International Review of Neurobiology: Supplement 1

INTERNATIONAL REVIEW OF Neurobiology

SUPPLEMENT 1

CARL C. PFEIFFER

New Jersey Neuropsychiatric Institute, Princeton, New Jersey

Table of Contents

Cover image

Title page

Inside Front Cover

Copyright

CONTRIBUTORS

PREFACE

Chapter 1: ZINC DEFICIENCY SYNDROME IN MAN: A HISTORICAL REVIEW

Publisher Summary

Chapter 2: CONGENITAL MALFORMATIONS OF THE NERVOUS SYSTEM IN ZINC-DEFICIENT RATS

Publisher Summary

I. Introduction

II. Gross Congenital Malformations in Zinc-Deficient Rats

III. Histopathology of Nervous System Malformations in Zinc Deficiency

IV. Concluding Remarks

Chapter 3: ACUTE STRESS AND TRACE ELEMENT METABOLISM

Publisher Summary

I. Introduction

II. Magnesium

III. Iron

IV. Copper

V. Zinc

VI. Manganese

VII. Cobalt

VIII. Other Trace Elements

IX. General Conclusions

Chapter 4: TRACE ELEMENTS AND BEHAVIOR

Publisher Summary

I. Introduction

II. Iron

III. Copper

IV. Manganese

V. Magnesium

VI. Zinc

VII. Discussion and Summary

Chapter 5: PATHOPHYSIOLOGY OF ZINC

Publisher Summary

I. Introduction

II. Chemical Structure and Reactivity

III. Competition with Other Metals

IV. Zinc and the Stability of Macromolecules

V. Evidence for the Interaction of Zinc with Cell Plasma Membrane

VI. Zinc and Stability of Lysosomes

VII. Zinc and Mitochondria

VIII. Zinc and Lipid Peroxidation

IX. Relevance of the Findings on Zinc to the Problem of Carcinogenesis

X. Zinc and the Wound

XI. Zinc and Collagen Metabolism

XII. Concluding Remarks

ACKNOWLEDGMENT

Chapter 6: IDIOPATHIC HYPOGEUSIA: A DESCRIPTION OF THE SYNDROME AND A SINGLE-BLIND STUDY WITH ZINC SULFATE

Publisher Summary

I. Introduction

II. Clinical History and Methods of Study

III. Discussion

Chapter 7: A STUDY OF ZINC DEFICIENCY AND COPPER EXCESS IN THE SCHIZOPHRENIAS

Publisher Summary

I. Introduction

II. Historical

III. Copper Studies in Schizophrenia

IV. Use of D-Penicillamine in Schizophrenia

V. Methods

VI. Results

VII. Discussion

SUMMARY OF EXPLORATORY STUDIES ON TRACE METAL BALANCE IN SCHIZOPHRENICS

AUTHOR INDEX

SUBJECT INDEX

Inside Front Cover

Associate Editors

W. ROSS ADEY, SIR JOHN ECCLES, D. BOVET, H.J. EYSENCK, WILLIAM F. BRIDGERS, C. HEBB, JOSÉ DELGADO and O. ZANGWILL

Consultant Editors

V. AMASSIAN, K. KILLAM, MURRAY B. BORNSTEIN, C. KORNETSKY, F. TH. BRUCKE, A. LAJTHA, P. DELL, B. LEBEDEV, J. ELKES, SIR AUBREY LEWIS, W. GREY WALTER, VINCENZO LONGO, R.G. HEATH, D.M. MACKAY, B. HOLMSTEDT, STEN MÅRTENS, P.A.J. JANSSEN, F. MORRELL, S. KETY, H. OSMOND and STEPHEN SZARA

Copyright

Copyright © 1972, by Academic Press, Inc.

all rights reserved.

no part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

ACADEMIC PRESS, INC.

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United Kingdom Edition published by

ACADEMIC PRESS, INC. (LONDON) LTD.

