Urinary Hepcidin in Thalassemic Syndromes.

Hepcidin, a 25 amino-acid peptide hormone synthesized in the liver, is the key regulator of iron homeostasis. Hepcidin inhibits intestinal iron absorption, recycling of iron in the macrophages and mobilization of iron from hepatic stores. Hepcidin expression is induced by iron loading and inflammation and is suppressed by anemia and hypoxia, but the relative influences of these modifiers are not well understood. Thalassemia syndromes represent a clinical setting where hepcidin is regulated by opposing influences of ineffective erythropoiesis and elevated iron load. We evaluated urinary hepcidin levels in 10 thalassemia intermedia (TI) patients who had no or very few transfusions (less than 5, and all completed more than 15 years ago), and 11 thalassemia major (TM) patients who were regularly transfused and iron chelated. All patients had beta-zero thalassemia (beta 39C→G non-sense mutation). When compared to the unrelated controls, urinary hepcidin was decreased in TI and increased in TM [median (interquartile range) in ng hepcidin/mg creatinine: controls 44 (27–66); TI 6 (5–9); TM 218 (116–470); all comparisons p<0.001 by One Way ANOVA with Dunn’s]. However, assessment of the hepcidin-to-ferritin ratio, an index of the appropriateness of hepcidin expression relative to the degree of iron loading, showed that the ratio was low in both thalassemia syndromes when compared to controls. The result suggests that even in TM patients, hepcidin is inappropriately low relative to the patients’ iron load. Importantly, in TM when measured over 1 week, hepcidin levels decreased in correlation with the patients’ rapidly decreasing Hb levels. In considering all the thalassemia patients together, urinary hepcidin levels correlated positively with serum ferritin and hemoglobin, and negatively with sTfR and serum erythropoetin. Multivariate analysis showed the strongest correlation with sTfR (r²=0.83).

The results indicate that in TI, the strong erythropoietic drive is the main regulator of hepcidin. The resulting hepcidin deficiency may be the cause of the increased iron absorption in TI. In TM, transfusions partially relieve the erythropoetic drive and increase the iron loading of macrophages thus raising hepcidin levels above those seen in TI. In the future, therapeutic use of hepcidin could restore normal iron homeostasis in some thalassemics, especially those not requiring transfusions.