A Redefinition of Zinc Deficiency - ACS Symposium Series (ACS

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Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 25, 2018 | https://pubs.acs.org Publication Date: January 20, 1983 | doi: 10.1021/bk-1983-0210.ch006

A Redefinition of Zinc Deficiency ROBERT I. HENKIN Georgetown University Medical Center, Center for Molecular Nutrition and Sensory Disorders, Washington, DC 20007 ROGER L. AAMODT National Institutes of Health, Bethesda, MD 20205 Based upon clinical data we have reclassified zinc deficiency using traditional, epidemiological techniques into three syndromes; these are acute, chronic and subacute zinc deficiency. Acute zinc deficiency is relatively uncommon and follows parenteral hyperalimentation or oral L-histidine administration. Chronic zinc deficiency is more common, usually resulting from chronic dietary lack of zinc. Subacute or marginal zinc deficiency is the most common of these syndromes. Based upon a recent survey it is estimated that there are 4 million people in the U.S. with this syndrome, the i n i t i a l symptom being dysfunction of taste and olfaction whereas treatment with exogenous zinc usually requires months before these symptoms return to normal. Diagnosis of these disorders was most efficacious following oral administration of Zn with subsequent evaluation of the kinetics of transfer of the isotope into various body tissues, the formulation of the data by compartmental analysis and the integration of the data by a systematic model of zinc metabolism. 65

Zinc deficiency is reflected in clinical syndromes which affect men and women of a l l ages and a l l socioeconomic and cultural classes in the U.S. It is neither prevalent in any specific area of the U.S. nor is i t associated with any specific or definitive biochemical marker, which can make its identification difficult and at times frustrating and confusing. Its presence is manifested by a wide spectrum of symptoms, from acute, life threatening problems to mild subclinical or marginal disorders which may only vaguely disturb the well being of people who suffer with these complaints. The acute problems are often seen in profoundly i l l patients treated in hospital whereas marginal or subclinical problems may be so vague that patients seek assistance outside traditional medical practice from practitioners employing hypnosis, chiropody or a l l encompassing nutritional therapies. 0097-6156/83/0210-0083$07.00/0 © 1983 American Chemical Society Inglett; Nutritional Bioavailability of Zinc ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


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These c h a r a c t e r i s t i c s d e s c r i b e a protean s e t of d i s o r d e r s whose prevalence i s u n c l e a r , whose symptomatology may v a r y from p a t i e n t t o p a t i e n t and which do not e x h i b i t s p e c i f i c biochemical markers or c l i n i c a l s e t p o i n t s by which to e s t a b l i s h t h e i r r e l e vance t o s p e c i f i c p a t h o l o g i c a l processes. They a l s o p o i n t out some of the d i f f i c u l t i e s which c l i n i c i a n s face i n d e a l i n g w i t h z i n c d e f i c i e n c y syndromes. An example may help c l a r i f y these d i a g n o s t i c d i f f i c u l t i e s . I r o n d e f i c i e n c y has been recognized as a common problem i n the U.S. f o r some time and i t s d e f i n i t i o n u s u a l l y presents l i t t l e d i f f i c u l t y since the m i c r o c y t i c , hypochromic anemia a s s o c i a t e d w i t h i t s presence can be observed through the use of simple and commonl y a p p l i e d l a b o r a t o r y t e s t s ( i . e . , e v a l u a t i o n of a red blood c e l l smear or measurement of blood hemoglobin and/or h e m a t o c r i t ) . A l though symptoms a s s o c i a t e d w i t h i r o n d e f i c i e n c y may be vague or misleading (e.g., f a t i g u e , n o n s p e c i f i c malaise, i n a b i l i t y t o conc e n t r a t e f o r prolonged periods) the a v a i l a b i l i t y of simple and s p e c i f i c d i a g n o s t i c l a b o r a t o r y t e s t s make the e v a l u a t i o n of t h i s problem s t r a i g h t f o r w a r d and w i t h i n current standards of p r a c t i c e of c l i n i c a l medicine. A d m i n i s t r a t i o n of exogenous i r o n i s commonly a s s o c i a t e d w i t h the c o r r e c t i o n of the abnormal l a b o r a t o r y t e s t s r e s u l t i n g i n r e m i s s i o n of the a s s o c i a t e d symptoms. Such i s not the case w i t h z i n c d e f i c i e n c y . While symptoms of z i n c d e f i c i e n c y can be as vague as those i n i r o n d e f i c i e n c y , there i s no simple d i a g n o s t i c t e s t which d e f i n e s the c o n d i t i o n . Zinc concentrations i n blood, u r i n e o r h a i r commonly do not a c c u r a t e l y r e f l e c t body z i n c s t a t u s (.1-3)· Although z i n c i s the major t r a c e element found i n f i x e d body t i s s u e s l e s s than 1% of the approximate 2.5 g of t o t a l body z i n c i s c i r c u l a t i n g i n blood (4) w h i l e f o r i r o n , the major t r a c e element found i n the c i r c u l a t i o n , over 50% of the approximate 4.0 g of t o t a l body i r o n i s found i n blood and blood forming systems (5). Because z i n c has m u l t i p l e f u n c t i o n s and i s widely d i s t r i b u t e d i n the body, i t s d e f i c i e n c y can a f f e c t many body t i s s u e s . I n add i t i o n , e f f e c t i v e treatment of z i n c d e f i c i e n c y may r e q u i r e prolonged a d m i n i s t r a t i o n of l a r g e amounts of the metal w i t h s p e c i f i c counter i o n s , a s t r a t e g y which may not be apparent t o p h y s i c i a n s u n f a m i l i a r w i t h these d i s o r d e r s . While z i n c d e f i c i e n c y syndromes have been known f o r many years, and t h e i r prevalance noted i n d i v e r s e groups of people world wide, only r e c e n t l y have any i d e n t i f i a b l e patterns of some of these syndromes been formulated and the u n d e r l y i n g mechanisms s t a t e d , however t e n t a t i v e l y . These syndromes can be complex, p r e sent both i n c h i l d r e n and a d u l t s of both sexes and i n c l u d e s i n g l e or m u l t i p l e organ systems. These c o m p l e x i t i e s can cause d i f f i c u l t y f o r both p a t i e n t s and p h y s i c i a n s seeking an understanding of these processes. Laboratory t e s t s used t o d e f i n e these syndromes a l s o may be confusing or inadequate (1-4). U r i n a r y z i n c e x c r e t i o n may be lower than normal, a t normal l e v e l s , or e l e v a t e d , as much as 3-10

Inglett; Nutritional Bioavailability of Zinc ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


