Zinc deficiency in anorexia nervosa

JOURNAL OF ADOLESCENT HEALTH CARE 1987;WOO4O6

eficiency In Anorexi Nervosa ECCA L, KATZ, M.D., LUCILLE 8. HURLEY,

CARL L. KEENt P

PH.D.,

., IRIS F. LETT, M.D.,

KATHLEEN M. KELLAMS-HARRISON,

M.S.R.D.,

J. GLADER, B.A.

Adoleefente with anorexia nervosa were evahated I and biochemical evidence of z

for

whether these patients would a double-blind, ra trolled trial was conducted. The mean zkc intake of the anorexicgroup calculatedon the basis of three-daydietaryrecordswas 7.7 f 5.2 mg/day,which is significantly below the recommended daily allowance of 15 mg for adolescents (pe0.001). The mean urinary zinc excretion in ihe anorexic group was a57.1 t 212.7 @24 hours cornparedto 749.9 * 897.8 pg/24 hours in the control goup ()r~O,OlE~. This result suggests that the zinc status of anorexianewosa patients may be compromiseddue to an inadequatezinc intake. Zinc supplementation(50 mg elemental zinc/day) was followed by a decrease in the d by the Zung level of depression and anxiety as a on Scale (pZO.05)and the Sta hP hventory (.jKO.O!J), respectively. Our data i~di~duele with anorexia nervoea may be at deficiency end may teepond favorably after rupplemenhth.

zinc

vitamin or mineral deficiencies are rarely reported. There are, however, some striking similarities between the clinical picture of zinc deficiency and anorexia nervosa, including weight loss, growth retardation, delayed sexual development (I), mood disturbances (2,3), poor appetite (4), skin changes, and hair loss (5). These similarities prompted our investigation of the zinc status of patients with anorexia nervosa. There are several case reports describing single patients with anorexia nervosa who responded favorably after zinc supplementation (6-8); however, no prospective, controlled study of zinc supplementation in anorexia nervosa has been published. This present study assessed adolescent patients with anorexia nervosa for the presence of clinical signs and symptoms associated with zinc deficiency. To determine if zinc supplementation would benefit patients with anorexia nervosa, a double-blind, randomized, controlled trial was conducted.

KBYWORDS: SR

Methods Subjects

Anorexia nervosa is characterized by severe weight loss from self-starvation, yet symptoms or signs of ?‘w tI@ Didsion @AddeM ~~~~

Medicine, LbPyartmentof Pediatrics,

bkwsity M&d C&w and the Department

of Nutrition,

M.D., Department of -Cornell Medical Cen-

400

The study population consisted of 15 patients who satisfied the DSM III criteria for anorexia nervosa (9). Patients were recruited through the eating disorders clinic and the inpatient psychiatric unit at the Children’s Hospital at Stanford. Fourteen of the 15 patients enrolled in the study participated in the clinical trial. The study population ranged in age from 14.25 to 18.66 years, with a mean age of 16.42 years. All

0 Society for Adolescent IMedicine, 1987 Published by EkevierScience PubIishing Co., Inc., 52 Vanderbilt Ave., New York, NY 10017

September1987

subjects were white except for one Hispanic. The male/female ratio was 1:14. The duration of weight loss ranged from three months to six years, with a mean of 1.5 years. Weight loss ranged from 15% to 41% of their original body weight, with a mean of 28%. Sixty-five percent of the sample accomplished weight loss by caloric restriction alone; the remainder admitted to engaging in binge-eating and purging behavior. Twenty normal controls matched for age, sex, and race who were within + 25% of normal weight for height and age (using growth charts derived from the National Healtlh Examination Survey Data, (10)) were enrolled for biochemical analyses of serum and urine and taste acuity testing. Taste acuity testing was included because of the-reported decrease in taste acuity associated with a variety of zinc-deficient states (11). Control subjects were recruited from the adolescent clinic and local high schools. Written informed consent was obtained from the subjects, controls, and their parents. Procedure At entry into the study, a medical history and a physical examination, including height, weight, stage of secondary sexual development, and skinfold thicknesses (biceps, triceps, subscapular, and suprailiac) for body fat determinations were performed. Taste acuit]l testing followed the standardized procedure described by Henkin et al. (12). Detection and recognition thresholds were obtained for representatives of four taste qualities: NaCl for salty, sucrose for sweet, HCl for sour, and urea for bitter. The total number of solutions that could be correctly distinguished from water and identified by the subject were summarized by a taste detection and recognition scolre, respectively (maximum for each 20 points). Mood was assessed using the Zung Depression Scale (13) and the State-Trait Anxiety Inventory (14). The Zung Depression Scale is a self-rating scale comprised of 20 items, each relating to a specific characteristic of depression. The State-Trait Anxiety Inventory contains separate self-report scales for measuring two distinct anxiety concepts: state anxiety, a transitory emotional state characterized by subjective feelings of tension and apprehension, which may vary in intlensity and fluctuate over time, and trait anxiety, which refers to relatively stable individual differences in anxiety proneness. For the Zung Depression Scale and the State-Trait Anxiety Inventory, a low score indicates little or no depres-

