Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Abstract

Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.

Keywords: Dysmetabolic iron overload syndrome, Hepcidin, Iron overload, Metabolic syndrome, Non-alcoholic fatty liver disease, Nonalcoholic steatohepatitis

Core tip: Hyperferritinemia with normal transferrin saturation and mostly mild hepatic iron deposition is a frequent finding in subjects with non-alcoholic fatty liver disease. Excess iron in non-alcoholic fatty liver disease (NAFLD) patients is referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and ameliorates NAFLD histology The mechanisms contributing to iron excess in fatty liver include impaired iron export from hepatocytes and mesenchymal Kupffer.