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f o l d normal. Serum, plasma and e r y t h r o c y t e z i n c concentrations may be normal, low or h i g h . H a i r z i n c l e v e l s may be lower than normal or normal. Zinc treatment has not always provided a usef u l method f o r assessing d e f i c i e n c y , even r e t r o s p e c t i v e l y . T r e a t ment embodying replacement of l o s t z i n c has commonly produced a r e m i s s i o n of many of the symptoms of these syndromes provided body z i n c was r e s t o r e d to normal. However, o r a l a d m i n i s t r a t i o n of z i n c may not be of v a l u e i n treatment of these d i s o r d e r s i f other aspects of z i n c metabolism are abnormal, e.g., z i n c b i n d i n g or storage i n t i s s u e s or t r a n s p o r t i n blood. Indeed, c o n t r o l l e d c l i n i c a l t r i a l s of the e f f i c a c y of z i n c treatment have not yet been c a r r i e d out f o r s e v e r a l s p e c i f i c d i s o r d e r s of z i n c metabolism. In an attempt to formulate our present knowledge about these d i s o r d e r s i t seemed u s e f u l to d e f i n e some of the c l i n i c a l and b i o chemical markers which accompany these syndromes even though they may be n e i t h e r s p e c i f i c nor d i a g n o s t i c . To do t h i s , we have a t tempted to re-evaluate z i n c d e f i c i e n c y i n i t s broadest sense and to organize i t i n t o major d i a g n o s t i c c l a s s i f i c a t i o n s using t r a d i t i o n a l , c l i n i c a l techniques. In so doing our hope i s to e l u c i d a t e the i n c i d e n c e , symptomotology and c h a r a c t e r i s t i c s of these syndromes. C l i n i c a l D e f i n i t i o n s of Zinc D e f i c i e n c y Syndromes Acute Zinc D e f i c i e n c y Acute z i n c d e f i c i e n c y i s the most e a s i l y i d e n t i f i a b l e of the z i n c d e f i c i e n c y syndromes. This i s a r e l a t i v e l y uncommon form of the syndrome o c c u r r i n g e x p e r i m e n t a l l y f o l l o w i n g the o r a l a d m i n i s t r a t i o n of L - h i s t i d i n e (6) or c l i n i c a l l y , f o l l o w i n g p a r e n t e r a l hyperalimentation (7-12) w i t h the i n t r a venous a d m i n i s t r a t i o n of h i g h concentrations of glucose and f r e e amino a c i d s (Table I ) . Symptoms of t h i s d i s o r d e r are not d i a g n o s t i c , and i t i s easy to understand the dismay of a p h y s i c i a n viewing a young i n f a n t w i t h an erythrematous, i n t r a c r u r a l rash unresponsive to a n t i b i o t i c or a n t i f u n g a l therapy which disappears w i t h i n 24 hours a f t e r i n i t i a t i o n of z i n c treatment. The d i a g n o s i s becomes somewhat s i m p l i e r , i f , i n a d d i t i o n to the erythrematous, i n t r a c r u r a l l e s i o n s , the p a t i e n t a l s o e x h i b i t s paranychia, d i a r rhea, s c a t t e r e d b u l l o u s l e s i o n s and impaired h e a l i n g of cuts and scratches but these a d d i t i o n a l symptoms may not be present. Acute z i n c d e f i c i e n c y i n a d u l t s i s u s u a l l y a s s o c i a t e d w i t h s p e c i f i c signs and symptoms a s s o c i a t e d w i t h the r a p i d and prog r e s s i v e l o s s of body z i n c . The i n i t i a l symptoms of t h i s c o n d i t i o n i s almost u n i f o r m l y anorexia (6,JL3), a symptom a l s o seen e a r l y i n experimental z i n c d e f i c i e n c y i n animals made d e f i c i e n t by l i m i t a t i o n of d i e t a r y z i n c (14 >.M) · Anorexia i s commonly followed by t a s t e and smell d y s f u n c t i o n , then hypogeusia and hyposmia ( l o s s of t a s t e and s m e l l a c u i t y , r e s p e c t i v e l y ) , followed by dysosmia and dysgeusia. Increased u r i n a r y z i n c e x c r e t i o n has been observed from the f i r s t day of t h i s syndrome w i t h as much as 1% of the t o t a l body




TABLE I ACUTE ZINC DEFICIENCY

ETIOLOGY:

O r a l L - H i s t i d i n e (16-64 gm) P a r e n t e r a l Hyperalimentation

ONSET:

3-14 days

INCIDENCE:

Infrequent

SYMPTOM APPEARANCE Anorexia Hypogeusia Hyposmia Dysgeusia Dysosmia Mental Confusion Cerebellar Dysfunction Ataxia Rash Buccal Lesions Acute Toxic Psychosis

ZINC CHANGES + U r i n a r y Zn

Ψ Serum Zn Ψ Zn-65 Retention


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z i n c excreted d a i l y (6). Decreased serum z i n c c o n c e n t r a t i o n u s u a l l y occurs l a t e r but i t i s small i n r e l a t i o n to the marked e l e v a t i o n of u r i n a r y z i n c e x c r e t i o n . O r a l a d m i n i s t r a t i o n of Z n to p a t i e n t s w i t h acute z i n c d e p l e t i o n has been a s s o c i a t e d w i t h decreased r e t e n t i o n (13) of the isotope i n d i c a t i n g a measureable l o s s of body z i n c r a t h e r than simply body z i n c r e d i s t r i b u t i o n . P e r s i s t e n t acute body z i n c l o s s has r e s u l t e d i n many symptoms i n a d d i t i o n to t a s t e and smell d y s f u n c t i o n i f l o s s e s continue at s i g n i f i c a n t l e v e l s f o r periods of 14 days or more. These symptoms i n c l u d e mental confusion, c e r e b e l l a r d y s f u n c t i o n , i n c l u d i n g i n t e n t i o n tremor and a t a x i a , an erythrematous, i n t r a c r u r a l r a s h , bucc a l e p i t h e l i a l l e s i o n s and u l c e r s , and acute t o x i c psychosis ( 6 ) . The a l t e r e d mental s t a t e of these p a t i e n t s can be r e l a t e d to the r a p i d d e p l e t i o n of the r e l a t i v e l y high z i n c content i n the l i m b i c system of the b r a i n (16 ,JL7), demonstrating that z i n c can c r o s s the blood b r a i n b a r r i e r b i d i r e c t i o n a l l y , dependent upon the g r a d i e n t , and that i t can be r e a d i l y m o b i l i z e d from b r a i n t i s s u e . Treatment of t h i s d i s o r d e r w i t h o r a l or p a r e n t e r a l z i n c i s almost u n i f o r m l y a s s o c i a t e d w i t h the c o r r e c t i o n of a l l aspects of t h i s d i s o r d e r . Even w i t h continued a d m i n i s t r a t i o n of L - h i s t i d i n e l a r g e amounts of exogenous z i n c were e f f e c t i v e i n c o r r e c t i n g the signs and symptoms of t h i s d i s o r d e r (6) w i t h the a n o r e x i a , t a s t e and s m e l l d y s f u n c t i o n , a t a x i a and mental symptoms r e t u r n i n g to or toward normal w i t h i n 24 hours, the s k i n or e p i t h e l i a l l e s i o n s r e q u i r i n g days of therapy (6). Cessation of L - h i s t i d i n e administ r a t i o n f o r 2-4 days was not s u c c e s s f u l e i t h e r i n producing symptom r e m i s s i o n (6) or i n r e t u r n i n g body z i n c l e v e l s to normal. I t was o n l y a f t e r a d m i n i s t r a t i o n of exogenous z i n c that the signs and symptoms of t h i s d i s o r d e r were c o r r e c t e d , c o n s t i t u t i n g r e p l a c e ment of l o s t body z i n c s t o r e s . In i n f a n t s , commonly neonates given p a r e n t e r a l hyperaliment a t i o n , the erythrematous, i n t r a c r u r a l r a s h , paranychia and occas i o n a l b u l l o u s s k i n l e s i o n s are e a r l y signs of t h i s d i s o r d e r , a l though the i n a b i l i t y to console the i n f a n t may be the e a r l i e s t , most s e n s i t i v e , yet most d i f f i c u l t to evaluate, symptom of t h i s d i s o r d e r {Table 1, (18)}. B a c t e r i a l and f u n g a l c u l t u r e s of the s k i n l e s i o n s are o f t e n negative and there i s u s u a l l y no a s s o c i a ted f e b r i l e c o n d i t i o n (18). Serum e l e c t r o l y t e s and blood gases are commonly w i t h i n normal l i m i t s . Serum z i n c l e v e l s may be lower than 10 y g / d l and may provide the simplest and most u s e f u l l a b o r a t o r y t e s t of t h i s d i s o r d e r (18*^20)· O r a l or p a r e n t e r a l zinc administration i s u s u a l l y associated with a rapid remission of these symptoms although changes i n serum z i n c c o n c e n t r a t i o n may l a g the c l i n i c a l changes observed (18). Increased u r i n a r y z i n c e x c r e t i o n coupled w i t h decreased serum z i n c c o n c e n t r a t i o n and the observed symptoms f o l l o w acute z i n c d e p l e t i o n w i t h enough consistency that i t i s r e l a t i v e l y simple f o r an a l e r t p h y s i c i a n to e s t a b l i s h the d i a g n o s i s . However, i t i s t h i s awareness and the protean nature of the symptoms which comp l i c a t e i t s d i a g n o s i s . Indeed, the f u l l - b l o w n c l i n i c a l p i c t u r e