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Library of Congress Catalog Card Number: 59-13822

printed in the united states of america

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

WILLIAM R. BEISEL,     United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland (53)

DIANE A. BRONZERT,     National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland (125)

DONALD F. CALDWELL,     The Lafayette Clinic and Wayne State University, Detroit, Michigan (83)

MILOS CHVAPIL,     Arizona Medical Center, Department of Surgery, University of Arizona, Tucson, Arizona (105)

SHARON L. ELIAS,     Arizona Medical Center, Department of Surgery, University of Arizona, Tucson, Arizona (105)

WILLIAM T. FRIEDEWALD,     National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland (125)

ROBERT I. HENKIN,     National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland (125)

LUCILLE S. HURLEY,     Department of Nutrition, University of California, Davis, California (7)

VENELIN ILIEV,     New Jersey Neuropsychiatric Institute Bureau of Research in Neurology and Psychiatry, Princeton, New Jersey (141)

DONALD OBERLEAS,     Wayne State School of Medicine, Detroit, Michigan and the Veterans Administration Hospital, Allen Park, Michigan (83)

ROBERT S. PEKAREK,     United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland (53)

CARL C. PFEIFFER,     New Jersey Neuropsychiatric Institute, Princeton, New Jersey (141)

ANANDA S. PRASAD,     Wayne State University School of Medicine, Detroit, Michigan and the Veterans Administration Hospital, Allen Park, Michigan (1, 83)

MORTON S. RAFF,     National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland (125)

JANET N. RYAN,     Arizona Medical Center, Department of Surgery, University of Arizona, Tucson, Arizona (105)

PAUL J. SCHECHTER,     National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland (125)

RUTH E. SHRADER,     Department of Nutrition, University of California, Davis, California (7)

CHARLES F. ZUKOSKI,     Arizona Medical Center, Department of Surgery, University of Arizona, Tucson, Arizona (105)

PREFACE

In his book, Nutrition in a Nutshell, Roger J. Williams emphasizes the need for adequate trace metal nutrients for all forms of plant and animal life. All biochemists agree with this fact since life as it evolved in sea water made use of the many trace elements in the earth’s crust. The major components of sea water—sodium, potassium, calcium, and magnesium phosphates and carbonates—are used in gross quantities by the body, while the minor components are deftly woven into the action of many essential enzymes or used specifically, as in the case of iron and iodine.

Frequently, overemphasis is placed on a single trace nutrient as the scientific community becomes aware of specific deficiencies. Such overemphasis is now occurring with iron in bread. Wheat flour is no longer ground whole wheat, but rather pure starch and protein to which have been added three vitamins and a trace of iron. This flour is then called enriched in spite of the fact that 23 nutrients have been removed in the milling and refining process. The present political hassle involves the addition of more iron without any consideration of the addition of trace nutrients zinc, manganese, chromium, vanadium, or nickel, all of which may be important to man.

In the meanwhile, man’s environment in the form of building materials has changed so that galvanized iron plumbing has been replaced with copper, and as a result, drinking water may now have no zinc and an excess of copper. Thus the total ecology of man and his trace nutrients needs careful reassessment, with study of the biological interaction of paired and triplet trace metals.

This supplementary volume of the International Review of Neurobiology represents a first report in the study of the interaction of trace nutrients.

CARL C. PFEIFFER

ZINC DEFICIENCY SYNDROME IN MAN: A HISTORICAL REVIEW*

Ananda S. Prasad,     Wayne State University School of Medicine, Detroit, Michigan and the, Veterans Administration Hospital, Allen Park, Michigan

