A n n a l s o f C l i n i c a l a n d L a b o r a t o r y S c i e n c e , V o l . 5 , N o . 2 Copyright © 1975, Institute for Clinical Science

Current Status of Zinc Deficiency in the Pathogenesis o f Neurological, Dermatological and Musculoskeletal Disorders*

F. WIILLIAM SUNDERMAN, JR., M.D.

Department of Laboratory Medicine, University of Connecticut School of Medicine,

Farmington, CT 06032

ABSTRACT

Recent clinical and experimental studies suggest that zinc deficiency may play an important role in the pathogenesis of (1) acrodermatitis entero­pathica, and in certain cases of (2 ) hypogonadal dwarfism, (3 ) congenital malformations, (4) hypogeusia and hyposmia, (5 ) nyctalopia and (6) im­paired wound healing. Disturbances of zinc metabolism also occur in a broad spectrum of other clinical disorders. The pathophysiological factors which are responsible for hypozincemia include: (1 ) nutritional deficiency and/or intestinal malabsorption of zinc; (2) hyperzincuria secondary to aminoaciduria; (3) hormonal effects (cortisol, growth hormone, estrogens); (4 ) hypoalbuminemia; and (5) effects of leukocytic endogenous mediator. The clinical diagnosis of zinc deficiency in patients with specific neurological, dermatological and musculoskeletal disorders is complicated by the complex interactions of these pathophysiological factors and by the need for more dependable laboratory indices of zinc deprivation.

In trodu ction

During the past decade, advances in knowledge of zinc metabolism have greatly enhanced the clinical applications of zinc analyses for the diagnosis of human dis­eases. Several authoritative reviews have been published on the clinical pathology of zinc.17’25’62’94-103’134’135 In a recent paper, the present author has summarized meth­ods for zinc analysis in biological materials by atomic absorption spectrometry and

* Supported by U.S. Atomic Energy Commis­sion Grant AT( 11-1)-3140 and by Contract No. HSM 99-72-24 from the National Institute of Oc­cupational Safety and Health.

has tabulated normal values for zinc in human serum, plasma, and urine.151 In the present paper, attention has been focused upon (1) recent discoveries which have implicated zinc deficiency in the pathogen­esis of specific neurological, dermatological and musculoskeletal disorders, and (2) re­cent investigations which have identified pathophysiological factors that affect zinc metabolism in man.

A croderm atitis E n tero p ath ica Within the past year, Moynahan98 has

reported that acrodermatitis enteropathica (Danbolt’s disease) may be a genetically

ZINC D EFIC IEN C Y 133

determined disorder of zinc metabolism. Acrodermatitis enteropathica was described in 1943 by Danbolt and Closs,24 and the clinical and pathological features have been delineated by numerous investigators.1’32’40’ 77,iio,i32,i6o j n }3rjef) acrodermatitis entero­pathica is a lethal, autosomal, recessive trait which usually occurs in infants of Italian, Armenian or Iranian lineage. The disease is not present at birth, but typically develops in the early months of life, soon after weaning from breast feeding. Derma- tological manifestations include progressive bullous-pustular dermatitis of the extrem­ities and the oral, anal and genital areas, combined with paronychia and generalized alopecia. Infection with Candida albicans is a frequent complication. Ophthalmic signs may include blepharitis, conjuncti­vitis, photophobia and comeal opacities. Gastrointestinal disturbances are usually severe, including chronic diarrhea, malab­sorption, steatorrhea and lactose intoler­ance. Neuropsychiatric signs include irrit­ability, emotional disorders, tremor and occasional cerebellar ataxia. The patients generally have retarded growth and hypo­gonadism. Prior to the serendipitous dis­covery of diiodohydroxyquinolone therapy in 1953 by Dillaha and coworkers,27 pa­tients with acrodermatitis enteropathica in­variably died from cachexia, usually with terminal respiratory infection. Although di­iodohydroxyquinolone has been used suc­cessfully for the therapy of this condition for 20 years, the mechanism of drug action has never been elucidated. It now seems possible that the efficacy of diiodohy­droxyquinolone might be related to the formation of an absorbable zinc-chelate, inasmuch as diiodohydroxyquinolone is a derivative of 8-hydroxyquinoline, a chelat­ing agent.96

