IRON METABOLISM AND ANEMIA PAN AMERICAN HEALTH ORGANIZATION Pan American Sanitary Bureau, Regional Office of the WORLD HEALTH ORGANIZATION 1969 IRON METABOLISM AND ANEMIA Proceedings of a symposium held during the Eighth Meeting of the PAHO Advisory Committee on Medical Research 9 June 1969 Scientific Publication No. 184 PAN AMERICAN HEALTH ORGANIZATION Pan American Sanitary Bureau, Regional Ofice of the WORLD HEALTH ORGANIZATION 525 Twenty-third Street, N.W. Washington, D.C. 20037, U.S.A. 1969 PAHO ADVISORY COMMITTEE ON MEDICAL RESEARCH Dr. Hernán Alessandri Dr. Robert Q. Marston Ex-Decano, Facultad de Medicina Director, National Institutes of Health Universidad de Chile Bethesda, Maryland, U.S.A. Santiago, Chile Dr. Walsh McDermott Dr. Otto G. Bier Chairman, Department of Public Health Director, PAHO/WHO Immunology Research Cornell University Medical College and Training Center New York, New York, U.S.A. Instituto Butantan Sao Paulo, Brazil Dr. James V. Neel Chairman, Department of Human Genetics Dr. Roberto Caldeyro-Barcia University of Michigan Medical School Jefe, Departamento de Fisiopatología Ann Arbor, Michigan, U.S.A. Facultad de Medicina Universidad de la Repúiblica Professor Roger Revelle Montevideo, Uruguay Harvard University Center for Population Studies Dr. Philip P. Cohen Cambridge, Massachusetts, U.S.A. Chairman, Department of Physiological Chemistry The University of Wisconsin Dr. Marcel Roche Madison, Wisconsin, U.S.A. Director, Instituto Venezolano de Investigaciones Científicas Dr. René Dubos Caracas, Venezuela Member and Professor The Rockefeller University Dr. John C. Waterlow New York, New York, U.S.A. Director, Tropical Metabolism Research Unit University of the West Indies Dr. Herman E. Hilleboe Kingston, Jamaica Director, Division of Public Health Practice School of Public Health and Administrative Professor Abel Wolman Medicine Emeritus Professor of Sanitary Engineering and Columbia University Water Resources New York, New York, U.S.A. The Johns Hopkins University Baltimore, Maryland, U.S.A. Dr. Bernardo A. Houssay Director, Instituto de Biología y Medicina Dr. Salvador Zubirán Experimental Director, Instituto Nacional de la Nutrición Buenos Aires, Argentina México, D.F., Mexico Dr. M. Martins da Silva, Secretary Chief, Department of Research Development and Coordination Pan American Health Organization Washington, D.C., U.S.A. PAN AMERICAN HEALTH ORGANIZATION Pan American Sanitary Bureau Dr. Abraham Horwitz, Director iii Symposium on IRON METABOLISM AND ANEMIA Moderator: Dr. Marcel Roche PARTICIPANTS Dr. Joginder Chopra Dr. Pauline M. Harrison Department of Health Services Department of Biochemistry Pan American Health Organization The University of Sheffield Washington, D.C., U.S.A. Sheffield, England Col. Marcel E. Conrad Dr. John J. Kevany Department of Hematology Department of Health Services Walter Reed Army Institute of Research Pan American Health Organization Washington, D.C., U.S.A. Washington, D.C., U.S.A. Dr. James Cook Dr. Miguel Layrisse Department of Medicine Sección de Fisiopatología University of Washington School of Medicine Instituto Venezolano de Investigaciones Seattle, Washington, U.S.A. Científicas Caracas, Venezuela Dr. William H. Crosby Department of Medicine Dr. Luis Sánchez-Medal New England Medical Center Hospitals Instituto Nacional de la Nutrición Boston, Massachusetts, U.S.A. México, D.F., Mexico Dr. Clement A. Finch Dr. Carl V. Moore Division of Hematology Department of Internal Medicine University of Washington School of Medicine Washington University School of Medicine Seattle, Washington, U.S.A. St. Louis, Missouri, U.S.A. Dr. Yaro Ribeiro Gandra Dr. Marcel Roche Departamento de Nutrico Instituto Venezolano de Investigaciones Faculdade de Higiene e Saúde Pública Científicas Sao Paulo, Brazil Caracas, Venezuela Dr. M. Martins da Silva, Secretary Department of Research Development and Coordination Pan American Health Organization Washington, D.C., U.S.A. iv CONTENTS Page Opening Statement Marcel Roche ..................................................... 1 The Biochemistry of Iron Pauline M. Harrison........................................ 2 The Control of Iron Balance by the Intestinal Mucosa William H. Crosby ........................................... 21 The Role of Protein in Iron Absorption Marcel E. Conrad.................................................. 27 Intersubject and Intrasubject Variation of Iron Absorption James D. Cook ............................................. 35 Iron Absorption from Food Miguel Layrisse........................................... 38 Iron Losses Clement A. Finch....................................................... 43 General Discussion ............................................................... 