ZINCDEFICIENCY BNANOREXIA NERVOSA

401

sion 01 anxiety, and a high score shows clinically significant depression or anxiety.

Appetite was assessed using the Visual Analogue Eating Behavior Scale, which measures hunger for certain foods on a lo-point Likert scale from very hungry to not at all hungry (15). Prior to enrohnent in the study, subjects were asked to keep a diet record on three consecutive days to assess zinc intake. Zinc intake was calculated using a data base derived from the USDA Handbooks of Food Composition, the Ohio State Data Bank, the food industry, and journal articles (16). Blood was collected from the antecubital vein between 8:00 A.M. and 10:00 A.M. after an overnight fast. The lo-cc samples were drawn into metal-free plastic syringes (Safety-Monovettes, W. Sarstedt, Inc., NJ) fitted with stainless-steel needles. Blood was allowed to clot before centrifugation. The sera were pipetted into metal-free plastic contaimers and frozen at - 20°C until assayed for zinc, iron, copper, calcium, and magnesium. Urine collections for zinc excretion were begun at 8:00 A.M. and continued for the following 24 hours. Urine was collected in metal-free plastic containers and refrigerated. The 24-hour volume was recorded, and an aliquot was removed and stored in a plastic container at -20°C until analyzed. Trace metal determinations were performed by the Department of Nutrition at the University of California at Davis using atomic absorption spectrophotometry (17). Following the initial evaluation, the subjects with anorexia nervosa were randomly assigned in a double-blind procedure to one of two groups. One group received zinc sulfate (220 mg containing 50 mg of elemental zinc), and the other received a placebo identical in appearance and taste. Patients were instructed to take one tablet daily at bedtime during the six months of study. To monitor compliance, patients received the capsules packaged in numbered pill dispensers and were instructed to return to the clinic at the end of each month with their dispenser and any remaining pills. A monthly pill count was performed. Patients in both groups received a conventional therapeutic regimen for anorexia nervosa including psychotherapy, behavioral modification, and nutritional rehabilitation. During the six-month clinical trial, patients were assessed once a month by history, physical examination, taste acuity testing, and mood assessment. Follow-up laboratory studies, including serum and urinary zinc determinations, were also obtained at monthly intervals. Outcome variables assessed for this study in-

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KATZ ET AL.

eluded weight gain, resumption of menstrual periods, increase in height, advancement of sexual maturation, improvement in appetite and taste acuity, mood changes, and resolution of skin and/or hair abnormalities.

Statistical Analysis

Tablr: 1. Biochemical Analyses

-

at Baseline (mean 2 SD)

Anorexics (tr = 15) Controls (PI = 20)

Urinary zinc excretion (&24 hours) Serum zinc (&dl) Serum iron (&dl) Serum copper (@dl)

257.1 73.9 78.4 79.7

% 212.7 -f 13.0 -t 28.9 * 17.9

749.9 80.1 87.6 87.9

+ 897.8” rt 16.5 k 40.1 -+. 11.9

“p
The significance of the difference between the mean values of serum and urinary zinc levels and the mean taste detection and recognition scores in the anorexic and control groups was calculated using the MannWhitney test. The relationship between zinc levels and the dependent variables (weight loss, depression, taste acuity, etc,) was examined using Spearman rank correlation cwfficients and stepwise linear regression. The difference in outcome of the treatment and placebo groups in the clinical trial was evaluated by comparing the tnean regression coefficients or slopes for each dependent variable versus time. The significance of this difference was calculated using the Student’s t-test.