In 1973, Moynahan and Barnes6’99 stud­ied a two-year-old girl with severe acro­dermatitis enteropathica who was being treated with diiodohydroxyquinolone and

a lactose-deficient synthetic diet. The clin­ical response to this therapy was not satis­factory, and the physicians sought to iden­tify contributory factors. They found that the concentration of zinc in the patient’s serum was profoundly reduced and, there­fore, they administered oral ZnS04. The skin lesions and gastrointestinal symptoms cleared completely, and the patient was discharged from the hospital. When ZnS04 was inadvertently omitted from the child’s regimen, she suffered a relapse which promptly responded when oral ZnS04 was reinstituted. In their initial reports, Moyna­han and Barnes6’99 attributed zinc defi­ciency in this patient to the synthetic diet. However, Moynahan97’98 later recognized that the dermatitis and alopecia in acro­dermatitis enteropathica were similar to the dermal lesions which had been re­ported in zinc-deficient rats,38 and he be­gan to suspect that a genetic abnormality of zinc metabolism might be fundamental to the pathogenesis of acrodermatitis en­teropathica.97 Moynahan tested this hy­pothesis by administration of ZnS04 to nine additional patients, while completely withdrawing diiodohydroxyquinolone from their therapeutic regimens. All of the chil­dren became completely free of symptoms, and the prepubertal children experienced rapid increase in rate of growth.98 The dra­matic therapeutic efficacy of ZnS04 in acrodermatitis enteropathica has been in­dependently confirmed by Portnoy and Molokhia118 and Michaelsson.93a Studies of the metabolism of 65Zn need to be performed in patients with acrodermatitis enteropathica in order to elucidate the metabolic defect. It may be speculated that these subjects could be genetically deficient in the soluble zinc-binding pro­tein which has been isolated from rat jejunal mucosa by Kowarski et al84 and which is apparently involved in active trans­port of zinc across the intestinal mucosa.

1 3 4 SUNDERM AN

H ypogonadal Dw arfism

The syndrome of zinc-deficient hypo­gonadal dwarfism was first reported in 1963 by Prasad and his associates122’123’127’128 and has been studied extensively by these workers.120’121’125 The subjects in these stud­ies have been adolescent males with dwarf­ism, retardation of sexual maturation, iron- deficiency anemia and hepatosplenomegaly, who live in rural Iran and Egypt. The laboratory and clinical evidence of zinc- deficiency in these subjects has included:(1) low concentrations of zinc in plasma, erythrocytes and hair; (2 ) low excretions of zinc in urine and sweat; (3 ) increased turnover of 65Zn in plasma; (4) low cumu­lative excretions of 65Zn in urine and feces; and (5 ) skeletal growth and gonadal de­velopment after dietary zinc supplementa­tion. Zinc deficiency in these subjects ap­parently is the result of interference with zinc absorption owing to the large amount of phytate which is present in the native diet.125 Ronaghy and coworkers133 have re­ported a thorough two-year study of zinc supplementation in malnourished Iranian school-boys in which they have been con­firmed that oral ZnS04 provides an un­equivocal stimulus to skeletal growth. Cag- giano et al15 in New York have reported a 21-year-old Puerto Rican man with dwarf­ism, hypogonadism and zinc deficiency. Within three months after zinc supplemen­tation was instituted, this man’s height in­creased by seven cm; his genitalia became significantly larger; and he developed sec­ondary sexual characteristics. Sandstead et al135 in Tennessee have described a 20-year-old man with regional enteritis, growth failure and hypogonadism who re­sponded to oral zinc supplementation. On the basis of these several reports, zinc de­ficiency can be regarded a pathogenetic factor in certain cases of human hypo­gonadal dwarfism.

