National Institutes of Health, Bethesda, MD 20205 Based upon clinica
deficiency using traditional
niques into three syndromes; these are acute, chronic and subacute zinc deficiency. Acute zinc deficiency i s relatively uncommon and follows parenteral hyperalimen- tation or oral L-histidine administration. Chronic zinc deficiency i s 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 usu- ally requires months before these symptoms return to normal. Diagnosis of these disorders was most effica- cious following oral administration of Zn
65with subse- quent evaluation of the kinetics of transfer of the iso- tope 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.
Zinc deficiency i s reflected in clinical syndromes which af-
fect men and women of a l l ages and a l l socioeconomic and cultural
classes in the U.S. It i s neither prevalent in any specific area
of the U.S. nor i s i t associated with any specific or definitive
biochemical marker, which can make i t s identification difficult
and at times frustrating and confusing. Its presence is manifested
by a wide spectrum of symptoms, from acute, life threatening prob-
lems to mild subclinical or marginal disorders which may only vag-
uely disturb the well being of people who suffer with these com-
plaints. The acute problems are often seen in profoundly i l l pa-
tients treated in hospital whereas marginal or subclinical prob-
lems may be so vague that patients seek assistance outside tra-
ditional medical practice from practitioners employing hypnosis,
chiropody or a l l encompassing nutritional therapies.
84 NUTRITIONAL BIOAVAILABILITY OF ZINC
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 p r o t e a n s e t o f d i s o r d e r s whose p r e v a l e n c e 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 b i o c h e m i c a l markers o r c l i n i c a l s e t p o i n t s by which t o 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 p r o c e s s e s . 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 f a c e 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 h e l p 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 r e c o g n i z e d as a common problem i n t h e 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 p r e s e n t s l i t t l e d i f - f i c u l t y s i n c e 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 t h e use of simple and common- l 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 r e d blood c e l l smear o r 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 m i s l e a d i n g (e.g., f a t i g u e
c e n t r a t e f o r prolonged p e r i o d s
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 o f 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 c u r r e n t standards of p r a c t i c e of c l i n i c a l m e d i c i n e . A d m i n i s t r a t i o n of exogenous i r o n i s com- monly 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 t h e 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 t h e a s s o c i a t e d symptoms.
Such i s not t h e 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 , t h e r e 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 t h e c o n d i t i o n . Z i n c c o n c e n t r a t i o n s i n b l o o d , u r i n e o r h a i r commonly do n o t 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)· A l t h o u g h 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 t h e 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 w i d e l y d i s t r i b u t e d i n t h e 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 a d - d 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 p r o - longed a d m i n i s t r a t i o n o f l a r g e amounts of the m e t a l 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 y e a r s , and t h e i r p r e v a l a n c e noted i n d i v e r s e groups of people world wide, o n l y r e c e n t l y have any i d e n t i f i a b l e p a t t e r n s of some of these syndromes been f o r m u l a t e d and t h e 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 b o t h i n c h i l d r e n and a d u l t s of b o t h 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 u n d e r s t a n d i n g of these processes.
L a b o r a t o r y t e s t s used t o d e f i n e these syndromes a l s o may be c o n f u s i n g o r 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 , o r e l e v a t e d , as much as 3-10
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
f o l d normal. Serum, plasma and e r y t h r o c y t e z i n c c o n c e n t r a t i o n s 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. Z i n c treatment has not always p r o v i d e d a u s e - f u l method f o r a s s e s s i n g 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 p r o v i d e d body z i n c was r e s t o r e d t o 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 o t h e r a s -
p e c t s of z i n c metabolism a r e 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 b l o o d . 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.
