Biology Reference
In-Depth Information
with serum ferritin concentrations in the normal range undergo serum TfR
determination. In this limited setting, an increased TfR concentration identi-
fied patients who lacked stainable marrow iron [14]. Other investigators have
confirmed the value of TfR in the diagnosis of ACD, either alone [20] or as a
ratio with ferritin [21].
Pathophysiology
It has been known for many years that the severity of ACD is correlated with
the activity of the associated disease [4, 22]. This observation, as well as the
need to find a common pathophysiologic mechanism encompassing disorders
of microbial, autoimmune, and malignant origins, led investigators to consid-
er mediators of the immune and inflammatory response, such as tumor necro-
sis factor (TNF), interleukin-1 (IL-1), and the interferons (IFN) as factors
potentially involved in the development of ACD. Concentrations of these
cytokines increase in patients with disorders associated with ACD [23-28].
Three major processes are involved in the pathogenesis of ACD. A modest
(<10%) shortening of red-cell survival creates a demand for a slight increase
in red cell production by the bone marrow. The marrow cannot respond ade-
quately, however, because of impaired erythropoiesis and impaired mobiliza-
tion of reticuloendothelial system iron stores [29]. The impairment of erythro-
poiesis, in turn, results from two processes: blunting of the expected increment
erythropoietin (EPO) production in response to anemia; and a decreased
response of the erythroid progenitors to EPO. The inflammatory cytokines can
be implicated in all of these processes [30]. A physiologic correlation is pro-
vided by the observation that TNF blockade by a monoclonal antibody in ane-
mic patients with rheumatoid arthritis results in increased hemoglobin con-
centrations [31]. Indeed, the effects of neutralizing antibodies to TNF and
IFN-
on erythroid colony formation
in vitro
in patients with renal failure has
been used to implicate ACD mechanisms in the anemia of uremia [32]. It has
been suggested that a relative deficiency of the anti-inflammatory cytokine IL-
10 may contribute to the pathogenesis of ACD [33].
γ
Shortened red cell survival
Anemic patients with rheumatoid arthritis (a widely used clinical example of
ACD) show an inverse correlation between IL-1 concentrations and red cell
survival [34]; similar results occur in mice after exposure to TNF
in vivo
[35].
The mechanism of this inhibition is unclear. Possible explanations include
neocytolysis (hemolysis of the youngest red cells) in response to a reduction
in EPO concentrations (discussed later) [36], or the effects of nitric oxide, a
known second messenger of cytokine effects, on erythrocyte rigidity [37].