C on gen ital M alfo rm ation s

Maternal zinc deficiency may play a role in the pathogenesis of congenital anomalies in man.68*'143 This hypothesis has arisen on the basis of findings by Hurley and coworkers69’70’71’72 that short­term depletion of zinc in maternal rats results in a wide variety of congenital anomalies in the offspring. Warkany and Petering158’159 have furnished independent confirmation of these observations. For ex­ample, administration of a zinc-deficient diet to pregnant rats for only six days (i.e. from the 7th to 12th days of gestation) produced nine percent incidence of con­genital anomalies, including hydroceph­alus, exencephalus, cleft lip and palate, as well as occular and skeletal malforma­tions.159 The homeostatic regulation of plasma zinc concentration is dependent upon constant availability of dietary zinc, and pregnant rats are apparently unable to mobilize zinc from body stores for the benefit of their fetuses.71 Thus, Dreosti et al29 have shown that administration of a zinc-deficient diet to pregnant rats for only one day produced a 38 percent reduc­tion in plasma zinc concentration. Swener- ton et al152 have reported that uptake of 3H-thymidine into DNA is reduced in 12- day embryos of rats which ingested zinc- deficient diets. Based upon this observation and the recent discovery that DNA-poly- merase is a Zn-metalloprotein,141 Hurley and Shrader71 have proposed that impaired DNA synthesis in zinc-deprived embryos prolongs the mitotic cycle and reduces the number of neural tube cells, leading to malformations of the central nervous sys­tem. Sever and Emanuel143 have suggested that the exceptionally high rates of human malformations of the central nervous sys­tem in Alexandria, Egypt and Shiraz, Iran23 might be caused by maternal zinc deficiency. Henkin56 has studied human maternal-fetal interrelationships of zinc by measuring zinc concentrations in maternal

ZINC D EFIC IEN C Y 1 3 5

serum, umbilical cord serum and amniotic fluid obtained after uncomplicated preg­nancies with normal deliveries at term. He found that the mean concentration of zinc in maternal serums (48 jxg per dl, S.E. ± 3) was significantly less than that in umbilical cord serums (83 ¡xg per dl, S.E. ± 3 ). The zinc concentration in amniotic fluid averaged 32 ¡xg per dl, S.E. ± 12. In­sofar as the author can ascertain, compar­able measurements have not been per­formed in instances of congenital malfor­mations.

H ypogeusia an d H yposm iaAn association between trace metal de­

ficiency and hypogeusia (diminished taste sensation) was first reported in 1967 by Henkin et al.62 These investigators56’61’81 found hypogeusia in 23 (32 percent) of a group of 73 patients with rheumatoid ar­thritis, scleroderma, cystinuria or idio­pathic pulmonary fibrosis who were being treated with D-penicillamine. D-penicilla- mine treatment in these subjects produced copper deficiency, as evidenced by dimin­ished concentrations of serum copper and ceruloplasmin. In contrast, hypogeusia was found in only only four of 100 patients with Wilsons disease who were receiving D-penicillamine treatment for copper over­load. Henkin et al61’62 reasoned that copper depletion might be responsible for the greater incidence of hypogeusia in the first group of patients. In support of this hy­pothesis, they found that oral administra­tion of C u (II) to four of these patients resulted in improvement of hypogeusia, even though D-penicillamine treatment was continued without interruption.62 Henkin and Bradley60 subsequently reported that oral administration of either Ni (II) , Z n(II), or C u (II) improved taste acuity in patients with hypogeusia. Hambidge et al53 observed five children in whom hy­pogeusia was associated with poor growth, anorexia and low concentrations of zinc in hair. After dietary supplementation with

