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The role of zinc in anorexia nervosa: Etiology and treatment
Medical
THE
Hypotheses
ROLE
OF ZINC
5:
731-736,
1979.
IN ANOREXIA
NERVOSA:
R. Bakan, Department of Basic of Technology, Burnaby, B.C.
ETIOLOGY
AND
TREATMENT
Health Sciences, B.C. Canada. V5G 3H2
Institute
ABSTRACT Zinc deficiency may play a role in the etiology of anorexia nervosa. The symptoms of anorexia nervosa and zinc deficiency are similar in a number of respects, e.g., weight loss, loss of appetite, amenorrhea in females, impotence in males, nausea and skin lesions. In both conditions females under 25 are most at risk. and dietary habits may also be involved Stress, estrogen in the complex of factors which create or exacerbate a zinc deficiency and result in anorexia nervosa. It is proposed that clinical trials of zinc therapy be undertaken to test its effectiveness in the treatment of anorexia nervosa. anorexia
nervosa,
zinc,
estrogen INTRODUCTION --
Theories concerning the etiology ot anorexia nervosa range from an array of psychosocial approaches to those stressing physiological, particularly hypothalamic dysfunction, variables Treatments based on these theories or on clinical (1). observation also display a wide range of approaches. While there has been increasing interest in physiological approaches none of the many papers in this area has investigated recently, the possible role of zinc in either the etiology or the treatment of anorexia nervosa. The symptoms of anorexia nervosa bear a striking resemblance to those of zinc deficiency. In both conditions, patients exhibit loss of weight, disorders of appetite, food intake and sexual development as well as skin lesions and nausea. The population most at risk for both anorexia nervosa and zinc deficiency is made up of females between 12 and 25. The roles of estrogens, stress, dieting and diet in inducing or increasing zinc deficiencies in females in this age group are discussed in relation to the onset of anorexia nervosa. 731
A clinical trial of zinc supplementation is suggested. This would provide a low risk method of assessing the effectiveness of zinc in the treatment of anorexia nervosa. DISCUSSION Anorexia
nervosa
The etiology and treatment of anorexia nervosa has been a puzzle to practitioners since it was first described by Gull (1). The combination of emotional disturbance and endocrine dysfunction characteristic of patients has made differential diagnosis difficult (2). Current operational criteria for anorexia nervosa (3) are: 1.
Refusal t-o maintain body weight over a minimal normal weight for age and height.
2.
Weight loss of at least 25% of original body weight.
3.
Disturbance of body image with inability to accurately perceive body size.
4.
Intense fear of becoming obese which does not diminish as weight loss progresses.
5.
No known medical illness that could account for the weight loss and anorexia.
6.
Amenorrhea
in females and impotence in males
(2).
Anorexia nervosa occurs primarily in adolescent and young adult females (3), with male incidence estimated at 5 - 15% (4). There has been a dramatic increase in the reported incidence of the disease in the last 20 years (5). Current estimates of the annual incidence range from . 24 (6) to 1.6 (7) per 100,000 population. In females in the high-risk age group between 12 and 18 years the disorder may be as prevalent as 1 in 200 (8). Zinc deficiency Zinc deficiency has an adverse effect on normal sexual development in both males and females (9) resulting in hypoIt also results gonadism in males and amenorrhea in females. in anorexia, hypogeusia, growth retardation, failure to thrive (10) and lesions of the skin (11). Under stress, when patients lose both zinc and pyrodoxine, a characteristic psychosis may develop (12). While the incidence of zinc deficiency is unknown it appears to be common (10) and has been observed in all income There are indications that even a mild depletion of classes. zinc can be detrimental (10). Prasad (13) has pointed out that while extreme deficiencies of zinc are easily recognized, Sandstead marginal deficiencies are more difficult to detect. (14) found that teen age and college age females are most likely 732
to exhibit Stress,
marginal
estrogen
to deficient
and dietary
intakes
of zinc.
