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Normochromic, normocytic anaemia 

Normochromic, normocytic anaemia
Chapter:
Normochromic, normocytic anaemia
Author(s):

D.J. Weatherall

DOI:
10.1093/med/9780199204854.003.220505_update_001

August 28, 2014: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Chapter reviewed June 2011—no substantial updates required.

Updated on 30 Nov 2011. The previous version of this content can be found here.
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Essentials

A mild normochromic, normocytic anaemia is a common finding and usually a consequence of other diseases, including (1) anaemia of chronic disorders—associated with chronic infection, all forms of inflammatory diseases, and malignant disease; mechanism unknown but likely to involve multiple factors; typically leads to a reduction in the serum iron concentration with concurrent reduction in the level of transferrin, hence saturation of the iron binding capacity is usually normal or only slightly reduced; (2) other disorders—including renal failure, hypothyroidism, hypopituitarism, marrow failure (aplastic anaemia, infiltration, pure red-cell aplasia), acute blood loss, and polymyalgia rheumatica. Treatment is that of the underlying condition, with a therapeutic trial of corticosteroids justified—after exclusion of underlying blood dyscrasias and paraproteinaemias—in elderly patients with anaemia in association with a very high sedimentation rate.

Introduction

A mild normochromic anaemia is one of the most frequent findings in every branch of clinical practice. It is important to decide whether the anaemia is of significance and how far it should be investigated.

The first decision to be made is whether the blood findings represent ‘anaemia’ for the particular patient. The haemoglobin concentration varies considerably at different ages and there is a wide range of ‘normal’ values. Knowledge of any previous blood count is particularly useful since a haemoglobin value in the lower range of normal may represent anaemia in a patient previously known to have a higher haemoglobin when in good health.

Most of the normochromic, normocytic anaemias are a consequence of other diseases; a minority reflect a primary disorder of the blood. The most common causes are summarized in Box 22.5.5.1.

Anaemia of chronic disorders (ACD)

This is the rather unsatisfactory phrase used to describe the most common of the normochromic, normocytic anaemias, i.e. those found in association with chronic infection, all forms of inflammatory diseases, and malignant disease. It is important for clinicians to be able to identify the main features of this type of anaemia. Although it may be mild and asymptomatic, the presence of this blood picture should always alert the clinician to the possibility of there being a serious underlying disease.

Pathogenesis

The precise mechanism of the anaemia of chronic disorders is still not understood. Several different pathological processes that occur in response to inflammation conspire to cause a defective proliferation of red cell progenitors. In addition, at least in some cases, there may be a mild haemolytic component.

The most constant feature of ACD is a low serum iron level despite adequate iron stores in the reticuloendothelial elements of the bone marrow. This abnormal accumulation of iron in the storage cells, together with a low serum iron level in the blood, suggests that there is a block in the release of iron to the developing red cell precursors. There is also a reduced concentration of transferrin, and turnover studies suggest that this reflects a decreased rate of production. Recent studies in mice and in patients with liver tumours secreting the iron-regulatory protein hepcidin suggest, which occur in many inflammatory conditions, can result in many of the abnormalities of iron metabolism seen in ACD.

Several studies have found a mild shortening of the red-cell lifespan in ACD, which appears to be due to an extracorpuscular factor and not to an intrinsic abnormality of the red cells. The red-cell survival is not markedly shortened; if marrow function were normal it should be able to compensate for the reduced survival. However, there is a defect in the proliferation of red-cell progenitors in ACD. This may reflect inadequate iron delivery or the effect of cytokines produced as a response to infection, or both. There also seems to be a subnormal erythropoietin response for the degree of anaemia, possibly arising from the action of various cytokines.

Recent studies have identified a number of cytokines that inhibit haemopoiesis in bone marrow culture and reduce the output of erythropoietin in hepatoma cell lines. The relevance of these in vitro studies to the generation of ACD in patients with such a diversity of associated disorders is uncertain. It is very unlikely that one mechanism will be found to account for such diverse abnormalities. Rather, it appears that ACD is a by-product of the acute phase reaction, probably augmented by a variety of different cytokine responses.

Clinical and laboratory findings

The anaemia of chronic disorders is usually mild. In patients with severe inflammation the haematocrit may fall to levels at which symptoms are experienced. Although the anaemia is usually normocytic and normochromic there may be mild hypochromia with a slight reduction in the mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV), particularly in children. Occasionally there may be marked microcytosis. Microcytosis should prompt consideration of concomitant iron deficiency, especially in patients who might have gastrointestinal bleeding, e.g. individuals with inflammatory bowel disease or rheumatoid arthritis on aspirin. The reticulocyte count is in the normal range.

The most important finding is a reduction in the serum iron concentration. Because there is a concurrent reduction in the level of transferrin, the per cent saturation of the iron binding capacity is usually normal or only slightly reduced. This observation clearly distinguishes ACD from true iron deficiency anaemia (Table 22.5.5.1). This distinction can also be confirmed by measuring the serum ferritin level, which is usually in the normal range or slightly elevated in patients with ACD while it is low in those who are iron deficient.