ZnS04, taste acuity was normalized in each of these children, and the concentrations of zinc in hair increased. Schecter and co­workers139 reported a trial of oral Z nS04 therapy in adult patients with idiopathic hypogeusia. In two-thirds of these patients, hypogeusia began during or after an illness such as an acute upper respiratory infec­tion, while in the remaining one-third of these patients, hypogeusia did not follow any apparent malady. In most of these sub­jects, hypogeusia was associated with hy­posmia (diminished olfactory sensation). In this study, improved taste acuity oc­curred in 12 (67 percent) of 18 patients who were treated with oral ZnS04 in dos­age of 100 mg per day. In comparison, im­proved taste acuity was experienced by only four (22 percent) of 18 patients while they were receiving a placebo. Additional evidence of an association between hypo­geusia and altered zinc metabolism has been reported by Cohen et al20 in patients with thermal burns. Hypogeusia was de­tected in 16 of 19 patients with severe burns. In the burned patients with hypo­geusia, the mean concentration of serum zinc was decreased and the mean excretion of zinc in urine was increased. Henkin and Smith65 have noted that hypogeusia and hyposmia frequently develop in patients with acute viral hepatitis, a condition which is commonly associated with hypo- zincemia.66 The various studies which have been cited suggest that deficiencies of zinc and other trace metals are involved in the pathogenesis of hypogeusia and hyposmia, but the pathogenetic mechanisms remain obscure.75 Culliton22a has reported on the current controversy in this matter.

N yctalop iaA possible relationship between zinc de­

ficiency and nyctalopia (night blindness) has arisen from the recent discovery that zinc influences the metabolism of retinol (vitamin A alcohol).145 Saraswat and

T A B L E I

Clinical Trials of Oral ZnSO^* in Healing of Sores

1 3 6 SUNDERM AN

In vestigators Date Lesions No. o f Patients Controls Treated

Observation on R eepithelializat'ion Rate

Pories et a l 115-117 1966 Pilonidal sinus 10 10 2-fold increase vs controls

Cohen^ 1968 Bedsores 0 6 Improvement

Husain73 1969 Leg ulcers 52 52f >2-fold increase vs controls

Barcia5 1970 Pilonidal sinus 10 10 No influence vs controls

Greaves & Skillen1*5 1970 Leg ulcers 0 18 Complete healing in 11; partial healing in 7

Serjeant et a£142 1970 Leg ulcers 17 17f 3-fold increase vs controls

Myers & Cherry101 1970 Leg ulcers 16. I6f No influence vs controls

Clayton1® 1972 Leg ulcers 5 5f Slower in treated i?s controls

Greaves & Ives1*1* 1972 Leg ulcers 18 18f No influence Vs controls

Hallbook & Lanner48 1972 Leg ulcers 14 13 4-fold increase vs controls in pts. with low serum Zn; no influence vs controls in pts. with normal serum Zn

*ZnS0 4 , 220 mg t.i.d. tDouble-blind study

Arora138 have found that concentrations of serum retinol are lower in zinc-deficient lambs than in zinc-supplemented controls. Smith et al145 have reported that zinc is necessary for the mobilization of retinol from the liver, and they have observed that zinc-deficient rats are unable to main­tain normal plasma concentrations of ret­inol. Moreover, Smith and coworkers146 have observed that zinc-deficient rats have diminished concentrations of serum retinol- binding protein, a low molecular weight «-globulin. Smith and coworkers145 have found correlation between diminished se­rum concentrations of zinc and retinol in children who reside in a ghetto locality in Baltimore. Henkin and Smith66 have re­ported correlation between diminished concentrations of plasma zinc and plasma retinol-binding protein in patients with viral hepatitis. On the basis of these find­ings, Henkin and Smith66 have suggested that alterations of zinc metabolism may in­fluence the concentration of plasma retinol-

binding protein. Halsted and Smith51 have speculated that there also may be a zinc requirement for the conversion of retinol (vitamin A alcohol) to retinal (vitamin A aldehyde) by retinene reductase in the retina. There is obviously a need for con­trolled clinical trials of zinc supplementa­tion in patients (e.g. chronic liver disease) who have impaired visual adaptation to darkness, and especially in those patients who are unresponsive to vitamin A supple­mentation.61’82

