The central role played by hepcidin in the pathogenesis of ACD suggests that measurement of hepcidin levels might be a useful diagnostic tool in the evaluation of possible ACD. The first measurements of hepcidin relied on extraction from urine, and were laborious, but more recently mass spectrometric and immunological methods to measure levels in urine and serum have been developed with potential for clinical use, and some are now commercially available.
Elevated serum hepcidin levels have been observed in a variety of inflammatory diseases, including rheumatological conditions, inflammatory bowel disease, infections, multiple myeloma, non-Hodgkin lymphoma and critical illness. However, whilst hepcidin levels will usually be elevated in these inflammatory anaemias, levels may not be elevated in patients who have co-existent ACD and iron deficiency as the inflammation-induced increase in hepcidin production will be opposed by the effects of iron deficiency: indeed the long-term effects of hepcidin may to be produce iron deficiency through reduced intestinal iron absorption, so the use of hepcidin levels to diagnose ACD will need to be evaluated carefully. Hepcidin levels may therefore be more useful in distinguishing patients with pure ACD from those with combined ACD and iron deficiency and this may be of therapeutic value. Further standardization and investigation is probably required before hepcidin levels come into routine and widespread clinical use however.
Whether the anaemia observed in some elderly patients has the same pathogenesis as ACD has been a subject of considerable debate. In a large study of patients aged 65 years and over, the relationships between urinary hepcidin, iron status, anaemia and inflammatory markers were investigated: surprisingly, urinary hepcidin levels were closely associated with markers of iron status but not with inflammatory markers, raising the possibility that hepcidin-independent pathways may contribute to hypoferraemia and anaemia in ACD, or that hepcidin levels may only be elevated in settings of overt inflammation.
Growth differentiation factor 15
Growth differentiation factor 15 (GDF15) is an erythropoiesis-derived hormone that is markedly increased in β-thalassaemia and congenital dyserythropoietic anaemia, and inhibits hepcidin expression, contributing to the iron overload seen in these anaemias. Levels of GDF15 have been studied in patients with ACD, ACD/IDA and IDA. Subjects with both ACD and ACD/IDA showed significantly higher levels of GDF15 than patients with IDA, and GDF15 concentrations correlated with interleukin-1β, suggesting that inflammation induces GDF15 expression, although the pathophysiological relevance of this is unclear.