title: The role of iron in alcohol-mediated hepatocarcinogenesis.
abstract: Alcoholic liver disease (ALD) is the major liver disease in the developed world and characterized by hepatic iron overload in ca. 50% of all patients. This iron overload is an independent factor of disease progression, hepatocellular carcinoma and it determines survival. Since simple phlebotomy does not allow the efficient removal of excess iron in ALD, a better understanding of the underlying mechanisms is urgently needed to identify novel targeted treatment strategies. This review summarizes the present knowledge on iron overload in patients with ALD. Although multiple sides of the cellular and systemic iron homeostasis may be affected during alcohol consumption, most studies have focused on potential hepatic causes. However, it should not be overlooked that more than 90% of the major iron pool, the hemoglobin-associated iron, is efficiently recycled within the human body and it is also strongly affected by alcohol. The few available studies suggest various molecular mechanisms that involve iron regulatory protein (IRP1), transferrin receptor 1 (TfR1), and the systemic iron master switch hepcidin, but not classical mutations of the HFE gene. Notably, reactive oxygen species (ROS), namely, hydrogen peroxide (H2O2), are powerful modulators of these iron-steering proteins. For instance, depending on the level, H2O2 may both strongly suppress and induce the expression of hepcidin that could partly explain the anemia and iron overload observed in these patients. More studies with appropriate ROS models such as the novel GOX/CAT system are required to unravel the mechanisms of iron overload in ALD to consequently identify molecular-targeted therapies in the future.
authors.affiliation: Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121, Heidelberg, Germany, sebastian.mueller@urz.uni-heidelberg.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mueller
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rausch
mesh_terms: D000818:Animals; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000150:complications*; D008108:Liver Diseases, Alcoholic / Q000209:etiology*; D008113:Liver Neoplasms / Q000209:etiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000431:Ethanol; D007501:Iron