zinc - pediatrics · 410 zinc be a potential complication of intestinal malab-sorption syndromes....
TRANSCRIPT
Committee on Nutrition
408 PEDIATRICS Vol. 62 No. 3 September 1978
Zinc
Zinc recently achieved the status of a micronu-
trient of established importance in human nutri-tion and medicine. Although a biological role forzinc was recognized more than 100 years ago, the
first cases of human zinc deficiency were not
described until the early 1960s. These initialreports’ -� were related to the syndrome of adoles-
cent nutritional dwarfism found in children inEgypt and Iran. However, inadequate zinc in the
diet was not appreciated as a nutritional problemin infants and children in the United States67 until
the 1970s. Recent advances in technology-con-current with and partly responsible for progressin our understanding of the physiologic roles andnutritional importance of this metal-are begin-fling to permit application of new knowledgeabout 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 enzymeshave now been identified, including at least onein 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 proteinyn”’ Although the biochemical correlates
of the features of zinc deficiency have not been
elucidated completely, adverse effects on nucleicacid metabolism and protein synthesis may beresponsible, in part, for the impaired growth and
development that are prominent signs of thezinc-deficient state both before and after birth.
Maternal zinc deficiency in the rat results inintrauterine 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 braingrowth and of subsequent learning ability and
behavioral development. ‘ � Postnatally, the mostprominent 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 isimpaired.” Zinc is necessary for normal kerato-
genesis, and zinc-deficient animals may manifestalopecia, a variety of skin lesions,’ and impairedwound healing.’� Skeletal lesions, diarrhea, and an
increased susceptibility to infection are other
documented symptoms of zinc deficiency. Zincmay participate in the synthesis, storage, and/orrelease of insulin from the beta cells. However,
the effects of zinc deficiency on plasma insulinlevels and glucose tolerance have been inconsis-
tent.’#{176}Mobilization of vitamin A from the liver isdecreased in zinc-deficient rats, and serum vita-
mm A levels are depressed.’5 Zinc is necessary for
normal growth at a cellular level, which mayexplain why the nutritional requirements for this
metal are particularly high in the young of allspecies investigated. Requirements for the youngmale animal may be higher than those for thefemale.”
Zinc Metabolism and Body Distribution
Zinc is absorbed via the small intestine. A lowmolecular 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 bodycontains approximately 2 gm of zinc, which is
about half the body content of iron and 20 timesthat of copper.” Highest concentrations of zincoccur in the choroid of the eye and in thespermatozoa. Concentrations exceeding 100 �g/gm are present in hair, nails, the prostate gland,and bone; and liver, kidney, muscle, and skin haveabout 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
equilibrium with a small amino acid-bound frac-
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AMERICAN ACADEMY OF PEDIATRICS 409
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 alsocontains substantial quantities of dietary zinc that
were not absorbed.
Dietary Sources and Nutritional
Requirements
Approximate nutiitional requirements for zinccan 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% to60% of that ingested. In general, meats and fishare the best known sources of zinc, and the zinc
from animal protein is better absorbed than thatfrom vegetable sources. Phytate and fiber in the
diet decrease the availability of the zinc for
absorption,2o and the use of soy protein as meatand milk substitutes may adversely affect zinc
nutriture. Substantial quantities of zinc can belost during food processing, such as the milling ofwheat and the refining of sugars.2’ White bread,refined sugars, vegetables other than legumes,
and fruits contain relatively little zinc. Publishedinformation on the zinc content of foods222� isnow adequate enough to permit a reasonable
estimate of total dietary zinc intake, which canvary 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 twomonths of lactation. The zinc concentration
declines further as lactation progresses. In cow’s
milk the zinc concentration ranges from 2 to 7mg/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’smilk 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 ofthe relative bioavailability of zinc from differentmilk sources.
Zinc Deficiency Encountered in PediatricPractice
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 maleinfants fed a milk formula containing less than 2mg of zinc per liter2; these formulas were in
widespread use until 1975, when it became ageneral practice to supplement them with zinc toa level equivalent to that of cow’s milk. Less
information is available on the zinc nutriture ofchildren, but some otherwise healthy school-agedchildren may have a suboptimal zinc intake, with
adverse effects on appetite, taste perception, andgrowth.” 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 parenteralnutrition without zinc supplements. Some of
these children have developed a syndrome similar
to acrodermatitis enteropathica, including anal
and orificial skin lesions, diarrhea, alopecia, anddepression.
