PRESIDENT’S SYMPOSIUM FROM
THE
2013 SOUTHERN REGIONAL MEETING
Iron Metabolism: Bedside to Bench and Back Robert T. Means, Jr, MD
Key Indexing Terms: Iron metabolism; Hepcidin; Hemochromatosis. [Am J Med Sci 2013;346(5):402.]
O
ne of the prerogatives of the outgoing Southern Society for Clinical Investigation President is to choose the topic and speakers for the Presidential Symposium at the annual meeting. The choice of topic for the 2013 Symposium, “Iron Metabolism: Bedside to Bench and Back,” has its genesis in a rejection letter I received some 15 years ago. Of course, rejection letters are an occupational hazard of the academic career and I have received my fair share, but this is 1 of only 3 that I remember in detail. The letter indicated that the reviewers were generally positive about the quality of the manuscript, but the editor had chosen not to accept it for publication because papers on iron were not of interest to internal medicine physicians. While I think the editor was shortsighted (at the time, I would have expressed it more colorfully), it is only fair to say that his assessment of his reading audience’s interest may have been correct. Unless you were actually in the iron research field, it was not apparent that much was occurring. The last “big thing” in iron, the description of the regulation of ferritin and transferrin expression by iron response elements, was a decade old and largely of interest to erythropoiesis investigators.1 The serum-soluble transferrin receptor had been identified around the same time, but its niche in the diagnosis of iron deficiency was not established.2 The discovery of the HFE gene in hereditary hemochromatosis had only just occurred and its clinical utility was not yet clear.3 When I lectured on the laboratory evaluation of iron status in the late 1990s, at least 90% of my material had been present in the lecture on that topic I attended as a second year medical student in 1980. All that changed around 2000, with the simultaneous discovery of the antimicrobial peptide hepcidin by 2 separate groups, and the demonstration of its role in the regulation of iron metabolism.4,5 The study of hepcidin has revolutionized the understanding of the regulation of iron metabolism in health and in disease,6 and aspects of this enhanced understanding and its implications for clinical medicine are explored in the 2 papers that follow. In the first paper, Dr. Cindy Roy presents an overview of the current understanding of the regulation of iron metabolism.
Dr. Roy trained in one of the leading laboratories working on hepcidin and has herself become a rising star in the field as an independent investigator. The hepcidin-driven animal model of the anemia of chronic disease that Dr. Roy et al7 developed is probably the strongest evidence for the role of hepcidin in that syndrome. While much of the attention generated by hepcidin has revolved around its putative role in anemia of chronic disease,8 it is my opinion that the demonstration of actual or functional hepcidin deficiency as the unifying feature of the various disorders comprising hereditary hemochromatosis is a more significant advance in unraveling the pathogenesis of a disease. Dr. James Barton, a distinguished senior clinical investigator who has contributed much to our understanding of the natural history and management of hemochromatosis, provides a clinical and historical perspective on hemochromatosis in the second paper. I am grateful to Drs. Roy and Barton for their contributions to this symposium, and I hope that the readers will agree that papers on iron are of interest, after all. REFERENCES 1. Hentze MW, Rouault TA, Caughman SW, et al. A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci U S A 1987;84:6730–4. 2. Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990;75:1870–6. 3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399–408. 4. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:7806–10. 5. Krause A, Neitz S, Mägert HJ, et al. LEAP-1, a novel highly disulfidebonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480:147–50. 6. Means RT Jr. Hepcidin and iron regulation in health and disease. Am J Med Sci 2013;345:57–60. 7. Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 2007;109:4038–44. 8. Beutler E. Unlocking the mysteries of iron homeostasis and of the anemia of chronic disease: is hepcidin the key? Blood 2003;102:775.
From the Office of the Dean and Department of Internal Medicine, University of Kentucky College of Medicine and VA Medical Center, Lexington, Kentucky. Dr. Means is a consultant to Xenon Pharmaceuticals, which is developing hepcidin-related therapeutics. He is also an editor of 2 forthcoming textbooks to which Drs. Roy and Barton have contributed chapters. Correspondence: Robert T. Means, MD, University of Kentucky College of Medicine, 138 Leader Avenue, Room 240, Lexington, KY 40506-9983 (E-mail: [email protected]).
