Forging iron links

Hepcidin is a tiny protein that packs a lot of punch. It acts as a potent negative regulator of iron absorption and mobilization. Mouse hepcidin mRNA levels have been shown to be exquisitely sensitive to body-iron stores, erythroid demand, hypoxia, and inflammation. But until recently, little was known about hepcidin responses in human patients.

Last year we showed that patients with a unique presentation of the anemia of chronic disease expressed inappropriately high levels of hepcidin mRNA, and we proposed that hepcidin was responsible for the abnormalities of iron metabolism (defective absorption, macrophage iron retention) observed clinically (Weinstein et al, Blood. 2002;100:3776-3781). We speculated that it might play a fundamental role in the anemia of chronic disease in general. In this issue Nemeth and colleagues (page 2461) present impressive results that lend strong support to that conclusion. They find dramatic elevations in hepcidin protein levels in urine from patients with anemia and inflammation. There is every reason to believe that serum hepcidin concentrations are similarly elevated.

Classical teaching implicates inflammatory cytokines in the pathogenesis of the anemia of chronic disease, and elaborate models have been put forth to explain how they might directly affect iron distribution and erythropoiesis. But Nemeth et al's discovery that IL-6 induces hepcidin expression supports a much simpler explanation for the abnormal iron homeostasis observed in this disorder. Although it remains to be seen how much of the picture of anemia of chronic disease can be explained by this one little iron hormone, it now appears quite possible that cytokine induction of hepcidin expression might be most of the story.

Nemeth et al have also followed urine hepcidin in a patient with acute bacterial sepsis. Consistent with its labile regulation in mice and its role in the anemia of chronic disease, levels are markedly elevated at presentation, and they normalize as the infection comes under antibiotic control. This raises the intriguing possibility that hepcidin might serve as a novel marker for acute bacterial infections.