els of zinc, copper, iron, magnesium, and calcium in the anorexic and control groups were not statistically significant. The mean tota! detection and recognition scores for taste were significantly lower in the anorexic than in the control group (Table 2). In addition, the anorexic patients had significantly lower dekction and recognition scores for sweet tastes. Bitter, salty, and sour scores were not significantly lower in the anorexic group. To determine how much of the variance in serum and urinary zinc levels could be accounted for by the degree and duration of weight loss, a stepwise linear regression analysis was performed. The percentage weight lost as percent of normal weight for height and age accounted for 29.6% of the variance Results in urinary zinc levels and the duration of weight loss Clinical and Biochemical Assessment accounted for an additional 16.5% of the variance. Therefore, the degree and duration of weight loss The mean age of menarche of the anorexic sample accounted for 46.1% of the variance in urinary zinc was 13.8~ 1.4 years. This age is significantly delayed compared to a normal white sample (~~=3I.Q05) levels (F=5.14, yCO.05). The degree and duration of weight loss did not, however, account for a sig(IS). Qf the 14 female subjects, 10 had secondary nificant proportion of the variance in serum zinc amenorrhea with a mean duration of 8.4 -t 7.0 levels. months, The one patient with primary amenorrhea Serum zinc was a significant predictor of the level was a cross-country runner. Three patients had irof depression as assessed by the Zung Depress, sion Scale (F=5.29), pGI.05). Both serum and of ehe anorexic group urinary zinc levels were negatively correlated with showed a delay in their stage of pubic hair develdepression. opment ofbetween 1 and 2 standard deviations comto a sample of normal British girls (19). Fifty Table 2. Taste Acuity Results at Baseline Median r loss during the period of DetectionlRecognition Thresholds had skin abnormalities of recent onwt, most nly roughness and dryness Anorexics (81= 15) Controls (II = 24) of the extremities. Sucrose (mm/L) 30130 15115” The mean zinc intake of the anorexic group calNaCl (mm/L) 30160 30130 culated on the basis of three-day dietary records was HCI (mm/L) 316 313 Urea (mm/L) 150/l 50 1201150 day, significantly below the recomallowance of 15 mg for adolescents The mean urinary zinc excretion in the anorexic group was 257.1 + 212.7 Il.s/a4 hours compared to hours in the control group e differences in the serum lev-

Total detection/ recognition score (Maximum score = 20120 “y<0.01/<0.005. ‘p<0.01/<0.05.

17.3115.4

18.8/17.6h

ZfNC DEFICIENCY IN ANOREXIA

September 1987

Thirteen of the 14 subjects enrolled in the clinical trial completed the six-month follow-up. One patient dropped out and was excluded from the analysis. Six patients received zinc and seven placebo. There were no significant differences between the zinc-supplementation and placebo groups prior to the intervention with regard to weight, height, stage of sexual maturation, taste function, appetite, mood, menstrual function, skin findings, hair loss, or zinc levels. The zinc-supplemented group showed a significant decrease in their level of depression as assessed by the Zung Depression Scale after six months (Figure 1). The zinc-supplemented group also showed a significant decrease in their level of anxiety as assessed by the State-Trait Anxiety Inventory (Figure 2). The zinc-supplemented group demonstrated a greater weight gain and increase in height, improved taste function, greater advancement of sexual maturation, and resolution of skin abnormalities. These differences did not reach statistical significance.

Discussion that individuals with anorexia nerrisk for zinc deficiency due to an intake. Only 1 of our 15 subjects the recommended daily allowance

75 70 65 60 55 50 45 4c 3:

3 t I

t

0

1

,

2

403

Both groups showed a rise in their 24hour urinary zinc levels during the six-month follow-up period during which nutritional rehabilitation was undertaken. However, the mean urinary zinc excretion remained lower in the placebo group than in the zinc-supplementation group throughout the sixmonth interval. Serum zinc levels did not change significantly in either group during the follow-up period. At the completion of the clinical trial, the mean zinc intake of the placebo group was 8.3 mg/ day, still significantly below the recommended daily allowance of 15 mg/day. Taste detection and recognition scores had returned to normal in both groups at the six-month follow-up. Patient compliance was estimated to be slightly better in the zincsupplementation group; however, poor compliance was not a significant problem in either group.