I n an attempt t o f o r m u l a t e our present knowledge about these d i s o r d e r s i t seemed u s e f u l t o d e f i n e some of the c l i n i c a l and b i o - c h e m i c a l markers which
may be n e i t h e r s p e c i f i
tempted t o r e - e v a l u a t e z i n c d e f i c i e n c y i n i t s broadest sense and to o r g a n i z e 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 u s i n g t r a - d i t i o n a l , c l i n i c a l t e c h n i q u e s . I n so doing our hope i s t o 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 Z i n c D e f i c i e n c y Syndromes
Acute Z i n c 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. T h i s 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 h y p e r a l i m e n t a t i o n (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 c o n c e n t r a t i o n s of g l u c o s e 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 v i e w i n g 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 r a s h u n r e s p o n s i v e t o a n t i b i o t i c or a n t i f u n g a l therapy which d i s a p p e a r s 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 p a r a n y c h i a , d i a r - r h e a , 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 c u t s and s c r a t c h e s but these a d d i t i o n a l symptoms may not be p r e s e n t .
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 s i g n s and symptoms a s s o c i a t e d w i t h the r a p i d and p r o - g 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 a n o r e x i a (6,JL3), a symptom a l s o seen e a r l y i n e x p e r i m e n t a l 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) · A n o r e x i a i s commonly f o l l o w e d by t a s t e and s m e l l d y s f u n c t i o n , then hypogeusia and hy- posmia ( 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 ) , f o l l o w e d by dysosmia and d y s g e u s i a .
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
NUTRITIONAL BIOAVAILABILITY OF ZINC
TABLE I
ACUTE ZINC DEFICIENCY
ETIOLOGY:
ONSET:
INCIDENCE:
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 H y p e r a l i m e n t a t i o n 3-14 days
I n f r e q u e n t
SYMPTOM APPEARANCE A n o r e x i a
Hypogeusia Hyposmia Dysgeusia Dysosmia
M e n t a l C o n f u s i o n C e r e b e l l a r D y s f u n c t i o n A t a x i a
Rash
B u c c a l L e s i o n s
Acute T o x i c P s y c h o s i s
ZINC CHANGES + U r i n a r y Zn
Ψ Serum Zn
Ψ Zn-65 R e t e n t i o n
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
z i n c e x c r e t e d 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 o c c u r s l a t e r but i t i s s m a l l i n r e l a t i o n t o 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 n6 5
t o 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 de- creased r e t e n t i o n (13) of the i s o t o p e 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 s m e l l d y s f u n c t i o n i f l o s s e s c o n t i n u e a t s i g n i f i c a n t l e v e l s f o r p e r i o d s of 14 days or more. These symptoms i n c l u d e mental c o n f u s i o n , 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 , buc- c 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 p s y c h o s i s ( 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 t o 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 h i g h z i n c content i n the l i m b i c system of the b r a i n (16 ,JL7) demonstratin t h a z i n
the blood b r a i n b a r r i e
g r a d i e n t , and t h a t i t ca be r e a d i l y m o b i l i z e d fro b r a i 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 o r 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 a s p e c t s 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 s i g n s 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 ) . C e s s a t i o n of L - h i s t i d i n e a d m i n i s - t 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 symp- tom 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 t o 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 t h a t the s i g n s 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 .