Publisher Summary

This chapter discusses zinc deficiency syndrome in man and presents the case study of Iranian patients who suffered from malnutrition and had iron and zinc deficiency. The total amount of available iron in the diet of those patients was insufficient, and excessive sunburn and sweating probably caused greater iron loss from the skin. Geophagia further decreased iron absorption. Following a well-balanced nutritious diet in the hospital for six months, a remarkable improvement in the clinical picture occurred. Pubic hair appeared and an increase in the size of the penis and testis was noted. Linear growth resumed, and the skin became normal. Zinc deficiency is known to affect growth and gonads adversely in various species of experimental animals. The zinc content of many foodstuffs parallels their iron content and inasmuch as heavy metals may form insoluble complexes with organic phosphate compounds in the diet. The chapter also presents the case study of some Egyptian dwarfs. Their clinical features were remarkably similar to those of Iranian subjects, except that the Iranian patients exhibited more pronounced hepatosplenomegaly, and they all gave a history of geophagia; however, none of them had any parasitic infestations. The majority of Egyptian patients had both schistosomiasis and hookworm infestations, and none of them gave a history of geophagia.

In July 1958 I arrived at Shiraz, Iran, after having completed training in Internal Medicine at the University of Minnesota Hospital. Shiraz is a beautiful city located 600 miles south of Tehran at a height of 5000 feet. I was sent there by the Iran Foundation to assist Dr. Hobart A. Reimann in setting up a residency training program in Medicine at the Nemazee Hospital, Shiraz. This hospital was built in 1955 at a cost of ten million dollars which was donated by a philanthropist, Mohammed Nemazee, an Iranian born in Shiraz.

Soon after my arrival, I got involved in teaching Medicine at the Medical School and Saadi Hospital (city hospital). In the fall of 1958, Dr. James A. Halsted, who was then a Fulbright Professor of Medicine at Shiraz Medical School, brought to my attention a 21-year-old patient at Saadi Hospital who looked like a 10-year-old boy and had severe anemia. In addition to dwarfism and anemia, he had hypogonadism, hepatosplenomegaly, rough and dry skin, mental lethargy and geophagia. The nutritional history was interesting in that this patient ate only bread made of wheat flour, and the intake of animal protein was negligible. He consumed nearly one pound of clay daily. Later it became known to us that the habit of geophagia is not uncommon in the villages around Shiraz. On further investigations, it was obvious that this patient had severe iron deficiency. There was no evidence of blood loss. Hookworm and schistosomiasis infestations are not seen in that part of Iran.

This syndrome appeared most fascinating inasmuch as I had not seen or heard of this condition before, although Iranian physicians seem to have been aware of this disorder. We were able to gather ten additional, similar cases in a short period of time. These were admitted to Nemazee Hospital for a complete investigation.

Results of all the liver function tests including serum proteins were within normal limits, with the exception of the serum alkaline phosphatase activity, which increased consistently following institution of a good diet (Prasad et al., 1961). Liver biopsies were unremarkable. X-rays of the bones revealed delayed skeletal maturation. On biopsy, the testis appeared infantile. Clinically no evidence for hypothyroidism or hypoadrenalism could be elicited.

The probable factors responsible for anemia in these patients were: (1) the total amount of available iron in the diet was insufficient; (2) excessive sunburn and sweating probably caused greater iron loss from the skin than would occur in a temperate climate; and (3) geophagia may have further decreased iron absorption, as has been observed by Minnich et al. (1968). In every case, the anemia was completely corrected by administration of oral iron (Prasad et al., 1961).

Following institution of a well-balanced nutritious diet in the hospital for six months, a remarkable improvement in the clinical picture occurred (Prasad et al., 1961). The pubic hair appeared and an increase in the size of the penis and testis was noted. Linear growth also resumed and the skin became normal. It became obvious that the clinical picture in these subjects was related to malnutrition.