habits
Many clinical reports (4) suggest that anorexic behaviour is first manifested in response to new and stressful situations such as puberty, marriage or entering college. Sandstead (1.4) has observed that females whose zinc status is marginally deficient may be adversely affected if they experience unusual stress. In addition this group, that is females under 25, is also the segment of the population most likely to be affected by the action of estrogen on the metabolism of zinc. Teen age and college age females experience increased levels of estrogen naturally and also in many cases through the ingestion of oral contraceptives. The majority of the studies of the effects of oral contraceptives on plasma or serum zinc concentrations indicate a significant decrease in the levels of these concentrations after ingestion of oral contraceptives. There is now unanimous agreement (15) that serum copper and ceruloplasmin are consistently elevated in users of oral contraceptives. The majority of studies indicate that the estrogen component of the oral contraceptive is responsible for the increase. Since plasma copper and ceruloplasmin concentrates are often inversely related to plasma zinc concentration, depressed serum zinc concentration in oral contraceptive users may be a result of increased serum copper and ceruloplasmin concentration. Naturally increasing levels of estrogen during puberty and young adulthood may also have the effect in some females of inducing a zinc deficiency with consequent disorders of taste, appetite and menstruation. It is now known (4) that amenorrhea, which has long been assumed to be the consequence of anorexia nervosa frequently precedes the onset of anorexia nervosa, often Young women who do not menstruate are by a number of years. often prescribed oral contraceptives to regulate or induce menstruation. In addition, many adolescent and young females use oral contraceptives to control fertility. It would be helpful to know whether oral contraceptive users have higher frequencies of anorexia nervosa and whether the increased incidence over the past 20 years in this disorder is in any way related to the increased use of oral contraceptives by this age If zinc levels are depressed by estrogen and if zinc group. deficiency is involved in the etiology of anorexia nervosa, then it would follow that users of oral contraceptives should have a higher incidence of anorexia nervosa than non-users. It would also shed some light on the predominance of young females exhibiting anorexia nervosa, especially around the onset of puberty. Anorexia nervosa is antedated in many cases by “normali' social dieting (4) _ Why do some who begin the almost ubiquitous ritual of dieting persist long after they have attained the 733
cultural ideal of slimness? If there is a connection between zinc deficiency and the onset of anorexia nervosa an answer to this question may be found in considering the following observations. Teen agers frequently consume soya products such as commercially available hamburgers and frankfurters. These soya products contain phytic acid phosphorous a substance which has been shown to inhibit the absorption of zinc. If these young persons, particularly females, also restrict their dietary intake in order to lose weight, the combination of these two factors during a period of growth may result in a borderline or zinc deficient state (16). The additional use of oral contraceptives, which have been reported to decrease plasma zinc levels (15), may further decrease zinc levels to a deficiency state. The teen aged female who begins "normal" dieting but cannot stop may be suffering from a zinc deficiency produced in the manner described above. Treatment
of anorexia nervosa
The treatment of anorexia nervosa has involved an array of behavioural, chemical and even surgical approaches (4). None of these has proven uniquely effective (1, 4, 17) and the safety of some of them has been questioned (18). Zinc supplementation has been successfully employed in the treatment of hypogeusia (191, poor growth and appetite 1201, hypogonadism (15) and the inhibition of sexual maturation (21). Its level of toxicity is low (22, 23). It is inexpensive and readily available. Clinical trials of zinc therapy in the treatment of anorexia nervosa would seem warranted in view of the nature of the symptoms of the disorder, the age and sex of those who exhibit it, the relative safety of zinc therapy, and the lack of evidence that current methods of treatment of anorexia nervosa are both safe and effective. CONCLUSION It has been proposed that zinc deficiency may be involved Support for this propoin the etiology of anorexia nervosa. sition is presented on the basis of the striking similarities abnormal sexual between the symptoms of the two conditions: development, disorders of appetite, weight loss, skin lesions. Other symptoms of anorexia nervosa such as vomiting, distorted body image and lanugo may also prove to be related to zinc The population most at risk for both disorders are deficiency. females between puberty and age 25. The possibility that stress, estrogen and dietary habits may be involved in the chain of factors leading to the development of zinc deficiency and of In view of the lack of anorexia nervosa is also discussed. effectiveness of current treatments of anorexia nervosa, and the relative safety of zinc therapy, it is proposed that clinical trials of zinc therapy be carried out to test the effectiveness of this approach to anorexia nervosa.