I n i n f a n t s , commonly neonates g i v e n p a r e n t e r a l h y p e r a l i m e n - t a t i o n , the erythrematous, i n t r a c r u r a l r a s h , p a r a n y c h i a and o c c a - s 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 s i g n s 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 c o n s o l e 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 , y e t most d i f f i c u l t t o e v a l u a t e , 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 n e g a t i v e and t h e r e 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 p r o v i d e the s i m p l e s t 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 z i n c a d m i n i s t r a t i o n i s u s u a l l y a s s o c i a t e d w i t h a r a p i d r e m i s s i o n of these symptoms a l t h o u g h 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 c o n s i s t e n c y t h a t 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 p r o t e a n nature of the symptoms which com- p 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
88 NUTRITIONAL BIOAVAILABILITY OF ZINC 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 o r a d u l t s can, as n o t e d , be c o n f u s i n g and m i s t a k e n 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 Z i n c 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 experimen- t 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 o r 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 n o t e a t 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 s m a l l s t a t u r e ( o f t i m e s below the 5 t h p e r c e n t i l e f o r h e i g h t and weight) and poor s c h o o l 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 e n t e r o p a t h i c a ) } o r a c - q u i r e d (28-30) forms of t h i s d i s o r d e r , which occur i n some p a - t 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 n e o n a t a l o r p e r i n a t a l p e r i o
was f i r s t r e p o r t e d i n I r a
h i b i t e d s h o r t 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 t o b i n d i n g e s t e d z i n c p r e f - e r e n t i a l l y , making the m e t a l l e s s a v a i l a b l e f o r a b s o r p t i o n 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). P h y t a t e (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 t h a t c o u l d b i n d z i n c l e a v i n g i t r e l a t i v e l y u n a v a i l a b l e 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 p a r a - s i t e s , may have been r e s p o n s i b l e f o r some a s p e c t s of the anemia and hepatosplenomegaly r e p o r t e d i n the I r a n i a n and E g y p t i a 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 (22,23). Some i n v e s t i g a t o r s have con- s 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 a b s o r b a b l e z i n c l i g a n d s i n human m i l k than t h a t 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 e n t e r o p a t h i c a i n i n f a n t s , the symptom complex becoming apparent o n l y 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 o b s e r v a t i o n s have spawned c o n s i d e r a b l e c o n t r o v e r s y between proponents of c i t r a t e (36,37) o r 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 t h e onset of t h i s d i s o r d e r . I n c h i l d r e n , a n o r e x i a , d i a r r h e a , i r - r i t a b i l i t y and s h o r t 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 - i n g may appear as e a r l y s i g n s . A l t h o u g h t a s t e and s m e l l d y s - f u n c t i o n a r e common components of t h i s syndrome they may be o v e r - shadowed by the more a c u t e 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 c o n c e n t r a t i o n s i n t h i s syndrome. P a - t i e n t s w i t h c h r o n i c r e n a l d i s e a s e , w i t h c l i n i c a l s i g n s and symp- toms 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 e l e v a t e d r e d blood c e l l z i n c l e v e l s (40-42) whereas plasma z i n c c o n c e n t r a t i o n s have been r e p o r t e d as e i t h e r low, normal or e l e v a t e d (40-^4)· P a - t 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
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
TABLE I I
CHRONIC ZINC DEFICIENCY
ETIOLOGY: D i e t a r y Lack
A b s o r p t i o n I n h i b i t i o n Abnormal Zn Ligand Chroni l F a i l u r Cance
ONSET: Months, Years
INCIDENCE: Moderate (10% of growth r e t a r d e d c h i l d r e n , 5 t h c e n t i l e )
SYMPTOM APPEARANCE ZINC CHANGES
C h i l d r e n
Short S t a t u r e Ψ H a i r Zn
Hypogeusia Serum Zn
P i c a Ψ S a l i v a r y Zn
Hyposmia U r i n a r y Zn
P a r a n y c h i a RBC Zn
Rash + Zn-65 A b s o r p t i o n
D i a r r h e a A d u l t s
Hypogeusia Ψ H a i r Zn
Hyposmia Ψ Serum Zn
Hypogonadism U r i n a r y Zn
Short S t a t u r e RBC Zn
D i a r r h e a Ψ Zn Enzymes
Poor Wound H e a l i n g Serum T, LH
90 NUTRITIONAL BIOAVAILABILITY OF ZINC
serum z i n c l e v e l s t h a t 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 e l e v a t e d 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 h i g h e r than norm- a l i f the a n o r e x i a 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 t o the e f f e c t s of c h r o n i c weight l o s s ( 4 8 ) . I n s e v e r a l d i s - o r d e r s of c h r o n i c 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 v a l u e
(1-3,49). Some z i n c enzymes, plasma t e s t o s t e r o n e o r 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 ( 5 0 ) . C e l l u l a r immunity may a l s o be i m p a i r e d i n p a t i e n t s w i t h c h r o n i c uremia ( 5 1 ) . S t u d i e s of o r a l a b s o r p t i o n of Z n6 5 i n 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 have produced r e s u l t s c o n s i s - t e n t w i t h i m p a i r e d 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 t o be lower tha l (53) However Z n6 5 a b s o r p t i o i n these p a t i e n t s o v e r l a p
range, a phenomenon whic y y emphasize (54,
55).
