Hepcidin is the primary regulator of iron homeostasis: hepcidin modulates iron availability by promoting the internalization and degradation of ferroportin, a key iron transporter and so far the only identified mammalian iron exporter, which is essential for both iron absorption in the duodenum and recycling of iron/iron efflux by macrophages. Hepcidin is a negative regulator of iron absorption and mobilization; high hepcidin levels turn off both duodenal iron absorption and release of iron from macrophages while low hepcidin levels promote iron absorption and heme iron recycling/iron mobilization from macrophages. Thus, hepcidin levels are expected to be high in iron overload states and diminished in iron deficient states. Hepcidin production can be induced by inflammation, which explains the reduced availability of iron in the anemia of chronic disease, whereas anemia and hypoxia have been shown to increase iron absorption and mobilization by decreasing hepcidin production.1
Previous work on assessing urinary levels of hepcidin was carried out using methods that required mass spectrometry detection and thus are of limited availability.2,3 Low levels of serum hepcidin have been reported using mass spectrometry detection in blood donors donating at least 13 whole blood units in a 2-year time span.4 Measurements of prohepcidin, the precursors of the biologically active 25 aa hepcidin, have been generally disappointing because they seem to be poorly correlated with hepcidin and unresponsive to known hepcidin regulators.5
The work by Ganz et al validates an immunoassay for human hepcidin levels in serum, which has a lower limit of detection of 5 ng/mL and yields a normal range for serum hepcidin of 29 to 254 ng/mL in men and 16 to 288 ng/mL in women. The assay has enough sensitivity to detect changes in serum hepcidin due to diurnal variation and in response to oral iron.
The next challenge will be to demonstrate what is the additional value of these measurements compared with the traditional diagnostic repertoire for iron metabolism disorders. In particular, what will this assay add to the information presently conveyed by serum ferritin? Since both ferritin and hepcidin are similarly affected by changes in iron availability and inflammation, careful studies will be required to demonstrate the unique additional value of measuring serum hepcidin. The authors correctly point out in their work that hepcidin can change on a time scale much shorter than that of ferritin, and several iron overload conditions, including beta thalassemia, exhibit elevated serum ferritin in conjunction with an abnormally low serum hepcidin. Inappropriately high levels of serum hepcidin are also seen in familial forms of iron-refractory iron deficiency anemia due to mutation in TMPRSS6, a negative regulator of hepcidin transcription.6,7 Perhaps the greatest promise for the clinical applicability of this new assay for serum hepcidin resides with the diagnosis of iron deficiency at infancy. An abnormally low serum hepcidin could identify infants at the earliest phase of development of iron deficiency before changes in either ferritin or reticulocyte/red cell parameters take place. If such an assay were to be made available and validated for urine samples, it could simplify the screening for iron deficiency of infants. An abnormally low serum or urinary hepcidin could also be of value for identifying adult women who require iron supplementation therapy without using any other laboratory tests. It remains to be seen if the serum hepcidin assay could also help in better identifying patients with anemia of chronic disease and concomitant iron deficiency or patients with anemia of chronic renal failure, both of which are nonresponsive to erythropoietic-stimulating therapies. Finally, in patients with iron defi-ciency anemia and low ferritin, will an abnormally high hepcidin be of help in identifying patients who are unresponsive to oral iron therapy and require intravenous iron supplements? The availability of this assay opens the way to a variety of exciting studies on iron metabolism in human diseases.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
- © 2008 by The American Society of Hematology