Anaemia of chronic disease

Published on 03/04/2015 by admin

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18

Anaemia of chronic disease

Anaemia of chronic disease (ACD) is a term used to describe a type of anaemia seen in a wide range of chronic inflammatory, infective and malignant diseases (Table 18.1). The anaemia often becomes apparent during the first few months of illness and then remains fairly constant (Fig 18.1). It is rarely severe (haemoglobin ≥90 g/L; packed cell volume (PCV) ≥0.30) but there is some correlation with the intensity of the underlying illness. For instance, in infection the anaemia is often more marked where there is a persistent fever and in malignancy where there is widespread dissemination. Patients may suffer no symptoms from their anaemia or have only slight fatigue. The importance of this type of anaemia arises not from its severity but from its ubiquity. It is widely misunderstood (for such a common disorder) and ill patients are frequently subjected to excessive haematological investigation and unnecessary treatment with haematinics. The term ACD should not be used to describe other causes of anaemia such as haemolysis or bleeding which may also complicate chronic disorders. It has been argued that the designation ACD is inappropriate but other suggested terms (e.g. anaemia of inflammation) appear even less satisfactory. The anaemia of chronic renal failure is variously referred to as ACD although it has its own specific features (see p. 96).

Pathophysiology

The causation of the anaemia of chronic disease has been extensively studied but questions remain. Key factors in aetiology are summarised in Figure 18.2. Inflammatory cytokines such as tissue necrosis factor (TNF) and interleukin-1 and -6 are implicated in all of these processes.

There is a modest shortening of red cell lifespan which leads to an increased demand for bone marrow production. The marrow struggles to respond adequately as there is blunting of the expected increase in erythropoietin secretion and also diminished responsiveness of erythroid precursor cells to erythropoietin. Hepcidin, a peptide hormone, appears to be an important mediator of ACD. This acute phase reactant protein is released from the liver following stimulation by interleukin-6. Actions of hepcidin include inhibition of microbial infection, macrophage iron recycling and intestinal iron absorption. Its role in iron balance and transport is mediated via binding to ferroportin, the major cellular iron efflux protein. Patients with inflammation and anaemia have elevated serum and urine levels of hepcidin. Abnormalities of iron metabolism are well documented in ACD. These include:

The high prevalence of ACD has led to the suggestion that it may have some benefits for those with chronic inflammation. Perhaps withdrawal of iron by increased storage in the reticuloendothelial system limits its availability to microorganisms or tumour cells. Decreased haemoglobin levels reduce the oxygen-carrying capacity of the blood and might reduce the oxygen supply to unwelcome microorganisms and cells. Cell-mediated immunity is probably strengthened by reduced levels of metabolically active iron in the circulation as iron inhibits the activity of IFN-γ.

Diagnosis

Most patients will have a documented chronic disorder and a moderate anaemia. On occasion the anaemia is a more dominant feature and the underlying cause is not immediately apparent. The anaemia is usually of normochromic normocytic type although it can be slightly hypochromic microcytic. The blood film appearance is often unremarkable but there may be changes ‘reactive’ to the underlying disorder such as a neutrophil leucocytosis, thrombocytosis and rouleaux formation. There is a reticulocytopenia. Inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are often raised. Serum iron concentration and transferrin concentration are usually reduced. The serum ferritin level is normal or high (as an acute phase reactant). In practice, ACD is most commonly confused with mild iron deficiency anaemia, particularly if the MCV and MCH are reduced. However, the two forms of anaemia should be distinguishable as in uncomplicated iron deficiency the transferrin concentration is elevated and the ferritin level is low. In difficult cases the serum transferrin receptor concentration and the serum transferrin receptor-ferritin index may be useful (Table 18.2). Measurement of the percentage of hypochromic red cells or reticulocyte haemoglobin content can be helpful in detecting coexistent iron-restricted red cell production in a patient with ACD. Reliable hepcidin assays are under development and are likely to enter routine clinical practice. Bone marrow examination is not routinely required but where performed will show normal or increased marrow iron stores with decreased marrow sideroblasts (Fig 18.3).

Table 18.2

Comparison of clinical and laboratory findings in ACD and iron deficiency anaemia

Characteristic ACD Iron deficiency
Severity of anaemia Hb usually ≥90 g/L Very variable
Symptoms of anaemia Usually mild May be severe
Coexistent chronic disease Yes Variable
Red cell indices (MCV, MCH) Normochromic Hypochromic
  Normocytic1 Microcytic
Blood film appearance Often normal or reactive2 Hypochromia
    Microcytosis
    Poikilocytosis
    Target cells
Serum iron Reduced Reduced
Transferrin concentration Reduced or normal Increased
Ferritin Normal or increased Reduced3
Serum transferrin receptor Normal Increased
Serum transferrin receptor-ferritin index4 Low High
Marrow iron stores Normal or increased Reduced

1May be slightly hypochromic microcytic.

2‘Reactive’ changes in a blood film may accompany the underlying disorder; possible abnormalities include rouleaux formation, a neutrophil leucocytosis and thrombocytosis.

3Unless there is a coexistent acute phase response when the ferritin level may be normal.

4Transferrin receptor concentration divided by serum ferritin concentration (or log of plasma ferritin concentration).

It should be remembered that anaemia in a patient with a chronic medical disorder may be of multifactorial origin. It is important not to misdiagnose ACD as something else but equally it cannot be assumed that every patient with longstanding disease and a low haemoglobin has only ACD.

Management

As the anaemia is usually non-severe and not progressive, the management is primarily that of the underlying disorder. The rationale for treating the anaemia itself is to avoid immediate deleterious effects (e.g. on the cardiovascular system), to improve quality of life, and possibly to improve the prognosis of the underlying condition.

Occasionally, patients cannot adequately compensate for the anaemia and require blood transfusion. Recombinant human erythropoietin and its derivatives can be effective in relieving anaemia, particularly in rheumatoid arthritis and malignancy. Their use is restricted by concerns of increased risk of thromboembolic events and higher rates of tumour recurrence; they should only be used selectively and in the lowest effective dose. In the absence of coexistent iron deficiency, oral iron supplements are rarely helpful. Intravenous iron may be beneficial, especially if combined with erythropoietin, but there is limited experience outside the field of renal medicine. Further studies are needed to evaluate the effect of amelioration of the anaemia on the course of the underlying disease. Possible future therapies for ACD include alternative stimulators of erythropoiesis, hepcidin antagonists and novel anti-inflammatory agents.

Anaemia of chronic disease (ACD)

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