The c l i n i c a l d i a g n o s i s of c h r o n i c 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 d e p l e t e d 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 p r o t e a n n a t u r e can c o m p l i c a t e 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 c o n s i d e r 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 suc- c 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 s m a l l amount of z i n c i s necessary t o r e s t o r e normal f u n c t i o n i n 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 , o f t e n o n l y 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 ( 5 6 ) . Diodoquin, a drug which appears t o a s s i s t z i n c absorp- t 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). I n some p a t i e n t s , l a r g e r amounts of z i n c g i v e n f o r prolonged p e r i o d s of time a r e necessary to produce symptom r e m i s s i o n . I n the o n l y double b l i n d study p e r - formed 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 c o n f u s i n g 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 Z i n c D e f i e n c y Subacute z i n c d e f i c i e n c y i s the ma- j 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, e s t i m a t e s suggest t h a t 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 t o a v a r i e t y of d i s o r d e r s which do n o t , a t f i r s t g l a n c e , appear to have any s p e c i f i c r e l a t i o n s h i p t o a m e t a b o l i c d i s e a s e p r o c e s s {(Table I I I ) (60)}. Indeed, the mechanisms by which a v i r a l i l l - n e s s , 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. I n a d d i t i o n , to c o m p l i c a t e 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
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
TABLE I I I SUBACUT
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:
INCIDENCE:
Days, Weeks, Months 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 A b s o r p t i o n Ψ T o t a l Body Zn
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 p r o t e a n as those of the acute or c h r o n i c z i n c d e f i c i e n c y syndromes and p r o v i d e no s p e c i a l d i a g n o s t i c c l u e s t o the e t i o l o g y of these problems. However, the most o b v i o u s symptoms a s s o c i a t e d 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 s m e l l d y s - f u n c t i o n , hypogeusia, hyposmia, d y s g e u s i a and dysosmia (60).
These are the major, and o f t i m e s the o n l y , symptoms a s s o c i a t e d w i t h t h i s d i s o r d e r . A l t h o u g h acute and c h r o n i c 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 s m e l l d y s f u n c - t i o n they a l s o have o t h e r , more e a s i l y r e c o g n i z e d d y s f u n c t i o n s 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 o t h e r 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 o n l y subacute z i n c d e f i c i e n c y can p r e s e n t w i t h t a s t e and s m e l l d y s f u n c t i o n as the major or o n l y set of c l i n i c a
t i o n .
Thus, subacute z i n c d e f i c i e n c y may r e p r e s e n t one of the most d i f f i c u l t d i a g n o s t i c c h a l l e n g e s of a l l z i n c d e f i c i e n c y s y n - dromes. A l t h o u g h serum and e r y t h r o c y t e z i n c c o n c e n t r a t i o n s 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 ( 6 1 ) , 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 ex- c r e t i o n may be normal, e l e v a t e d 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 a b s o r p t i o n 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 Z n ^5 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 a d m i n i s t e r e d 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 concen- t 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, a t f i r s t g l a n c e , appear to be q u e s t i o n a b l e .
