Hereditary
hemochromatosis is a genetic
iron overload disease related to a mutation within the HFE gene that controls the expression of
hepcidin, the master regulator of systemic
iron metabolism. The natural stable
iron isotope composition in whole blood of control subjects is different from that of
hemochromatosis patients and is sensitive to the amount of total
iron removed by the phlebotomy treatment. The use of stable
isotopes to unravel the pathological mechanisms of
iron overload diseases is promising but hampered by the lack of data in organs involved in the
iron metabolism. Here, we use Hfe -/- mice, a model of hereditary
hemochromatosis, to study the impact of the knock-out on
iron isotope compositions of erythrocytes, spleen and liver.
Iron concentration increases in liver and red blood cells of Hfe -/- mice compared to controls. The
iron stable
isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of
iron heavy
isotopes in Hfe -/- mice. In contrast, no difference in the
iron concentration nor
isotope composition is observed in spleen of Hfe -/- and control mice. Our results in mice suggest that the observed increase of whole blood
isotope composition in
hemochromatosis human patients does not originate from, but is aggravated by,
bloodletting. The subsequent rapid increase of whole blood
iron isotope composition of treated
hemochromatosis patients is rather due to the release of hepatic heavy
isotope-enriched
iron than augmented
iron dietary absorption. Further research is required to uncover the
iron light
isotope component that needs to balance the accumulation of hepatic
iron heavy
isotope, and to better understand the
iron isotope fractionation associated to metabolism dysregulation during hereditary
hemochromatosis.