TRACE ELEMENTS ANO IRON IN HUMAN METABOLISM

TRACE ELEMENTS ANO IRON IN HUMAN METABOLISM

TOPICS IN HEMATOLOGV Series Editor: Maxwell M. Wintrobe, M.D. University of Utah, Salt Lake City THE RESPIRATORY FUNCTIONS OF BLOOD Lars Garby, M.D. and Jerry Meldon, M.D. HEMOLYTIC ANEM IA IN DISORDERS OF RED CELL METABOLISM Ernest Beut1er, M.D. TRACE ELEMENTS AND IRON IN HUMAN METABOLISM Ananda S. Prasad, M.D., Ph.D.

TRACE ELEMENTS ANO IRON IN HUMAN METABOLISM Ananda s. Prasad, M.D., Ph.D. Wayne State University School of Medicine and Department of Medicine, Harper-Grace Hospital Detroit, Michigan and Veterans Administration Hospital Allen Park, Michigan SPRINGER SCIENCE+BUSINESS MEDIA, LLC

Library of Congress Cataloging in Publication Data Prasad, Ananda Shiva. Trace elements and iron in human metabolism. (Topics in hematology) Inc1udes bibliographies and index. 1. Trace element metabolism. 2. lron metabolism. 1. Title. Il. Series. [DNLM: 1. Trace Elements - Metabolism. 2. Iron - Metabolism. QU130.3 P911tj QP534.P7 612'.3924 78-13446 ISBN 978-1-4684-0795-2 ISBN 978-1-4684-0795-2 ISBN 978-1-4684-0793-8 (ebook) DOI 10.1007/978-1-4684-0793-8 1978 Springer Science+Business Media New York Originally published by Plenum Publishing Corporation in 1978 Softcover reprint of the hardcover I st edition 1978 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

TOMYFAMILY

FOREWORD Each year, it becomes more apparent that trace elements play an important role in human metabolism. The concept is no longer new. The literature on the subject is voluminous. Dr. Prasad, who has been interested in this field for many years, has undertaken the enormous task of bringing our knowledge together in a comprehensive fashion. This monograph should prove very informative and extremely useful to everyone who is concemed with human disease and with the maintenance of good health. His coverage of the subject is broad. Because ofthe importance of iron, in addition to "trace" elements, in human metabolism and nutrition, a chapter dealing with iron has been included. Maxwell M. Wintrobe, M.D. vii

PREFACE It has been known for several decades that many elements are present in living tissues, but it was not possible to measure their precise concentrations until recently. They were therefore referred to as occurring in "trace" amounts, and this practice led to the use of the term "trace elements." Although techniques now available are such that virtually ali trace elements can be determined with reasonable accuracy, the designation "trace elements" remains in popular usage. During the past two decades, remarkable advances have taken place in the field of trace-element research. Although deficiencies of iron and iodine in man have been known for many years, it is only recently that the essentiality of zinc and copper in human metabolism and nutrition has been recognized. Thirty-five years ago, carbonic anhydrase was recognized to be the only enzyme requiring zinc, but now there are approximately seventy related metalloenzymes known for which zinc is needed. The essential role of zinc in growth and development and its basic role in deoxyribonucleic acid (DNA) synthesis have been established only in the past decade. Recent developments demonstrate that zinc therapy may have a widespread role in various disease processes associated with conditioned deficiency of zinc. Indeed, zinc therapy for patients with acrodermatitis enteropathica has now become a lifesaving measure. It is also becoming clear that besides nutritional deficiency of zinc, conditioned deficiency of this element due to several disease states is probably not uncommon. Awareness of this possibility is likely to uncover many other clinical conditions in which zinc therapy may prove to be beneficial. Zinc appears to have a fundamental anticalcium action at the cellmembrane le vei. This mechanism could account for the inhibitory action of zinc on a number of cells, including inflammatory cells and platelets. Ifthis ix