Im p aired W ound H ealingIn 1966, Pories and collaborators115’116’117

reported that oral administration of ZnS04 to military personnel with marsupialized pilonidal sinuses was attended by a two­fold increase in the rate of reepithelializa- tion. The authors’ conclusion that ZnS04 can promote the healing of cutaneous sores and wounds has been a subject of contro­versy during the ensuing seven years. As summarized in table I, clinical investiga­

ZINC D EFIC IEN C Y 1 3 7

tions by Cohen,19 Husain,73 Greaves and Skillen,45 and Serjeant et al142 have sub­stantiated the beneficial effects of ZnS04 on wound healing, whereas studies by Barcia,5 Myers and Cherry,101 Clayton,18 and Greaves and Ive44 have failed to dem­onstrate any therapeutic benefit. Hallbook and Lanner48 found that the reepitheliali- zation rate of venous leg ulcers was en­hanced by ZnS04 in patients who initially had diminished concentrations of serum zinc, but they did not find any benefit in patients whose initial measurements of se­rum zinc were within the normal range. On the other hand, Husain et al74 did not observe any relationship between response to zinc treatment of venous leg ulcers and the initial measurements of plasma zinc. Flynn et al35’36 reported profound hypo- zincemia and delayed wound healing in patients who received long-term corticos­teroid therapy following bilateral adre­nalectomy and in patients who received corticosteroids for treatment of collagen disorders. Wound healing was enhanced in these subjects following oral zinc sup­plementation. Carruthers16 and Henkin59 have independently reviewed the conflict­ing clinical evidence, and have concluded that administration of ZnS04 to patients who are zinc-deficient is one of the factors which accelerates the healing of cutaneous wounds. This conclusion is supported by studies in experimental animals which have demonstrated that: (1) healing of incised wounds is impaired in rats with dietary zinc deficiency;102’129’135’136 (2) syn­thesis of desoxyribonucleic acid (D N A ), ribonucleic acid (RN A ), collagen and non­collagen proteins is reduced in skin and connective tissues from rats with dietary zinc deficiency;34’92’149 (3) zinc supplemen­tation does not augment wound healing in normal rats;46’88 and (4) zinc supplementa­tion does augment wound healing in chron­ically ill rats.31 If a clinician accepts the conclusion that zinc supplementation pro­

motes wound healing in zinc-deficient pa­tients, the clinician is then confronted with the difficult question of how to diagnose zinc deficiency. As Henkin59 has empha­sized, there is no ready answer to this question, owing to the complex interac­tions of pathophysiological mechanisms which influence zinc metabolism.

P ath oph ysio logical M ech an ism s o f H ypozincem ia

The various pathophysiological mecha­nisms which have been implicated in the production of hypozincemia include: (1) nutritional deficiency and/or intestinal malabsorption of zinc;12’15’90’125’135 (2 ) in­creased urinary excretion of zinc secondary to aminoaciduria (e.g. histidine and cys­teine), frequently associated with tissue catabolism;33’41’42’56’124 (3 ) zinc losses in sweat during profuse perspiration;22’68’128’153 (4 ) diminution of serum zinc secondary to hypoalbuminemia;11’66 (5 ) alteration of body zinc pools and increased urinary ex­cretion of zinc secondary to adrenal release of cortisol and pituitary release of growth hormone (e.g. following stress);28’47’57’58’63 (6 ) alteration of body zinc pools produced by endogenous estrogens (e.g. pregnancy) or exogenous estrogens (e.g. oral contra­ceptives);13’50’76’134 and (7 ) alteration of body zinc pools produced by ‘leukocytic endogenous mediator” ( LEM ) .8,7S’i°4>i05’i°9 LEM is a heat-labile protein released from sensitized polymorphonuclear leukocytes, which produces prompt hypozincemia68’105 with concommitant increase in hepatic zinc.109 LEM is apparently involved in many facets of the “acute phase reac­tion,”30’78’79’108 and there is evidence that LEM may be responsible for the hypo­zincemia which occurs during acute infec­tions and inflammatory conditions.10’119 The hypozincemia which is produced by LEM , (as well as that which is seen in uremia),21 is mediated by redistribution of zinc within body pools, without zinc deficiency neces-

