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Zinc is a micronutrient of extraordi-
nary versatility and ubiquity in biolo-
gy.

1,2

It is intimately involved with and

has a diversity of roles in the funda-
mental processes of cellular growth
and differentiation. Zinc is involved in
maintaining the integrity of ion chan-
nels and biologic membranes and in
the structure and function of steroid
hormone receptors, and it has a key
role at the catalytic sites of a wide and
heterogeneous range of enzymes.
Though still not well understood, this
element also appears to be an intracel-
lular regulatory ion, possibly including
participation in the regulation of gene
expression. Its exceptional ability to
form flexible, strong, but readily ex-
changeable ligands is utilized through-
out biology.

3

Because of zinc’s fundamental roles

in cell growth and differentiation, the
young growing organism is especially
vulnerable to adverse effects from in-
adequate zinc. In a similar vein, cells
with a rapid rate of turnover, notably
those of the immune and gastrointesti-
nal systems, are most vulnerable to the
depredations of zinc deficiency.

In contrast to the clinical presenta-

tions of deficiencies of other micronu-
trients of public health importance,
those of zinc deficiency are neither
unique nor pathognomonic. However,
though often subtle, in accord with
zinc’s participation in so many differ-
ent facets of biology, they are pervasive
and very important. Together with the
dearth of specific clinical features,
there is a concomitant lack of specific
laboratory biomarkers for zinc deficien-

cy.

4

Zinc homeostasis is not sufficiently

effective to prevent the diminution of
the size of metabolically critical pools
of zinc

5

and the onset of insidious clin-

ical features of zinc deficiency when
the quantity of bioavailable zinc is lim-
ited. However, it is effective in main-
taining circulating plasma zinc concen-
trations, at least in the face of relatively
short-term restriction of zinc intake,

6

thus complicating the detection of de-
ficiency states.

These characteristics of the biology

and metabolism of zinc have resulted in
exceptional dependence on rigorous,
controlled, randomized trials of zinc
supplementation, not only to define the
benefit of this type of intervention but
to confirm hypotheses of the etiologic
role of zinc deficiency in the disease
under investigation. Such trials have
been undertaken for many years with
positive outcomes, including studies in
North America,

7

but it is this decade

that has witnessed the conduct of a

Z

Z

inc, diarrhea, and pneumonia

J Pediatr 1999;135:661-4.

Copyright © 1999 by Mosby, Inc.

0022-3476/99/$8.00 + 0

9/18/103360

See related articles, p. 657,

p. 683, and p. 689.

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large number of well-designed, large-
scale intervention studies, the results of
which have led to a notable escalation
of interest in the public health impor-
tance of this micronutrient. These re-
cent studies have been located princi-
pally in developing countries, focusing
especially on outstanding causes of
morbidity and mortality globally, that
is, diarrhea and pneumonia, and associ-
ated clinical features. The latter include
compromised velocity of physical
growth

8

and dysfunction of the central

nervous system.

9,10

Malaria is notable

among other infectious diseases for
which there is strong preliminary evi-
dence for a beneficial effect of zinc.

11,12

To link together the studies, under-

taken in many countries and several
continents, of the effects of zinc sup-
plements on the incidence and preva-
lence of diarrhea and pneumonia and
to reach definitive conclusions has
been the achievement of the Zinc In-
vestigators’ Collaborative Group

13

in

this issue of The Journal. This pooled
analysis of data from many studies has
provided convincing evidence of the
effectiveness of zinc in preventing di-
arrhea and pneumonia in children
throughout the world. The magnitude
of this effect is notable, and this analy-
sis, together with the underlying stud-
ies, has made a major contribution to
confirming the public health implica-
tions of zinc. Though zinc supplements
may be ineffective in some circum-
stances if other nutrient deficiencies
co-exist,

10

it is quite remarkable how

effective zinc has proven as a single
nutrient supplement. The effect on
prevention of pneumonia accounts for
the entire estimated contribution of
malnutrition as a risk factor.

14

These results, together with other re-

cent reports highlighting the clinical
and biologic importance of this metal,
have served to reinforce and extend
the need for accelerated research di-
rected to achieving a more comprehen-
sive understanding of the roles of zinc
in biology and in human nutrition and
health. They have also provided an im-

pelling rationale for developing and
testing treatment and especially strate-
gies for prevention of zinc-related mor-
bidity and mortality in childhood.

The formulation of effective preven-

tion strategies depends first on deter-
mining whether the positive results of
these studies are attributable to the cor-
rection of an underlying deficiency state
or are the result of a pharmacologic ef-
fect of the zinc supplement. Typically,
these studies have lacked baseline data
on diet, a deficiency that, however chal-
lenging, needs to be addressed in the
next generation of studies. However,
there are other factors that point to the
correction of a deficiency state. For ex-
ample, many studies were accompanied
by a response in velocity of physical
growth. An earlier meta-analysis served
to confirm the effects of zinc supple-
ments in enhancing linear growth veloc-
ity and weight gain in growth-retarded
children.

8

It has been long established

that zinc has no pharmacologic effect on
growth and that any growth response to
zinc in an adequately designed study
provides prima facie evidence of a pre-
ceding growth-limiting zinc deficien-
cy.

15

The association between growth

failure and infectious disease, especially
diarrhea and pneumonia, is well docu-
mented,

16

and it seems implausible that

the benefits on growth velocity result-
ed from correction of zinc deficiency
while the decreased incidence of diar-
rhea and pneumonia was the result of a
pharmacologic effect of the same mi-
cronutrient. Other factors are consistent
with or supportive of a non-pharmaco-
logic effect, including the baseline
hypozincemia, which is unlikely to be
attributable to an acute phase re-
sponse

8

; the modest quantities of zinc

administered in these trials; and a plau-
sible mechanistic explanation, that is,
functional impairment of the immune
system.

17

For diarrhea, there are other

supportive factors, including abnor-
malities of intestinal transport mecha-
nisms, which have been documented in
experimental zinc deficiency,

18,19

and

the long-recognized prominence of di-

arrhea among the clinical features re-
sulting from severe zinc deficiency in
the inborn error of zinc metabolism
acrodermatitis enteropathica.

20

Why does zinc deficiency occur?

Breast milk provides quite modest and
progressively decreasing quantities of
zinc

21

but with relatively favorable

bioavailability.

22

Though neonatal

stores of this element do not compare
with those of iron, the zinc status of the
breast-fed infant delivered at term is
typically good for 4 to 6 months. As
with iron, however, breast milk alone
is not an adequate source of zinc after
the first 4 to 6 months and probably
even earlier if birth weight is low.

23

Routine fortification of infant formulas
in North America has almost certainly
reduced the risk of zinc deficiency in
infants, though it appears that nutri-
tional zinc deficiency still occurs in
young North American children.

24

Those at greatest risk for zinc deficien-
cy are older infants and young children
whose diets do not include animal
products. This, of course, is the rule
rather than the exception in develop-
ing countries. In many communities
the quantity of zinc is not low in ab-
solute terms, but its bioavailability is
poor. The high quantity of phytic acid
in vegetable products, especially grains
and legumes, is regarded as the princi-
pal culprit.

25

Excessive losses of en-

dogenous zinc in diarrheal fluids may
contribute to zinc deficiency.

Zinc supplements are of proven value

in evaluation of the benefits of correct-
ing zinc deficiency. They are also of
benefit in treating established disease.

26

In this context, the addition of zinc to
oral rehydration solutions or alterna-
tive nutrient-containing gruels merits
further consideration. The long-term
use of zinc supplements to prevent de-
ficiency is not only logistically more
challenging but raises the specter of nu-
trient-nutrient interactions and a domi-
no effect that is already a significant
concern associated with measures to re-
duce iron deficiency. It is encouraging
that once zinc deficiency is corrected

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with zinc supplements, the benefits
may endure for at least several weeks.
In those communities in which veg-
etable food staples are relatively low in
zinc, quite possibly the result of miner-
al losses during refining (especially of
grain products), fortification with zinc
(and, typically, iron) is a logical long-
term strategy. An alternative approach
is plant breeding to increase the miner-
al content of indigenous crops.

27

When the principal factor is high di-

etary phytate with high phytate/zinc
molar ratios, the preferred strategy is to
reduce the phytate content of the major
food staples. A variety of strategies have
important potential,

28

ranging from

local community education programs to
decrease the phytate (eg, by fermenta-
tion before cooking) to plant breeding
strategies designed to introduce low
phytate mutants

29

into indigenous grains.

Evaluation of these strategies must
include quantitative measurements of
their short- and long-term effects on
zinc homeostasis,

30

as well as evalua-

tion of their public health potential.

In conclusion, the largest historical

decrease in morbidity and mortality
caused by infectious disease was expe-
rienced not with the modern antibiotic
and vaccine era, but after the intro-
duction of clean water and effective
sewer systems. The enormous appeal
of correcting zinc deficiency is that in
normalizing the function of cells in
multiple tissues, it enhances the child’s
ability to combat disease states and
not just single infectious organisms.
Thus, on a worldwide public health
level, it is likely to be more economi-
cally feasible than vaccines directed
against specific organisms.

The work highlighted in this issue

13

indicates that the stage is set for another
concerted public health effort, directed
at enhancing the nutritional status of
the world’s children, in which attention
to zinc must be a priority.

Michael Hambidge, MD

Nancy Krebs, MD

Section of Nutrition,

Department of Pediatrics

University of Colorado Health

Sciences Center

Denver, CO 80262

R

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