Committee on Nutrition
Zinc
Zinc recently achieved the status of a
micronu-trient of established importance in human
nutri-tion and medicine. Although a biological role for
zinc was recognized more than 100 years ago, the
first cases of human zinc deficiency were not
described until the early 1960s. These initial
reports’ - were related to the syndrome of
adoles-cent nutritional dwarfism found in children in
Egypt
and Iran. However, inadequate zinc in thediet was not appreciated as a nutritional problem
in infants and children in the United States67 until
the 1970s. Recent advances in
technology-con-current with and partly responsible for progress
in our understanding of the physiologic roles and
nutritional importance of this metal-are
begin-fling to permit application of new knowledge
about zinc in clinical pediatrics.
Biochemistry and Physiologic Roles
The biologic importance of zinc stems
primari-ly from its key role in many vital enzyme
systems.” More than 40 zinc-containing enzymes
have now been identified, including at least one
in every major enzyme classification.” Examples
include carbonic anhydrase, alkaline phosphatase,
alcohol and glutamic dehydrogenases, and
car-boxypeptidases. Moreover, zinc appears to have a
major role in nucleic acid metabolism and protein
yn”’ Although the biochemical correlates
of the features of zinc deficiency have not been
elucidated completely, adverse effects on nucleic
acid metabolism and protein synthesis may be
responsible, in part, for the impaired growth and
development that are prominent signs of the
zinc-deficient state both before and after birth.
Maternal zinc deficiency in the rat results in
intrauterine growth retardation and a high
mci-dence and wide spectrum of congenital
malfor-mations in the offspring. ‘ ‘ Perinatal zinc
deficien-cy in the rat can cause impairment of brain
growth and of subsequent learning ability and
behavioral development. ‘ Postnatally, the most
prominent features of zinc deficiency in the
young animal are anorexia and growth
retarda-tion,TM and utilization of absorbed food is impaired.
In later stages of development, zinc deficiency
causes hypogonadism and delayed sexual
matura-tion. Pituitary function appears to remain intact,
but testosterone synthesis in the testes is
impaired.” Zinc is necessary for normal
kerato-genesis, and zinc-deficient animals may manifest
alopecia, a variety of skin lesions,’ and impaired
wound healing.’ Skeletal lesions, diarrhea, and an
increased susceptibility to infection are other
documented symptoms of zinc deficiency. Zinc
may participate in the synthesis, storage, and/or
release of insulin from the beta cells. However,
the effects of zinc deficiency on plasma insulin
levels and glucose tolerance have been
inconsis-tent.’#{176}Mobilization of vitamin A from the liver is
decreased in zinc-deficient rats, and serum
vita-mm A levels are depressed.’5 Zinc is necessary for
normal growth at a cellular level, which may
explain why the nutritional requirements for this
metal are particularly high in the young of all
species investigated. Requirements for the young
male animal may be higher than those for the
female.”
Zinc Metabolism and Body Distribution
Zinc is absorbed via the small intestine. A low
molecular weight ligand secreted by the pancreas
appears to have a physiologic role in the
absorp-tion process,’7 but the mechanisms are not
completely understood. The adult human body
contains approximately 2 gm of zinc, which is
about half the body content of iron and 20 times
that of copper.” Highest concentrations of zinc
occur in the choroid of the eye and in the
spermatozoa. Concentrations exceeding 100 g/
gm are present in hair, nails, the prostate gland,
and bone; and liver, kidney, muscle, and skin have
about 50 .tg/gm wet weight. Lower
concentra-lions are present in other tissues; for example,
erythrocytes contain 12 to 14 tg of zinc per gram,
and most of this zinc is incorporated into carbonic
anhydrase. The zinc in plasma (approximately 90
.tg/dl) is bound to albumin, and a-macroglobulin,
and transferrin. The albumin-bound zinc is in
frac-tion, and the latter is thought to be the major
source of the zinc excreted in the urine.’5
Approx-imately 0.5 mg of zinc is excreted each day in the
urine of adults, and a similar quantity is excreted
in the sweat. The primary route of excretion of
endogenou.s zinc is via the feces, which also
contains substantial quantities of dietary zinc that were not absorbed.
Dietary Sources and Nutritional Requirements
Approximate nutiitional requirements for zinc
can now be given. The first recommended dietary
allowances for zinc for children were published in
1974” by the Food and Nutrition Board of the National Academy of Sciences. The recommenda-tions for infants and children are 3 mg/day from
birth to 6 months, 5 mg/day from 6 to 12 months,
10 mg/day from 1 to 10 years, and 15 mg/day for
older children and adolescents. The requirements
depend to some extent on the weight and age of
the infant or child and on the rate of growth.
Moreover, the bioavailability of this metal varies
considerably according to the dietary source. The
quantity of zinc absorbed may range from 20% to
60% of that ingested. In general, meats and fish
are the best known sources of zinc, and the zinc
from animal protein is better absorbed than that
from vegetable sources. Phytate and fiber in the
diet decrease the availability of the zinc for
absorption,2o and the use of soy protein as meat
and milk substitutes may adversely affect zinc
nutriture. Substantial quantities of zinc can be
lost during food processing, such as the milling of
wheat and the refining of sugars.2’ White bread,
refined sugars, vegetables other than legumes,
and fruits contain relatively little zinc. Published
information on the zinc content of foods222 is
now adequate enough to permit a reasonable
estimate of total dietary zinc intake, which can
vary considerably depending on the individual’s
diet.
The zinc concentration in human colostrum reaches as high as 20 mg/liter,25 and in breast
milk it averages 3 mg/liter for the first one to two
months of lactation. The zinc concentration declines further as lactation progresses. In cow’s
milk the zinc concentration ranges from 2 to 7
mg/liter, with a mean of about 3.5 mg/liter.
There is some evidence that the bioavailability of
the zinc for the human infant is less from cow’s
milk than from human milk. Cow’s milk formulas
are now generally supplemented with zinc to a level of 3 to 4 mg/liter, and larger supplements
have been added to soy-based formulas. However,
clarification of the optimal quantity of zinc
supplement depends on a better understanding of
the relative bioavailability of zinc from different
milk sources.
Zinc Deficiency Encountered in Pediatric Practice
Zinc deficiency in infants and children can
result from inadequate dietary intake, impaired
absorption, excessive excretion, and an inherited
defect in zinc metabolism. Impaired growth has
been documented in otherwise healthy male
infants fed a milk formula containing less than 2
mg of zinc per liter2; these formulas were in
widespread use until 1975, when it became a
general practice to supplement them with zinc to
a level equivalent to that of cow’s milk. Less
information is available on the zinc nutriture of
children, but some otherwise healthy school-aged
children may have a suboptimal zinc intake, with
adverse effects on appetite, taste perception, and
growth.” A high incidence of low biochemical
indices of zinc nutriture has been reported among
preschool-aged children from low-income
fami-lies.27 More severe zinc depletion has occurred in
children2” and adults29 receiving total parenteral
nutrition without zinc supplements. Some of
these children have developed a syndrome similar
to acrodermatitis enteropathica, including anal
and orificial skin lesions, diarrhea, alopecia, and
depression.