T h i s 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 s i m u l t a n e o u s l y . Thus, measurements of impaired z i n c a b s o r p t i o n (3t49t6»0) and lower than normal c o n c e n t r a t i o n s 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) c o n f i r m 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 d e r i v e d from s t u d i e s of compartmental a n a l y s e s of the k i n e t i c d a t a obtained from these pa- t i e n t s f o l l o w i n g o r a l Z n6 5 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 a r e a s over the l i v e r and t h i g h , i n red b l o o d 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 d a t a by means of a mathematical model i n which a l l of these d a t a c o u l d be c o n s t r a i n e d and f i t t e d s i m u l t a n e o u s l y
(67,69). By c a r r y i n g out these p r o c e s s e s we were a b l e to c a l c u - l a t e parameters which were b o t h n e c e s s a r y 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 a b l e t o measure lower than
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
normal t i s s u e z i n c c o n c e n t r a t i o n s i n some of t h e p a t i e n t s (Table V ) . I n o r d e r t o understand t h e 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 q u e s t i o n s about the n a t u r e 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 f o r m u l a t i o n s c o u l d awareness of t h e i s s u e s u n d e r l y i n g 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 o f Z i n c D e f i c i e n c y
A s e r i e s of q u e s t i o n s r a i s e d by t h e above a m b i g u i t i e s may be h e l p f u l t o f o r m u l a t e a r e d e f i n i t i o n o f z i n c d e f i c i e n c y . I n i t i a l l y f o u r q u e s t i o n s can be r a i s e d . They a r e : (1) How can z i n c de- f i c i e n c y be d e f i n e d ? (2) Why do 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 , e x h i b i t t a s t e and s m e l l 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 t h e wide range of z i n c a b s o r p t i o i p a t i e n t w i t h subacut z i n d e f i c i e n c y ? , and (4) Does z i n c treatmen
d e f i c i e n c y a d e q u a t e l y c o r r e c symptom
p r o c e s s e s , 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 o f Z i n c D e f i c i e n c y . I t i s c l e a r t h a t z i n c d e f i c i e n c y can be d e f i n e d o n l y w i t h d i f f i c u l t y s i n c e t h e z i n c con- t e n t o f 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 p r o v i d e a de- f i n i t i v e e s t i m a t e o f body z i n c s t a t u s (1.-3) . I t i s a l s o n o t pos- s i b l e t o r e l y on t h e c o n c e n t r a t i o n o f z i n c i n s e v e r a l body t i s s u e s to e s t i m a t e body z i n c s t a t u s s i n c e d i f f e r i n g c o n c e n t r a t i o n s i n d i f - f e r e n t t i s s u e s l e a d t o n o n - d e f i n i t i v e c o n c l u s i o n s .
With these n e g a t i v e s i n v i e w i t seemed important t o determine i f z i n c d e f i c i e n c y c o u l d be d e f i n e d 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 n6 5, a f t e r an o v e r n i g h t 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 s m e l l d y s f u n c t i o n was 55% r a n g i n g from 17% t o 100% (3,49,60), whereas i n normals ab- s 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 h i g h e r than t h a t measured i n t h e 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 c o n t e n t ; i . e . , an i n - creased a b s o r p t i o n of z i n c a s s o c i a t e d w i t h decreased body z i n c s t o r e s . However, t h i s i s not t h e case f o r human z i n c d e f i c i e n c y s i n c e mean a b s o r p t i o n o f 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 t h e f a c e 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 s m e l l 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 o t h e r d i s o r d e r s (56) and r a i s e fundamen- t 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 s t o r e s have been a s s o c i a t e d w i t h
94 n u t r i t i o n a l b i o a v a i l a b i l i t y o f z i n c TABLE IV
COMPARISON OF ABSORPTION AND EXCRETION OF Zn-65
IN NORMAL VOLUNTEERS AND IN PATIENTS WITH SUBACUTE Zn DEFICIENCY
CONDITIONS NORMALS PATIENTS
V i + . 1 4 6 + . 0 0 5 . 1 5 0 ± . 0 0 7
Vu . 0 0 9 + . 0 0 1 . 0 0 7 ± . 0 0 1
VF . 1 3 8 + . 0 0 6 . 1 4 4 ± . 0 0 7
Va . 3 6 ± . 0 5 . 1 1 ± . 0 2 *
V r
. 3 5 + . 0 5 . 1 0 ± . 0 1 *
00* A . 6 9 + . 0 3 . 4 3 ± . 0 4
LF 2 . 7 + . 2 1 . 4 ± . 2 *
L( 1 5 , 2 4 ) 73 ± 1 3 26 ± 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 d e f i n e d as the mass t r a n s p o r t 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 C1 5 to C2i^ c a l c u l a t e d as the
1 product of L ( 2 4 , 1 5 ) ( M1 5)
M i s d e f i n e d as the mass, i n mg, of compartment C^
L-LJ i s d e f i n e d as the f r a c t i o n of z i n c i n compartment Cj t r a n s f e r r e d to compartment C. per u n i t time. I t s u n i t s a r e day-1 and r e p r e s e n t the*3rate constant from compartment j i n t o compartment i .