Table 22.5.5.1 Distinction between iron-deficiency anaemia and anaemia of chronic disorders

Iron deficiency

Anaemia of chronic disorders

Red cells

Hypochromic microcytic

Normochromic or slightly microcytic

Bone marrow

Sideroblasts

Absent

Absent

Storage iron

Absent

Present or increased

Serum iron

Low

Low

Total iron-binding capacity

Normal or high

Low or normal

Percentage saturation

Low

Normal

Serum ferritin

Low

Normal

The bone marrow appearance is unremarkable. There may be a slight deficiency of red cell progenitors. Iron staining shows a paucity of iron in the red cell precursors and an accumulation of iron in the storage elements of the marrow. Again, this distinguishes ACD from true iron deficiency in which there is an absence of both sideroblasts and storage iron. The abnormal distribution of iron in an adequately stained sample, together with the low serum iron level, is the true hallmark of ACD and a finding that should always be followed up by a search for an underlying inflammatory or neoplastic condition.

Other forms of normochromic, normocytic anaemia

Other causes of this type of blood picture are summarized in Box 22.5.5.1.

Renal failure

Normochromic, normocytic anaemia is a common presenting feature of renal disease. The features of the anaemia of renal failure are discussed in more detail in the section on blood changes in systemic disease.

Endocrine disease

The hypometabolism observed in hypopituitary and hypothyroid states reduces demand for oxygen in the tissues and, therefore, output of erythropoietin. This is probably the principal factor in the development of the mild normochromic, normocytic anaemia which is observed in some patients with these conditions.

Bone marrow failure

Nonspecific anaemia is a common feature of bone marrow failure. It may occur in the pure red cell aplasias or as part of aplastic anaemia.

Acute blood loss and early iron deficiency

Blood loss from the gastrointestinal or genitourinary tract may be sufficient to cause anaemia but as long as the iron stores are sufficient to maintain an output of normal red cells the anaemia is normochromic and normocytic. This picture is seen in early cases of bleeding or intermittent bleeding. There is usually a slight increase in the reticulocyte count, reflecting an increased rate of proliferation of red cell progenitors.

Polymyalgia rheumatica and giant cell arteritis

Polymyalgia rheumatica (see Chapter 18.10.4) is nearly always associated with a moderate normochromic, normocytic anaemia together with a marked increase in the erythrocyte sedimentation rate. However, particularly in elderly patients, anaemia may be the presenting feature. The symptoms of polymyalgia or cranial arteritis may be minimal or even absent. This common variant of the polymyalgia syndrome should always be considered in old people with anaemia and a very high sedimentation rate who do not have paraprotein in the blood. The anaemia responds quite dramatically to corticosteroids.

Management

Mild, nonspecific anaemias should always be investigated because they may be the first indication of a serious underlying disease. It is important to try to distinguish ACD from iron deficiency or other nonspecific normochromic, normocytic anaemias. In ACD, the serum iron level is low and there is a normal saturation of the iron binding capacity. It is worth carrying out a bone marrow examination to study the distribution of iron between the red cell precursors and the storage cells. If the pattern of ACD is observed, it is important to carry out a careful search for chronic inflammation or neoplastic disease. The most common causes of ACD which give rise to diagnostic problems are low-grade urinary infections, chronic sinus infection, and occult malignancy.

The treatment of anaemias of this type is essentially that of the underlying disease. In the subgroup of elderly patients presenting with this type of anaemia in association with a very high sedimentation rate, in whom underlying blood dyscrasias and paraproteinaemias have been excluded, it is justifiable to give a therapeutic trial of corticosteroids, and to proceed to further investigations only if there is no immediate and dramatic response characteristic of the polymyalgia syndromes. Early recognition of the true diagnosis may save weeks of fruitless investigation for a nonexistent neoplasm.

The principal difficulty in the management of this condition is encountered in those case in which it is impossible to correct the underlying disorder, e.g. patients with advanced malignant disease or intractable rheumatoid arthritis. It has been found that the quality of life is undoubtedly improved for many patients of this type if the haemoglobin concentration is raised. This may be achieved by instituting a regular blood transfusion regimen. As an alternative approach, a number of disorders of this type have been treated with erythropoietin at varying doses. A limited number of trials, some of which were placebo-controlled, have suggested that at least some patients with malignant disease, rheumatoid arthritis, or AIDS experience a useful rise in the haemoglobin concentration using this approach. A full response may be delayed for up to 2 months.

Further reading

Ganz T (2011). Hepcidin and iron regulation, 10 years later. Blood, 117, 4425–33.Find this resource:

Gardner LB, Benz EJ (2005). Anemia of chronic diseases. In: Hoffman R, et al. (eds) Hematology, basic principles and practice, 4th edn, pp. 465–71. Churchill Livingstone, New York.Find this resource: