Arising from: Pietrangelo A and Trautwein C (2004) Nat Clin Pract Gastroenterol Hepatol 1: 39–45

In their review “Mechanisms of Disease: the role of hepcidin in iron homeostasis—implications for hemochromatosis and other disorders”, Antonello Pietrangelo and Christian Trautwein gave a clear overview of the role of hepcidin in iron homeostasis.1 Here, we would like to point out that their Table 1 suggests that serum hepcidin data are available, whereas, as far as we know, no sound methods and data have been published on the measurement of serum hepcidin concentrations. Instead, urine hepcidin measurements are currently used for clinical experiments.

The detection and quantification of hepcidin in plasma and serum have been hampered by technical difficulties. It has been difficult to develop immunochemical methods because the small size of hepcidin (25 amino acids) and conservation between animal species makes the production of specific antihepcidin antibodies complex. Nevertheless, Ganz and colleagues2 successfully developed an immunochemical assay for the detection and quantification of urine hepcidin, but this assay seems to be available in their laboratory only. Urine hepcidin assays seem to be preferable for studies on iron metabolism because plasma hepcidin levels are below the detection limit of the currently used methods. This might be due to the fact that free serum hepcidin is very quickly cleared from the bloodstream by binding to ferroportin and its subsequent cellular internalization.3 Furthermore, the remaining free hepcidin is efficiently removed by glomerular filtration. The subsequent appearance of hepcidin in the urine must be explained by incomplete reabsorption, either physiologically or as a consequence of an impairment in the tubular reabsorption process during chronic inflammatory diseases.

We cannot exclude, however, that serum hepcidin is poorly recognized by currently used antihepcidin antibodies because it might have a different conformation to urine hepcidin. The difficulties of serum hepcidin measurements are underscored by anecdotal cases that report on the measurement of hepcidin (or its propeptide) in serum,4,5 in which hepcidin levels seemed to correlate less with clinical diagnosis and body iron parameters than urine hepcidin levels.2

As a result, we think that we should all join forces to tackle and overcome the technical problems that prevent reliable measurements of hepcidin in serum and urine. An accurate and precise method for the quantification of serum hepcidin and a more widely available assay for the quantification of urine hepcidin would allow experimental clinical studies that provide more insight into the in vivo regulation of hepcidin to be carried out. This is essential if we are to explore the possibility of modulating hepcidin as a new tool for the treatment of different human iron-dependent disorders.