734
REFERENCES 1.
Lupton M, Simon L, Barry V, Klawans HL. Minireview: Life Sciences Biological aspects of anorexia nervosa. 18: 1341, 1976.
2.
Hurd HP, Palumbo PJ, Gharib H. Hypothalamic-Endocrine Mayo Clinic Procedings dysfunction in anorexia nervosa. 52: 711, 1977.
3.
Halmi K. Anorexia Nervosa: Recent investigations p. 137 Vol 29 (WP Creger, in Annual Review of Medicine. CH Coggins, EW Hancock, eds) Annual Reviews, Palo Alto, Cal., 1978.
4.
Bemis KM. Current approaches to the etiology and treatment of anorexia nervosa. Psychological Bulletin 85: 593, 1978.
5.
Bruch H.
6.
Acta Psychiatrica Theander S. Anorexia Nervosa. Scandinavica Suppl 214, 1970.
7.
Kendell ER, Hall DJ, Hailey A, Babigian HM. The epidemiology of anorexia nervosa. Psychological Medicine 3: zoo, 1973.
8.
Bruch H. Anorexia nervosa and its differential diagnosis. Journal Nervous and Mental Diseases 141: 555, 1966.
9.
Underwood EJ. Trace Elements in Human and Animal Nutrition. Academic Press, New York, 1977.
Basic Books, N.Y.
Eating Disorders.
1973.
Zinc deficiency in infants and 21 in Trace Elements in Human (AS Prasad, Doberleas, eds) 1976.
10.
Hambridge KM, Walravens PA. preadolescent children p. Health and Disease vol 1 Academic Press, New York,
11.
Thomsen K. Zinc, liver cirrhosis and anorexia nervosa. Acta Dermatovener 58: 283, 1978.
12.
Pfeiffer CC. Behavioural Toxicology. Bulletin 14: 48, 1978.
735
Psychopharmacology
13.
Prasad AS. Deficiency of zinc in man and its toxicity p. 8 in Trace Elements in Human Health and Disease vol 1 (AS Prasad, D Oberleas, eds) Academic Press, New York, 1976.
14.
Sandstead HH. Zinc Nutrition in the United States. American Journal of Clinical Nutrition 26: 1251, 1973.
15.
Smith JC, Brown ED. Effects of oral contraceptive agents on trace element metabolism - a review p. 315 in Trace Elements in Human Health and Disease vol 2 (AS Prasad, D Oberleas, eds) Academic Press, New York, 1976.
16.
Spencer H, Osis and retention Human Health eds) Academic
17.
Hsu LKG, Crisp AH, Harding B. Lancet 1: 61, 1979.
18.
Bruch H. Anorexia nervosa in American Handbook of Psychiatry (S Arieti, ed) Basic Books, New York, 1974.
19.
Henkin RI, Schulman JD, Schulman CB, Bronzert DA. Changes in total, non-diffusible, and diffusible plasma zinc Journal of Pediatrics 82: and copper during infancy. 831, 1973.
20.
Hambridge KM, Hambridge C, Jacobs M, Baum JD. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in Pediatric Research 6: 868, 1972. children.
21.
Halsted JA, Ronaghy HA, Abadi P, Amirhakemi GH, Barakat RM, Reinhold JG. Zinc deficiency in man. American Journal of Medicine 53: 277, 1972.
22.
Hallbook T, Lanner E. Lancet 2: ulcers.
23.
Simkin PA. Oral zinc sulphate in rheumatoid Lancet 2: 539, 1976.
D, Kramer L, Norris C. Intake, excretion of zinc in man p. 345 in Trace Elements in and Disease vol 1 (AS Prasad, D Oberleas, Press, New York, 1976. Outcome of anorexia nervosa.
Serum-zinc and healing of venous leg 780, 1972.
