Long-term sequelae of HFE deletion in C57BL/6 × 129/O1a mice, an animal model for hereditary haemochromatosis

Background: HFE knockout mice (C57BL/6 × 129/O1a strain) mimic the functional aberrations of human hereditary haemochromatosis (HH) in short-term experiments. The present study investigates functional and morphological long-term changes. Methods: HFE^0/0, HFE^+/0 and HFE^+/+ mice were maintained on iron-rich and control diets for 2 weeks, 3, 12 and 18 months. Light microscopic tissue iron distribution, pathomorphological alterations, tissue iron content and oxidative stress were analysed in liver, pancreas, spleen, gastrointestinal tract, kidneys and myocardium. Additionally, duodenal ⁵⁹Fe absorption and ⁵⁹Fe whole body loss were measured. Results: Iron distribution between organs and microscopic iron deposition in the tissues resembled the patterns described in HH. After 3 months of iron-rich feeding duodenal ⁵⁹Fe absorption decreased to ∼15% of iron-adequate controls but remained about twice as high in HFE^0/0 as in HFE^+/+ mice. Hepatic iron concentrations reached only half the values known to induce hepatic fibrosis in rats and humans, while whole body ⁵⁹Fe loss was about twice as high. Consequently no hepatic fibrosis developed, although massive hepatocellular iron deposition and indication for oxidative stress were observed. Conclusion: C57BL/6 × 129/O1a HFE^0/0 mice mimic HH iron distribution and the regulation of intestinal iron absorption after long-term feeding. However, characteristic morphological late changes in untreated HH are not modelled.