Anemia of chronic disease

Anemia of chronic disease, increasingly referred to as "anemia of inflammation", is a form of anemia seen in chronic illness, e.g. from chronic infection, chronic immune activation, or malignancy. New discoveries suggest that the syndrome is likely primarily the result of the body's production of hepcidin, a master regulator of human iron metabolism.

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Pathophysiology

In response to inflammatory cytokines, the liver produces increased amounts of hepcidin. Hepcidin in turn stops ferroportin from releasing iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportin expression, and probably directly blunting erythropoiesis by decreasing the ability of the bone marrow to respond to erythropoietin.

Before the recent discovery of hepcidin and its function in iron metabolism, anemia of chronic disease was seen as the result of a complex web of inflammatory changes. Many investigators still hold this view while adding hepcidin to their description of this complexity, while others appear to feel that hepcidin is likely to be the most important factor in producing the condition. (Contrast, for example, the tone of the referenced articles by Andrews vs. Weiss and Goodnough, below.) Hepcidin offers an attractive Occam's Razor (parsimonious) explanation for the condition, but not enough experiments have been performed to establish yet whether it alone can account for the changes of anemia of chronic disease.

For instance, in addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow produces both red blood cells and white blood cells from the same precursor stem cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This effect may be an important cause for the effective inhibition of erythropoiesis described earlier, even when erythropoietin levels are normal, and even aside from the effects of hepcidin.

In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacterial pathogens in the body, while producing more immune cells to fight off infection. Bacteria, like most life forms, depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow to produce red blood cells. These cells require iron for their massive amounts of hemoglobin which allow them to transport oxygen.

Because anemia of chronic disease can be the result of non-bacterial causes of inflammation, future research is likely to investigate whether hepcidin antagonists might be able to treat this problem.

Anemia of chronic disease as it is now understood is to at least some degree separate from the anemia seen in renal failure in which anemia results from poor production of erythropoietin, or the anemia caused by some drugs (like AZT, used to treat HIV infection) that have the side effect of inhibiting erythropoiesis. In other words, not all anemia seen in people with chronic disease should be diagnosed as anemia of chronic disease. On the other hand, both of these examples show the complexity of this diagnosis: HIV infection itself can produce anemia of chronic disease, and renal failure can lead to inflammatory changes that also can produce anemia of chronic disease.

Diagnosis

Anemia of chronic disease is often a mild normocytic anemia, but can sometimes be more severe, and can sometimes be a microcytic anemia; thus, it often closely resembles iron-deficiency anemia. Indeed, many people with chronic disease can also be genuinely iron deficient, and the combination of the two causes of anemia can produce a more severe anemia. As with iron deficiency, anemia of chronic disease is a problem of red cell production. Therefore, both conditions show a low reticulocyte production index, suggesting that reticulocyte production is impaired and not enough to compensate for the decreased red blood cell count.

While no single test is always reliable to distinguish the two causes of disease, there are sometimes some suggestive data:

• In anemia of chronic disease without iron deficiency, ferritin levels should be normal or high, reflecting the fact that iron is stored within cells, and ferritin is being produced as an acute phase reactant but the cells are not releasing their iron. In iron deficiency anemia ferritin should be low.

• TIBC should be high in genuine iron deficiency, reflecting efforts by the body to produce more transferrin and bind up as much iron as possible; TIBC should be low or normal in anemia of chronic disease.

If the importance of hepcidin in this condition is borne out, tests to measure hepcidin or cellular expression of ferroportin may one day be useful, but neither are available as validated clinical assays.

Examination of the bone marrow to look for the absence or presence of iron, or a trial of iron supplementation (pure iron deficiency anemia should improve markedly in response to iron, while anemia of chronic disease will not) can provide more definitive diagnoses.

Treatment

The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully. Barring that, many patients with anemia of chronic disease simply live with the effects of the anemia as part of enduring the limits placed on them by other aspects of their underlying medical conditions. In more severe cases, transfusions or several versions of commercially-produced erythropoietin can be helpful in some circumstances; both approaches are costly.

References

• Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. Journal of Clinical Investigation 113(9):1251-3. May 2004.
• Weiss G and Goodnough LT. Anemia of chronic disease. New England Journal of Medicine 352(10):1011-1023. March 10, 2005. PMID: 15758012
• Schrier, SL. Anemia of chronic disease (anemia of chronic inflammation). Up-to-Date (requires subscription). Accessed December 2005.