6 5


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of z i n c d e f i c i e n c y e i t h e r i n i n f a n t s or a d u l t s can, as noted, be confusing and mistaken f o r s e v e r a l other c l i n i c a l d i s o r d e r s . Chronic Zinc D e f i c i e n c y Chronic z i n c d e f i c i e n c y i s more common than acute z i n c d e f i c i e n c y o c c u r r i n g i n a d u l t s experiment a l l y f o l l o w i n g a d m i n i s t r a t i o n of z i n c d e f i c i e n t d i e t or n a t u r a l l y f o l l o w i n g the i n t a k e of a d i e t low i n z i n c (21-23). I t a l s o has been observed i n c h i l d r e n who commonly do not eat z i n c r i c h foods (24,25). C h i l d r e n w i t h t h i s c o n d i t i o n may e x h i b i t small s t a t u r e (oftimes below the 5 t h p e r c e n t i l e f o r height and weight) and poor school performance {(25) Table I I } . I n f a n t s w i t h t h i s c o n d i t i o n can e x h i b i t genetic{(26", 27) a c r o d e r m a t i t i s enteropathica)} or a c quired (28-30) forms of t h i s d i s o r d e r , which occur i n some pat i e n t s f o l l o w i n g s u b s t i t u t i o n of cow's m i l k f o r human m i l k i n the neonatal or p e r i n a t a l p e r i o d (29,30). Chronic z i n c d e f i c i e n c y was f i r s t reported i n I r a n andTTgypt (22,23) i n a d u l t s who exh i b i t e d short s t a t u r e , hepatosplenomegaTy7~iron d e f i e n c y anemia and hypogonadism. These symptoms were, i n p a r t , r e l a t e d t o the i n t a k e of z i n c l i g a n d s which appeared to bind ingested z i n c p r e f e r e n t i a l l y , making the metal l e s s a v a i l a b l e f o r absorption i n the g a s t r o i n t e s t i n a l t r a c t (31). Dwarfism was a l s o observed i n these p a t i e n t s (22,23). Phytate (31), o x a l a t e s ( 32_), and forms of f i ber (33,34) have been suggested as l i g a n d s that could bind z i n c leaving i t r e l a t i v e l y unavailable f o r e f f e c t i v e g a s t r o i n t e s t i n a l a b s o r p t i o n . Other f a c t o r s , i n c l u d i n g p i c a , and i n t e s t i n a l paras i t e s , may have been r e s p o n s i b l e f o r some aspects of the anemia and hepatosplenomegaly reported i n the I r a n i a n and Egyptian pat i e n t s w i t h t h i s d i s o r d e r (22,23). Some i n v e s t i g a t o r s have cons i d e r e d the presence of p u t a t i v e l y more e f f e c t i v e l y absorbable z i n c l i g a n d s i n human m i l k than that i n cow's m i l k r e s p o n s i b l e f o r the delayed appearance of a c r o d e r m a t i t i s enteropathica i n i n f a n t s , the symptom complex becoming apparent only a f t e r the i n t r o d u c t i o n of cow's m i l k i n t o the d i e t (29,30,36-39). These l a t t e r observations have spawned considerable controversy between proponents of c i t r a t e (36,37) or p i c o l i n a t e (38,39) as the major z i n c l i g a n d s i n human m i l k . C h i l d r e n may e x h i b i t d i f f e r e n t symptoms than a d u l t s a t the onset of t h i s d i s o r d e r . I n c h i l d r e n , anorexia, d i a r r h e a , i r r i t a b i l i t y and short s t a t u r e may be apparent whereas i n a d u l t s t a s t e and s m e l l d y s f u n c t i o n , hypogonadism and poor wound h e a l ing may appear as e a r l y s i g n s . Although t a s t e and smell dysf u n c t i o n are common components of t h i s syndrome they may be overshadowed by the more acute symptoms of d i a r r h e a and l e t h a r g y . A number of important and, as y e t , unexplained d i s c r e p a n c i e s are apparent i n t i s s u e z i n c concentrations i n t h i s syndrome. Pat i e n t s w i t h chronic r e n a l d i s e a s e , w i t h c l i n i c a l signs and symptoms of z i n c d e f i c i e n c y show c o n s i s t e n t l y elevated red blood c e l l z i n c l e v e l s (40-42) whereas plasma z i n c concentrations have been reported as e i t h e r low, normal or elevated (40-^4)· Pat i e n t s w i t h Kwashiorkor and symptoms of z i n c d e f i c i e n c y have


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TABLE I I


CHRONIC ZINC DEFICIENCY

ETIOLOGY:

D i e t a r y Lack Absorption I n h i b i t i o n Abnormal Zn Ligand Chronic Renal F a i l u r e Cancer

ONSET:

Months, Years

INCIDENCE:

Moderate (10% of growth retarded c h i l d r e n , 5th c e n t i l e )

SYMPTOM APPEARANCE

ZINC CHANGES

Children Short Stature Hypogeusia Pica Hyposmia Paranychia Rash Diarrhea

Ψ H a i r Zn Serum Zn Ψ S a l i v a r y Zn U r i n a r y Zn RBC Zn + Zn-65 Absorption

Adults Hypogeusia Hyposmia Hypogonadism Short Stature Diarrhea Poor Wound Healing

Ψ H a i r Zn Ψ Serum Zn U r i n a r y Zn RBC Zn Ψ Zn Enzymes Serum T, LH



90

NUTRITIONAL BIOAVAILABILITY OF

ZINC

serum z i n c l e v e l s that are lower than normal (45,46) but h a i r z i n c l e v e l s which are normal or even elevated r a t h e ~ t n a h below normal as might be expected i n i t i a l l y (47). U r i n a r y z i n c e x c r e t i o n may be lower than normal i f d i e t a r y z i n c i s low, but higher than norma l i f the anorexia a s s o c i a t e d w i t h t h i s syndrome i s prominent, r e l a t e d to the e f f e c t s of chronic weight l o s s (48). In s e v e r a l d i s orders of chronic z i n c d e f i c i e n c y , serum or plasma z i n c l e v e l s may be normal, h i g h or low and thus of l i m i t e d d i a g n o s t i c value (1-3,49). Some z i n c enzymes, plasma t e s t o s t e r o n e or LH may be decreased i n p a t i e n t s w i t h hypogonadism or w i t h azospermia (50). C e l l u l a r immunity may a l s o be impaired i n p a t i e n t s w i t h chronic uremia (51). Studies of o r a l a b s o r p t i o n of Z n i n patients w i t h a c r o d e r m a t i t i s enteropathica have produced r e s u l t s c o n s i s tent w i t h impaired a b s o r p t i o n (52) w i t h t o t a l body z i n c l e v e l s suspected to be lower than normal (53). However, Z n absorption i n these p a t i e n t s overlaps the lower end of the normal a b s o r p t i o n range, a phenomenon which has o n l y r e c e n t l y been emphasized (54, 55). The c l i n i c a l d i a g n o s i s of chronic z i n c d e f i c i e n c y i s s i m p l i f i e d i f z i n c i s depleted from most body t i s s u e s . However, the long time p e r i o d necessary f o r the appearance of symptoms of t h i s syndrome and i t s protean nature can complicate i t s c l i n i c a l d i a g n o s i s , e s p e c i a l l y i f p h y s i c i a n s do not consider i t s presence. Treatment w i t h exogenous z i n c has g e n e r a l l y r e s u l t e d i n succ e s s f u l r e m i s s i o n of the symptoms of t h i s syndrome. However, a remarkably small amount of z i n c i s necessary to r e s t o r e normal function i n patients with acrodermatitis enteropathica, often only s l i g h t l y more than the recommended d a i l y d i e t a r y allowance f o r z i n c (56). Diodoquin, a drug which appears to a s s i s t z i n c absorpt i o n , has a l s o been u s e f u l i n the treatment of some p a t i e n t s w i t h a c r o d e r m a t i t i s e n t e r o p a t h i c a (57). In some p a t i e n t s , l a r g e r amounts of z i n c given f o r prolonged p e r i o d s of time are necessary to produce symptom r e m i s s i o n . In the o n l y double b l i n d study performed i n p a t i e n t s w i t h p u t a t i v e z i n c d e f i c i e n c y i n Egypt, placebo was as e f f e c t i v e as z i n c i n t r e a t i n g the d i s o r d e r (58). These r e s u l t s o f f e r a confusing p i c t u r e of response to therapy which emphasizes some of the d i f f i c u l t i e s w i t h the c l i n i c a l a p p r e c i a t i o n of these problems. Subacute Zinc Defiency Subacute z i n c d e f i c i e n c y i s the maj o r c l i n i c a l z i n c d e f i c i e n c y syndrome i n the U.S. Based upon a n a t i o n a l survey of s m e l l f u n c t i o n performed i n 1980, estimates suggest that t h i s syndrome may a f f e c t as many as 4 m i l l i o n people (59). The e t i o l o g y of subacute z i n c d e f i c i e n c y i s r e l a t e d to a v a r i e t y of d i s o r d e r s which do not, at f i r s t glance, appear to have any s p e c i f i c r e l a t i o n s h i p to a metabolic disease process {(Table I I I ) (60)}. Indeed, the mechanisms by which a v i r a l i l l ness, head i n j u r y , s u r g i c a l procedures, or a l l e r g i c r h i n i t i s may produce lowered body z i n c l e v e l s are s t i l l unknown. In a d d i t i o n , to complicate t h i s problem f u r t h e r , the onset of t h i s syndrome can occur r e l a t i v e l y q u i c k l y , over days, or more s l o w l y , over 6 5

6 5



6.