Vu,Vp 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 , r e s p e c t i v e l y . VF = L ( 0 , 2 5 ) ( M2 5) .
Va r a t e of z i n c a b s o r p t i o n and i s L ( 1 5 , 2 4 )( Μ 2 ^ ) V^ r a t e of z i n c r e a b s o r p t i o n
<» the f r a c t i o n of z i n c absorbed i n the g u t . vi-t-vr KG i + (Vi + yr)
m
Where K§Jx i s the maximum r a t e of z i n c a b s o r p t i o n
and i s an e f f e c t i v e M i c h a e l i s Menten e q u i l i b r i u m constant Lu = Vu/M1 5
LF - (1 - cc) (L24,15)
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
i n c r e a s e d z i n c a b s o r p t i o n and i n c r e a s e d body z i n c s t o r e s a s s o c i a - ted w i t h decreased z i n c a b s o r p t i o n ( c f , Weigard, E. and K i r c h - gessner, M., Homeostatic adjustments i n z i n c d i g e s t i o n to w i d e l y v a r y i n g z i n c i n t a k e , Nutr. Metab. 22:101-112, 1978). I n a d d i t i o n , the decreased body z i n c s t o r e s i n the r a t have been a s s o c i a t e d w i t h decreased a c t i v i t y of s e v e r a l z i n c dependent enzymes, a c o n d i t i o n which i s not observed u n i f o r m l y i n humans.
One s i m p l i s t i c manner of d e a l i n g w i t h these data i s t o assume some g a s t r o i n t e s t i n a l b l o c k t o the a b s o r p t i o n of z i n c which would account f o r the symptoms of the p a t i e n t s as w e l l as the lower than normal a b s o r p t i o n . T h i s would be an a c c e p t a b l e s o l u t i o n p r o v i d e d a l l o t h e r d a t a were c o n s i s t e n t , which they are n o t . Serum z i n c c o n c e n t r a t i o n s i n these p a t i e n t s extended over a wide range as d i d u r i n a r y z i n c e x c r e t i o n . Both of these v a l u e s should be below norm- a l i f z i n c a b s o r p t i o n were the major or o n l y d e f e c t i n these pa t i e n t s . S i m i l a r l y , re
a wide range, a l b e i t mea
l a t t e r f i n d i n g becomes more d i f f i c u l t to e x p l a i n when i t i s l e a r n e d t h a t treatment w i t h l a r g e amounts of exogenous z i n c does not i n c r e a s e these red blood z i n c l e v e l s although serum z i n c con- c e n t r a t i o n and u r i n a r y z i n c e x c r e t i o n b o t h r i s e s i g n i f i c a n t l y (61).
I n order t o d e a l w i t h these complex problems a l l d a t a from the o r a l Z n6 5 s t u d i e s obtained i n p a t i e n t s w i t h t a s t e and s m e l l d y s f u n c t i o n were organized and submitted to compartmental a n a l y -
s i s (!ËL>Ç9)witn t n e subsequent development of a model ( F i g u r e 1)
which accounted f o r a l l the d a t a obtained over the e n t i r e p e r i o d of these s t u d i e s , both p r i o r t o 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 , demon- s t r a t e d t h a t not o n l y 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 im- p 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 t h a t 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 t h a t 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^. B v t n e u s e °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 b o t h necessary and s u f f i c i e n t t o 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 - n i q u e s i t was p o s s i b l e t o 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 c o u l d be d e f i n e d 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 t o compare p a t i e n t s w i t h normals so t h a t 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 c o u l d be i d e n t i f i e d . The major problems presented w i t h these techniques are t h a t they are time consuming, cumbersome, expensive and a r e p r e s e n t l y un- a v a i l a b l e i n many areas of the U.S.
