Hepcidin: we always knew you were there

Comment on Papanikolaou et al, page 4103

Papanikolaou and colleagues have provided us with a key missing piece of pathophysiologic data that goes far in explaining the basis for iron-loading disorders.

We knew that iron absorption from the gut was controlled by a sensor(s) that somehow detected erythropoietic drive but also responded to iron stores, presumably mostly in the liver. So in iron deficiency anemia it made sense that the combined need for increased erythropoiesis and the decreased iron stores should provide complementary and coherent signals that lead to increased iron absorption, but we didn't know the mediator(s). Conversely, the huge increase in body iron stores in classical hereditary hemochromatosis should have lead to decreased iron absorption but did not. Worse, we couldn't understand why iron absorption continued to be increased in the severe β-thalassemias, despite enormous increases in iron stores. In lectures to our students, we wisely asserted that erythropoietic signals override iron store signals. This paper explicitly explores the conflicting impact of erythropoietic drive versus the status of iron stores and identifies hepcidin as the key player.

Although it was not specifically the subject of this paper, we were also puzzled by the chronic anemia in patients who had inflammatory disease and neoplasia because when we looked at Prussian blue stains of their marrow aspirates we frequently saw iron-laden macrophages. In contrast, the patients were anemic with mean corpuscular volumes (MCVs) usually at the lower range of normal and low serum iron levels, thereby suggesting a lack of iron availability.

It appears that the actions of the mediator hepcidin provide an explanation for the anemia of chronic inflammation and neoplasia and for the several genetic causes of iron overload syndromes. Hepcidin is synthesized in the liver and its synthesis is increased in inflammation probably by action of the cytokine interleukin 6 (IL-6).¹  The action(s) of hepcidin, once murky, are becoming clear. In the gut, iron is taken into mucosal cells, but iron transfer from mucosal cells to plasma is controlled by the iron exporter channel ferroportin. Hepcidin binds to ferroportin and causes its degradation, thus blocking efficient transfer of iron from the gut mucosa to the plasma and functionally blocking iron absorption.²  Similarly, hepcidin interacting and degrading ferroportin blocks transfer of iron out of macrophages, nicely accounting for the apparent iron-deficiency anemia and iron-loaded macrophages we see in inflammatory diseases.

In this study, very careful measurement of urinary hepcidin is made in severe forms of β-thalassemia, congenital dyserythropoietic anemia, and 2 forms of juvenile hemochromatosis. With rare exceptions, the urinary hepcidin, which should have been very high because of the severe iron overload, was low or even absent. The exceptions were the 2 subjects with type IV juvenile hemochromatosis who had ferroportin mutations and very high urinary hepcidin levels. One wonders if the defective ferroportin could not bind to and remove hepcidin, thereby accounting for its build up.

So we now know how inflammation via IL-6 causes increased synthesis of hepcidin but we still don't know how the overloading of iron stores and particularly the drive for erythropoiesis turns off hepcidin. ▪