|Neoplastic Disorders :
Hodgkin`s disease, lung and breast carcinoma.
Anemia of chronic disease is
characterized by a small decrease of the half-life of red cells, caused
either by a disturbance of the iron metabolism or by resistance to
mechanisms of these characteristics will now be discussed:
A) Half-life of erythrocyte
A mechanism responsible for
the reduction of the half-life of the erythrocytes would be its damaging
when passing through injured tissue or the liberation, by these tissues, of
membrane activate factors. Another possibility is the activation of the
phagocyte system as a general mechanism of defense, resulting on a
prematurely destruction of the normal blood cells.
B) Iron metabolism
The defect appears to be on
the holding and non release of iron by the phagocyte system for the
circulating transferrins, thus preventing iron reutilization.
During inflammatory process,
cytokine liberation, as interleukin-1, seems to induce the increase of
ferritin translation in macrophages, capturing iron and preventing
liberation for transferrin. Interleukin-1 would also increase the macrophage
avidity for iron, possibly by inducing lactoferrin liberation by neutrophil.
This joint iron protein would capture free iron and transfer it rapidly to
Another mechanism related to
the disturbance of iron would be the utilization of transferrin for other
purposes during chronic inflammation or malignant process, decreasing its
availability for iron transportation from its storage site to developing red
C) Alterations on the level
of bone marrow
In chronic disease with
presence of anemia, erythropoietin levels increase, due to tissue hipoxia.
Notwithstanding, the marrow response to this increase is not proportional,
which suggests mechanisms of resistance to erythropoietin action.
One of the suggested mechanism
is related to increase of levels of interleukin-1 and others circulating
cytokine observed on inflammatory process. It was established that this
increase is proportional to anemia level.
Interleukin-1 acts on
lymphocytes leading to liberation of interferon g. The last inhibits
erythropoiesis by restraining the development of red cells colonies in the
bone marrow. Furthermore, interleukin would contribute to the liberation of
colonies stimulating factor (CSF) of granulocyte-macrophage which would
reinforce the idea of increasing iron capture by these cells.
Another acting citokines would
be high tumor necrosis factor (TNF a) in patients with carcinoma, rheumatoid
arthritis, parasites, virus and bacterial infections, which would act on the
cells of the bone marrow stroma liberating interferon b. The last, in turn,
would inhibit the red cell series colony formation.
The low concentration of serum
iron seems also to be responsible for erythropoiesis.
In face of those
considerations we can conclude that the relative collapse on the bone marrow
plays an important role, we could say the most important, on the development
of chronic disease anemia.
Clinical and Laboratorial
The chronic disease anemia is
generally light and moderate, its symptoms being masqueraded by the
underlying disease. There are no characteristic clinical findings of this
type of anemia except for nonspecific alterations (cutaneous mucosa
paleness, tachycardia,…). So, the diagnosis depends on laboratorial
It generally presents as
normochromic-normocytic, but in one third of the cases it presents as
hipochromic-microcytic indicating progressive disease associated with iron
The presence of a low iron
serum level is necessary condition for the diagnosis. The serum
concentration of transferrin is reduced as is its percent saturation. The
serum level of ferritin is increased.
In chronic inflammation,
certain plasma proteins called acute phase proteins, like gamma globulin,
C3, haptoglobin, a1-antitrypsin, fibrinogen, are increased by force of
stimulation of interleukin-1, tumor necrosis factor and cytokine liberated
by activated macrophage. The increase of these proteins lead to increase of
The bone marrow structure and
cellularity on biopsy and aspiration, are generally normal, except for
alterations occasioned by underlying disease. When examining the bone
marrow, the most important factor is related to the iron stock. In specific
colorations, the iron may be found on the macrophage or as functional iron
in nucleated red cells where they are seen as inclusion bodies (sideroblast)
on normal conditions. In chronic disease anemia the iron stocks are
increased in the bone marrow, due to the higher quantity of iron in the
macrophages . Nevertheless it is observed that the proportion of sideroblast
Thus, the association of iron
stock increased, low serum iron levels and sideroblast in bone marrow is
characteristic of chronic disease anemia and is not found on any other
Others Chronic Diseases
Uremic syndrome is almost
always accompanied by anemia. It may be very serious but is almost always
moderate due to compound mechanisms (blood flux redistribution, reduction of
blood affinity for O2). The pathology is due to a decrease in erythropoietin
secretion by sick kidneys and, on lower levels, to accumulation of toxic
substances in plasma, that together lead to the decrease of erythropoiesis.
In renal failure, due to
thrombotic thrombocytopenic purpura or hemolytic uremic syndrome occurs a
serious anemia of hemolytic uremic type with characteristically morphologic
changes in erythrocytes.
· Laboratorial Findings:
normochromic-normocytic anemia with normal exam of bone marrow. In one third
of cases we observe in the exam of peripheral blood, typical carving
erythrocytes (spinal cells) that are treated as a simple finding without
repercussion for the development of anemia. The decrease on the number of
erythrocytes indicates that the defect is the lower production of red
1) Gastrointestinal bleeding as a qualitative defect on platelet function.