HENKIN AND

AAMODT


TABLE I I I SUBACUTE ZINC DEFICIENCY

ETIOLOGY:

D i e t a r y Lack V i r a l URI (PIHH) Head I n j u r y Unknown

ONSET:

Days, Weeks, Months

INCIDENCE:

4 m i l l i o n i n U.S.

SYMPTOM APPEARANCE Hypogeusia Hyposmia Dysgeusia Dysosmia

ZINC CHANGES + Serum Zn + RBC Zn Ψ WBC ALK PO^'ase 4- Zn-65 Absorption Ψ T o t a l Body Zn


91


92

NUTRITIONAL BIOAVAILABILITY OF

ZINC

weeks or months. The symptoms of t h i s d i s o r d e r are as protean as those of the acute or chronic z i n c d e f i c i e n c y syndromes and provide no s p e c i a l d i a g n o s t i c c l u e s to the e t i o l o g y of these problems. However, the most obvious symptoms associated w i t h t h i s most common form of z i n c d e f i c i e n c y are t a s t e and smell dysf u n c t i o n , hypogeusia, hyposmia, dysgeusia and dysosmia (60). These are the major, and oftimes the o n l y , symptoms associated w i t h t h i s d i s o r d e r . Although acute and chronic z i n c d e f i c i e n c y syndromes can a l s o be c h a r a c t e r i z e d by t a s t e and smell dysfunct i o n they a l s o have other, more e a s i l y recognized dysfunctions a f f e c t i n g s k i n , g a s t r o i n t e s t i n a l t r a c t , neuromuscular system or other body systems a l l o w i n g t h e i r d i a g n o s i s to be made somewhat e a s i e r . Of a l l the z i n c d e f i c i e n c y syndromes only subacute z i n c d e f i c i e n c y can present w i t h t a s t e and smell d y s f u n c t i o n as the major or only set of c l i n i c a l symptoms manifested by the c o n d i tion. Thus, subacute z i n c d e f i c i e n c y may represent one of the most d i f f i c u l t d i a g n o s t i c challenges of a l l z i n c d e f i c i e n c y syndromes. Although serum and erythrocyte z i n c concentrations may be s i g n i f i c a n t l y lower than normal i n these p a t i e n t s (61), these l e v e l s may a l s o be w e l l w i t h i n normal l i m i t s . U r i n a r y z i n c exc r e t i o n may be normal, elevated or depressed (62). S a l i v a r y z i n c c o n c e n t r a t i o n i s u s u a l l y below the normal mean but i t may a l s o be w i t h i n the normal range (64,65). Measurements of s a l i v a r y g u s t i n can be u s e f u l i n some p a t i e n t s (3_,49) but i t i s not n e c e s s a r i l y d i a g n o s t i c (3,49)· Measurements of z i n c absorption are a l s o not d i a g n o s t i c f o r a f t e r o r a l a d m i n i s t r a t i o n of Zn^ a b s o r p t i o n has v a r i e d over a wide range, from 17 - 100% of the administered dose (3,49,60). These r e s u l t s emphasize the v a r i a b i l i t y of z i n c concent r a t i o n i n body t i s s u e s i n t h i s syndrome and the l a c k of a s i n g l e , s p e c i f i c f u n c t i o n a l t e s t by which these p a t i e n t s may be c l a s s i f i e d as z i n c d e f i c i e n t . Indeed, because these r e s u l t s are so v a r i a b l e the c l a s s i f i c a t i o n of these p a t i e n t s as z i n c d e f i c i e n t may, at f i r s t glance, appear to be questionable. This v a r i a b i l i t y i n s i n g l e t e s t s i s not apparent, however, when s p e c i f i c t e s t s of t i s s u e and body z i n c s t a t u s are examined simultaneously. Thus, measurements of impaired z i n c absorption (3 49 6»0) and lower than normal concentrations of t i s s u e and body z i n c i n p a t i e n t s w i t h t h i s d i s o r d e r (66-69) confirm the d i a g n o s i s of subacute z i n c d e f i c i e n c y w i t h c e r t a i n t y (Tables IV, V ) . The r a t i o n a l e f o r t h i s c l a s s i f i c a t i o n was derived from s t u d i e s of compartmental analyses of the k i n e t i c data obtained from these patients following o r a l Z n a d m i n i s t r a t i o n , measurement of z i n c r e t e n t i o n i n s e v e r a l body t i s s u e s , i n c l u d i n g areas over the l i v e r and t h i g h , i n red blood c e l l s , plasma, u r i n e and s t o o l , and by s y n t h e s i z i n g these data by means of a mathematical model i n which a l l of these data could be constrained and f i t t e d simultaneously (67,69). By c a r r y i n g out these processes we were able to c a l c u l a t e parameters which were both necessary and s u f f i c i e n t to i d e n t i f y these p a t i e n t s . We were a l s o able to measure lower than 5

t

t

6 5


6.

HENKIN AND

AAMODT


93

normal t i s s u e z i n c concentrations i n some of the p a t i e n t s (Table V ) . I n order to understand the b a s i s of t h i s f o r m u l a t i o n s p e c i f i c questions about the nature of z i n c d e f i c i e n c y had t o be r a i s e d and answers attempted. Only through these formulations could awareness of the i s s u e s underlying z i n c d e f i c i e n c y be c l a r i f i e d .


C r i t i c a l Questions of Zinc

Deficiency

A s e r i e s of questions r a i s e d by the above ambiguities may be h e l p f u l t o formulate a r e d e f i n i t i o n of z i n c d e f i c i e n c y . I n i t i a l l y four questions can be r a i s e d . They are: (1) How can z i n c def i c i e n c y be defined? (2) Why do p a t i e n t s w i t h subacute z i n c def i c i e n c y , e x h i b i t t a s t e and smell d y s f u n c t i o n as t h e i r major, o f t e n t h e i r o n l y , symptom complex? (3) What i s the meaning of the wide range of z i n c absorption i n p a t i e n t s w i t h subacute z i n c d e f i c i e n cy?, and (4) Does z i n c treatment of p a t i e n t s w i t h subacute z i n c d e f i c i e n c y adequately c o r r e c t the c l i n i c a l symptoms of the disease processes, and i f s u c c e s s f u l , by what mechanisms do these changes occur? 1. D e f i n i t i o n s of Zinc D e f i c i e n c y . I t i s c l e a r that z i n c d e f i c i e n c y can be defined only w i t h d i f f i c u l t y since the z i n c content of a s i n g l e body f l u i d or t i s s u e l e v e l cannot provide a def i n i t i v e estimate of body z i n c s t a t u s (1.-3) . I t i s a l s o not poss i b l e t o r e l y on the c o n c e n t r a t i o n of z i n c i n s e v e r a l body t i s s u e s to estimate body z i n c s t a t u s since d i f f e r i n g concentrations i n d i f f e r e n t t i s s u e s lead t o n o n - d e f i n i t i v e conclusions. With these negatives i n view i t seemed important t o determine i f z i n c d e f i c i e n c y could be defined q u a n t i t a t i v e l y by means of any set of l a b o r a t o r y t e s t s . I n an attempt t o c l a r i f y t h i s , a s e r i e s of s t u d i e s were c a r r i e d out f o l l o w i n g o r a l a d m i n i s t r a t i o n of Z n , a f t e r an overnight f a s t , i n normal v o l u n t e e r s (55) and i n p a t i e n t s w i t h subacute z i n c d e f i c i e n c y (3,49,60,66). As noted above, mean z i n c a b s o r p t i o n i n p a t i e n t s w i t h t a s t e and smell d y s f u n c t i o n was 55% ranging from 17% to 100% (3,49,60), whereas i n normals abs o r p t i o n v a r i e d from 42 t o 84% w i t h a mean of 65%, a v a l u e s i g n i f i c a n t l y higher than that measured i n the p a t i e n t s (55,_60). I f z i n c d e f i c i e n c y were s i m i l a r t o i r o n d e f i c i e n c y , then a lowered t o t a l body z i n c content should be expected t o y i e l d r e s u l t s s i m i l a r to those observed w i t h low t o t a l body i r o n content; i . e . , an i n creased absorption of z i n c associated w i t h decreased body z i n c s t o r e s . However, t h i s i s not the case f o r human z i n c d e f i c i e n c y since mean absorption of z i n c i n these p a t i e n t s i s s i g n i f i c a n t l y lower than normal (3^49^60) i n the face of what appears t o be a lower than normal t o t a l body z i n c s t a t u s (60,69). These r e s u l t s , i n p a t i e n t s w i t h t a s t e and smell dysfunction,"~~Ire c o n s i s t e n t w i t h r e s u l t s obtained i n s i m i l a r s t u d i e s i n p a t i e n t s w i t h cancer (55), d e r m a t o l o g i c a l (55), and other d i s o r d e r s (56) and r a i s e fundament a l problems about mechanisms of human z i n c d e f i c i e n c y . These d i s c r e p a n c i e s i n human z i n c metabolism a r e not apparent i n the r a t i n which decreased body z i n c stores have been associated w i t h 6 5


