title: Liver and iron metabolism--a comprehensive hypothesis for the pathogenesis of genetic hemochromatosis.
abstract: It is hypothesized that a homozygous C282Y mutation of the HFE gene prohibits the assembly of the transferrin-receptor 1 (TFR1) with the divalent metal transporter (DMT1) as the main iron update complex in hepatocytes membrane. Thus, the cellular influx of transferrin-bound iron from the endosomal compartment into the cytasol is compromised. As a consequence, transferrin saturation increases while concomitantly a cytosolic iron deficiency state develops. This in turn triggers the suppression of hepcidin synthesis in hepatocytes. Its impaired release into the bloodstream, causes the increased intestinal iron absorption of hemochromatosis. Excessively absorbed iron cannot be used by the erythron as a surplus for hemoglobin synthesis and is therefore trapped in ferritin complexes of RES macrophages. The ferritin is thereafter released into the bloodstream and taken up by hepatocytes for final disposal. In the lysosomal compartment ferritin is degraded to hemosiderin. Here, the release of excessive iron molecules may induce cellular injury via free radicals. The phenotypic expression of genetic hemochromatosis may depend on the activity of the erythron to use transferrin-bound-iron for heme synthesis. Therefore, a high erythron requirement for iron can utilize excess iron and may represent the rationale of phlebotomy therapy in this disease.
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany. wolfgang_stremmel@med.uni-heidelberg.de
authors.forename: W
authors.initials: W
authors.lastname: Stremmel
authors.forename: M
authors.initials: M
authors.lastname: Karner
authors.forename: E
authors.initials: E
authors.lastname: Manzhalii
authors.forename: W
authors.initials: W
authors.lastname: Gilles
authors.forename: T
authors.initials: T
authors.lastname: Herrmann
authors.forename: U
authors.initials: U
authors.lastname: Merle
mesh_terms: D000818:Animals; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological
chemical_list: D007501:Iron