Hepatotoxicity Of Experimental Hemochromatosis

Abstract

In hereditary hemochromatosis, the liver is the major recipient of the excess absorbed iron, and after several years of high tissue iron concentrations, fibrosis and, eventually, cirrhosis develop. Complications of cirrhosis are the most common causes of death in patients with hereditary hemochromatosis. Despite the convincing clinical evidence for the hepatotoxicity of excess iron, the specific pathophysiologic mechanisms responsible for hepatocyte injury and hepatic fibrogenesis in chronic iron overload are poorly understood. In our laboratory, experimental hemochromatosis is achieved by feeding rats a diet supplemented with carbonyl (elemental) iron. The pattern of distribution and the degree of hepatic iron overload are qualitatively and quantitatively comparable to that seen in human hereditary hemochromatosis. We have demonstrated evidence of iron-induced mitochondrial and microsomal lipid peroxidation and a variety of associated organelle functional abnormalities, followed by, portal fibrosis, in rats with chronic iron overload. Recent work from our laboratory has shown an increase in the hepatic levels of malondialdehyde (MDA), as well as significantly impaired mitochondrial metabolism of this product of peroxidized lipids, in iron-loaded rats. Additionally, other investigators have reported that MDA causes an increase in both collagen production and in procollagen I gene expression in cultured human fibroblasts. Taken together, these data suggest that aldehydic byproducts resulting from iron-induced lipid peroxidation could be an important initiating factor leading to increased hepatic fibrogenesis in iron overload. In the liver, lipocytes (Ito cells) represent the most likely source of increased collagen production, and with dietary iron overload, hepatocytes are the most likely source of the increase in hepatic MDA. Therefore, aldehydic peroxidation products may serve as a link between hepatocellular lipid peroxidation and subsequent hepatic fibrosis in iron overload, either by directly stimulating lipocyte collagen production or by activating Kupffer cells to release profibrogenic cytokines.