Anemia of chronic disease

Anemia of chronic disease or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver, which in turn shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells (e.g. macrophages). As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis.

Anemia of chronic disease
Other namesAnemia of chronic inflammation

Anemia of chronic inflammation is the preferred term since not all chronic diseases are associated with this form of anemia.

Classification

Anemia of chronic disease is usually mild but can be severe. It is usually normocytic, but can be microcytic.[1] The presence of both anemia of chronic disease and dietary iron deficiency results in a more severe anemia.

Pathophysiology

Anemia is defined by hemoglobin (Hb) concentration

  • < 13.0 g/dL (130 g/L) in males
  • < 11.5 g/dL (115 g/L) in females

In response to inflammatory cytokines, increasingly IL-6,[2] 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 provides a unifying explanation for the condition, and more recent descriptions of human iron metabolism and hepcidin function reflect this view.[3]

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.;[4] (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 inflammatory diseases.[1] Neoplastic disorders include Hodgkin’s disease lung and breast carcinoma and non-infectious inflammatory diseases include celiac disease,[5] 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 kidney failure in which anemia results from reduced 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 kidney failure can lead to inflammatory changes that also can produce anemia of chronic disease.

Diagnosis

While no single test is reliable to distinguish iron deficiency anemia from the anemia of chronic inflammation, there are sometimes some suggestive data:

  • In anemia of chronic inflammation without iron deficiency, ferritin is normal or high, reflecting the fact that iron is sequestered within cells, and ferritin is being produced as an acute phase reactant. In iron deficiency anemia ferritin is low.[1]
  • Total iron-binding capacity (TIBC) is high in iron deficiency, reflecting production of more transferrin to increase iron binding; TIBC is low or normal in anemia of chronic inflammation.

Treatment

The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible.

Parenteral iron is increasingly used for anemia in chronic renal disease[6] and inflammatory bowel disease.[7][8]

Erythropoietin can be helpful, but this is costly and may be dangerous.[9][10] Erythropoietin is advised either in conjunction with adequate iron replacement which in practice is intravenous, or when IV iron has proved ineffective.[7][8]

Limiting some microbes' access to iron can reduce their virulence, thereby potentially reducing the severity of infection. Blood transfusion to patients with anemia of chronic disease is associated with a higher mortality, supporting the concept.[11]

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See also

References
  1. Weng, CH; Chen JB; Wang J; Wu CC; Yu Y; Lin TH (2011). "Surgically Curable Non-Iron Deficiency Microcytic Anemia: Castleman's Disease". Onkologie. 34 (8–9): 456–8. doi:10.1159/000331283. PMID 21934347.
  2. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T (2004). "IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin". Journal of Clinical Investigation. 113 (9): 1251–3. doi:10.1172/JCI20945. PMC 398432. PMID 15124018.
  3. Nemeth E, Ganz T (2006). "Regulation of iron metabolism by hepcidin". Annu. Rev. Nutr. 26 (1): 323–42. doi:10.1146/annurev.nutr.26.061505.111303. PMID 16848710.
  4. Maury CPJ, Andersson LC, Teppo AM et al. Mechanism of anemia in rheumatoid arthritis: Demonstration of raised interleukin-1 beta concentrations in anemic patients and of interleukin-1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukemia (HEL) cells in vitro. Annals of the Rheumatic Diseases 47 (1988) 972-978.
  5. Leffler DA, Green PH, Fasano A (Oct 2015). "Extraintestinal manifestations of coeliac disease". Nat Rev Gastroenterol Hepatol (Review). 12 (10): 561–71. doi:10.1038/nrgastro.2015.131. PMID 26260366. ‘Anaemia of chronic disease’ (a form of anaemia associated with inflammation) is seen in ~25% of patients with coeliac disease.2
  6. Zager RA (September 2006). "Parenteral iron compounds: potent oxidants but mainstays of anemia management in chronic renal disease". Clin J Am Soc Nephrol. 1 Suppl 1: S24–31. doi:10.2215/CJN.01410406. PMID 17699373.
  7. "Archived copy" (PDF). Archived from the original (PDF) on 2013-06-21. Retrieved 2012-08-08.CS1 maint: archived copy as title (link)
  8. "Archived copy" (PDF). Archived from the original (PDF) on 2013-11-02. Retrieved 2012-08-08.CS1 maint: archived copy as title (link)
  9. Anemia of chronic disease at Mount Sinai Hospital
  10. Zarychanski R, Houston DS (2008). "Anemia of chronic disease -- a harmful disorder, or a beneficial, adaptive response?". Can. Med. Assoc. J. 179 (4): 333–7. doi:10.1503/cmaj.071131. PMC 2492976. PMID 18695181.
  11. Zarychanski, R; Houston, DS (Aug 12, 2008). "Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response?". CMAJ : Canadian Medical Association Journal. 179 (4): 333–7. doi:10.1503/cmaj.071131. PMC 2492976. PMID 18695181.
Classification
External resources
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