The explanation for growth and gonadal failure remained a puzzle. Such changes are not seen due to iron deficiency under experimental conditions (Beutler, 1964). On the other hand, zinc deficiency is known to affect growth and gonads adversely in various species of experimental animals (Underwood, 1971). In addition to growth failure and testicular atrophy, skin changes (parakeratosis), were described in zinc-deficient pigs by Tucker and Salmon in 1955. The zinc content of many foodstuffs parallels their iron content and inasmuch as heavy metals may form insoluble complexes with organic phosphate componds in the diet (such as phytate in wheat bread), we speculated that the factors responsible for unavailability of iron may also have affected the availability of zinc (Vallee, 1959). Increasing activity of serum alkaline phosphatase has been noted to occur in zinc-deficient pigs following administration of zinc to such animals (Luecke, 1966). Thus, in the Iranian cases, dwarfism and changes in the testis, skin, and serum alkaline phosphatase activity could have been explained on the basis of nutritional zinc deficiency.

This clinical syndrome was previously observed in 1910 by Lemann in the United States. However, it was not related to a nutritional deficiency. Reimann reported similar patients from Turkey (Reimann, 1955), but detailed descriptions were not given and he considered a genetic defect as a possible explanation for certain aspects of the clinical picture. Our detailed clinical report from Iran appeared in 1961 (Prasad et al., 1961). Although we had no data to document zinc deficiency in our patients, nonetheless this possibility was considered at that time.

In October 1960, I met Dr. William J. Darby of Vanderbilt University in Cairo, Egypt. We both agreed that an investigation of zinc metabolism in patients with dwarfism and hypogonadism in the Middle East was warranted. With Dr. Darby’s support, facilities for research were made available at US Naval Medical Research Unit No. 3, in Cairo, Egypt. Other investigators, Drs. August Miale, Jr., Harold H. Sandstead, Arthur Schulert, and Z. Farid, joined me in the investigation of zinc metabolism in the dwarfs.

The clinical features of Egyptian dwarfs were remarkably similar to those of Iranian subjects, except for the following: (1) the Iranian patients exhibited more pronounced hepatosplenomegaly and they all gave a history of geophagia, but none of them had any parasitic infestations, and (2) the majority of Egyptian patients had both schistosomiasis and hookworm infestations and none of them gave a history of geophagia.

After extensive studies, it was demonstrated that the Egyptian patients had zinc deficiency (Prasad et al., 1963a). This conclusion was based on the facts that the zinc concentration in plasma, red cells, and hair was decreased; and ⁶⁵Zn studies showed that the plasma zinc turnover rate was greater in the patients. The 24-hour exchangeable pool was smaller, and the excretion of ⁶⁵Zn in stool and urine was less than in the control subjects (Prasad et al., 1963a). Liver function tests and biopsy failed to show evidence of cirrhosis of the liver in these subjects. Furthermore, in contrast to cirrhotic patients, who excrete abnormally high quantities of zinc in urine, these patients excreted less of stable zinc in urine, as compared to the controls (Prasad et al., 1963c).

Further studies in Egypt showed that the rate of growth was greater in patients who received supplemental zinc as compared to those who received iron instead or only an animal-protein diet, which consisted of bread, beans, lamb, chicken, eggs, and vegetables (Sandstead, 1967). Pubic hair appeared in all cases within 7 to 12 weeks after supplementation was started. Genitalia became normal in size, and secondary sexual characteristics developed within 12 to 24 weeks in all patients receiving zinc. On the other hand, such changes were observed in a comparable length of time neither in the iron-supplemented group nor in the group on an animal-protein diet alone. Thus, the growth retardation and gonadal hypofunction in these subjects were related to deficiency of zinc. The anemia was due to iron deficiency and responded well to oral iron treatment alone. Recently, similar studies have been carried out in Iranian dwarfs (Ronaghy et al., 1970), and the results confirm our earlier reports from Egypt (Sandstead et al., 1967), thus establishing the essential role of zinc for human growth and gonadal functions. These results were gratifying to physicians because the symptoms of zinc deficiency were reversible even though they had been exhibited for a very long time. This syndrome has been reported in females also (Ronaghy et al., 1970).