94

nutritional

bioavailability

of

zinc

TABLE IV COMPARISON OF ABSORPTION AND EXCRETION OF Zn-65 IN NORMAL VOLUNTEERS AND IN PATIENTS WITH SUBACUTE Zn DEFICIENCY


CONDITIONS

NORMALS

PATIENTS

Vi+

.146

+

.005

.150

±

.007

V

.009

+

.001

.007

±

.001

.138

+

.006

.144

±

.007

.36

±

.05

.11

±

.02*

.35

+

.05

.10

±

.01*

.69

+

.03

.43

±

.04

.26

+

.04

.18

±

.03

+

.2

±

.2*

V

u

F

V

a

V

r

00* A

L

2.7

F

L

73

(15,24)

1.4 26

±13

±3*

mg/kg/day day"* ρ < 0.01 **

f r a c t i o n of g a s t r o i n t e s t i n a l Zn absorbed

V

i s defined as the mass transport i n u n i t s of mg/day

V.

r a t e of z i n c t r a n s f e r from C product of L ( 2 4 , 1 5 )

1

(M

1 5

to C i^ c a l c u l a t e d as the 2

)

1 5

M

i s defined as the mass, i n mg, of compartment C^

L-LJ

i s defined as the f r a c t i o n of zinc i n compartment Cj trans f e r r e d to compartment C. per u n i t time. I t s u n i t s are day-1 and represent the* rate constant from compartment j i n t o compartment i . 3

V ,Vp u

t o t a l z i n c e x c r e t i o n r a t e i n t o u r i n e and f e c e s , ively.

V

V

F

=

L(0,25)(M

2 5

and i s L ( 1 5 , 2 4 ) ( Μ 2 ^ )

r a t e of z i n c absorption

a

V^

r a t e of zinc

Ç9) subsequent development of a model (Figure 1) which accounted f o r a l l the data obtained over the e n t i r e period of these s t u d i e s , both p r i o r to and a f t e r treatment w i t h exogenous z i n c (69). These r e s u l t s , compared i n normal v o l u n t e e r s , demons t r a t e d that not only was a b s o r p t i o n of z i n c s i g n i f i c a n t l y imp a i r e d i n the p a t i e n t s compared w i t h the normal v o l u n t e e r s (Table IV) but a l s o that the r a t e a t which z i n c was absorbed was s i g n i f i c a n t l y lower i n the p a t i e n t s than i n the normals (3_,55^60) and that t h e i r t o t a l body l e v e l of z i n c was lower than i n the normals (60^69^. °f t h i s model i t was a l s o p o s s i b l e to s p e c i f y those c o n d i t i o n s which were both necessary and s u f f i c i e n t to i d e n t i f y p a t i e n t s w i t h z i n c d e f i c i e n c y (60_,69). With these t e c h niques i t was p o s s i b l e to i d e n t i f y , by o b j e c t i v e c r i t e r i a , l a b o r a t o r y t e s t s by which p a t i e n t s w i t h subacute z i n c d e f i c i e n c y could be defined q u a n t i t a t i v e l y . I t was a l s o p o s s i b l e to measure v a r i o u s t i s s u e and t o t a l body z i n c l e v e l s and to compare p a t i e n t s w i t h normals so that p a t i e n t s w i t h z i n c d e f i c i e n c y could be i d e n t i f i e d . The major problems presented w i t h these techniques are that they are time consuming, cumbersome, expensive and are p r e s e n t l y una v a i l a b l e i n many areas of the U.S. 2. Why are t a s t e and smell d y s f u n c t i o n the major c l i n i c a l problems i n p a t i e n t s w i t h subacute z i n c d e f i c i e n c y ? I t i s important to recognize that subacute z i n c d e f i c i e n c y i s u s u a l l y a m i l d or marginal form of the d e f i c i e n c y . I t i s a l s o important to r e c ognize that the e a r l i e s t signs of both acute and chronic z i n c def i c i e n c y , i . e . , during the period when the d e f i c i e n c y i s beginning to be manifested, are those of t a s t e and smell d y s f u n c t i o n . These 6 5

s i s

w i t n

B v

t n e

t n e

u s e


Inglett; Nutritional Bioavailability of Zinc ACS Symposium Series; American Chemical Society: Washington, DC, 1983. UPPER GASTROINTESTINAL TRACT

OTHER TISSUES


Ν

Os

Inglett; Nutritional Bioavailability of Zinc ACS Symposium Series; American Chemical Society: Washington, DC, 1983. t

9

t5

t

6S

8

The circles are labeled Ci for the Ci compartment. The arrows represent rate constants, the Lnj> defined as the fraction of zinc in compartment Cj transferred to compartment C i per unit time. The plasma, red blood cell, and liver subsystems are indicated by C , Cs, Ce, and Cs, C ,and C«, respectively. Cn in the liver subsystem, which is set off by dotted lines, did not appear in the original, short term model (67) but was required in the extended model as explained in the text. Thus, the circles and arrows depicted here, except for those related to Ct*, are those defined in the original short term model (67). The rectangles illustrate the result of reducing the original, short term model. The upper rectangle includes all of the rapidly turning over compartments defined in the original short term model. This rectangle shows the constituents of C in the reduced model. The lower rectangle includes the entire upper gastrointestinal tract and is called Cn in the reduced model. Cs, Ce, Cst, and Cts are slowly turning over compartments and they are kept in this form in the reduced model. The numbers shown in thisfigureare from a representative patient, patient 4, in the group reported. The upper numbers indicate data obtained before, the lower number during, oral zinc loading. If only one number appears, no change occurred during zinc loading. To exemplify the rate constant, the arrow from C to C» represents L( ,D, which has a value of 75/day. The rate constants are reported with and without SD. Those without SD are taken from the original short term model where SD were shown; these numbers are included here simply to show the basis for combining the compartments into a single composite compartment as explained in the text. Those rate constants with SD are derived from the data obtained in this representative patient and werefittedto the reduced model. To exemplify the masses, the mass of the plasma compartment Ci is 3.1 mg before, and 4.2 mg during, oral zinc loading. Numbers without SD are the masses in the rapidly turning over compartments; the sum of these numbers is the mass of the reduced compartment described above. Masses with SD were derived from the data obtained in this representative patient and werefittedto the reduced model. Zn is introduced into the first compartment of the upper gastrointestinal tract as indicated by the asterisk. Dietary intake is indicated by the double arrow.

th

Figure 1. In this model of zinc metabolism in humans circles represent compartments and arrows represent transfer pathways. (Reproduced with permission from Ref. 69.)



