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CHAPTER 37 (AI), is not only more reflective of the pathophysiology of ACD but also
includes anemia of critical illness, a condition that presents similarly to
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ANEMIA OF CHRONIC ACD but develops within days of the onset of illness. An anemia similar
to AI is seen in some older individuals in the absence of an identifiable
DISEASE chronic disease; this condition is sometimes referred to as unexplained
anemia of elderlies or anemia of aging (Chap. 9).
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AI is characterized by inadequate erythrocyte production in the
setting of low serum iron and low iron-binding capacity (i.e., low trans-
Tomas Ganz ferrin) despite preserved or even increased macrophage iron stores in
the marrow. The erythrocytes are usually normocytic and normochro-
mic but can be mildly hypochromic and microcytic. Anemia of criti-
2
cal illness can develop acutely (within days) in intensive care settings
SUMMARY where the effects of infection or inflammation are exacerbated by
disease-related or iatrogenic blood loss or red cell destruction, which by
Most patients suffering from chronic infection, chronic inflammation, or some themselves are not sufficiently severe to cause anemia. Anemia of aging
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with various malignancies develop a mild to moderate anemia. This anemia, is diagnosed in the older when a normocytic normochromic anemia
designated anemia of chronic disease or anemia of chronic inflammation, is with low serum iron and preserved iron stores develops without an iden-
characterized by a low serum iron level, a low to normal transferrin level, and tified underlying disease. Older patients in this defined subset typically
a high to normal ferritin level. The anemia is caused by the direct and indi- have an elevated sedimentation rate and/or elevated C-reactive protein
rect inhibitory effects of inflammatory cytokines on erythrocyte production. (CRP), a high plasma interleukin (IL)-6 concentration, and frailty.
Among the cytokines, interleukin-6 has a central role, acting by increasing Anemia of chronic kidney disease (CKD) usually develops as
hepatocyte production of the iron-regulatory hormone hepcidin. Hepcidin chronic renal disease progresses and generally becomes more severe
with decreasing creatinine clearance (Fig. 37–1). The anemia presents
then blocks the release of iron from macrophages and hepatocytes, causing similarly to AI but because the kidney is the main site of erythropoietin
the characteristic hypoferremia associated with this anemia, and limiting the (EPO) production in adults, the progressive destruction and fibrosis of
availability of iron to the developing erythrocytes. Effective treatment of the the kidneys causes relative EPO deficiency, which frequently dominates
underlying disease restores normal erythropoiesis. When this is not possible, the pathogenesis of this anemia. Patients with polycystic kidney dis-
and treatment is necessary, therapeutic trials have revealed that the anemia is ease are often at least partially spared of the anemia, whereas patients
often responsive to pharmacologic doses of erythropoietin. with bilateral nephrectomy are particularly severely affected by EPO
Anemia of chronic kidney disease presents similarly to anemia of inflam- deficiency. Systemic inflammation, true iron deficiency and decreased
mation but because the kidneys are the predominant site of erythropoietin clearance of hepcidin are common consequences of the underlying dis-
production, the pathogenesis of this anemia is frequently dominated by rel- ease and dialysis treatments, and one or more of these factors frequently
ative erythropoietin deficiency, where erythropoietin concentrations in serum worsen anemia or diminish the response to EPO therapy.
Physicians have known about the pale appearance of patients with
are lower than expected for the severity of anemia. Systemic inflammation chronic infections for hundreds of years. In 19th-century Europe, tuber-
from underlying renal disease, or induced by dialysis treatments and their culosis was the major killer and the pallor associated with this disease
complications, contributes to pathogenesis in a manner similar to anemia of was romanticized in the art literature of the time. The first measure-
inflammation. Circulating hepcidin concentrations may also rise because of its ments of red cell mass revealed the association between inflammation
decreased renal clearance. Suppressive effects of uremia on erythropoiesis and and anemia. Discussing “the alterations in the condition of the Blood
blood losses from hemodialysis may contribute to anemia in end-stage renal in Inflammation” in Section 372 of the 1859 edition of the Principles
4
disease. A combination of erythropoiesis–stimulating agents and intravenous of Human Physiology, William B. Carpenter described this connection
iron is usually effective in reversing anemia but overtreatment may worsen between inflammation and anemia (author’s parentheses): “With this
overall outcomes. increase in the proportion of fibrin and colorless corpuscles (leuko-
cytes), separately or in combination, there is a diminution of the pro-
portion of the red corpuscles, albumen and the salts of the blood.” In
1961, 100 years later, Maxwell Wintrobe, in the fifth edition of Clini-
DEFINITION AND HISTORY cal Hematology, used the term “simple chronic anemia” for the nor-
5
mocytic anemia associated with the majority of infections and chronic
The term anemia of chronic disease (ACD) or anemia of chronic disor- systemic diseases. He described anemia associated with inflammation
ders refers to mild to moderately severe anemia (hemoglobin [Hgb] 7 as a common subtype. Wintrobe proposed “profound alterations in iron
to 12 g/dL) associated with chronic infections and inflammatory disor- and porphyrin metabolism” as the likely cause, and referred to his own
ders and some malignancies. The newer name, anemia of inflammation experiments that showed a decrease in erythrocyte survival of only 27
1
percent, which “could easily be met by increased erythropoiesis if the
bone marrow functional capacity were not impaired.” Despite advances
in our understanding of the pathophysiology of this very common form
Acronyms and Abbreviations: ACD, anemia of chronic disease; AI, anemia of of anemia, our knowledge is incomplete.
inflammation; CKD, chronic kidney disease; CPG, clinical practice guideline; CRP, Anemia of CKD became a common problem in the 1960s when
C-reactive protein; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; IDA, hemodialysis became widely available and allowed prolonged survival
iron-deficiency anemia; IL, Interleukin; KDIGO, The Kidney Disease Improving Global of patients with end-stage renal failure. Anemia of CKD was usually
Outcomes; sTfR, soluble transferrin receptor; TfR, transferring receptor; TNF, tumor severe enough to limit activities of daily living and was treated by blood
necrosis factor. transfusions until the late 1980s when recombinant EPO became widely
available, and alleviated the most severe forms of this anemia.

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