Anemia of chronic disease
|Anemia of chronic dz|
|Classification and external resources|
Anemia of chronic disease, also referred to as anemia of inflammatory response, or ACD, 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 largely the result of the body's production of hepcidin, a master regulator of human iron metabolism.
ACD is the most common anemia found in hospitalized patients.
In response to inflammatory cytokines, increasingly IL-6, the liver produces increased amounts of hepcidin. Hepcidin in turn causes increased internalisation of ferroportin molecules on cell membranes which prevents release from 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. Over the last few years, however, many investigators have come to feel that hepcidin is the central actor in producing anemia of chronic inflammation. Hepcidin offers an attractive Occam's Razor (parsimonious) explanation for the condition, and more recent descriptions of human iron metabolism and hepcidin function reflect this view.
In addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow produces both white blood cells and red 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 additional cause for the decreased erythropoiesis and red blood cell production seen in anemia of inflammation, even when erythropoietin levels are normal, and even aside from the effects of hepcidin. Nonetheless, there are other mechanisms that also contribute to the lowering of hemoglobin levels during inflammation: (i) Inflammatory cytokines suppress the proliferation of erythroid precursors in the bone marrow; (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival of circulating red cells is shortened.
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. Almost all bacteria 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-infective causes of inflammation, future research is likely to investigate whether hepcidin antagonists might be able to treat this problem.
Anemia of chronic disease may also be due to neoplastic disorders and non-infectious inflammmatory diseases. Neoplastic disorders include Hodgkin’s disease lung and breast carcinoma and non-infectious inflammmatory diseases include rheumatoid arthritis and systemic lupus erythematosus.
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.
It has been theorized that anemia of chronic disease has an evolutionary history. As mentioned earlier, iron is needed by many life forms, such as bacteria. Limiting a pathogen’s access to iron can reduce its virulence, thereby potentially protecting against infection and increasing an individual’s survival and overall fitness. It may be important not to treat this defense as a disease, because blood transfusions among critically ill patients is associated with a higher mortality.
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 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.
Examination of the bone marrow to look for the absence or presence of iron may in theory be a helpful diagnostic tool. However, the invasiveness, inconvenience, cost and pain limit the utility of this investigation; 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 that inflammation is present, but can not exclude that iron deficiency is also present if the patient fails to respond to oral iron.
The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely completely possible with current medical treatment. 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, as this condition is often poorly treated either with altered diet, or with oral iron.
Parenteral iron is increasingly used, and guidelines recommend its use in IBD and CKD. Commercially-produced erythropoietin can be helpful in some circumstances. This is costly, and may be dangerous. Erythropoietin is advised either in conjunction with adequate iron replacement which in practice is intravenous, or when IV iron has proved ineffective.
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