Altered iron homeostasis
Low serum iron levels are a common feature of ACD: mice injected with pro-inflammatory cytokines, IL-1 and TNF-alpha developed low serum irons and anemia and in human volunteers, injection of IL-6 caused reduction in serum iron levels and transferrin saturation, This effect is now known to be mediated via a 25 amino acid polypeptide hormone known as hepcidin.
Hepcidin is produced by liver cells (and to a lesser extent fat cells and macrophages) and plays a key role in the regulation of iron balance and transport. The hormone’s actions work through its binding to ferroportin, the major protein for removing iron from cells, resulting in the blockade of iron export from body iron stores in macrophages and liver cells; Also inhibition of iron absorption by the duodenum occurs, although recent evidence suggests that this may be caused by downregulation of another transport protein, divalent metal transporter-1 (DMT-1) rather than ferroportin. The combined effect is to restrict iron availability for erythropoiesis, sometimes referred to as a state of ‘functional iron deficiency’, (which is why ACD is often microcytic rather than normocytic as most of the text books assert, and to result in iron accumulation in tissue macrophages. Hepcidin overexpression in transgenic mice reproduces many of the features of ACD and hepcidin levels are raised in a variety of inflammatory disorders. Once bound to ferroportin, the ligand-receptor complex is internalized and degraded, and cellular iron export ceases.
Normally, regulation of hepcidin production occurs through recognition of iron levels and erythropoietic activity. Thus iron excess stimulates hepcidin production, leading to reduced iron absorption and switching off iron release from tissue stores. Conversely, in iron deficiency, hepcidin production is suppressed, enabling increased iron absorption and release of storage iron: similar changes occur when erythroid activity increases.
In inflammatory conditions, hepcidin production is increased, and IL-6 has been shown to be a potent inducer of hepcidin via STAT-3signaling. There is also evidence of a role for other inflammatory cytokines, including IL-1 and bone morphogenetic proteins (BMPs) 2, 4, 6 and 9.
Parallel processes can be seen in malignant conditions. For example, in patients with Hodgkin lymphoma, hepcidin levels were closely correlated with levels of IL-6, rather than other cytokines whereas a recent study suggests that BMP-2, rather than IL-6, is the key inducer of hepcidin in patients with multiple myeloma: hepcidin levels in patients with myeloma inversely correlate with hemoglobin levels, and anti-BMP-2 antibodies blocked the hepcidin-inducing activity of sera from patients with myeloma more consistently than anti-IL-6.
That the erythropoietic and inflammatory pathways regulating hepcidin production may be separate was suggested by a recent study: using a rat model of ACD, it demonstrated that animals with ACD rendered iron-deficient by phlebotomy had lower hepcidin levels than animals with ACD alone. Similar findings were noted in patients with ACD/IDA when compared to individuals with ACD, and the former were able to absorb dietary iron and mobilize iron from macrophage stores. This is an important observation if hepcidin levels are to be incorporated into the diagnostic pathway for patients with ACD.