The pathogenesis of the rare, inherited disease,acrodermatitis enteropathia, is now known to be
attributable to a serve zinc deficiency,bo�12 whichis probably secondary to an inherited defect inzinc absorption.’3 This is the most severe humanzinc 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 ina sufficient dose to overcome the deficiency. Anincreased susceptibility to infection is characteris-
tic of acrodermatitis enteropathia, and it may berelated in part to zinc-responsive defects in leuko-
cyte function.’� Women with this disease whohave survived without zinc therapy have infantswith a high incidence of congenital malforma-
tions similar to those observed in zinc-deficientrats.’5
Acquired zinc deficiency can occur as a result
of impaired absorption of this metal. The largequantities of phytate” and fiber�” in the diet of
the rural population in Iran are thought to bemajor etiologic factors in the zinc deficiency of
adolescents with nutritional dwarfism in that
country. ‘ � Although information remainssketchy, conditioned zinc deficiency appears to
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410 ZINC
be a potential complication of intestinal malab-sorption syndromes. If steatorrhea is present, zincmay 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 fromchronic blood loss, excessive sweating, or hyper-
zincuria may also lead to a significant depletion of
this metal. Hyperzincuria has been proposed as amechanism for zinc depletion in persons withsickle cell disease.4’ Excessive urinary loss of zincoccurs in a variety of other conditions, includingcatabolic states,4’ liver diseases such as acuteinfectious hepatitis,43 burns,44 diabetes mellitus,45
and the nephrotic syndrome. Ia�rogenic 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.l�i
The earliest and frequently the only sign of zincdeficiency in infants and young children is adecline in growth velocity, which may be accom-
panied by an obvious impairment of appetite.
Pica may occur,5#{176} and abnormalities of tasteperception may be demonstrable.6 When nutri-
tional zinc deficiency is severe, growth suppres-sion is severe, sexual maturation is arrested, andsymptoms may include any or all of those thatoccur 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 thisassay, a number of limitations and potential
pitfalls have to be considered:
1. The risk of sample contamination duringcollection or processing is substantial. Containerswith rubber caps should not be used.
2. The mean value for normal subjects isapproximately 90 �.&g/dl of plasma, with a lowerlimit of normal of 65 to 70 jig/dl. However,significant variations still exist between differentlaboratories. 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 ofother circumstances.
Currently, it is not known if the normal rangeof plasma zinc levels for infants is lower than thatfor children and adults.
Determination of the zinc concentration in hair
may also be useful,” but this test should not beregarded as a substitute for determining theplasma zinc levels because there is no correlation
between zinc levels in plasma and hair. However,a low hair zinc level appears to be useful in thedetection of chronic, mild zinc deficiency in
children in whom the plasma zinc level may not
necessarily be depressed at the time of a solitaryblood collection. Hair zinc concentrations less
than 70 ,�g/gm may provisionally be consideredabnormal; this may apply to levels up to 100pg/gm. However, it is not certain that these levelsalso apply to infants and toddlers. The hair
analyses should be restricted to a short section ofhair taken from close to the scalp. Hair zinc
concentrations are affected by variations in therate 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 confirmationof moderate or severe deficiency states, in the
detection of hyperzincuria, and in monitoring theresults of therapy (e.g., in acrodermatitis entero-
pathica). Serum alkaline phosphatase levels maybe depressed, and an increase in activity afterzinc 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 intakeis helpful. If the intake is or has been low and
there are nonspecific symptoms such as declininggrowth percentiles and feeding problems, a trialof 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 bodyweight per day, a quantity similar to the upperlimits of the range of normal dietary intake,5’ isprobably both adequate and safe. Somewhatlarger quantities may be needed if there isimpaired 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 theoptimal quantities of zinc for the individualpatient. Patient on long-term intravenous feedingshould have plasma zinc determinations at regu-lar intervals. If the plasma zinc levels decline (or
cannot be determined), sufficient quantity of zinc
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AMERICAN ACADEMY OF PEDIATRICS 411
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 thereare excessive losses, for example via jejunostomyfluids.
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 usedto treat infants and children without evidence ofzinc deficiency, and the dose should be sufficient
only to treat the deficiency. Although zinc thera-
py is sometimes prescribed for children withlearning 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, evenat a relatively low dose. Thus, an alternative,
soluble zinc salt, such as the acetate, should be
used. An example of a convenient solution forinfants and young children is 13 mg of zincacetate (approximately 1 mg of zinc) per millili-
ter. This dosage form can be administered in twoor 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 isprolonged), levels should be monitored, at least in
plasma, to ensure that they do not exceed thephysiologic range. Although increasing the zinc/copper ratio of rat diets has been reported as acause of hypercholesterolemia,55 this condition
appears to be related to an absolute deficiency ofcopper. Nevertheless, a gross excess of zinc caninterfere 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. Inthe 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 nutritionalzinc deficiency. Although the extent of this condi-
tion is unknown, some preventative measureshave 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 thesemeasures 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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1978;62;408Pediatrics Zinc
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