2) Loss of iron due to bleeding, leading to iron deficiency anemia
3) Folate deficiency because of inadequate ingestion or loss during
B) Endocrine Failure
The erythrocytes production is
affected by various hormones, including T4, testosterone, glucocorticoids.
Therefore, endocrine failure situations are generally accompanied by light
or moderate normochromic-normocytic anemia.
In hypothyroidism and
hypopituitarism, anemia is related to a reduced requirements of O2
transportation as there is a reduction in its consumption when there is no
presence of thyroid hormone or growth hormone.
Anemia of mixedema is
normochromic-normocytic, though there is a major incidence of anemia of iron
deficiency in those patients. Development of iron deficiency may also occur
leading to microcytosis, but plasma volume may be decreased along with the
mass of erythrocytes, so anemia of hypothyroidism may stay hidden.
In Addison`s disease there is
also a decrease on plasma volume and hemoconcentration as a consequence,
which keep normal hemoglobin levels.
C) Anemia of hepatic disease
In chronic hepatic disease,
light to moderate anemia is observed, varying between normocytic or a little
macrocytic. There is increase on plasma volume which makes the hematocrit
lower. Bone marrow tends to be normal, however the reduction on erythrocytes
half-life is not compensated by erythropoiesis. In alcoholic patients, the
direct suppressive action of alcohol over erythropoiesis also makes anemia
· Anemia chronic
The first necessity is to make
the diagnosis of the inflammatory disease or tumor, which underlies the
presentation of laboratorial parameters of anemia. Other causes of anemia
also have to be discarded. When facing a more serious anemia than expected,
it is essential to investigate another factors, as loss of blood, use of
some kind of drugs or iron deficiency.
The treatment of the base
disease is the first and generally sufficient step to recover hematological
state. If concurrent iron deficiency is not ruled out, then iron must be
replaced. However, when this possibility is rejected iron replacement
becomes contraindicate because of the physiologic mechanisms of this anemia.
The utilization of
erythropoietin is sometimes indicated if treatment for the underlying
disease is not effective or not possible. Although it increases the
hematocrit, the administration of recombining erythropoietin may exacerbate
low iron in serum.
Cobalt stimulates the
liberation of erythropoietin and recover anemia levels but is
contraindicated for its toxic effects. For the same reason androgen steroids
are not indicated.
Red cells may be transfused,
if the anemia is symptomatic, which is not common in isolated anemia of
chronic inflammatory disease.
Treatment of chronic
inflammatory disease without addressing the underlying disease must be
avoided if possible.
· Anemia of uremia
Treatment must be based on
reversion or not progression of renal failure. Hemodialysis, by taking out
substances that are said to be toxic and that affect erythropoiesis,may lead
to recovery of hemoglobin levels.
The utilization of recombining
erythropoietin on uremic patient is indicated and allows correction or
important symptoms recover of anemia. 100 to 150 u/Kg of RhEPO are
prescribed 3 times a week, subcutaneous or intravascular(IV). The lower the
erythropoietin endogenous levels and the more severe the anemia, the better
are the results.
· Anemia of endocrine
The treatment is based on
· Anemia of hepatic
Anemia endures while hepatic
function is compromised, but it can be restored by restoration of hepatic
It is necessary , during the
exam of a patient with anemia, to exclude other causes of anemia that may
aggravate or mask the anemia of chronic disease. Some things to be
1. The chronic blood loss or
non absorption of iron, that may occur in some chronic disorders,could also
be present, causing more severe anemia. In these cases, the presence of
sideroblasts, characteristic of the chronic disease anemia, is not seen. It
is important to pay attention to this fact, because in this case, it might
be useful to supplement with iron.
2. The suppression of the
marrow by radio or chemotherapeutic agents and drugs should be considered.
In these case the differential diagnosis must be made by the marrow
examination and laboratorial findings, such as high levels of serum iron in
marrow suppression disease or Coombs + in hemolytic process.
3. Metastatic invasion of
tumor cells in the marrow may aggravate or mimic a chronic disease anemia.
4. Cancer patients are
frequently malnourished and so may acquire folate deficiency.
5. Hemolytic anemia may be
considered in patients with disseminated malignancy, which obviously will
aggravate the anemia of chronic disease.
In general, patients with
chronic disease have a poor alimentation that leads to deficient immunity
and also aggravates the anemia .
F.A.Rice,Art : Anemia of
chronic disease;,Cls March 1, 1996.
Means R.T.J.R, Krants J.B:
Progress in understanding the phatogenesis of the anemia of chronic disease.
Blood 1992:1639; 80:1639.
Eschbach J.C, Egrie J.C,
Downing M.R, Browne J.R, Adamsen J.W: Correction of the anemia of and-stage
renal disease with recombinant human erythropoetin. Results of combined
phase I and II clinical trial. N Engl J Med 1987;316 : 73-78.
Wilson, Martin, Fauci, Kasper :Harrison`s principles of internal medicine,;
Hematology, 5o ed.
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