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Pathogenic pathways involved in hepatic iron overload, and interference of iron chelators with fibrogenic processes

Hereditary hemochromatosis (HC) is the most common hereditary disease in European populations. Moreover, iron excess is a major cause of organ disease in many other pathologic conditions. The pathogenesis of HC and iron-driven tissue damage and fibrosis is still unclear.

We have used an integrated approach to investigate in animal models, hepatic stellate cells (HSCs), the key players in liver fibrosis, and human cells, the basis for deranged iron homeostasis in HC, the dynamic of iron-driven fibrogenesis as well as its prevention using iron chelators. We found that the key pathogenic event in HFE-HC is a failure of hepatocytes to produce hepcidin, an iron hormone that controls iron egress from macrophages and intestine and that Kupffer cells are dispensable for this activity. This does not apply to other forms of HC such as ferroportin-HC in which the primary event is a loss of iron export.

The resulting iron excess and oxidative stress in HC leads to activation of HSC and liver fibrosis. Active fibrogenesis in HSC is associated with loss of heme oxygenase, decreased carbon monoxide production and increased sinusoidal tone in the liver. In this settings, we discovered that iron chelators che prevent fibrogenesis and activation of HSC.

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