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C H A P T E R 36

DISORDERS OF IRON HOMEOSTASIS:

IRON DEFICIENCY AND OVERLOAD

Gary M. Brittenham

Iron is an essential nutrient required by every cell in the body. Both on Control of Iron Homeostasis by Hepcidin and Ferroportin and
decreases and increases in the amount of iron may be clinically Chapter 35).
important. If too little iron is available (iron deficiency), limitations
on the synthesis of physiologically active iron-containing compounds
can have harmful consequences. If too much iron accumulates (iron Direct Measures
overload) and exceeds the body’s capacity for safe transport and
storage, iron toxicity may produce widespread organ damage and The direct measures of body iron status yield quantitative, specific,
death. The body, with no effective means to excrete excess iron, relies and sensitive determinations of body or tissue iron stores. Quantita-
upon control of iron absorption to maintain homeostasis. This tive phlebotomy provides a direct measure of total mobilizable storage
chapter focuses on the clinical application of recent remarkable pro- iron. Quantitative phlebotomy is inapplicable to most anemic disor-
gress in understanding the molecular mechanisms that preserve iron ders but occasionally is useful in the diagnostic evaluation of some
balance. forms of iron overload (e.g., in patients with hereditary hemochro-
Iron disorders are principally abnormalities in the amount or matosis who do not undergo liver biopsy). Bone marrow aspiration
distribution of body iron. A fundamental advance has been the and biopsy can provide information about (1) macrophage storage
recognition that the interaction of hepcidin, the iron regulatory iron by semiquantitative grading of marrow hemosiderin stained with
hormone, with ferroportin, the cellular iron export channel, is Prussian blue (Fig. 36.2) or, if needed, by chemical measurement of
primarily responsible for the quantity and tissue disposition of body nonheme iron; (2) iron supply to erythroid precursors by determining
iron. Hepcidin controls iron absorption, use, and storage by binding the proportion and morphology of marrow sideroblasts (i.e., normo-
to and inducing the degradation of ferroportin, decreasing iron blasts with visible aggregates of iron in the cytoplasm); and (3) general
entry into plasma from macrophages, hepatocytes, and intestinal morphologic features of hematopoiesis. Bone marrow aspiration and
enterocytes (see box on Control of Iron Homeostasis by Hepcidin biopsy are useful in studies of iron deficiency, but they are of limited
and Ferroportin and Chapter 35). Hepcidin expression is suppressed applicability in the evaluation of iron overload because no informa-
with iron deficiency, hypoxia, or increased erythropoietic demand but tion about the extent of hepatocyte iron deposition is provided. In
stimulated with iron overload, inflammation, or infection. Genetic the evaluation of iron overload, liver biopsy is the best direct test for
and acquired disorders with a deficiency in hepcidin production or assessing iron deposition, permitting quantitative measurement of the
with ferroportin resistance to hepcidin action produce iron overload. nonheme iron concentration and histochemical examination of the
Hepcidin excess due to genetic causes produces iron-deficiency pattern of iron accumulation in hepatocytes and macrophages
anemia, but acquired forms, such as those associated with infec- (Kupffer cells).
tion, inflammation, or malignancy, result in iron sequestration and Direct methods for assessing iron status have the disadvantages of
anemia. being invasive procedures, with their attendant discomfort, lack of
acceptability to patients, and, in the case of liver biopsy, risk. A variety
of noninvasive means of measuring tissue iron stores has been devel-
LABORATORY EVALUATION OF IRON STATUS oped and applied in clinical studies, including determination of
hepatic magnetic susceptibility, computed tomography, and magnetic
Because iron disorders primarily produce quantitative abnormalities resonance imaging (MRI). MRI, the most widely available method,
in the amount and tissue distribution of iron, laboratory evaluation can provide information about iron deposition in the liver, spleen,
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of iron status relies on indicators of iron supply and storage. The pancreas, heart, and brain. When available as appropriately calibrated
principal routes of iron movement, the amounts and distribution of and validated techniques, these noninvasive methods are helpful in
the major iron pools, and the sites of hepcidin control of iron entry the diagnosis and management of iron overload, but, they lack the
into plasma are shown in Fig. 35.1. The continuum of changes with accuracy required to detect iron deficiency.
increased or decreased body iron content is illustrated in Fig. 36.1,
which shows schematically the amounts of erythroid iron and storage
iron together with the division of iron stores between hepatocyte and Indirect Measures
reticuloendothelial macrophage deposits and with characteristic
values for some clinically available indicators of iron status. Indirect measures of body iron status have the advantages of ease and
Body iron supply and stores can be evaluated by both direct and convenience, but all are subject to extraneous influences and lack
indirect means, but no single indicator or combination of indicators specificity, sensitivity, or both. When used to estimate body iron
is ideal for evaluation of iron status in all clinical circumstances. As stores, all of the available indirect measures are influenced not only
body iron content decreases from the iron-replete normal to the by total body iron stores but also by the effects of acute or chronic
amounts found in iron-deficiency anemia or as it increases to the changes in plasma hepcidin (see box on Control of Iron Homeostasis
magnitudes found in the various forms of iron overload, each avail- by Hepcidin and Ferroportin). Assays for plasma and urinary hepci-
able measure reflects in a different manner the continuum of changes din are not yet generally available for clinical use, but they are under
shown in Fig. 36.1. In addition, each indicator may be affected by development and will likely be helpful in the evaluation of patients
coexisting conditions that modulate hepcidin expression, such as with disorders of iron homeostasis.
infection, inflammation, cellular injury, malignancy, ineffective Measurement of the plasma ferritin concentration provides the
erythropoiesis, hypoxemia, liver disease, and malnutrition (see box most useful indirect estimate of body iron stores. The small amounts

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