98

NUTRITIONAL BIOAVAILABILITY

OF ZINC

r e s u l t s suggest that those z i n c pools subserving the t a s t e and smell systems are s m a l l , l a b i l e , and i n r a p i d e q u i l i b r i u m w i t h z i n c i n t a k e . Thus, w i t h too l i t t l e i n t a k e or w i t h e a r l y d e p l e t i o n of z i n c the f i r s t systems t o be a f f e c t e d a r e those subserving t a s t e and o l f a c t i o n . 3. Why i s there such a wide range of z i n c absorption i n p a t i e n t s w i t h subacute z i n c d e f i c i e n c y ? While the answer to t h i s question i s u n c l e a r , the data suggest that z i n c absorption and i t s d i s t r i b u t i o n i n the human body i s unique and d i f f e r s s i g n i f i c a n t l y from i r o n absorption or that of other d i v a l e n t metal i o n s . Some data r e l e v a n t to t h i s question were obtained from the z i n c loading s t u d i e s c a r r i e d out i n our l a b o r a t o r y i n p a t i e n t s w i t h subacute z i n c d e f i c i e n c y (68,j>9). I f t h e i r o r a l z i n c load increased 10 f o l d the z i n c f r a c t i o n absorbed decreased by a f a c t o r of 5 (from 43% to 9%) w i t h a b s o r p t i o n i n c r e a s i n g by a f r a c t i o n of two (from 4.5 g/d to 10.6 g/d). P r e s e n t l y , data from normal v o l u n t e e r s are being analyzed under the same c o n d i t i o n s so that a d i r e c t comparison can be made. Data obtained by the use of the model allows f u r t h e r i n s i g h t i n t o t h i s problem. Ninety percent of t o t a l body z i n c i n norma l v o l u n t e e r s and i n p a t i e n t s w i t h t a s t e and smell d y s f u n c t i o n are found i n one l a r g e compartment ( C 3 ) which represents, p r i m a r i l y , z i n c i n muscle and p a r t l y z i n c i n bone (60,_69). I t i s the l a r g e s t body pool of z i n c . The r a t e constants i n t o and out of t h i s compartment from the r a p i d l y exchanging body z i n c pool ( ( ^ 5 ) which i n c l u d e s plasma a r e both v e r y slow. These r e s u l t s suggest that the z i n c content i n t h i s compartment and the r a t e constants i n t o and out of t h i s compartment are the c o n t r o l l i n g f a c t o r s not only i n z i n c absorption but a l s o i n other aspects of z i n c metabolism i n humans. Thus, some of the confusion about z i n c absorption may be r e l a t e d , i n p a r t , t o d i f f e r e n c e s i n steady s t a t e z i n c content as w e l l as the r a t e s of z i n c accumulation and l o s s i n t h i s p o o l . These concepts emphasize the need to consider s e v e r a l f a c t o r s p r i o r t o e s t a b l i s h i n g a d i a g n o s i s of z i n c d e f i c i e n c y . Not only i s i t necessary to know z i n c absorption through the g a s t r o i n t e s t i n a l t r a c t but a l s o the type of z i n c binding l i g a n d s i n the gast r o i n t e s t i n a l t r a c t needed t o transport z i n c across the gut muc o s a l s u r f a c e , the presence of appropriate z i n c binding p r o t e i n s and the presence of t i s s u e s p e c i f i c z i n c storage p r o t e i n s t o note j u s t a few. D i f f e r e n c e s between g a s t r o i n t e s t i n a l absorption of i r o n and z i n c i n humans and l o c a l gut f a c t o r s which may i n f l u e n c e the absorption of these metals were r e c e n t l y discussed (Matseke, J.W., P h i l l i p s , S. F., Malagelada, J . R. and M c C a l l , J . T. Recovery of d i e t a r y i r o n and z i n c from the proximal i n t e s t i n e of healthy man: Studies of d i f f e r e n t meals and supplements. Amer. J . C l i n . Nutr. 33:1946-1953, 1980) and emphasize the importance of d i e t a r y f a c t o r s which can i n f l u e n c e human z i n c absorption. Only w i t h an understanding of these and other f a c t o r s can z i n c d e f i c i e n c y be defined c l e a r l y . P r e s e n t l y , such an awareness i s f a r from complete. 4. Does treatment w i t h z i n c c o r r e c t the t a s t e and smell dysf u n c t i o n observed i n p a t i e n t s w i t h subacute z i n c d e f i c i e n c y ? This


6.

HENKIN

AND

AAMODT


question can be answered only p r o v i d i n g that s p e c i f i c requirements and c r i t e r i a are met. F i r s t , prolonged d a i l y treatment f o r 2-4 months w i t h high doses of z i n c (100 mg of z i n c ion) i s u s u a l l y r e quired p r i o r to r e v e r s a l of these symptoms. An explanation f o r t h i s prolonged time period may r e l a t e to the hypothesis that compartment C must be saturated w i t h z i n c before the symptoms remit i n s p i t e of the l a b i l i t y and small s i z e of the z i n c pools subserving the t a s t e and smell systems. Thus, as i n an o l d c l i n i c a l saw, those systems which l o s e f u n c t i o n f i r s t may a l s o be those which r e g a i n f u n c t i o n l a s t when appropriate treatment i s g i v e n . These hypotheses are based, as noted p r e v i o u s l y , upon the slow r a t e of uptake and r e l e a s e of z i n c from t h i s major body z i n c p o o l . Second, these r e s u l t s must take i n t o c o n s i d e r a t i o n the negative r e s u l t s of the double b l i n d study we published i n 1976 (63). In t h i s study placebo was as e f f e c t i v e as z i n c i n r e s t o r i n g t a s t e and smell to normal p a t i e n t s w i t h t a s t e and smell d y s f u n c t i o n . The important c o n s i d e r a t i o n here i s that recent s t u d i e s i n d i c a t e that no more than 25% of p a t i e n t s w i t h t a s t e and smell d y s f u n c t i o n would be expected to e x h i b i t z i n c d e f i c i e n c y (3,60) and that a l l placebo responders analyzed i n a subsequent study (3,60) were found i n the group of p a t i e n t s who were z i n c s u f f i c i e n t . Thus, the p r i o r double b l i n d study e x h i b i t e d a s e r i o u s f l a w i n that our knowledge of body z i n c s t a t u s was s e v e r e l y l i m i t e d both before and during the study. This l a c k of knowledge, forced the i n c l u s i o n i n t o the study of many p a t i e n t s who were not z i n c d e f i c i e n t and who would not be expected to be z i n c responsive. The reasons f o r t h e i r r e sponsiveness to placebo i s s t i l l unclear (3,j>0,j>3) although seve r a l hypotheses have been advanced to e x p l a i n t h i s r e s u l t (3 ,60). T h i r d , a subsequent s i n g l e b l i n d study was c a r r i e d out i n pat i e n t s w i t h proven subacute z i n c d e f i c i e n c y (3,j60) and p o s i t i v e r e s u l t s w i t h z i n c treatment i n c o r r e c t i n g the t a s t e and smell d y s f u n c t i o n were obtained. In t h i s study i f only p a t i e n t s who were r e l a t i v e l y low absorbers of Z n ( i . e . , z i n c absorption more than 2SD below the mean l e v e l of absorption of normal v o l unteers) were evaluated then i n i t i a l treatment w i t h placebo was shown to be e f f e c t i v e i n c o r r e c t i n g t h e i r symptoms; subsequent treatment w i t h placebo produced a r e t u r n to or toward f u n c t i o n a l l o s s of t a s t e and smell a c u i t y . As a c l i n i c a l technique to obt a i n some u s e f u l estimate of body z i n c s t a t u s s a l i v a z i n c concent r a t i o n appeared h e l p f u l and, when t h i s index was used as a measurement of treatment success or f a i l u r e there was a s i g n i f i c a n t p o s i t i v e c o r r e l a t i o n both i n the previous souble b l i n d study (63) as w e l l as i n the present s i n g l e b l i n d study (3*60). These r e s u l t s i n d i c a t e that u n t i l there was c o r r e c t i o n of s a l i v a z i n c concentration to normal there was no a s s o c i a t e d c o r r e c t i o n of the hypogeusia (3,_60,_63). I f no changes i n s a l i v a z i n c occurred there was no measurable improvement i n t a s t e a c u i t y . These s t u d i e s were f u r t h e r supported by s t u d i e s of g u s t i n i n d u c t i o n i n p a t i e n t s w i t h hypogeusia and subacute z i n c d e f i c i e n c y (60). Treatment w i t h z i n c i n these p a t i e n t s not only returned t a s t e f u n c t i o n to normal but 3


