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552 Part VI: The Erythrocyte Chapter 37: Anemia of Chronic Disease 553

Insufficient iron reaches the sites of heme synthesis in developing ery- HYPOFERREMIA AND INCREASED SERUM
throcytes, leading to the substitution of zinc. Moreover, the number of TRANSFERRIN
sideroblasts, nucleated erythrocyte precursors that stain for iron with
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Prussian blue, is decreased in AI. A further indication of the limiting Hypoferremia, a decrease in serum iron concentration, is a defining fea-
role of iron in patients with AI but no evidence of iron deficiency is ture of AI and, in the absence of iron therapy, is also commonly seen
that coadministration of parenteral iron can resolve the resistance in anemia of CKD. It develops within hours of the onset of infection
of AI to EPO. 50,51 Attempts to treat AI with iron alone generally have or severe inflammation. The concentration of the iron-binding protein,
been less successful, as iron became rapidly trapped in the macrophage transferrin (measured as total iron binding capacity), is moderately
compartment. 1,52,53 decreased in AI, unlike in IDA in which transferrin concentration is
In the context of anemia of CKD, increased zinc protoporphyrin increased. The decrease in transferrin concentrations develops more
and decreased reticulocyte Hgb is also characteristic of functional iron slowly than the decrease in serum iron levels because of the longer half-
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deficiency during intense bursts of erythropoiesis stimulated by phar- life of transferrin (8 to 12 days) compared to the turnover of plasma
macologic doses of EPO derivatives. 54 iron (approximately 90 minutes).

Inhibition of Intestinal Absorption of Iron and Other Factors
Leading to Systemic Iron Deficiency INCREASED SERUM FERRITIN
In longstanding AI, erythrocytes can become hypochromic and micro- Serum ferritin concentrations, which reflect iron stores and inflamma-
cytic, partly because progressive depletion of iron stores worsens the tion, are increased in AI but decreased in iron deficiency. Thus, serum
iron restriction. Intestinal absorption of iron is inhibited 55–57 during ferritin is useful in differential diagnosis in patients with low serum
inflammation by an IL-6 and hepcidin-mediated mechanism. 58–62 Only iron concentrations. Depleted iron stores in patients with coexisting
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1 to 2 mg of the daily iron needed for erythropoiesis comes from the diet inflammation may result in intermediate ferritin levels (Table 37–2
and most adults have 400 to 2000 mg of iron stores (Chap. 42); therefore, and Fig. 37–3) because ferritin is an acute-phase protein and inflam-
a considerable amount of time is needed to deplete the stored iron. True matory cytokines increase ferritin synthesis. In this situation, iron
iron deficiency can eventually develop in chronic inflammatory dis- deficiency should be suspected if ferritin concentrations are less than
eases, especially in children who have smaller iron stores and an addi- 60 mcg/L. Soluble transferrin receptor (sTfR) levels (Table 37–2)
tional requirement for iron because of body growth, or in conditions increase with increased demand of the erythroid marrow for iron but
where IL-6 levels are particularly high, such as systemic-onset juvenile inflammation may have a direct suppressive effect on sTfR. As a result,
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chronic arthritis. The anemia in these children was accompanied by sTfR is increased in iron deficiency but, unlike ferritin, it is unchanged
an appropriate EPO increase, but was unresponsive to oral iron replace- or decreased during infection or inflammation. Although these prop-
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ment. The anemia was corrected, at least partially, by parenteral iron. erties should make sTfR a useful diagnostic parameter alone or in com-
In anemia of CKD, several additional factors may contribute to bination with ferritin, the use of sTfR in practice has been hampered
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true iron deficiency, including the blockade of intestinal iron absorption by inadequate standardization and inconsistent reports of its clinical
by higher hepcidin concentrations from its decreased renal clearance utility. Another promising marker that may differentiate AI from sys-
and the blood losses from hemodialysis, phlebotomy for laboratory temic iron deficiency is serum hepcidin, as very low serum hepcidin
studies, and occult gastrointestinal bleeding. levels in the setting of hypoferremia are diagnostic of systemic iron defi-
ciency. However, the assays have not yet been standardized and the clin-
Summary of Pathogenesis ical utility of hepcidin measurements in differential diagnosis of anemia
AI is primarily the result of slightly decreased red cell survival and of has not yet been tested in large heterogeneous patient populations. 68
macrophage iron sequestration leading to iron-restricted erythropoie- Low serum ferritin concentrations are indicative of iron deficiency
sis. Depending on the underlying disease, the condition is compounded in anemia of CKD but normal or even high ferritin concentrations
by inadequate EPO production, suppressive effect of inflammation on do not preclude a clinical response (increased Hgb) after parenteral
erythropoietic precursors, or depletion of iron stores. Anemia of CKD is iron therapy. In these settings, high ferritin levels may largely reflect
dominated by the effects of relative EPO insufficiency but inflammation inflammation, and augmented iron supply may be needed to overcome
and blood loss also contribute to its pathogenesis. “functional iron deficiency,” that is, to provide sufficient iron supply
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for pulsatile erythropoiesis stimulated by intermittently administered
CLINICAL FEATURES pharmacologic doses of EPO or its derivatives. 69
The clinical manifestations of AI and anemia of CKD are usually
obscured by the signs and symptoms of the underlying disease. Mod- MARROW IRON STAIN
erate anemia (Hgb <10 g/dL) can exacerbate the symptoms of preex- Marrow aspiration or biopsy is rarely required for the diagnosis of AI.
isting ischemic heart disease or respiratory disease, or contribute to In general, the marrow is normal, unless the underlying disease alters
fatigue and exertional intolerance. More severe untreated anemia seen the picture. The most important information obtained from marrow
mainly with CKD may cause extreme fatigue, dyspnea on exertion, and examination is the content and distribution of iron. Iron in a marrow
high-output congestive heart failure. The diagnosis is based on clinical preparation can be found as storage iron in the cytoplasm of macro-
features found in conjunction with typical laboratory abnormalities. phages or as functional iron in nucleated red cells. In normal indi-
viduals, a few Prussian blue–staining particles can be found inside or
LABORATORY FEATURES adjacent to many macrophages. Approximately one-third of nucleated
red cells contain one to four blue inclusion bodies and such cells are
The erythrocytes in AI and anemia of CKD are usually normocytic and called sideroblasts. Both sideroblasts and macrophage iron are absent
normochromic but, with increasing severity or duration, can sometimes in iron deficiency. In contrast, sideroblasts are decreased or absent but
become hypochromic and eventually microcytic. The absolute reticu- macrophage iron is increased in AI. The increase in storage iron in
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locyte count is normal or slightly elevated. association with a decreased level of circulating iron and a decreased

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