736
arthritis.
THE
Hypotheses
ROLE
OF ZINC
5:
731-736,
1979.
IN ANOREXIA
NERVOSA:
R. Bakan, Department of Basic of Technology, Burnaby, B.C.
ETIOLOGY
AND
TREATMENT
Health Sciences, B.C. Canada. V5G 3H2
Institute
ABSTRACT Zinc deficiency may play a role in the etiology of anorexia nervosa. The symptoms of anorexia nervosa and zinc deficiency are similar in a number of respects, e.g., weight loss, loss of appetite, amenorrhea in females, impotence in males, nausea and skin lesions. In both conditions females under 25 are most at risk. and dietary habits may also be involved Stress, estrogen in the complex of factors which create or exacerbate a zinc deficiency and result in anorexia nervosa. It is proposed that clinical trials of zinc therapy be undertaken to test its effectiveness in the treatment of anorexia nervosa. anorexia
nervosa,
zinc,
estrogen INTRODUCTION --
Theories concerning the etiology ot anorexia nervosa range from an array of psychosocial approaches to those stressing physiological, particularly hypothalamic dysfunction, variables Treatments based on these theories or on clinical (1). observation also display a wide range of approaches. While there has been increasing interest in physiological approaches none of the many papers in this area has investigated recently, the possible role of zinc in either the etiology or the treatment of anorexia nervosa. The symptoms of anorexia nervosa bear a striking resemblance to those of zinc deficiency. In both conditions, patients exhibit loss of weight, disorders of appetite, food intake and sexual development as well as skin lesions and nausea. The population most at risk for both anorexia nervosa and zinc deficiency is made up of females between 12 and 25. The roles of estrogens, stress, dieting and diet in inducing or increasing zinc deficiencies in females in this age group are discussed in relation to the onset of anorexia nervosa. 731
A clinical trial of zinc supplementation is suggested. This would provide a low risk method of assessing the effectiveness of zinc in the treatment of anorexia nervosa. DISCUSSION Anorexia
nervosa
The etiology and treatment of anorexia nervosa has been a puzzle to practitioners since it was first described by Gull (1). The combination of emotional disturbance and endocrine dysfunction characteristic of patients has made differential diagnosis difficult (2). Current operational criteria for anorexia nervosa (3) are: 1.
Refusal t-o maintain body weight over a minimal normal weight for age and height.
2.
Weight loss of at least 25% of original body weight.
3.
Disturbance of body image with inability to accurately perceive body size.
4.
Intense fear of becoming obese which does not diminish as weight loss progresses.
5.
No known medical illness that could account for the weight loss and anorexia.
6.
Amenorrhea
in females and impotence in males
(2).
Anorexia nervosa occurs primarily in adolescent and young adult females (3), with male incidence estimated at 5 - 15% (4). There has been a dramatic increase in the reported incidence of the disease in the last 20 years (5). Current estimates of the annual incidence range from . 24 (6) to 1.6 (7) per 100,000 population. In females in the high-risk age group between 12 and 18 years the disorder may be as prevalent as 1 in 200 (8). Zinc deficiency Zinc deficiency has an adverse effect on normal sexual development in both males and females (9) resulting in hypoIt also results gonadism in males and amenorrhea in females. in anorexia, hypogeusia, growth retardation, failure to thrive (10) and lesions of the skin (11). Under stress, when patients lose both zinc and pyrodoxine, a characteristic psychosis may develop (12). While the incidence of zinc deficiency is unknown it appears to be common (10) and has been observed in all income There are indications that even a mild depletion of classes. zinc can be detrimental (10). Prasad (13) has pointed out that while extreme deficiencies of zinc are easily recognized, Sandstead marginal deficiencies are more difficult to detect. (14) found that teen age and college age females are most likely 732
to exhibit Stress,
marginal
estrogen
to deficient
and dietary
intakes
of zinc.
