Iron Perturbations in Human Non-Alcoholic Fatty Liver Disease (NAFLD): Clinical Relevance and Molecular Mechanisms

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the insulin resistance syndrome and thus a frequent cause of elevated liver enzymes. The term "insulin-resistance associated hepatic iron overload syndrome (IR-HIOS)" has been coined to describe the frequent association of hepatic steatosis with increased levels of serum ferritin, normal or slightly elevated transferrin saturation and mild hepatic iron deposition. There is mounting evidence that increased iron stores in insulin resistance are associated with an unfavorable course of the disease and an increased prevalence of associated conditions such as diabetes, hypertension or cardiovascular disease. Iron depletion via phlebotomy has been demonstrated to improve several aspects of the insulin-resistance syndrome. Multiple interactions have been observed between molecules of iron and glucose metabolism. On a molecular level, impaired iron export has been demonstrated to be the principal mechanism of iron accumulation in fatty liver disease. Obesity-related inflammation, low ferroxidase activity associated with low copper bioavailability and decreased expression of the iron export molecule ferroportein have so far been identified as contributors to increased iron accumulation in human NAFLD.