Page 578 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 37 Anemia of Chronic Diseases 493

−/−
Hence liver specific Smad4 mice show an attenuated response to in cancer, wounds, and ischemia, may be a negative regulator of
IL-6–mediated hepcidin transcription, and inhibitors of BMP also EPO synthesis. Further, autoantibodies to EPO associated with low
inhibit IL-6–mediated transcription of hepcidin. In humans, injec- circulating EPO levels have been detected in subjects with systemic
tion with LPS dramatically increases IL-6 levels by hour 3, followed lupus erythematosus.
by an increase in urinary hepcidin by hour 6. Direct administration Perhaps the strongest argument for a causative role of EPO in
of IL-6 to humans also leads to increased prohepcidin and decreased ACD is that exogenous EPO can partially reverse ACD. Evidence
serum iron. In patients with ACD, increased prohepcidin serum suggests that exogenous administration of EPO may result in
concentrations are associated with decreased expression of ferroportin decreased levels of hepcidin, via a recently recognized EPO-driven
along with increased ferritin accumulation in circulating monocytes. suppressor of hepcidin, erythroferrone, thus leading to improve-
Finally, the functional iron depletion mediated by hepcidin may ment in anemia and iron sequestration. 17,18 In rats, low-dose EPO
itself augment direct cytokine inhibition of erythropoiesis through the normalized endothelial function, vascular inflammation, and oxida-
14
aconitase/iron response protein (IRP) axis. A central contribution tive stress suggesting that EPO may also decrease inflammation.
to net inhibited erythropoiesis in an inflammatory and functionally Inhibition by IFN-ɣ can be reversed by EPO. Moreover, the capac-
iron-depleted state is mediated through an iron-sensing switch. With ity of patient-derived monocytes from patients with inflammatory
normal iron levels, heme synthesis and EPO responsiveness are main- bowel disease to secrete TNF predicts the therapeutic response to
tained, in part, through a functioning aconitase enzyme bound to an exogenous EPO.
iron-sulfur molecule. However in an iron-depleted state, aconitase
ceases to function as an enzyme and becomes an RNA-binding IRP,
thereby modulating transcription and translation of iron-regulated DIAGNOSIS
15
proteins. Experimentally, anemia develops following inhibition of
aconitase activity, with impaired erythroid progenitor differentiation Because ACD is both common and multifactorial, an unequivocal
15
and viability via a protein kinase C dependent pathway. This anemia diagnosis may be challenging. Further, it is not uncommon that
can be abrogated experimentally through repletion of the downstream primary hematologic defects are accompanied by inflammation, or
14
metabolic intermediate isocitrate. Strikingly, in these models, iron vice versa, so other factors that also result in anemia, such as nutri-
depletion uniquely sensitizes erythroid cells to suppression by inflam- tional deficiency, blood loss, hemolysis, renal failure, and primary
matory cytokines, and this, too, was mitigated by treatment with bone marrow disorders need to be considered. Chronic inflam-
isocitrate. matory bowel diseases are frequently associated with both chronic
gastrointestinal bleeding secondary to the underlying disease and its
treatment (with nonsteroidal antiinflammatory drugs [NSAIDs] and
Cytokines Leading to Direct Inhibition of Erythropoiesis glucocorticoids). Iron deficiency can also be secondary to decreased
iron absorption, as in autoimmune gastritis and celiac disease. Up
Proliferation and differentiation of erythroid precursors is impaired to 70% of the anemia associated with RA may be multifactorial.
in patients with ACD. Studies support a role for TNF-α, IL-1, and Of the 184 patients admitted to intensive care units, most patients
perhaps IL-6 in this inhibition. There is good evidence that IFN with anemia were found to have EPO levels and iron study results
directly inhibits erythropoiesis, such as highly purified CFU-E from consistent with ACD; however, 13% also had nutritional causes
murine spleens in a dose-dependent manner. In vitro studies show of anemia (iron, folate, or vitamin B12 deficiency). Finally, the
that IFN-ɣ modulates cytokine responses and expression of genes contribution of frequent phlebotomy in the hospitalized patients
that are involved in the proliferation of hematopoietic stem cells, with anemia should not be underestimated (see box on Diagnosis of
thus affecting self-renewal. IFN-ɣ can also decrease responsiveness of Anemia of Chronic Diseases).
erythroid progenitors to EPO. In vivo and in vitro studies show that Contributing causes of anemia, including hemolysis, nutritional
IFN-ɣ treatment of erythroid progenitors increases the expression of deficiency, or sequestration should be evaluated. Iron deficiency plus
the transcription factor PU.1. Since PU.1 directly interacts with the ACD should be strongly considered in patients with systemic inflam-
major erythroid transcription factor GATA-1, it is postulated that mation and a low or “normal” serum ferritin concentration. While
IFN-ɣ treatment affects erythroid progenitors by a PU.1 dependent some investigators argue that a ferritin level greater than 50 ng/
mechanism. 16 mL excludes any component of iron deficiency even in inflamma-
Serum levels of TNF correlate inversely with the hemoglobin tory states, a meta-analysis of iron studies in clinical reports from
levels and, in RA, with the number of erythroid burst-forming units. 1842 subjects with serum ferritin levels above 45 ng/mL showed a
Treatment with anti-TNF improves proliferation and decreases apop- prevalence of iron deficiency of 6.7%; 3.5% of 1368 subjects with a
tosis of erythroid progenitor cells. However, the effect of TNF on serum ferritin level of greater than 100 ng/mL had iron deficiency.
erythropoiesis is likely indirect, mediated by the local release of other
cytokines including IFN from accessory cells, since the inhibitory
effect of TNF on CFU-E was completely abrogated by neutralizing
antibodies against IFN-β but not by antibodies to IFN-ɣ or IL-1. Diagnosis of Anemia of Chronic Diseases (Fig. 37.2)
Similarly, the effects of IL-1 also appear to be indirect since growth of
purified CFU-E is inhibited by IL-1 only in the presence of adherent The diagnosis of ACD is primarily one of exclusion and is often difficult.
T lymphocytes. This inhibition can be reversed by antibodies to Various laboratory tests have been suggested, but few have proven
IFN-ɣ, suggesting that IL-1 leads to lymphocyte secretion of IFN. value in the general population because ACD occurs in too large a
variety of acute and chronic illnesses. The best way to diagnose ACD, at
least provisionally, is to document an anemia of underproduction (i.e.,
Cytokines Leading to Decreased low reticulocyte index) with low serum iron and low transferrin levels
Erythropoietin Secretion and normal to elevated serum ferritin level in the setting of a systemic,
usually inflammatory, illness. A thorough search may be necessary to
document the precise underlying illness.
EPO is the essential hormone that induces erythropoiesis. Inflam- Other causes of anemia, such as hemolysis, nutritional deficiency, or
matory conditions are associated with insufficient EPO levels relative sequestration, should be ruled out, and a component of iron deficiency
to the degree of anemia. Mice injected with LPS have decreased should be strongly considered in a patient with systemic inflammation
expression of EPO mRNA in kidneys and decreased circulating levels and a low or “normal” serum ferritin concentration. These other causes
of EPO. In tissue culture, IL-1α, IL-1β, and TNF-α significantly of anemia often accompany ACD. Bone marrow examination is usually
not essential for the diagnosis but may be necessary to rule out other
lowered EPO production. IL-1β also inhibited EPO production in diagnoses, including malignancy (e.g., myelodysplastic syndrome),
perfused rat kidneys. In addition, animal models have suggested infection, or iron deficiency.
that vascular endothelial growth factor, which is commonly elevated