Page 576 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 37

ANEMIA OF CHRONIC DISEASES

Lalitha Nayak, Lawrence B. Gardner, and Jane A. Little

Anemia of chronic disease (ACD) is frequently also called “anemia span also contribute to anemia that cannot be explained by hepcidin
of inflammation” since it is associated with a variety of diseases alone. Hence the pathogenesis of ACD is multifactorial and complex
1
including inflammatory conditions, infections, and malignancy. The (Fig. 37.1).
cause of ACD is multifactorial and includes both inhibition of red Although Cartwright and Wintrobe describe a modest decrease
blood cell (RBC) production and mildly decreased RBC life span in the life span of the RBC in ACD, RBCs from patients with
(Table 37.1). Teleologically, ACD may serve to decrease infectious ACD have a normal life span when infused into normal subjects,
virulence by organisms such as malaria and schistosomiasis in a suggesting an abnormality in the surrounding milieu rather than
2
nutrient-depleted host. Malignancies may also be potentiated in an intrinsic RBC defect. However, the decrease in life span of red
an iron-rich environment in humans. Once described as a “bag of cells is insufficient to explain the degree of anemia. Patients with RA
unsolved questions,” ACD has become a much smaller bag since the have elevated levels of inflammatory cytokines that could theoreti-
3
identification of the antimicrobial molecule hepcidin. Hepcidin, a cally enhance erythrophagocytosis and anemia. Similarly, mice with
mediator of both innate immunity and iron regulation, plays a major elevated interferon-ɣ (IFN-ɣ) levels (transgenically or exogenously
role in the pathogenesis of ACD. administered) have reduced RBC survival because of RBC removal
by cytokine-stimulated macrophages.
Macrophages play a central role in iron homeostasis and par-
DESCRIPTION AND EPIDEMIOLOGY ticipate in the reutilization of iron from senescent red cells, which
supplies more than 95% of the daily iron requirements for normal
ACD is a normocytic and normochromic anemia of underproduc- physiologic processes including erythropoiesis. During inflammation,
tion that usually is mild–moderate, with hemoglobin levels in the there is iron retention in the macrophage-phagocytic system and
6
8 to 9.5 gm/L range. The anemia can, however, be severe and the decreased delivery of iron for erythropoiesis. Studies using labeled
mean corpuscular volume may be reduced, sometimes dramatically, iron show normal iron incorporation into RBCs. This is consistent
in up to one-third of patients with ACD. ACD is the second most with the concept that under inflammatory conditions iron release,
4
common cause of anemia, after iron deficiency anemia, and is the but not utilization, is primarily impaired. Activation of immune cells
most frequent anemia in hospitalized patients. Over a 2-month during infections, autoimmune processes, and cancer also leads to the
period of observation, 52% of hospitalized patients with unexplained production of numerous cytokines that induce hepcidin production
anemia met laboratory criteria for ACD. Patients older than 60 in the liver. Hepcidin binds to the iron export protein ferroportin
years of age had a 24% 3-year incidence of ACD. Anemia is also and interferes with cellular iron export through internalization
3
extremely common in cancer; 39% of cancer patients were found and degradation of ferroportin. When ferroportin is lost in the
to be anemic. Chemotherapy with or without radiation therapy jejunum, absorption of dietary iron is reduced and serum iron levels
increases the incidence of anemia to 63% and 42% respectively. are depressed. The same mechanism also inhibits iron export from
3
Human immunodeficiency virus (HIV) infection is often associated macrophages, aggravating the low serum iron levels and enhancing
with anemia with a prevalence as high as 55.8%, directly proportional iron retention in the macrophage. 7
to the burden of symptoms. Rheumatoid arthritis (RA) is associated Hepcidin-independent mechanisms also contribute to altered
with mild anemia, with a prevalence from 33% to 60%. The degree iron homeostasis and are mainly orchestrated by cytokines. Tumor
of anemia is associated with elevations in markers and/or mediators necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IFN-ɣ
of inflammation, such as erythrocyte sedimentation rate (ESR), all increase uptake of transferrin and nontransferrin bound iron by
C-reactive protein (CRP), or interleukin-6 (IL-6) level. altering the expression of transferrin-receptor-1 (Tfr1) and divalent
Diverse diseases not conventionally considered “inflammatory,” metal transporter-1 (DMT1) respectively. In addition, many of these
such as congestive heart failure, obesity, renal failure, and diabetes, cytokines, including IL-4, IL-10, and IL-13, contribute to increased
have been associated both with an ACD-type anemia and with iron storage within the monocytes/macrophages by increasing the
cytokine abnormalities more typically associated with inflammatory expression of ferritin both transcriptionally and posttranscription-
conditions (e.g., elevated IL-6 and CRP in kidney disease or CRP ally. Transcription of ferroportin is also inhibited by IFN-ɣ and
and fibrinogen in myocardial infarction). Because of the absence of lipopolysaccharide (LPS) thereby contributing to iron sequestration
definitive diagnostic criteria or laboratory tests, however, epidemio- in macrophages.
logic studies in ACD are at the least confounded by this underlying In addition to effects on iron, a direct inhibition of erythropoiesis
heterogeneity. and relative deficiency of EPO are seen in ACD. EPO inhibition
has been attributed to inflammatory cytokines. In vitro removal of
bone marrow-adherent cells (mostly macrophages and monocytes)
ETIOLOGY AND PATHOGENESIS from patients with ACD leads to increased erythroid colony forma-
tion. This effect is lost after coculture with ACD-adherent cells,
ACD is a heterogeneous disorder marked by a low serum iron and by but not by coculture with control bone marrow-derived adherent
disturbances in iron homeostasis. Unlike true dietary iron deficiency, cells. Patients with RA have decreased erythroid burst-forming units
iron is present in the macrophages and total body iron may be normal (BFU-E) that are inversely proportional to circulating TNF levels.
or elevated. Research over the last decade suggests that synthesis of In parallel, culture with serum from patients with RA and anemia
the iron regulatory antimicrobial peptide hepcidin is induced by inhibits BFU-E proliferation, while serum from nonanemic RA
inflammatory cytokines during acute and chronic disorders, leading patients does not.
5
to a state of functional iron deficiency. In addition, other factors such In addition, data from clinical studies have documented a relative
as blunted erythropoietin (EPO) production and reduced RBC life deficiency of EPO in many chronic diseases associated with anemia.

491