1 3 8 SUNDERM AN

Conditions Associated with Hypozincemia

TABLE I I

Myocardial infarction52 s54,88^89^156

Acute infections8 »^ *10>52*88»107

Viral hepatitis56

Hepatic cirrhosis1l>tt9,52J126,13It)155>157

Carcinomatosis7 »25 >91

Leukemias and lymphomas2 »134

Pernicious anemia134»161

Chronic uremia2 1»52>93>140>161

Malabsorption states^0 »157

Kwashiorkor137

sarily being present.10 Therefore, reliance cannot be placed solely upon measurements of plasma zinc for the diagnosis of zinc deficiency.

A tabulation of clinical conditions which are associated with hypozincemia is pre­sented in table II. The several pathophysio­logical mechanisms which have been men­tioned may function to varying degrees in these several disorders. In order to assess zinc nutriture in patients, it is frequently desirable to measure zinc in diverse biolog­ical samples, including urine,21’59’157 blood cells 2’39’155 hair 12>53>83>112>130>13i,i5o sweat 22>68’ 128,162 saliva)ioo an{j amniotic fluid.56 Studies with caution for diagnostic purposes, ow­ing to the long residence time of 65Zn in the human body148 and the presence of zinc in DNA polymerase144 and reverse transcriptase.3’114 As additional approaches to assessment of zinc nutriture, measure­ments of zinc in plasma ultrafiltrates56’84’68 of 65Zn are invaluable for clinical re­search,147’148 but should be approached and spinal fluid may be attempted. Con­sideration may also be given to measure­ments of urinary excretion of zinc before and after infusion of chelating agents such as calcium-EDTA (edathamil) or DTPA ( diethylenetriaminepentaacetic acid).147 F i­

Alcoholism16 2

Mongolism52 »^5

Psoriasis43

Surgical stress33»35j88»141

Cushing’s syndrome57

Acromegaly58

Pregnancy50,76,134

Chronic debilitation (e.g. paraplegia11*, cystic fibrosis52)

Drugs (estrogens, oral contraceptives13’50, corticosteroids 3 5,36,63)

nally, in many cases it is desirable to per­form a therapeutic trial of oral supplemen­tation with ZnS04.

D ifficu lties in M easu rem en ts o f Zinc in P la sm a an d O ther B iological M ateria ls

Methods for zinc analysis in body fluids and excreta are beyond the scope of this discussion, and have been thoroughly con­sidered in several recent articles.28’58’85’108’151 However, it is germane to emphasize that errors in sampling and analysis frequently contribute to the difficulties of clinical evaluation of zinc metabolism. As Versieck et al154 and Ronaghy et allss have reported, specimen collection and analytical per­formance are often inadequate, and zinc contamination is rampant. As a conse­quence, grossly inaccurate measurements of zinc in plasma and other biological samples are encountered. In the present author’s experience, the following proce­dures are essential in order to achieve valid analytical results:

Fasting patient under basal conditions. Blood should be collected between 6 and 8 A.M., while the patient remains in bed after a 15 hour overnight fast. This pre­caution is necessary in order to avoid flue-

ZIN C D EFIC IEN C Y 1 3 9

TABLE III

Circadian Variations of Zinc Concentrations in Serum or Plasma

Authors Date No. o f Subjects

Specimen * Zinc Concentrations a t Specified Times

Units and S t a t i s t ic a l Parameters

Hellwege55 1970 15# s 8 A.M. 129(85-170)

12 Noon 6 P.M. 111(75-145) 100(65-120)

yg/dl; mean (range)

Lifschitz & Henkin87

1971 10 s 6 A.M. -8 ± 2.5

2 P.M. 10 P.M. +2.5 ± 2.5 +7 ± 2.5

% change;"^" mean± S.E.

