Neoplastic Disorders :
Hodgkin`s disease, lung and breast carcinoma.
Pathogenesis
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 erythropoietin
action.
The physiopathological
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 macrophage.
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
cells.
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
Findings
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 findings.
It generally presents as
normochromic-normocytic, but in one third of the cases it presents as
hipochromic-microcytic indicating progressive disease associated with iron
deficiency.
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 sedimentation
rate.
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 is reduced.
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
disease.
Others Chronic Diseases
Anemia
A) Uremia
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 series.
· Complications:
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 analysis.
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
more severe.
Treatment
· Anemia chronic
inflammation
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
failure
The treatment is based on
hormonal replacement.
· Anemia of hepatic disease
Anemia endures while hepatic
function is compromised, but it can be restored by restoration of hepatic
function.
Considerations
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 considered
are:
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 .
References
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.
Isselbacher, Braunwald,
Wilson, Martin, Fauci, Kasper :Harrison`s principles of internal medicine,;
13o ed.
Willian J.Willians:
Hematology, 5o ed.
