persistent increase in iron influx subsets of the disorders leading to perinatal iron overload or focal
may eventually result in iron overload. The continuum of increased sequestration of iron have an established genetic basis. 20
body iron is shown in Fig. 36.1. Whatever the source and the sites
of excess iron deposition, when the accumulation overwhelms the
cellular capacity for safe storage, potentially lethal tissue damage is Etiology and Pathogenesis
the result. The toxic manifestations of iron overload vary with the
precise pathogenic defect responsible but are dependent on the Iron overload is caused by conditions that alter or bypass the normal
amount of excess iron, rate of iron accumulation, cellular pattern of control of body iron content by regulation of intestinal iron absorp-
deposition, and presence of complicating factors such as hepatitis or tion. The known forms of hereditary iron overload (see Table 36.3)
drug or alcohol use. have a common pathogenic origin in genetically determined