Hetland & Brubakk67

1973 13 s 8 A.M. 104 ± 12

11:30 A.M. 3 P.M. 96 ± 8 93 ± 9

yg/dl; mean ± S.D.

Burr14 1973 9 p 7 A.M. 115 ± 3

12 Noon 5 P.M. 1 0 1 + 3 89 ± 3

yg/dl; mean ± S.E.

Walkeret a l 1^

1973 20 P 9 A.M. 97(80-130)

1 P.M. 81(65-90)

yg/dl; mean (range)

* S .= serum,.P = plasma #Children tPercent deviation from each subject's 24 hour mean

tuations in plasma zinc concentrations ow­ing to the effects of exercise, food and circadian rhythms.111 In table III are given illustrative results from investigations in which zinc analyses were performed upon serum or plasma samples obtained from healthy subjects at various times of the day. Circadian variations of zinc concen­trations were found in all of these studies. In four of these five investigations, the mean concentrations of zinc were found to be significantly higher in the early morning specimens than in specimens which were obtained at other times.

Acid-toashed glassware. All glassware which is used for specimen collection, pro­cessing and analysis should be washed with nitric acid and rinsed with copious distilled-demineralized water. Acid-wash­ing is particularly important for syringes, blood-collection tubes, Pasteur pipets and plastic test-tubes. It may be noted that “lead-free” Vacutainer tubes* are not acid- washed by the manufacturer, and they are frequently contaminated with zinc.

Analysis of plasma rather than serum. It is preferable to analyze plasma rather than serum, since the concentration of zinc in

* Becton, Dickinson Co., East Rutherford, NJ.

serum averages 16 percent higher than in plasma, owing in part to platelet release of zinc during clotting.37 Each batch of hep­arin solution which is used as an anticoag­ulant should be tested to ensure that it is not contaminated with zinc. Hemolysis should be scrupulously avoided in mea­surements of plasma zinc, since erythro­cytes are rich in zinc-containing metallo- proteins (e.g. carbonic anhydrase).

Analytical quality control. Many labora­tories neglect to perform routine measure­ments of zinc in samples of pooled plasma and urine in order to monitor day-to-day variations in analytical results. Quality con­trol specimens should always be included with each batch of analyses. In addition, it is desirable to perform frequent mea­surements of the recovery of zinc added to plasma, urine and other materials, and to participate in inter-laboratory comparisons of zinc in “unknown” samples.

C onclusions

On the basis of the clinical and experi­mental studies which have been discussed, there is evidence that zinc deficiency may play an important role in the pathogenesis of (1 ) acrodermatitis enteropathica, and in

1 4 0 SUNDERM AN

certain cases of (2 ) hypogonadal dwarfism, (3 ) congenital malformations, (4) hypo- geusia and hyposmia, (5) nyctalopia and (6 ) impaired wound healing. Pfeiffer and Iliev115 have speculated on tenuous grounds that zinc deficiency may also be involved in schizophrenias, and Barbeau and Don­aldson4 have proposed a relationship be­tween zinc deficiency and epilepsy. The clinical diagnosis of zinc deficiency is com­plicated by complex interactions of several pathophysiological factors which induce hypozincemia in a wide variety of patho­logical conditions. Diagnosis of zinc defi­ciency is further complicated by practical problems in sampling and analysis of zinc in body fluids and excreta. A serious need exists for improved laboratory techniques for the diagnosis of zinc deficiency in man.