46 Human Iron Requirements Carl V. Moore............................................ 50 Iron-Deficiency Anemia in Latin American and Caribbean Populations Yaro R. Gandra..................................... 56 Iron Deficiency in Pregnancy and Infancy Luis Sánchez-Medal................................................ 65 The Relationship Between Hookworm Infection and Anemia Marcel Roche ..................................................... 72 Prevention of Iron-Deficiency Anemia loginder Chopra ...................................................... 78 General Discussion ............................................................... 81 v OPENING STATEMENT Marcel Roche, Moderator It would be safe to say, without any statistics at hand, that 1,000 million people in the world are iron deficient, and many of them actually have anemia. The problem is most acute in tropical areas, and anemias, particularly iron-deficiency anemias, are rampant in all the tropical and subtropical zones of the Americas. The attempt in this symposium is to present, in a short time, a general view of iron metabolism, extending from the basic concepts of chemistry and biochemistry to the epidemiological and therapeutic aspects of the problem. Specifically, we shall start by taking a look at basic aspects of hemo- globin transferrin-ferritin metabolism on the whole. Next, there will be four papers dealing with the question of absorption of iron-possibly the single most important influence on the production of iron-deficiency anemia. The subject will be approached from the point of view of mechanisms at the intestinal level; the effect of protein depletion- obviously very important to us, since many of the populations we are interested in are protein-depleted; intersubject and intrasubject variations; and findings to date on iron absorption from specific staples. After this, the old question of iron requirements will be dealt with. Turning to epidemiology, the particular aspects of iron deficiency and anemia that bear on the Western Hemisphere will be considered. Also, these matters will be looked at as they affect pregnancy and infancy. The relationship between anemia and hookworm disease will then be touched on briefly. The concluding presentation will round out the matter by dealing with the treatment and prophylaxis of iron deficiency. 1 THE BIOCHEMISTRY OF IRON. Pauline M. Harrison Structure and function in biological reversible combination with oxygen being a case iron compounds in point. The effect of the complex may be to allow the iron to function in a specific and The biochemistry of iron may be divided controlled manner. broadly into three interrelated aspects: the struc- A neutral iron atom contains 26 electrons, 18 ture and function of biological iron compounds, of which occur in the closed shells of the argon their synthesis and turnover, and the metabolic core. When ionized, two (ferrous) or three and functional relationships among the various (ferric) of the outer electrons are removed, leav- iron compounds. The present symposium is ing the inner electrons unchanged. The spins of largely devoted to human iron metabolism: the the outer electrons may be aligned in a variety body's requirements for iron, its absorption from of different ways, giving rise to differences in food, the turnover of iron compounds and the magnetic properties. Thus ferric iron, Fe3+, has maintenance of an iron balance, and the effects five outer electrons. In high-spin compounds, of iron deficiency. This paper will concentrate these have all their spins parallel to one another, on the structural and functional aspects of iron giving a large magnetic moment. In low-spin compounds, principally hemrnoglobin and myo- compounds, four of the electrons are aligned in globin, ferritin and hemosiderin, and transferrin. two antiparallel pairs, leaving a single unpaired Their syntheses and metabolic interrelationships electron and hence a small magnetic moment. will be touched on briefly. Ferric iron with three unpaired electrons is less Free ionic iron does not occur to any signifi- common. Ferrous iron normally has either four cant extent in living organisms because of its or no electrons unpaired. tendency to form complexes with many organic The biological properties of iron complexes compounds. Since quite low concentrations of may depend not only on the presence of a local- ionic iron are toxic, this has the biological ad- ized center of positive charge but also on the vantage of enabling iron to be stored, trans- tendency of iron to form directional covalent ported, or utilized in nontoxic forms. The bio- bonds with organic ligands. These ligands are chemistry of iron is therefore the biochemistry often, but not always, arranged in the form of of the complexes of which it