99

6 5



100

NUTRITIONAL

BIOAVAILABILITY

OF

ZINC

a l s o corrected the low l e v e l of s a l i v a r y g u s t i n to normal (70). Although these analyses provide u s e f u l data and important hypotheses d e f i n i t i v e acceptance of z i n c treatment f o r these symptoms cannot be obtained u n t i l a double b l i n d c l i n i c a l t r i a l i s c a r r i e d out using these techniques and hypotheses. We have attempted to mount such a study but have faced repeated d i f f i c u l t i e s i n i t s performance. From the z i n c model i t was p o s s i b l e to compare the t i s s u e concentrations of z i n c i n the p a t i e n t s w i t h normals. R e s u l t s i n d i c a t e d that p a t i e n t s e x h i b i t e d s i g n i f i c a n t l y lower l e v e l s of z i n c than normals i n e r y t h r o c y t e s , l i v e r and muscle, whereas z i n c conc o n c e n t r a t i o n i n t h e i r g a s t r o i n t e s t i n a l t r a c t was elevated above normal (Table V). These r e s u l t s emphasize again the n e c e s s i t y to o b t a i n measurements of body z i n c s t a t u s p r i o r to the d e f i n i t i o n of z i n c d e f i c i e n c y . From the z i n c model i t was a l s o p o s s i b l e t o determine those f a c t o r s which were both necessary and s u f f i c i e n t to d e f i n e subacute z i n c d e f i c i e n c y . These included the r a t e constant of z i n c absorption, the r a t e constant of z i n c exchange from 5 and C 3 i n the t h i g h (3,60). From these data i t was p o s s i b l e t o r e l a t e the d i f f e r e n c e s between the p a t i e n t s and normals to two major f a c t o r s , d i f f e r e n c e s i n (decreased) g a s t r o i n t e s t i n a l Z n absorption and decreased t r a n s f e r of Z n i n t o C 3 (Table V I ) . These r e s u l t s a l s o suggest two p o s s i b l e mechanisms f o r the z i n c impairment observed i n subacute z i n c d e f i c i e n c y . These a r e : 1. Down r e g u l a t i o n of z i n c c a r r i e r molecules i n which p a t i e n t s adapt to l e s s Zn i n c r i t i c a l body pools; and/or 2. An increase i n the e f f e c t i v e Michaelis-Menten constant. With our present knowledge i t i s not p o s s i b l e to choose between these two hypotheses. 6 5

6 5

Summary and Conclusions These s t u d i e s o f f e r a r e f o r m u l a t i o n of our present knowledge of z i n c d e f i c i e n c y i n a t r a d i t i o n a l , c l i n i c a l manner. This reformul a t i o n i s s i m i l a r to that used by most other i n v e s t i g a t o r s d e a l ing w i t h other c l i n i c a l problems. This r e f o r m u l a t i o n or r e d e f i n i t i o n on the b a s i s of acute, chronic and subacute z i n c d e f i c i e n c y , has allowed f o r the c l a s s i f i c a t i o n of z i n c d e f i c i e n c y syndromes w i t h respect to e t i o l o g y , i n c i d e n c e , onset, symptomatology and d i a g n o s t i c procedures. This r e f o r m u l a t i o n has a l s o allowed f o r the development of hypotheses by which t o t e s t the usefulness of the d e f i n i t i o n s and t o d e s c r i b e the c h a r a c t e r i s t i c s which d e f i n e each of the subcategories. I t i s c l e a r that subacute z i n c d e f i c i e n c y represents the most common form of z i n c d e f i c i e n c y encountered i n the U.S. and that both i t s d i a g n o s i s and e f f e c t i v e treatment are the most d i f f i c u l t of a l l the d e f i c i e n c y syndromes. The estimate of four m i l l i o n people i n the U.S. w i t h t h i s d i s o r d e r suggests that i t occurs much more f r e q u e n t l y than p r e v i o u s l y considered.



6.

HENKIN

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AAMODT

101


TABLE V COMPARISON OF Zn CONCENTRATIONS IN VARIOUS TISSUES IN NORMAL VOLUNTEERS AND IN PATIENTS WITH SUBACUTE Zn DEFIENCY

TISSUE CONCENTRATION (mg)

NORMALS

Plasma

.032

PATIENTS

±

.001

.039

±

.002

GI Tract M

2 4

.0051 ±

.002

.0062 ±

.003*

M

25

.35

±

.10

.32

±

.09

.96

±

.06

.54

±

.05*

.98

±

.06

.56

±

.05*

2.0

±

.3

1.3

±

.2*

5.3

±

.3

3.5

±

.5*

Erythrocytes M

6

RBC Mass L i v e r Region M

2 2

L i v e r Mass Thigh Region M 3 Thigh Mass M

3

32 3.8

± 3 ±

15 .5

2.7

± 2* ±

.3

M i s defined as the mass i n mg of z i n c i n compartment C i


102

NUTRITIONAL

BIOAVAILABILITY

OF

ZINC

TABLE V I


TWO FACTORS ARE NECESSARY AND SUFFICIENT TO DISTINGUISH NORMAL VOLUNTEERS FROM PATIENTS WITH SUBACUTE ZINC DEFICIENCY

1.

GASTROINTESTINAL Zn-65 ABSORPTION

v

V

a V .

+

V

r

K

G

I

max

GI

max ( V .

+

χ

Va,

r a t e of Zn

v

r a t e of Zn i n g e s t i o n

i>

v.

+

V

r

)

absorption

r a t e of Zn r e c y c l i n g s e c r e t i o n from plasma i n t o intestine

r

w x

2.

ι

v

V , max

maximum r a t e of Zn absorption

GI V , max'

e f f e c t i v e Michaelis-Menten e q u i l i b r i u m constant

r

TRANSFER OF Zn-65 INTO C

3

L (3,15) F r a c t i o n of C^ i n t h i g h Data are presented d e a l i n g w i t h a z i n c model by which t o t a l body z i n c mass and other parameters of z i n c metabolism can be measured q u a n t i t a t i v e l y such that p a t i e n t s w i t h subacute z i n c de f i c i e n c y can be d i f f e r e n t i a t e d from normals by a s e r i e s of l a b o r a t o r y t e s t s , a l b e i t cumbersome and expensive. The major symptom complex of subacute z i n c d e f i c i e n c y i s r e l a t e d to t a s t e and smell d y s f u n c t i o n and these symptoms are discussed r e l a t i v e t o the body d i s t r i b u t i o n of z i n c and the dysfunctions of z i n c d e f i c i e n c y . Pos s i b l e mechanisms by which z i n c c o r r e c t s the d e f i c i e n c y a r e d i s cussed. These r e s u l t s present a new approach t o the diagnosis and treatment of z i n c d e f i c i e n c y and help t o e x p l a i n the manner by which these syndromes occur, can be diagnosed and t r e a t e d .

Literature Cited 1. 2. 3.

Sandstead, H.H. Amer. J . Clin. Nutr. 1973, 26, 1251-60. Henkin, R. I. New Eng. J . Med. 1974, 291, 675-6. Henkin, R. I.; Aamodt, R. L . ; Foster, D.M. "The Clinical,


6.

4.


5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

HENKIN

AND AAMODT


103

Biochemical and Nutritional Aspects of Trace Elements"; Alan R. Liss, Inc., New York, NY, 1982 (In Press) Henkin, R. I.; Apgar, J.; Cole, J . F.; Coleman, J . E.; Cotterill, C. H.; Fleisher, M.; Goyer, R. Α.; Greifer, B.; Knezek, B. D.; Mushak, P.; Piscator, M.; Stillings, B. R.; Taylor, J. K.; Wolfe, D. A. "Zinc"; University Park Press, Baltimore, MD, 1979; p 123-72. Finch, C. "Iron"; University Park Press, Baltimore, MD, 1979; p 79-106. Henkin, R. I.; Patten, Β. M.; Re, P.; Bronzert, D.A. ARch. Neurol. 1975, 32, 745-51. Van R i j , Α.; McKenzie, J.M. "Trace Elements in Man and Ani mals III"; Arbeitskresi fur Tierernahrungsforschung, Weihenstephan, Freising-Weihenstephan, West Germany, 1978; p 288-91. Lowry, S. F.; Goodgame, Jr., J.T.; Smith, Jr., J.C.; Maher, M.M.; Makuch, R.W.; Henkin, R.I.; Brennan, M. F. Ann. Surg. 1979, 189, 120-8. Arakawa, Τ.; Tamura, T.; Igaraski, Y. Amer. J . Clin. Nutr. 1976, 29, 197. Fleming, C. R.; Hodges, R.E.; Hurley, L. S. Amer. J . Clin. Nutr. 1976, 29, 70. Hankins, D. Α.; Riella, M. D.; Scribner, Β. H.; Bragg, A. L. Surg. 1976, 79, 674. Kay, R. G.; Tosman-Jones, C.; Pylos, J . Ann. Surg. 1976, 183, 331. Henkin, R. I. Ann. N.Y. Acad. Sci. 1977, 300, 321-34. Chesters, J.K.; Quarterman, J . Brit. J . Nutr. 1973, 30, 553-66. McConnell, S. D.; Henkin, R.I. J . Nutr. 1974, 104, 1108-14. Donaldson, J.; St. Pierre, T.; Minnich, J . L . ; Burberi, A. Can. J. Biochem. 1973, 51, 87-92. Crawford, I. L . ; Connor, J . D. J . Neurochem. 1972, 19, 1451-8. Sivasubramanian, Κ. N.; Henkin, R. I. J . Ped. 1978, 93, 847-51. Hambidge, K.M. "Trace Element Metabolism in Animals II"; University Park Press, Baltimore, MD, 1973, p 171-183. Snita, S.; Ikedu, K.; Magusak, Α.; Hayosheda, Y. J . Pediatr. Surg. 1978, 13, 5. Prasad, A. S. "The Clinical, Biochemical and Nutritional As pects of Trace Elements"; Alan R. Liss, Inc., New York, NY, 1982 (In Press) Prasad, A. S.; Mulsted, J . Α.; Nadimi, M. Amer. J . Med. 1961, 31, 532. Prasad, A. S.; Miale, Jr.; Α.; Farid, Z.; Sandstead, H.H.; Schulert, A.R. J. Lab. Clin. Med. 1963, 61, 537. Hambidge, K.M.; Hambidge, C.; Jacobs, M.; Baum, J.D. Pediatr. Res. 1972, 6, 868-74. Hambidge, K.M.; Walravens, P. A. "Trace Elements in Human Health and Disease, I"; Academic Press, New York, NY, 1976, p 21-32. Danbolt, N.; Closs, K. Arch. Derm. Venereal. 1942, 23, 127-69. Moynahan, E. J . Lancet 1974, 21, 399-400.


