Iron and the liver

Iron is an important bio-catalyst of oxidation-reduction reactions in the cell and is essential for life. Paradoxically, it may also be lethal when the fraction of redox-active metal ions exceeds that sequestered in specialized proteins or cellular compartments, and uncontrolled production of free radical species may arise. The liver is the main body site for iron stores and central in the regulation of iron homeostasis. Important iron-proteins, such as hepcidin, the iron regulatory hormone, are specifically produced by the liver. Pathogenic mutations in hepatic iron transporters and regulators lead to hereditary iron overload diseases, including hemochromatosis. Iron toxicity depends on its excessive accumulation and is due to promotion of oxidant stress: free radicals and membrane oxidation by-products cause hepatocellular death by triggering organelle dysfunction, or by activating cells involved in hepatic inflammation and fibrogenesis, such as Kupffer cells and hepatic stellate cells. Xenobiotics and hepatotoxins as well as immunological and host defense mechanisms may cause subtle changes in the pool of redox-active metal ions and in metal compartmentalization that potentially contribute to hepatotoxic, inflammatory and fibrogenic events. The hepatotoxic and profibrogenic potential of metal ions, particularly iron, is dramatic at moderate levels of tissue metal overload in concomitance with other inciting insults, such as alcohol abuse and viral hepatitis. Removal of metal excess from the liver in iron overload diseases is beneficial and prevents progression toward cirrhosis. The development of drugs able to block catalytically active metals, particularly iron, may prove effective in other chronic liver diseases in which inflammatory, degenerative and fibrogenic processes are fueled by redox-active metal ions.