- Anemia of chronic disease
Name = PAGENAME
ICD9 = ICD9|285.2
MedlinePlus = 000565
eMedicineSubj = emerg
eMedicineTopic = 734
Anemia of chronic disease, increasingly referred to as "anemia of inflammation", is a form of
anemiaseen 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.
In response to inflammatory
cytokines, predominantly IL-6[cite journal | author=Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. | title=IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. | journal=J Clinical Invest. | year=2004| pages=1251–3| volume=113| issue=9| pmid=15124018 | doi=10.1172/JCI20945 ] , the liver produces increased amounts of hepcidin. Hepcidin in turn stops ferroportinfrom releasing iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportinexpression, and probably directly blunting erythropoiesisby decreasing the ability of the bone marrowto respond to erythropoietin.
Before the recent discovery of
hepcidinand 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 metabolismand hepcidin function reflect this view. [cite journal | author=Nemeth E, Ganz T. | title=Regulation of iron metabolism by hepcidin. | journal=Annu. Rev. Nutr. | year=2006| pages=323-42| volume=26| issue=1| pmid=16848710 | doi=10.1146/annurev.nutr.26.061505.111303]
Nonetheless, in addition to effects of iron sequestration, inflammatory cytokines promote the production of
white blood cells. Bone marrowproduces both red blood cellsand white blood cellsfrom the same precursor stem cells. Therefore, the upregulation of white blood cellscauses fewer stem cellsto differentiate into red blood cells. This effect may be an important additional cause for the decreased erythropoiesisand red blood cell production seen in anemia of inflammation, even when erythropoietinlevels 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 marrowto produce red blood cells. These cells require iron for their massive amounts of hemoglobinwhich 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 failurein which anemia results from poor production of erythropoietin, or the anemia caused by some drugs (like AZT, used to treat HIVinfection) 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.
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 reticulocyteproduction 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,
ferritinlevels 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 anemiaferritin should be low.
TIBCshould be high in genuine iron deficiency, reflecting efforts by the body to produce more transferrinand bind up as much iron as possible; TIBCshould be low or normal in anemia of chronic disease.
If the importance of
hepcidinin this condition is borne out, tests to measure hepcidin or cellular expression of ferroportinmay 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.
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,
transfusionsor several versions of commercially-produced erythropoietincan be helpful in some circumstances; both approaches are costly.
* [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=15124013 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15758012&query_hl=2 PMID: 15758012]
*Schrier, SL. Anemia of chronic disease (anemia of chronic inflammation). [http://www.uptodate.com Up-to-Date] (requires subscription). Accessed December 2005.
* [http://www.anemia.org National Anemia Action Council]
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