x PREFACE is true, zinc may have potential as an antiinflammatory agent in a variety of diseases, one of which would be rheumatoid arthritis. The essential role of copper in collagen synthesis, the role of chromium in glucose tolerance factor, the presence of selenium as an integral part of the enzyme glutathione peroxidase of human red cells, and the important role of manganese in the metabolism of cartilage clearly suggest that these elements have vital functions to perform in human metabolism. A proper understanding of their biochemical roles and the application of such knowledge to human diseases could predictably have a great impact on the future practice of medicine. In this book, ali elements known to be essential for man, such as iron, iodine, zinc, copper, manganese, selenium, chromium, and ftuoride, with the exception of cobalt, have been included. The only known function of cobalt in man appears to be related to its presence in the vitamin B 12 molecule. For this reason, this element is not discussed. A short discussion on the role of newer trace elements has been included, inasmuch as future research may implicate these elements in human health and disease. Although magnesium is usually not considered to be a trace element, its biochemical role in enzymatic functions is similar to that of other trace elements. For this reason, it has been included here. A considerable number of essential trace elements occupy positions in the periodic table between atomic numbers 23 and 34. This atomic-number interval includes two elements, gallium and germanium, for which no vital roles have been described so far. Future studies may uncover essential functions for these two elements. Toxic elements important for mao, such as cadmium, lead, and mercury, are also covered in this book. Recent studies indicate that the toxicity of cadmium and lead may be due to their adverse effects on zinc metalloenzymes. The toxicity of mercury may be diminished by supplementation with selenium in experimental aoimals. These observations emphasize the interactions of various elements and suggest possible means by which the toxicity of certain metals may be ameliorated. Competition for similar binding sites between zinc and copper, iron and copper, and iron and manganese is a well-known phenomenon. A thorough knowledge of these interactions may provide yet aoother means by which storage disorders such as Wilson's disease and hemochromatosis may be managed in the future. It is important, however, that one look at these leads very critically and not be indiscriminate in the medical usage of various trace elements in disease conditions. Physicians, biochemists, nutritionists, and medical researchers should tind this book useful, inasmuch as standard textbooks, generally speaking, have thus far not focused on these newer developments in the tield of trace elements. It is hoped that an awareness ofthe metabolic functions oftrace

PREFACE xi elements may lead to better management of some ofthe diseases associated with their abnormalities. 1 wish to thank Dr. Maxwell M. Wintrobe for his helpful suggestions. Ms. Karen Harrington, Clare Giska, Emily Quigley, and Maha Fakhouri provided secretarial help for which 1 am very grateful. 1 also wish to thank Doug Door, who checked many references in the library.

CONTENTS ESSENTIAL ELEMENTS 1. CHROMIUM Introduction............................................. 3 Biochemistry............................................ 4 Metabolism... 4 Clinic al Effects of Chromium Deficiency.................... 8 Clinical Effects of Chromium Excess....................... 11 Treatment of Chromium Poisoning.... 12 References.............................................. 12 2. COPPER Introduction............................................. 17 Biochemistry and Physiology.............................. 19 Role of Copper in Iron Metabolism......................... 28 Metabolism of Copper.................................... 31 Copper Deficiency in Humans... 37 Copper Excess... 39 References... 44 3. FLUORIDE Introduction............................................. 55 Biochemistry............................................ 55 Metabolism... 56 Clinical Effects of Fluoride Supplementation... 57 Clinical Effects of Fluoride Excess......................... 60 References.............................................. 60 xiii

xiv CONTENTS 4. IODINE Introduction............................................. 63 Metabolism and Biochemistry... 64 Iodine Deficiency and Thyroid Function... 71 Iodine Toxicity... 74 References.............................................. 74 5.IRON Introduction............................................. 77 Biochemistry............................................ 80 Metabolism... 84 Sources of and Requirement for Iron....................... 99 Iron Deficiency.......................................... 103 Acute Iron Poisoning..................................... 114 Sideroblastic Anemias... 115 Hemosiderosis and Hemochromatosis... 125 References.............................................. 139 6. MAGNESIUM Introduction............................................. 159 Biochemistry............................................ 159 Physiology and Metabolism in Man... 161 Magnesium Deficiency in Man............................. 170 Magnesium Toxicity...................................... 180 References........................................... 181 7. MANGANESE Introduction............................................. 191 Biochemistry............................................ 191 Metabolism... 193 Manganese Deficiency.................................... 196 Manganese Toxicity...................................... 198 References.............................................. 198 8. NEWER TRACE ELEMENTS Introduction............................................. 203 Nickel.................................................. 203 Vanadium............................................... 206 Silicon.................................................. 209 Tin... 211 References.............................................. 211

CONTENTS xv 9. SELENIUM Introduction............................................. 215 Biochemistry............................................ 215 Glutathione Peroxidase in Human Diseases.................. 225 Metabolism... 229 Selenium Deficiency...................................... 235 Selenium Toxicity........................................ 236 Medical Applications... 239 References............................................. 240 10. ZINC Introduction............................................. 251 Biochemistry and Physiology.............................. 253 Metabolism... 285 Zinc Deficiency in Man................................... 296 Hyperzincemia... 328 Zinc Toxicity............................................ 328 References.............................................. 329 TOXIC ELEMENTS 11. CADMIUM Introduction............................................. 349 Biochemistry and Metabolism... 349 Cadmium Toxicity... 353 References.............................................. 360 12. LEAD Introduction............................................. 363 Biochemistry............................................ 363 Metabolism... 364 Lead Toxicity... 365 References.............................................. 369 13. MERCURY Introduction............................................. 371 Biochemistry and Metabolism... 372 Mercury Toxicity... 373 References.............................................. 380 INDEX... 383