Our data suggest vosa may be at inadequate zinc was consuming

SELFWTING DEPRESSfON SCALE

NERVOSA

3

MONTHS

4

5

6

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JOURNAL OF ADOLESCENT HEALTH CARE Vol. 8, No, 5

KATZ ET AL.

STME-TWIT

go

RY

80 70 60 5Q 40 2

essive losses of zinc in sweat for zinc (15 mglday) that is characteristic of andue to the overacti further compromised the orexia nervosa may nts (20). It has also been of these ption may be impaired in that zinc tients with anorexia (21). At present, there is no single, reliable laboratory mmeter for the measurement of total-body zinc Serum zinc is the most widely used laboratory ria for assessing the body concentration. However, serum zinc when used alone may not be a reliable indicator of to body zinc. Although a low tive of impaired zinc nuserum zinc level is su found in zinc-depleted triture, normal levels patients. Factors that affect serum levels include hemolysis, protein binding, hormone-mediated redistribution of zinc from the intravascular pool into compartments, diurnal variation, and ased urinary excretion of zinc does appear to be a valid indicator of zinc deficiency (22). In zincQeficient patients, the cumulative excretion of h5zn in the urine is decreased, indicating body conservation-of the ion (24). In patients with chronic in-

3

4

5

6

Figure 2. Comprisxmof raw scores on State-Trait Anxiety inventory in zinc supplementation and placebo groups. Dots and bars or open rectangles representmean 2 SE. Zinc versus placeim p ~0.05.

flammatory bowel disease given an oral load of zinc, urinary zinc excretion remained abnormally low, whereas serum levels were variable (25). If dietary zinc intake is restricted experimentally, urinary ex-retion of zinc is decreased, suggesting that renal conservation may be important for the homeostatic control of zinc metabolism in man (26,27). Thus, urinary zinc excretion may be a more reliable indicator of zinc nutriture, provided cirrhosis (28), sickle cell disease (29), and chronic renal disease (30) are not present. Hyperzincuria and associated zinc deficiency have been observed in these conditions. The zinc status of our patients with anorexia nervosa appeared to be abnormal as evidenced by the markedly decreased rates of urinary zinc excretion. This decrease was most marked in patients with the greatest weight deficit and longest duration of illness. Serum zinc levels were not, however, significantly decreased. Taste abnormalities have been related to zinc de-

September1987

ficiency by some investigators (31,32). Hypoguesia has been observed in zinc-deficient subjects with liver disease (33), malabsorption (34,35), uremia (32), and following the experimental administration of histidine (2). Casper et al. observed that taste detection and recognition thresholds were elevated in 20 patients with anorexia nervosa compared to controls, with sour and bitter sensations being the most severely affected (36). Our data support the observation that patients with anorexia nervosa have a decrease in taste acuity. Mean total detection and recognition scores were significantly lower in the anorexic group than in the control group. However, in contrast to Casper’s findings, sweet sensation was most severely affected. McClain et al. observed that patients with Crohn’s disease and depressed serum zinc levels had a significant impairment of sweet detection when compared to normal patients; and Crohn’s patients with normal zinc levels (37). In our study, serum and urinary zinc levels did not correlate with taste detection or recognition scores, suggesting that factors other than zinc status may have contributed to the observed decrease in taste perception. The association between zinc deficiency and mood disturbances has been observed in a variety of clinical situations in animals and man. In prenatally zir+deficicnt rats, the incorporation of thymidine into brain DNA is decreased (38) and brain maturation is impaired (39). Significant behavioral changes, including learning and memory deficits (40-42) and aggression (43) have been reported in zinc-deficient rats and monkeys. In our anorexia nervosa patients, serum and urinary zinc levels were both negatively correlated with depression. In the clinical trial, the zinc-supplemented group showed a significant decrease in their level of depression and anxiety. Mood disturbance is a feature of inherited zinc deficiency, acrodermatitis enteropathica (44,45), and it has also been noted in patients who developed zinc deficiency during intravenous hyperalimentation (46). Prompt relief of the acquired depression occurred in these patients following zinc supplementation. Experimental acute zinc deficiency induced by histidine administration results in frank depression, cerebellar dysfunction, and disturbed mentation (2). These neuropsichiatric changes are thought to be due to impairment of zinc-related metabolic events that OCcur in the limbic system, cortex, and cerebellum, areas of the brain that normally have the highest concentration of zinc (47). Our study suggests that anorexia nervosa patients