104

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BIOAVAILABILITY OF


28. 29. 30. 31.

ZINC

Moynahan, E. J. and Barnes, P. W. Lancet 1974, 21, 399-400. Entwisle, B.G. Austral. J. Derm. 1965, 8, 13-21. Sunderman, Jr., F. W. Ann. Clin. Lab. Sci. 1975, 5, 132-45. Oberleas, D.; Muhrer, M. E.; O'Dell, B. L. "Zinc Metabolism"; C. C. Thomas, Springfield, IL, 1966, 32. Kelsey, J. This volume 33. Reinhold, J. G., Parsa, Α., Karimian, N . , Hammick, J. W.; J. Nutr. 1974, 104, 976-982. 34. Aamodt, R. L . ; Rumble, W.F.; Johnston, G. S.; Markley, E.S.; Volpe, T.; Henkin, R. I. Fed. Proc. 1980, 39, 651. 35. Hambidge, Κ. M.; Silverman, A. Arch. D i s . Child. 1973, 48, 567-568. 36. Hurley, L. S.; Lunnerdal, D. B. Nutr. Rev. 1980, 38, 295. 37. Hurley, L. S.; Lunnerdal, D. B. Ped. Res. 1981, 15, 166-7. 38. Evans, G. W. Nutr. Rev. 1980, 38, 137-41. 39. Evans, G. W.; Johnson, E. C. J. Nutr. 1980, 110, 1076-80. 40. Mansouri, K. J.; Halsted, Α.; Gumbos, E. A. Arch. Intern. Med. 1970, 125, 88-93. 41. Lindeman, R. D.; Baxter, D. J.; Yunice, Α. Α.; Kims, R. W., Jr.; Kraikit, S. Prog. Clin. Biol. Res. 1977, 14, 193-209. 42. Sandstead, H. H. Amer. J. Clin. Nutr. 1980, 33, 1509-1516. 43. Mahajan, S. K.; Prasad, A. S.; Rabbani, P.; Briggs, W. Α.; McDonald, F. D. J. Lab. Clin. Med. 1979, 693-698. 44. Bogden, J. D.; Oleske, J. M.; Weiner, B.; Smith, L. C., Jr.; Smith, L. C.; Majem, G. R. Amer. J. Clin. Nutr. 1980, 33, 1088-95. 45. Hansen, J. D. L . ; Lehmann. S. Afr. Med. J. 1969, 43, 1248-51. 46. Sandstead, H. H.; Shukry, A. S.; Prasad, A. S.; Gabr, M. K.; El Hifney, Α.; Mokhtar, N.; Darby, W. J. Amer. J. Clin. Nutr. 1965, 17, 15-26. 47. Kopito, I.; Schwachman, H. "The First Human Hair Symposium"; Medcom Press, New York, NY, 1974, p 83-90. 48. Spencer, H.; Samachson, J."Trace Element Metabolism in Animals"; Edinburgh, Scotland, 1970, p 312-14. 49. Henkin, R. I.; Aamodt, R. L . ; Babcock, A. K.; Agarwal, R. P.; Shatzman, A. R. "Perception of Behavioral Chemicals"; E l sevier/North Holland Biomedical Press, Amsterdam, The Nether lands, 1981, p 227-65. 50. Mahajan, S. K.; Prasad, A. S.; Briggs, W.A.; McDonald, F. D. Trans. Amer. Soc. Artif. Intern. Org. 1980, 26, 133-138. 51. Antonion, L. D.; Shalbomb, R. J.; Schechter, G. P. Amer. J. Clin. Nutr. 1981, 34, 1912-17. 52. Lombeck, I.; Schnippering, H. G.; Ritzl, F.; Feinendegen, L. E.; Bremer, H. J. Lancet 1975, 1, 855. 53. Lombeck, I.; Schnippering, H. G.; Kasperek, K.; Ritzl, F.; Kostner, H.; Feinendegen, L. E.; Bremer, H. J. Zeit. Kinderheilk. 1975, 120, 181-9. 54. Henkin, R. I.; Aamodt, R. L. Lancet 1975, 1, 1379-80. 55. Aamodt, R. L . ; Rumble, W. F.; Johnston, G. S.; Henkin, R. I. Amer. J. Clin. Nutr. 1981, 34, 2648-52.



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56. Nelder, Κ. H.; Hambidge, K.M. New Engl. J. Med. 1975, 292, 2648-52. 57. Dillaha, C . J . ; Lorincz, A. L; Aavick, O. R. J. Amer. Med. Assoc. 1953, 152, 509-12. 58. Prasad, A. S.; Miale, Α., Jr.; Farid, Z.; Sanstead, H.H.; Schulert, A. R.; Darby, W. J. Arch. Int. Med. 1963, 111, 40728. 59. Henkin, R. I. Olfactory Rev. 1981. 60. Henkin, R. I. "Looseleaf Series of Otolaryngology"; Harper and Row, New York, NY, 1982, p. 1-39. 61. Kosman, D. J.; Henkin, R. I. Amer. J. Clin. Nutr. 1981, 34, 118-19. 62. Henkin, R. I . , Schechter, P. J.; Raff, M.S.; Bronzert, D.A.; Friedewald, W. T. "Clinical Applications of Zinc Metabolism" C. C. Thomas, Springfield, IL, 1974, p 204-28. 63. Mallette, L. E.; Henkin, R. I. Amer. J. Med. Sci. 1976, 272, 164-74. 64. Henkin, R. I.; Mueller, C.; Wolfe, R. J. Lab. Clin. Med. 1975, 86, 175-80. 65. Henkin, R. I . ; Lippoldt, R. E.; Bilstad J.; Edelhoch, H. Proc. Nat. Acad. Sci. 1975, 72, 488-92. 66. Aamodt, R. L . ; Rumble, W. F.; Johnston, G. W.; Foster, D.; Henkin, R. I. Amer. J. Clin. Nutr. 1979, 32, 559-69. 67. Foster, D. M.; Aamodt, R. L . ; Henkin, R. I . ; Berman, M. Amer. J. Phyisol., 1979, 237, R340-R349. 68. Aamodt, R. L . ; Rumble, W. F.; Babcock, A. K.; Foster, D. M.; Henkin, R. I. Metabolism, 1982, 31, 326-34. 69. Babcock, A. K.; Henkin, R. I . ; Aamodt, R. L.; Foster, D. M.; Berman, M. Metabolism 1982, 31, 335-47. 70. Shatzman, A. R.; Henkin, R. I. Proc. Nat. Acad. Sci. 1981, 78, 3867-71. RECEIVED

October 13, 1982


A Redefinition of Zinc Deficiency - ACS Symposium Series (ACS

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