Endocrine Abstracts

Hepcidin is a small circulating 25-amino-acid cysteine-rich peptide first identified in human blood and urine. The hepcidin gene is expressed mainly in the hepatocytes, secreted in the circulation and cleared by the kidney. In mammals, convincing evidence indicates that hepcidin constitutes the master regulator of iron homeostasis; the circulating peptide acts to limit gastrointestinal iron absorption and serum iron by inhibiting dietary intestinal iron absorption and iron recycling by the macrophages. To limit iron egress, hepcidin binds to ferroportin, a transmembrane iron exporter, thereby inducing its internalization and subsequent degradation, leading to decreased export of cellular iron.

As befits an iron-regulatory hormone, hepcidin synthesis is induced by iron stores and inflammation and inhibited by anemia and hypoxia. The mechanisms regulating hepcidin expression are only beginning to be understood. Recent studies have highlighted two regulatory cascades: BMP/Smad signaling of hemojuvelin (a transmembrane protein whose mutation is leading to juvenile hemochromatosis) and IL-6/STAT3 signaling of inflammation.

Dysregulation of hepcidin is involved in the pathogenesis of a spectrum of iron disorders. Most of the iron overload syndromes known to date (Hereditary Hemochromatosis and secondary iron overloads) imply a reduction of hepcidin secretion. In contrast, excessive cytokine-induced hepcidin expression causes hypoferremia and contributes to the anemia of inflammation.

The emergence of hepcidin as the pathogenic factor in most systemic iron disorders should provide important opportunities for improving their diagnosis and treatment.