402
The American Journal of the Medical Sciences
Volume 346, Number 5, November 2013
THE
2013 SOUTHERN REGIONAL MEETING
Iron Metabolism: Bedside to Bench and Back Robert T. Means, Jr, MD
Key Indexing Terms: Iron metabolism; Hepcidin; Hemochromatosis. [Am J Med Sci 2013;346(5):402.]
O
ne of the prerogatives of the outgoing Southern Society for Clinical Investigation President is to choose the topic and speakers for the Presidential Symposium at the annual meeting. The choice of topic for the 2013 Symposium, “Iron Metabolism: Bedside to Bench and Back,” has its genesis in a rejection letter I received some 15 years ago. Of course, rejection letters are an occupational hazard of the academic career and I have received my fair share, but this is 1 of only 3 that I remember in detail. The letter indicated that the reviewers were generally positive about the quality of the manuscript, but the editor had chosen not to accept it for publication because papers on iron were not of interest to internal medicine physicians. While I think the editor was shortsighted (at the time, I would have expressed it more colorfully), it is only fair to say that his assessment of his reading audience’s interest may have been correct. Unless you were actually in the iron research field, it was not apparent that much was occurring. The last “big thing” in iron, the description of the regulation of ferritin and transferrin expression by iron response elements, was a decade old and largely of interest to erythropoiesis investigators.1 The serum-soluble transferrin receptor had been identified around the same time, but its niche in the diagnosis of iron deficiency was not established.2 The discovery of the HFE gene in hereditary hemochromatosis had only just occurred and its clinical utility was not yet clear.3 When I lectured on the laboratory evaluation of iron status in the late 1990s, at least 90% of my material had been present in the lecture on that topic I attended as a second year medical student in 1980. All that changed around 2000, with the simultaneous discovery of the antimicrobial peptide hepcidin by 2 separate groups, and the demonstration of its role in the regulation of iron metabolism.4,5 The study of hepcidin has revolutionized the understanding of the regulation of iron metabolism in health and in disease,6 and aspects of this enhanced understanding and its implications for clinical medicine are explored in the 2 papers that follow. In the first paper, Dr. Cindy Roy presents an overview of the current understanding of the regulation of iron metabolism.
Dr. Roy trained in one of the leading laboratories working on hepcidin and has herself become a rising star in the field as an independent investigator. The hepcidin-driven animal model of the anemia of chronic disease that Dr. Roy et al7 developed is probably the strongest evidence for the role of hepcidin in that syndrome. While much of the attention generated by hepcidin has revolved around its putative role in anemia of chronic disease,8 it is my opinion that the demonstration of actual or functional hepcidin deficiency as the unifying feature of the various disorders comprising hereditary hemochromatosis is a more significant advance in unraveling the pathogenesis of a disease. Dr. James Barton, a distinguished senior clinical investigator who has contributed much to our understanding of the natural history and management of hemochromatosis, provides a clinical and historical perspective on hemochromatosis in the second paper. I am grateful to Drs. Roy and Barton for their contributions to this symposium, and I hope that the readers will agree that papers on iron are of interest, after all. REFERENCES 1. Hentze MW, Rouault TA, Caughman SW, et al. A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci U S A 1987;84:6730–4. 2. Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990;75:1870–6. 3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399–408. 4. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:7806–10. 5. Krause A, Neitz S, Mägert HJ, et al. LEAP-1, a novel highly disulfidebonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480:147–50. 6. Means RT Jr. Hepcidin and iron regulation in health and disease. Am J Med Sci 2013;345:57–60. 7. Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 2007;109:4038–44. 8. Beutler E. Unlocking the mysteries of iron homeostasis and of the anemia of chronic disease: is hepcidin the key? Blood 2003;102:775.
From the Office of the Dean and Department of Internal Medicine, University of Kentucky College of Medicine and VA Medical Center, Lexington, Kentucky. Dr. Means is a consultant to Xenon Pharmaceuticals, which is developing hepcidin-related therapeutics. He is also an editor of 2 forthcoming textbooks to which Drs. Roy and Barton have contributed chapters. Correspondence: Robert T. Means, MD, University of Kentucky College of Medicine, 138 Leader Avenue, Room 240, Lexington, KY 40506-9983 (E-mail: [email protected]).
402
The American Journal of the Medical Sciences
Volume 346, Number 5, November 2013
