1 / 18

Molecular Pathophysiology of Iron Disorders

Molecular Pathophysiology of Iron Disorders. Tomas Ganz, PhD, MD Chaim Hershko, MD. Iron Economy. 2400 mg. 3- 4mg. 1000 mg. With permission from Pietrangelo A. N Engl J Med . 2004;350:2383-2397. Iron Concentration in Plasma Is Regulated. Too much iron = tissue and organ damage

lidia
Download Presentation

Molecular Pathophysiology of Iron Disorders

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Molecular Pathophysiology of Iron Disorders Tomas Ganz, PhD, MD Chaim Hershko, MD

  2. Iron Economy 2400 mg 3- 4mg 1000 mg With permission from Pietrangelo A. N Engl J Med. 2004;350:2383-2397.

  3. Iron Concentration in Plasma Is Regulated Too much iron = tissue and organ damage Too little iron = cellular dysfunction, anaemia Lentner C (ed). Geigy Scientific Tables, Vol 3. Basel: Ciba-Geigy,1984.

  4. Hepcidin—An Iron-Regulatory and Host Defense Peptide Hormone Hepcidin 50 mg IP/mouse 24 48 72 96 Time (hours) With permission from Rivera S, et al. Blood. 2005;106:2196-2199.

  5. Ferroportin 12 (or 10) transmembrane segment protein The only cellular iron exporter in vertebrates Present in the macrophages, duodenum, hepatocytes, and the placenta 518 512 450 45 127 203 206 324 343 61 115 393 493 537 96 186 471 152 23 228 362 80 307 374 C N Donovan A, et al. Nature. 2000;403:776-781. McKie AT, et al. Mol Cell. 2000;5:299-309. Abboud S, et al. J Biol Chem. 2000;275:19906-19921. Graphic courtesy of Tomas Ganz, PhD, MD.

  6. How Hepcidin Regulates Iron Spleen Hepcidin Hepcidin Liver Fpn Fpn Hepcidin Plasma Fe-Tf Fpn Bone marrow and other sites of iron usage Duodenum Nemeth E, et al. Science. 2004;306:2090-2093. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

  7. High Hepcidin Low Hepcidin Iron uptake Iron uptake Iron-exporting cells (duodenal enterocytes, macrophages, hepatocytes) ferritin ferritin Fpn Fpn X hepcidin Iron release into plasma Fe Fe Nemeth E, et al. Science. 2004;306:2090-2093. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

  8. Diseases of Hepcidin Dysregulation Iron Hepcidin Normal homeostasis Anaemia of Inflammation Iron-refractory iron-deficiency anaemia Hepcidin-secreting tumors Hereditary haemochromatosis Iron-loading Anaemias Ganz T. J Am Soc Nephol. 2007;18:394-400. Ganz T, Nemeth E. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203. Courtesy of Tomas Ganz, PhD, MD.

  9. HFE TfR2 Hepcidin HJV Hepcidin RBC Hepcidin Hereditary Haemochromatosis (Common) Liver Spleen Hepcidin deficiency, absolute or relative × × Plasma Fe-Tf × Bone marrow Duodenum Piperno A, et al. Blood. 2007;110:4096-4100. Papanikolaou G, et al. Blood. 2005;105:4103-4105. Nemeth E, et al. Blood.2005;105:1803-1806. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

  10. HFE TfR2 Hepcidin HJV Hepcidin RBC Hepcidin Hereditary Haemochromatosis (Rare) Liver Spleen = = = Plasma Fe-Tf Ferroportin resistance to Hepcidin Bone marrow Duodenum Fernandes A, et al. Blood. 2008; in press. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

  11. Hepcidin Hepcidin RBC Hepcidin Iron-loading Anaemias (-thal…) Liver Spleen Hepcidin deficiency × × Plasma Fe-Tf × Duodenum Bone marrow Nemeth E, Ganz T. Haematologica. 2006;91:727-732. Pak M, et al. Blood. 2006;108:3730-3735. Papanikolaou G, et al. Blood. 2005;105:4101-4105. Tanno T, et al. Nat Med. 2007;13;1096-1101. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD. Erythroid Signal

  12. Anaemia of Inflammation Hepcidin Hepcidin RBC Hepcidin Inflammation Spleen Liver × × Plasma Fe-Tf × Bone marrow Duodenum Nemeth E, et al. Blood. 2003;101:2461-2463. Nemeth E, et al. J Clin Invest. 2004;113:1271-1276. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

  13. Iron-Refractory Iron-Deficiency Anaemia (IRIDA) Iron deficiency despite adequate or increased iron intake Partially corrected by parenteral iron High hepcidin similar to anaemia of inflammation Mutations in hepcidin-regulatory protease matriptase-2 (TMPRSS6) Finberg KE, et al. Nat Genet. 2008;40:569-571. Du X, et al. Science. 2008;320:1088-1092.

  14. Unfinished Business… • How does extracellular iron regulate hepcidin? • Current model: holotransferrin + transferrin receptor 2 + transferrin receptor 1 + HFE + haemojuvelin + BMP receptor  transcription of hepcidin • How do intracellular iron stores regulate hepcidin? • Iron-regulatory proteins or other intracellular iron sensors? • How does matriptase-2 (TMPRSS6) participate in hepcidin regulation?

  15. Mechanisms Regulating Hepcidin Production • Iron-driven • Increased by high transferrin saturation and decreased by low plasma iron • TMPRSS6: iron deficiency-driven suppression of hepcidin expression? • Erythropoiesis-driven • GDF15 suppression of hepcidin • Inflammation-driven • Independent of iron- and erythropoiesis-driven mechanisms • Triggered by IL-6 and other cytokines

  16. Are There Compensatory Mechanisms That Limit Damage? • Hereditary haemochromatosis: surprising lack of severe infections despite harmful effects of excess iron on bacterial infections; cytokine-driven increased hepcidin? • Thalassaemia major: iron-driven increase of hepcidin production, limiting iron absorption? • Although compensatory mechanisms may limit possible damage to the organism, they are insufficient to prevent it

  17. Mechanisms of Iron Homeostasis • Intracellular • Dominated by the IRE-IRP mechanism • Extracellular • Dominated by hepcidin/ferroportin interactions • Intracellular and extracellular mechanisms may interact

  18. Future Hepcidin-Targeted Therapies • Limitations • Current therapies are effective and inexpensive;those targeting hepcidin are expected to be onerous and costly • Possible role • Hepcidin agonists and/or antagonists may be usefulin treating more-complex disorders, such as beta-thalassaemia, iron-loading anaemias, IRIDA, and anaemia of inflammation

More Related