habits
Many clinical reports (4) suggest that anorexic behaviour is first manifested in response to new and stressful situations such as puberty, marriage or entering college. Sandstead (1.4) has observed that females whose zinc status is marginally deficient may be adversely affected if they experience unusual stress. In addition this group, that is females under 25, is also the segment of the population most likely to be affected by the action of estrogen on the metabolism of zinc. Teen age and college age females experience increased levels of estrogen naturally and also in many cases through the ingestion of oral contraceptives. The majority of the studies of the effects of oral contraceptives on plasma or serum zinc concentrations indicate a significant decrease in the levels of these concentrations after ingestion of oral contraceptives. There is now unanimous agreement (15) that serum copper and ceruloplasmin are consistently elevated in users of oral contraceptives. The majority of studies indicate that the estrogen component of the oral contraceptive is responsible for the increase. Since plasma copper and ceruloplasmin concentrates are often inversely related to plasma zinc concentration, depressed serum zinc concentration in oral contraceptive users may be a result of increased serum copper and ceruloplasmin concentration. Naturally increasing levels of estrogen during puberty and young adulthood may also have the effect in some females of inducing a zinc deficiency with consequent disorders of taste, appetite and menstruation. It is now known (4) that amenorrhea, which has long been assumed to be the consequence of anorexia nervosa frequently precedes the onset of anorexia nervosa, often Young women who do not menstruate are by a number of years. often prescribed oral contraceptives to regulate or induce menstruation. In addition, many adolescent and young females use oral contraceptives to control fertility. It would be helpful to know whether oral contraceptive users have higher frequencies of anorexia nervosa and whether the increased incidence over the past 20 years in this disorder is in any way related to the increased use of oral contraceptives by this age If zinc levels are depressed by estrogen and if zinc group. deficiency is involved in the etiology of anorexia nervosa, then it would follow that users of oral contraceptives should have a higher incidence of anorexia nervosa than non-users. It would also shed some light on the predominance of young females exhibiting anorexia nervosa, especially around the onset of puberty. Anorexia nervosa is antedated in many cases by “normali' social dieting (4) _ Why do some who begin the almost ubiquitous ritual of dieting persist long after they have attained the 733
cultural ideal of slimness? If there is a connection between zinc deficiency and the onset of anorexia nervosa an answer to this question may be found in considering the following observations. Teen agers frequently consume soya products such as commercially available hamburgers and frankfurters. These soya products contain phytic acid phosphorous a substance which has been shown to inhibit the absorption of zinc. If these young persons, particularly females, also restrict their dietary intake in order to lose weight, the combination of these two factors during a period of growth may result in a borderline or zinc deficient state (16). The additional use of oral contraceptives, which have been reported to decrease plasma zinc levels (15), may further decrease zinc levels to a deficiency state. The teen aged female who begins "normal" dieting but cannot stop may be suffering from a zinc deficiency produced in the manner described above. Treatment
of anorexia nervosa
The treatment of anorexia nervosa has involved an array of behavioural, chemical and even surgical approaches (4). None of these has proven uniquely effective (1, 4, 17) and the safety of some of them has been questioned (18). Zinc supplementation has been successfully employed in the treatment of hypogeusia (191, poor growth and appetite 1201, hypogonadism (15) and the inhibition of sexual maturation (21). Its level of toxicity is low (22, 23). It is inexpensive and readily available. Clinical trials of zinc therapy in the treatment of anorexia nervosa would seem warranted in view of the nature of the symptoms of the disorder, the age and sex of those who exhibit it, the relative safety of zinc therapy, and the lack of evidence that current methods of treatment of anorexia nervosa are both safe and effective. CONCLUSION It has been proposed that zinc deficiency may be involved Support for this propoin the etiology of anorexia nervosa. sition is presented on the basis of the striking similarities abnormal sexual between the symptoms of the two conditions: development, disorders of appetite, weight loss, skin lesions. Other symptoms of anorexia nervosa such as vomiting, distorted body image and lanugo may also prove to be related to zinc The population most at risk for both disorders are deficiency. females between puberty and age 25. The possibility that stress, estrogen and dietary habits may be involved in the chain of factors leading to the development of zinc deficiency and of In view of the lack of anorexia nervosa is also discussed. effectiveness of current treatments of anorexia nervosa, and the relative safety of zinc therapy, it is proposed that clinical trials of zinc therapy be carried out to test the effectiveness of this approach to anorexia nervosa.
