Intestinal absorption of iron in HFE-1 hemochromatosis: local or systemic process?  Pierre Brissot, Marie-Bérengère Troadec, Olivier Loréal  Journal of Hepatology  Volume 40, Issue 4, Pages 702-709 (April 2004) DOI: 10.1016/j.jhep.2004.01.020

Fig. 1 Schematic representation of the hypothesis implicating a local effect of HFE gene product on the regulation of digestive iron absorption. A: Representation of the enterocyte maturation along the villus during the differentiation process: from the cryptic to the villus enterocyte. B: The cryptic enterocyte expresses Transferrin Receptor 1 which enables the cell to take up iron from the plasmatic transferrin by an endocytic process. The HFE molecule, associated with the beta2-microglobulin, could interact directly with Transferrin Receptor 1 and thus regulate the level of iron-transferrin uptake. This phenomenon would be necessary for intracellular iron of plasmatic origin to represent adequately the body iron status. C: After differentiation, the enterocyte expresses adequate levels of proteins involved in enterocyte iron uptake at apical and basolateral membranes. Journal of Hepatology 2004 40, 702-709DOI: (10.1016/j.jhep.2004.01.020)

Fig. 2 Schematic representation of the hypothesis favouring a putative local duodenal effect of C282Y HFE mutation (C, D) versus normal situation (A, B). C282Y HFE mutation could induce a modification of the interaction between HFE-beta2 microglobulin complex with Transferrin Receptor 1 and then alter its affinity for the transferrin receptor or its recycling (C). Such a situation could induce a low level of iron ingress in the enterocyte leading to a paradoxical iron deficiency of the enterocyte, leading, in turn, to an increase of digestive iron uptake by the apical enterocyte (D). Journal of Hepatology 2004 40, 702-709DOI: (10.1016/j.jhep.2004.01.020)

Fig. 3 Schematic representation of local and systemic hypotheses linking HFE gene product to iron metabolism. A: Cell types potentially involved during HFE-1 disease. B: Putative molecules playing a role in the development of iron overload during HFE-1 hemochromatosis. HFE normal gene is expressed in numerous cell types including duodenal enterocytes, macrophages and hepatocytes. All these cells are likely implicated at various levels in HFE-1 hemochromatosis. The first mechanism evoked to explain the development of iron overload in HFE-1 hemochromatosis was a local one at the duodenal enterocytic level (1). Complementary local mechanisms involved in the development of iron overload in HFE-1 GH could be: (1b) a direct effect of HFE mutation on macrophages leading to an abnormal iron egress from these cells which play quantitatively a critical role in iron bioavailability and metabolism, or (1c) interaction with hepatocyte proteins involved in iron uptake and storage. Recent data demonstrates that hepcidin, a peptide secreted in plasma by the hepatocytes, is involved in the development of iron overload during GH, suggesting that an HFE mutation may lead to the development of iron overload through an hormonal signal (2). Mechanisms leading to a decrease of hepcidin expression when HFE is C282Y mutated as well as the cellular targets of hepcidin are not known. Whether hepcidin expression is always dysregulated in case of C282Y mutation remains to be determined. Other genes may play a role. Thus, it has been demonstrated that hemojuvelin, which is to date not fully characterized, may modulate hepcidin expression by an unknown mechanism (3). Mechanisms leading to the development of iron overload in case of Transferrin Receptor 2 gene mutation (4) are not known. Interaction between HFE and Transferrin Receptor 2 as well as hemojuvelin must be investigated. Journal of Hepatology 2004 40, 702-709DOI: (10.1016/j.jhep.2004.01.020)