The pathogenesis of the rare, inherited disease,
acrodermatitis enteropathia, is now known to be
attributable to a serve zinc deficiency,bo12 which
is probably secondary to an inherited defect in
zinc absorption.’3 This is the most severe human
zinc deficiency syndrome yet identified; and, if it
is untreated in early childhood, death results. A
rapid, complete, and sustained clinical remission
is uniformly achieved with oral zinc therapy in
a sufficient dose to overcome the deficiency. An
increased susceptibility to infection is
characteris-tic of acrodermatitis enteropathia, and it may be
related in part to zinc-responsive defects in
leuko-cyte function.’ Women with this disease who
have survived without zinc therapy have infants
with a high incidence of congenital
malforma-tions similar to those observed in zinc-deficient
rats.’5
Acquired zinc deficiency can occur as a result
of impaired absorption of this metal. The large
quantities of phytate” and fiber” in the diet of
the rural population in Iran are thought to be
major etiologic factors in the zinc deficiency of adolescents with nutritional dwarfism in that
country. ‘ Although information remains
be a potential complication of intestinal
malab-sorption syndromes. If steatorrhea is present, zinc
may form insoluble complexes with fat and
phos-phates.’7 Therefore, the possibility of this
compli-cation should be considered in diseases such as
cystic fibrosis,” regional enteritis,39 and celiac
disease.4” Excessive zinc excretion resulting from
chronic blood loss, excessive sweating, or
hyper-zincuria may also lead to a significant depletion of
this metal. Hyperzincuria has been proposed as a
mechanism for zinc depletion in persons with
sickle cell disease.4’ Excessive urinary loss of zinc
occurs in a variety of other conditions, including
catabolic states,4’ liver diseases such as acute
infectious hepatitis,43 burns,44 diabetes mellitus,45
and the nephrotic syndrome. Iarogenic
hyperzin-curia occurs in association with the use of
chelat-ing agents,4” diuretics,47 corticosteroids,48 and
intravenous administration of protein
hydroly-sates and amino acid infusates.li
The earliest and frequently the only sign of zinc
deficiency in infants and young children is a
decline in growth velocity, which may be
accom-panied by an obvious impairment of appetite.
Pica may occur,5#{176} and abnormalities of taste
perception may be demonstrable.6 When
nutri-tional zinc deficiency is severe, growth
suppres-sion is severe, sexual maturation is arrested, and
symptoms may include any or all of those that
occur with acrodermatitis enteropathica.
Detection and Diagnosis
The possibility of zinc deficiency should be
considered if there are suggestive clinical
symp-toms or predisposing circumstances.
Confirma-tion can be provided by a low plasma zinc level.
However, despite the relative simplicity of this
assay, a number of limitations and potential pitfalls have to be considered:
1. The risk of sample contamination during
collection or processing is substantial. Containers
with rubber caps should not be used.
2. The mean value for normal subjects is
approximately 90 .&g/dl of plasma, with a lower
limit of normal of 65 to 70 jig/dl. However,
significant variations still exist between different
laboratories. Normal serum values are thought to
be slightly higher than those of plasma.
3. Plasma zinc levels can be depressed, even
without body depletion of this metal, during any
acute or chronic infections’ or in a number of
other circumstances.
Currently, it is not known if the normal range
of plasma zinc levels for infants is lower than that
for children and adults.
Determination of the zinc concentration in hair
may also be useful,” but this test should not be
regarded as a substitute for determining the
plasma
zinc levels because there is no correlationbetween zinc levels in plasma and hair. However,
a low hair zinc level appears to be useful in the
detection of chronic, mild zinc deficiency in
children in whom the plasma zinc level may not
necessarily be depressed at the time of a solitary
blood collection. Hair zinc concentrations less
than 70 ,g/gm may provisionally be considered
abnormal; this may apply to levels up to 100
pg/gm. However, it is not certain that these levels
also apply to infants and toddlers. The hair
analyses should be restricted to a short section of
hair taken from close to the scalp. Hair zinc
concentrations are affected by variations in the
rate of hair growth. Measurement of zinc
concen-trations in other tissues and fluids (e.g., saliva52) is
less well established. Twenty-four-hour urine
excretion rates can be useful in the confirmation
of moderate or severe deficiency states, in the
detection of hyperzincuria, and in monitoring the
results of therapy (e.g., in acrodermatitis
entero-pathica). Serum alkaline phosphatase levels may
be depressed, and an increase in activity after
zinc supplementation is commenced provides
useful confirmation of the diagnosis of zinc
defi-ciency.