2. Why a r e t a s t e and s m e l l 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 i m p o r t - ant t o r e c o g n i z e t h a t 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 m a r g i n a l form of the d e f i c i e n c y . I t i s a l s o important t o r e c - ognize t h a t the e a r l i e s t s i g n s of b o t h acute and c h r o n i c z i n c de- f i c i e n c y , i . e . , d u r i n g the p e r i o d when the d e f i c i e n c y i s b e g i n n i n g to be m a n i f e s t e d , are those of t a s t e and s m e l l d y s f u n c t i o n . These
Os OTHER TISSUES UPPER GASTROINTESTINAL TRACT Ν
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
Figure 1. In this model of zinc metabolism in humans circles represent compartments and represent transfer pathways. (Reproduced with permission from Ref. 69.) The circles are labeled Ci for the Ci
th compartment. The arrows represent rate constants, the Lnj> defined as the fraction of zinc in compartment Cj transferred to compartment Ci per unit time. The plasma, red blood cell, and liver subsystems are indicated by Ct, Cs, Ce, and Cs, C9,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 Ct5 in the reduced model. The lower rect- angle 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 this figure are from a representative patient, patient 4, in the group reported. The upper numbers indi- cate 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 Ct to C» represents L(8,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 were fitted to 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 were fitted to the reduced model.
6SZn is introduced into the first compartment of the upper gastrointestinal tract as indicated by the asterisk. Dietary intake is indicated by the double arrow.
98 NUTRITIONAL BIOAVAILABILITY OF ZINC r e s u l t s suggest t h a t those z i n c p o o l s s u b s e r v i n g t h e t a s t e and s m e l l systems a r e 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 o r w i t h e a r l y d e p l e - t i o n of z i n c t h e f i r s t systems t o be a f f e c t e d a r e those s u b s e r v - i n g t a s t e and o l f a c t i o n .
3. Why i s t h e r e such a wide range of 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 subacute z i n c d e f i c i e n c y ? While t h e answer t o t h i s q u e s t i o n i s u n c l e a r , t h e d a t a suggest t h a t z i n c a b s o r p t i o n and i t s d i s t r i b u t i o n i n t h e 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 a b s o r p t i o n o r t h a t o f o t h e r d i v a l e n t m e t a l i o n s . Some d a t a r e l e v a n t t o t h i s q u e s t i o n were obtained from t h e z i n c l o a d i n g 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 l o a d i n c r e a s e d 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% t o 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 t o 10.6 g/d). P r e s e n t l y
a n a l y z e d under t h e same
be made. Data o b t a i n e d by t h e use of t h e model a l l o w s f u r t h e r i n - s i g h t i n t o t h i s problem. N i n e t y percent of t o t a l body z i n c i n norm- a 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 s m e l l d y s f u n c t i o n a r e found i n one l a r g e compartment ( C 3 ) which r e p r e s e n t s , 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 t h e l a r g e s t body p o o l of z i n c . The r a t e c o n s t a n t s i n t o and out o f t h i s com- partment from the r a p i d l y exchanging body z i n c p o o l ( ( ^ 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 t h a t t h e z i n c content i n t h i s compartment and t h e r a t e c o n s t a n t s i n t o and out of t h i s compartment a r e t h e c o n t r o l l i n g f a c t o r s not o n l y i n z i n c a b s o r p t i o n but a l s o i n o t h e r a s p e c t s of z i n c metabolism i n humans.
Thus, some of t h e c o n f u s i o n about z i n c a b s o r p t i o n 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 o f z i n c a c c u m u l a t i o n and l o s s i n t h i s p o o l .
