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.

[ Back ] [ Up ] [ Next ]