Detection of marginal nutritional zinc
deficien-cy is particularly difficult. Except for laboratory
measurements, or in lieu of these if they are
unavailable, calculation of the dietary zinc intake
is helpful. If the intake is or has been low and
there are nonspecific symptoms such as declining
growth percentiles and feeding problems, a trial
of dietary zinc supplementation is justified.
Treatment
The quantity of zinc required for the treatment
of zinc deficiency depends on the circumstances.
For a simple nutritional deficiency,
supplementa-tion with 0.5 to 1 mg of zinc per kilogram of body
weight per day, a quantity similar to the upper
limits of the range of normal dietary intake,5’ is
probably both adequate and safe. Somewhat
larger quantities may be needed if there is
impaired intestinal absorption or an excessive loss
of zinc. All patients with acrodermatitis
entero-pathica should now be treated with 10 to 45 mg of
zinc per day. Therapy should be monitored in an
adequately equipped center to determine the
optimal quantities of zinc for the individual
patient. Patient on long-term intravenous feeding
should have plasma zinc determinations at
regu-lar intervals. If the plasma zinc levels decline (or
should be added to the infusate to provide 30 to
50 tg of zinc per kilogram of body weight per
day. Larger quantities may be required if there
are excessive losses, for example via jejunostomy
fluids.
Zinc has been used pharmacologically in the
management of surgical patients, in patients with
sickle cell disease, and in patients with
rheuma-toid arthritis.5 However, zinc should not be used
to treat infants and children without evidence of
zinc deficiency, and the dose should be sufficient
only to treat the deficiency. Although zinc
thera-py is sometimes prescribed for children with
learning disorders, there is no scientific basis for
this practice.
Zinc has been administered most frequently as
the sulfate; however, zinc sulfate can be a
gastrointestinal irritant in some individuals, even at a relatively low dose. Thus, an alternative,
soluble zinc salt, such as the acetate, should be
used. An example of a convenient solution for
infants and young children is 13 mg of zinc
acetate (approximately 1 mg of zinc) per
millili-ter. This dosage form can be administered in two
or three divided doses per day, preferably at least
one hour before meals.
Zinc is relatively low in toxicity, and, in
physi-ologic quantities, it appears to be entirely safe. If larger quantities are given (e.g., for
acrodermati-tis enteropathica or when supplementation is
prolonged), levels should be monitored, at least in
plasma, to ensure that they do not exceed the
physiologic range. Although increasing the zinc/
copper ratio of rat diets has been reported as a
cause of hypercholesterolemia,55 this condition
appears to be related to an absolute deficiency of
copper. Nevertheless, a gross excess of zinc can
interfere with copper absorption and metabo-lism.
Conclusions
Zinc deficiency can occur in infants and
chil-dren as a result of inadequate dietary zinc intake,
disturbed zinc metabolism secondary to
numer-otis disease states, and an inherited defect in zinc
metabolism in acrodermatitis enteropathica. In
the latter condition, the effects of zinc therapy
are dramatic and potentially lifesaving.
Symp-toms can also be severe in conditioned zinc
deficiency states, and it is clinically important to
recognize the need for zinc therapy in this condition. Clinically less severe, but probably
much more widespread, is marginal nutritional
zinc deficiency. Although the extent of this
condi-tion is unknown, some preventative measures
have recently been undertaken, including zinc
supplementation of “low-zinc” infant formulas
and zinc fortification of some ready-to-eat
break-fast cereals. But the effectiveness of these
measures will have to be assessed.
The possibility of zinc deficiency should be
considered in infants and children whose growth
percentile declines, even those who seem
other-wise healthy.
COMMITTEE ON NUTRITION
Lewis A. Barness, M.D., Chairman; Alvin M. Matier,
M.D., Vice-Chair,nan; Arnold S. Anderson, M.D.; Peter R. Dallman, M.D.; Gilbert B. Forbes, M.D.; Buford L. Nichols,
Jr., M.D.; Claude Roy, M.D.; Nathan J. Smith, M.D.; W. Allan Walker, M.D.; Myron Winick, M.D.
Consultant: K. Michael Hambidge, M.D.
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