These concepts emphasize t h e need t o c o n s i d e r 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 o n l y i s i t n e c e s s a r y t o know z i n c a b s o r p t i o n through t h e 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 t h e type of z i n c b i n d i n g l i g a n d s i n t h e gas- t r o i n t e s t i n a l t r a c t needed t o t r a n s p o r t z i n c a c r o s s t h e gut mu- c o s a l s u r f a c e , t h e presence of a p p r o p r i a t e z i n c b i n d i n g p r o t e i n s and t h e presence o f t i s s u e s p e c i f i c z i n c s t o r a g e 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 a b s o r p t i o n 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 a b s o r p t i o n of these m e t a l s were r e c e n t l y d i s c u s s e d (Matseke, J.W., P h i l l i p s , S. F., M a l a g e l a d a , 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 t h e p r o x i m a l i n t e s t i n e of h e a l t h y man:
S t u d i e s of d i f f e r e n t meals and supplements. Amer. J . C l i n . N u t r . 33:1946-1953, 1980) and emphasize t h e 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 a b s o r p t i o n . Only w i t h an under- standing 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 d e f i n e d 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 t h e t a s t e and s m e l l d y s - f 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 ? T h i s
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
q u e s t i o n can be answered o n l y p r o v i d i n g t h a t 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 h i g h doses of z i n c (100 mg of z i n c i o n ) i s u s u a l l y r e - q u i r e d p r i o r t o r e v e r s a l of these symptoms. An e x p l a n a t i o n f o r t h i s prolonged time p e r i o d may r e l a t e to the h y p o t h e s i s t h a t com- partment C3 must be s a t u r a t e d w i t h z i n c b e f o r e the symptoms r e m i t i n s p i t e of the l a b i l i t y and s m a l l s i z e of the z i n c p o o l s sub- s e r v i n g the t a s t e and s m e l l 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 a p p r o p r i a t e 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 t a k e i n t o c o n s i d e r a t i o n the n e g a t i v e r e s u l t s of the double b l i n d study we p u b l i s h e d i n 1976 (63). I n t h i s study placebo was as e f f e c t i v z i n i r e s t o r i n t a s t d s m e l l t normal p a t i e n t s w i t h t a s t
c o n s i d e r a t i o n here i s t h a
than 25% of p a t i e n t s w i t h t a s t e and s m e l l d y s f u n c t i o n would be expected t o e x h i b i t z i n c d e f i c i e n c y (3,60) and t h a t 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 t h a t 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 b o t h b e f o r e and d u r i n g the study. T h i s l a c k of knowledge, f o r c e d 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 t o be z i n c r e s p o n s i v e . The reasons f o r t h e i r r e - sponsiveness t o placebo i s s t i l l u n c l e a r (3,j>0,j>3) a l t h o u g h sev- e r a l hypotheses have been advanced t o 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 pa- t 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 s m e l l d y s f u n c t i o n were o b t a i n e d . I n t h i s study i f o n l y p a t i e n t s who were r e l a t i v e l y low absorbers of Z n6 5 ( i . e . , z i n c a b s o r p t i o n more than 2SD below the mean l e v e l of a b s o r p t i o n of normal v o l - u n t e e r s ) were e v a l u a t e d then i n i t i a l treatment w i t h placebo was shown t o 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 t o or toward f u n c t i o n a l l o s s of t a s t e and s m e l l a c u i t y . As a c l i n i c a l t e c h n i q u e t o ob- t a i n some u s e f u l e s t i m a t e of body z i n c s t a t u s s a l i v a z i n c concen- t 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 mea- surement 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 b o t h i n the p r e v i o u s souble b l i n d study (63) as w e l l as i n the p r e s e n t 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 t h a t u n t i l t h e r e was c o r r e c t i o n of s a l i v a z i n c c o n c e n t r a t i o n t o normal t h e r e 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 o c c u r r e d t h e r e 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 o n l y r e t u r n e d t a s t e f u n c t i o n t o normal but