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2. A u e r b a c h , S.: Zinc content of plasma, blood and erythrocytes in normal subjects and in patients with Hodgkin’s disease and various hematological disorders. J. Lab. Clin. Med. 65:628-637, 1965.

3 . A u l d , D. S., K a w a g u c h i , H., L iv in g s t o n ,D. M., a n d V a l l e e , B. L . : Reverse transcrip­tase from avian myeloblastosis virus: a zinc metalloenzyme. Biochem. Biophys. Res. Com­mun. 57:967-972, 1974.

4. B a r b e a u , A. a n d D o n a l d s o n , J.: Zinc, tau­rine and epilepsy. Arch. Neurol. 30:52-58,1974.

5. B a r c ia , P. J.: Lack of acceleration of heal­ing with zinc sulfate. Ann. Surg. 172:1048- 1050, 1970.

6. B a r n e s , P. M. a n d M o y n a h a n , E. J.: Zinc deficiency in acrodermatitis enteropathica: multiple dietary intolerance treated with synthetic diet. Proc. Roy. Soc. Med. 66:327- 329, 1973.

7. B e e l e y , J. M., Pa r k e , C . S., O w e n , G., a n d C o o p e r , R. D.: Serum zinc, bronchiectasis and bronchial carcinoma. Thorax 29:21-25,1974.

8. B e i s e l , W. R. a n d P e k a r e k , R. S.: Acute stress and trace element metabolism. Int. Rev. Neurobiol., Suppl. 1, 53-82, 1972.

9 . B e i s e l , W . R., P e k a r e k , R. S ., V a n O r m e r ,D., a n d W a n n e m a c h e r , R. W.: Influence of acute infection on the metabolism of zinc

and other trace elements. Psychopharmacol. Bull., pp. 34-35, 1971.

10. B e i s e l , W . R., P e k a r e k , R. S., a n d W a n n e ­m a c h e r , W . R., Jr.: The impact of infec­tious disease on trace-element metabolism of the host. Trace Element Metabolism in An­imals, vol. 2. Hoekstra, W. G., Suttie, J. W., Ganther, H. E., and Mertz, W ., eds., Uni­versity Park Press, Baltimore, pp. 217-240»1974.

11. B o y e t t , J. D. a n d S u l l i v a n , J. F . : Distri­bution of protein-bound zinc in normal and cirrhotic serum. Metabolism J9.-148-157,1970.

12. B r a d f ie l d , R. B ., L e e , T., a n d B a e r t l , J. M.: Hair zinc levels of Andean Indian children during protein-calorie malnutrition. Amer. J. Clin. Nutr. 22:1349-1353, 1969.

13. B r ig g s , M. H., B r ig g s , M., a n d A u s t i n , J.: Effects of steroid pharmaceuticals on plasma zinc. Nature 232:480-481, 1971.

14. B u r r , R. G.: B lo o d zinc in the spinal pa­tient. J. Clin. Path. 26:733-775, 1973.

15. C a g g ia n o , V., S c h n i t z l e r , R., S t r a u s s , W ., B a k e r , R. K., C a r t e r , A. C ., J o s e p h s o n , A. S., a n d W a l l a c h , S.: Zinc deficiency in a patient with retarded growth, hypogonad­ism, hypogammaglobulinemia and chronic infection. Amer. J . Med. Sci. 257:305-319,1969.

16. C a r r u t h e r s , R.: Oral zinc in cutaneoushealing. Drugs 6:161-164, 1973.

17. C h v a p i l , M., E l i a s , S. L., R y a n , J. N., a n d

Z u k o s k i , C. F.: Pathophysiology of zinc. Int. R e v . Neurobiol., Suppl. 1, pp. 105-124,1972.

18. C l a y t o n , R. J.: Double-blind trial of oral zinc sulphate in patients with leg ulcers. Brit. J. C lin . Pract. 26:368-370, 1972.

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