Anemia of chronic disease (ACD) 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. Hepcidin production and release 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. It is also known as anemia of inflammation, or anemia of inflammatory response.

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

Anemia is defined by hemoglobin (Hb) concentration

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 provides a unifying 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 time of circulating red cells is shortened.

Inflammatory cytokines beyond IL-6 — notably tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) — further impair erythropoiesis by reducing erythroid progenitor proliferation, promoting apoptosis of erythroid precursors, and blunting renal erythropoietin production. Inflammation may also shorten erythrocyte lifespan via oxidative damage and enhanced phagocytic clearance. These effects act together with hepcidin-driven iron sequestration to produce the characteristic normocytic (or sometimes microcytic) anemia of chronic disease.

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.