ZINC

DEFICIENCY

IN ANOREXIA

NERVOSA

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are at risk for zinc deficiency and that they may have an improvement in their depression and anxiety with zinc supplementation. In view uf these findings, it is ol’lr recommendation that patients with anorexia nervosa supplement their diet with 50 mg element::! zinc/day. We believe this dietary supplement should be a component of a conventional therapeutic regimen for anorexia nervosa along with ilsychotherapy, behavioral modification, and ntitrit.anal rehabilitation. There are no reports of toxicity resulting from this amount of supplemental zinc, ar d our patients did not experience any adverse effees from the medication during the clinical trial. This \,,ork was supported by the Robert Wood Johnson General Rdiattirs Academic Development Program. The authors wish to thank Dr. Ruth T. Gross for her invaluable advice and editorial assistance, Dr. Helena C. Kraemer for her assistant ; with the statistical analysis, dnd Mary Lasbury for her help in pi paring the manuscript.

1. Prasad AS, Halsted ]A, Nadimi M. Syndrome of iron deficiency anemia, hepatosplencmegaly, hypogonadism, dwarfism, and get*phagia. Am J Med 1961;31:532-46. 2. Henkin RI, I’,rtten BM, Re PK, et al. A syndrome zinc loss. Arci, Ncurol 1975;32:745-51.

of acute

3. Moynahan EJ. Zinc deficiency and disturbances of mood and visual behavior. Lancet 1976;1:91. 4. Hambidge KM, Hrmbidge C. Jacobs M, et al. Low levels of zinc in hair, anoreria, poor growth, and hypc_;uesia in children. Pediatr Res 1?172;6:868-74.

5. Kay RG, Tasman-Jones C. Zinc deficiency and intravenous feeding. Lancet 1975;2 605-6. 6. Thomsen K. Zinc, liver cirrhosis, and anorexia nervosa. Acta Derm Venereal (Stockh) 1978;58:283. 7. Esca SA, Brenner W, Nash K, et al. Kwashiorkor-like zinc deficiency syndrome in anorexia nervosa. Acta Derm Vcncreal (Stockh) 1979;59:361-4. 8. Bryce-Smith D, Simpson RID. Case of anorexia nervosa responding to zinc sulfate. Lancet 1984;2:350. 9. Diagnostic and statistical manual of mental disorders. 3rd Edition. Washington, American Psychiatric Association, 1980. 10. Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979;32:607-29. 11. Catalanotto FA. The trace metal zinc and taste. Am J Clin Nutr lY78;31:1098-103. 12. Henkin RI, Schecter PJ, Hoye R, et al. Idiopathic hypoguesia with dysguesia, hyposmia, and dysosmia. J Am Med ASSOC 1971;217:434-40. 13. Zung WWK. A self-rating depression scale. Arch Gen Esychiat 1965;12:63-70. 14. Spielberger CD, Gorsuch RL, Lushene RD. STAI Manual. Palo Alto, CA, Consulting Psychologists Eress, 1970. 15. Robinson RG, McHugh

PR, Folstein, MF. Measurement

of

406

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appetite disturbances in psychia;ric disorders. J Psych Res 16. 17.

18. 19. 20,

21. 22 23.

1975;12:59-68. Pennineton IA, Church HN. Food values of portions commonly &ed.-13th Edition. New York, Harper and Row, 1980. Clegg M, Keen, CL, Lonnerdal 8, et al. Mluence of ashing techniques on the analysis of trace elements in animal samples 1: wet sshing. Biol Trace Elem Res 1981;3:107-15. Zacharias L, Wurtman R. Age at menarche: Genetic and environmental influences. N Engl J Med 1969;280:868-75. Marshall WA, Tanner, JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1%9;44:291-303. Prasad AS, Schulert AR, Sandstead HH, et al. Zinc, iron, and nitro en content of sweat in normal and deficient subjects. J Lab e lin Med 1%3;62:84-9. Dinsmoa WW, Alderice JT, MeMaster D, et al, Zinc absorp tion in anorcxier ncrvosa. Lancet 1985;1!1&41-2. d AS Zinc deficicnsy in man. Am J Dis Child 1976;1?0:259-61. Scrtemons NW. Gn the assessmentof zinc and copper nutrlturc in man. Am J Clln Nutr

1979;8:8%-71.