Examples of zinc deficiency induced metabolically in human subjects by infection, malabsorption, and liver disease have been reported (Caggiano et al., 1969; MacMahon et al., 1968; Prasad, 1966). Caggiano and his associates (1969) studied a 21-year-old Puerto Rican man in New York who was extremely retarded in growth and was sexually underdeveloped. The patient gave a long history of chronic respiratory tract infection and had hypogammaglobulinemia. Detailed investigations suggested that the patient was zinc-deficient. A good nutritious diet and control of infection for 4 months were not accompanied by a significant increase in height or gonadal development. On the other hand, within 3 months after zinc supplementation he gained 7 cm in height. He developed secondary sexual characteristics, and onset of puberty became evident with increase in the size of the penis and testes.

An elderly woman and an infant, both of whom showed biochemical and clinical evidences of zinc deficiency due to malabsorption, were recently studied in Australia (MacMahon, 1968). The elderly woman had suffered from malabsorption for several years, and despite intensive conventional therapy she had thin, glazed skin that broke down with the mildest trauma; these wounds showed poor healing. After zinc therapy the ulcers healed promptly, and skin became resistant to mild trauma. In the case of so malnourished a patient, it is difficult to distinguish the effects on wound healing due to vigorous conventional therapy with a protein-rich diet (also rich in zinc), from the effects due to vitamins and blood transfusion, or zinc. But the type of lesion, the zinc levels in plasma, red blood cells, and urine, and the dramatic response after the commencement of zinc therapy, with the return of red blood cells and urinary levels to normal, all indicate that zinc therapy played a part in her recovery. The other patient, a 7-month-old infant, showed an excellent weight gain after zinc supplementation.

Zinc deficiency has been noted in patients with cirrhosis of the liver (Vallee, 1959; Prasad et al., 1965). These patients characteristically exhibit hyperzincuria. In view of the well-known effects of zinc deficiency in animals and man it is interesting to speculate whether the hypogonadism of alcoholics and patients with cirrhosis of the liver, which is usually attributed to a lack of estrogen, may actually be related to zinc deficiency. Lymphocytopenia is seen frequently in patients with cirrhosis of the liver, and this has been reported in rats made zinc-deficient (Dreosti et al., 1968). In chronically ill, debilitated individuals, and after major surgical procedures, poor wound healing may be related to a deficiency of zinc.

A recent study of plasma zinc levels in various clinical disorders showed that an abnormally low value can be seen in active tuberculosis, indolent ulcers, uremia, myocardial infarction, Down’s syndrome, cystic fibrosis with growth retardation, pregnancy, and in women taking oral contraceptives (Halsted and Smith, 1970). Although a low plasma zinc may be indicative of a low body zinc store, further investigations are necessary to establish definitely a zinc-deficient state in the above-mentioned clinical disorders.

There are several causes of zinc deficiency in human subjects in the Middle East: (1) unavailability of zinc from cereal diets normally consumed, (2) excessive blood loss due to hookworm infestation (seen in Egypt), and (3) loss of zinc by sweating in hot tropical climates (Prasad et al., 1963b). A metabolically induced zinc-deficient state could result from prolonged infections, cirrhosis of the liver, malabsorption, and other debilitating illnesses.

Undoubtedly, a greater awareness by physicians will determine the frequency with which the zinc-deficient state may be encountered in human subjects in other areas of the world, including the United States.

REFERENCES

Beutler, E.Gross F., ed. Iron Metabolism. Springer-Verlag: Berlin and New York, 1964:256.

Caggiano, V., Schnitzler, R., Strauss, W., Baker, R. K., Carter, A. C., Josephson, A. S., Wallach, S. Amer. J. Med. Sci. 1969; 257:305.

Dreosti, E. E., Tao, S. H., Hurley, L. S. Proc. Soc. Exp. Biol. Med. 1968; 128:169.

Halsted, J. A., Smith, J. C., Jr. Lancet. 1970; i:322.

Lemann, I. I. Arch.