734
REFERENCES 1.
Lupton M, Simon L, Barry V, Klawans HL. Minireview: Life Sciences Biological aspects of anorexia nervosa. 18: 1341, 1976.
2.
Hurd HP, Palumbo PJ, Gharib H. Hypothalamic-Endocrine Mayo Clinic Procedings dysfunction in anorexia nervosa. 52: 711, 1977.
3.
Halmi K. Anorexia Nervosa: Recent investigations p. 137 Vol 29 (WP Creger, in Annual Review of Medicine. CH Coggins, EW Hancock, eds) Annual Reviews, Palo Alto, Cal., 1978.
4.
Bemis KM. Current approaches to the etiology and treatment of anorexia nervosa. Psychological Bulletin 85: 593, 1978.
5.
Bruch H.
6.
Acta Psychiatrica Theander S. Anorexia Nervosa. Scandinavica Suppl 214, 1970.
7.
Kendell ER, Hall DJ, Hailey A, Babigian HM. The epidemiology of anorexia nervosa. Psychological Medicine 3: zoo, 1973.
8.
Bruch H. Anorexia nervosa and its differential diagnosis. Journal Nervous and Mental Diseases 141: 555, 1966.
9.
Underwood EJ. Trace Elements in Human and Animal Nutrition. Academic Press, New York, 1977.
Basic Books, N.Y.
Eating Disorders.
1973.
Zinc deficiency in infants and 21 in Trace Elements in Human (AS Prasad, Doberleas, eds) 1976.
10.
Hambridge KM, Walravens PA. preadolescent children p. Health and Disease vol 1 Academic Press, New York,
11.
Thomsen K. Zinc, liver cirrhosis and anorexia nervosa. Acta Dermatovener 58: 283, 1978.
12.
Pfeiffer CC. Behavioural Toxicology. Bulletin 14: 48, 1978.
735
Psychopharmacology
13.
Prasad AS. Deficiency of zinc in man and its toxicity p. 8 in Trace Elements in Human Health and Disease vol 1 (AS Prasad, D Oberleas, eds) Academic Press, New York, 1976.
14.
Sandstead HH. Zinc Nutrition in the United States. American Journal of Clinical Nutrition 26: 1251, 1973.
15.
Smith JC, Brown ED. Effects of oral contraceptive agents on trace element metabolism - a review p. 315 in Trace Elements in Human Health and Disease vol 2 (AS Prasad, D Oberleas, eds) Academic Press, New York, 1976.
16.
Spencer H, Osis and retention Human Health eds) Academic
17.
Hsu LKG, Crisp AH, Harding B. Lancet 1: 61, 1979.
18.
Bruch H. Anorexia nervosa in American Handbook of Psychiatry (S Arieti, ed) Basic Books, New York, 1974.
19.
Henkin RI, Schulman JD, Schulman CB, Bronzert DA. Changes in total, non-diffusible, and diffusible plasma zinc Journal of Pediatrics 82: and copper during infancy. 831, 1973.
20.
Hambridge KM, Hambridge C, Jacobs M, Baum JD. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in Pediatric Research 6: 868, 1972. children.
21.
Halsted JA, Ronaghy HA, Abadi P, Amirhakemi GH, Barakat RM, Reinhold JG. Zinc deficiency in man. American Journal of Medicine 53: 277, 1972.
22.
Hallbook T, Lanner E. Lancet 2: ulcers.
23.
Simkin PA. Oral zinc sulphate in rheumatoid Lancet 2: 539, 1976.
D, Kramer L, Norris C. Intake, excretion of zinc in man p. 345 in Trace Elements in and Disease vol 1 (AS Prasad, D Oberleas, Press, New York, 1976. Outcome of anorexia nervosa.
Serum-zinc and healing of venous leg 780, 1972.
736
arthritis.