24. PrasadAS,MialeA, Farid Z, et al. Zinc metabolism in pattcnts with the syncirome of iron bficiency anemia, hepatosple~tomegaly,dwarfism, and hypogonadism. J Clin Lab Med 1963;611:537-49, Nishi Y, Lifshitz F, Bclyne MA, et al. Zinc status and its nlrtisn to growth retardation in children with chronic intlnmmatory bowel disease. Am J Clin Nutr 1980;33:2613-21. 26. Hess PM,KingJC, Marten S. Zinc excretion in young women on low zinc htakes and oral contraceptive agent; J Nutr 1977;107:1610-20. 27. Prasad AS, Rabbani P, Abbasii A, et al. Experimental zinc deficiency in humans. Ann Intern Med 197&89:4$3-90. 28. Sullivan JF, Lankford PIG. Zinc metabolism and chronic alcoholism. Am J Clin Nutr 1965;19:S7-8. 29. Prasad AS, Schoomaker 88, Ortega J, et al. Zinc detkicncy in sickle cell disease. Clin Chem 197§;21: 30. ert JV, Udomkcamalcc EL Diagnostic indices of zinc dcfi%lencyin &ii&en Lab SCi 1981;11:428-33,

with renal diseases. Ann Clin

31. Henkin RI, Schecter PJ, Friedewald WT et al, A double-blind study of the effe& of zinc sulfate on taste and smell dyshnction. Am J Med !%i 1976;272:2&99.

32. Mahajan SK, Abbasii AA, Prasad AS, et al. Effects of oral zinc therapy on gonadal function in hemodialysis patients: A double-blind study. Ann Intern Med 1982;97:357-61. 33. Burch RE, Sackin A, Jetton MM, et al. Decreased taste and smell in cirrhosis. Gastmenterology 1974;67:A-4/781. 34. Solomons NW, Kharru KV, Sandstead HH, et al. Zinc nutrition in regional enteritis. Clin Res 1974;22:582a. 35. Solomons NW, Rosenberg IH, Sandstead HH. Zinc nutrition in celiac sprue. Am J Clin Nutr 1976;29:371-5. 36. Casper RC, Kirschner C, Sandstead HH, et al. An evaluation of trace metals, vitamins, and taste function in anorexia nervosa. Am J Clin Nutr 1980;33:1801-8. 37. McClain C, Souter C, Zieve L. Zinc deficiency: A complication of Crohn’s disease. Gastroenterology 1980;78:272-9. 38. Swenerton H, Shrader R, Hurley LS. ZincdeEctent embryos: Rcduccd thymidine incorporation. Science 1969;166: 1014-5. 39. Hurley LS, Swenerton H. Congenital malformations resulting from zinc deficiency in rats. Proe Sot Exp Biol Med 1966;1=692-6. 40. Halas ES, Heinrich MD, Sandstead NH. Long-term memory deficits in adult rats due to postnatal malnutrition. Physiol Behav 1979;;2,99l-7. 41. Peters DP. Effects of prenatal nutrition on learning and motivation in rats. Physiol Behav 1979;22Xt67-71. 42. Sandstead HH, Fosmire GJ, Halas ES, et al. Zinc deficiency: effects on brain and behavior of rats and rhesus monkeys. Teratology 1977;16:229-234. 43. Halas ES, Re nolds GM, Sandstead NH. Intrauterine nutrition and its etyfectson ression. Physiol Behav 1977;19:653661, 44. Moynahan EJ, Barnes PM. Zinc deficiency and a synthetic diet for lactose intolerance. Lancet 1973;1:676-7. 6, Moynahan EJ. Acrodermatitis enteropathica: A lethal inherited human zinc-deficiency disorder. Lancet 1974;2:399-400. 46. Kay RG, Tasman-Jones C, Pybus J, et al. A syndrome of acute zinc deficiency during total parenteral alimentation in man. Ann Surg 1976;183Xt1-40. 47. Tasman-Jones C. Zinc deficiency states. Adv Intern Med

1980;97-114.