Gender-related variations in iron metabolism and liver diseases

Abstract

The regulation of iron metabolism involves multiple organs including the duodenum, liver and bone marrow. The recent discoveries of novel iron-regulatory proteins have brought the liver to the forefront of iron homeostasis. The iron overload disorder, genetic hemochromatosis, is one of the most prevalent genetic diseases in individuals of Caucasian origin. Furthermore, patients with non-hemochromatotic liver diseases, such as alcoholic liver disease, chronic hepatitis C or nonalcoholic steatohepatitis, often exhibit elevated serum iron indices (ferritin, transferrin saturation) and mild to moderate hepatic iron overload. Clinical data indicate significant differences between men and women regarding liver injury in patients with alcoholic liver disease, chronic hepatitis C or nonalcoholic steatohepatitis. The penetrance of genetic hemochromatosis also varies between men and women. Hepcidin has been suggested to act as a modifier gene in genetic hemochromatosis. Hepcidin is a circulatory antimicrobial peptide synthesized by the liver. It plays a pivotal role in the regulation of iron homeostasis. Hepcidin has been shown to be regulated by iron, inflammation, oxidative stress, hypoxia, alcohol, hepatitis C and obesity. Sex and genetic background have also been shown to modulate hepcidin expression in mice. The role of gender in the regulation of human hepcidin gene expression in the liver is unknown. However, hepcidin may play a role in gender-based differences in iron metabolism and liver diseases. Better understanding of the mechanisms associated with gender-related differences in iron metabolism and chronic liver diseases may enable the development of new treatment strategies.

Keywords: Alcohol; Hemochromatosis; Hepatitis C; Hepcidin; Non-alcoholic steatohepatitis.

Figure 1

Regulation of hepcidin and iron metabolism. The key iron-regulatory hormone hepcidin is primarily synthesized in the parenchymal cells of the liver and is subsequently released into the circulation. The transcriptional regulation of hepcidin in the liver is regulated by various factors. Hepcidin released into the circulation in turn regulates iron metabolism by controlling the iron transport in the duodenum and iron export in the macrophages. Hepcidin achieves this by binding to the iron exporter protein ferroportin and inducing its internalization and degradation.