Zinc
Deficiency
A Public Health Problem? Harold H. Sandstead, MD
deficiency occurs in individuals and populations whose diets are low in sources of readily bioavailable zinc such as red meat, and high in unrefined cereals that are rich in phytate and dietary fibers. Dietary zinc deficiency was described nearly three decades ago among the poor of the Middle East. It is now known to occur in children and adolescents from widely diverse areas including Egypt, Iran, Turkey, China, Yugoslavia, Canada, and the United States; and among pregnant women from Iran, Turkey, the United Kingdom, Australia, and the United States. Major manifestations include retarded growth and development and an increased incidence of pregnancy complications. Other manifestations may include suppressed immunity, poor \s=b\ Zinc
healing, dermatitis, and impairments in neuropsychological functions. Precise information as to the numbers of people affected by dietary zinc deficiency is not available. Even so the nature of diets associated with zinc deficiency suggests that mild deficiency is common in some populations. (AJDC. 1991;145:853-859)
evidence of primary human zinc Prasad et al,1,2 who stud¬ ied Egyptian village boys. Subsequently, in 1967, the growth and sexual maturation of the zinc treatment were described.3 Coinci¬ boys following dent with the studies in Egypt, Halsted et al4 investigated the syndrome in growth-stunted adolescents from Iranian farm villages. They found that both boys and girls were affected. They also conducted controlled therapeutic trials of zinc in village schoolboys and showed that their growth improved subsequent to zinc repletion.
first unequivocal Theadolescent deficiency reported by was
improved
See also pp 860, 865, 871 and 877.
Adolescents with the Prasad-Halsted syndrome display growth retardation, delayed sexual maturation, and in most instances, iron deficiency (Figure). Plasma zinc levels are generally reduced. Measurements of zinc kinetics are severe
publication February 11, 1991. Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston. Presented at the Jack Metcoff Festschrift, Chicago, Ill, June 11,1990. Reprint requests to Department of Preventive Medicine, University of Texas Medical Branch, Ewing Hall J-09, Galveston, TX 77550\x=req-\ Accepted
for
From the
2774
(Dr Sandstead).
consistent with zinc deficiency in that isotopie tracers of zinc given intravenously rapidly disappear from the plasma, and their retention in the is Treatment with zinc and an adequate intake of other nutrients stimulated linear growth, maturation of the skeleton, and development of the genitalia and secondary sex organs to a greater extent than treatment with diet alone or diet and iron.3,4 From an examination of the settings in which the Prasad-Halsted syndrome occurs, it appears that the af¬ fected individuals represent index cases of a common problem among the poor. The syndrome is associated with poverty and the consumption of diets that include large
body prolonged.2
amounts of unleavened whole-meal wheat bread, a rich source of phytate. Red meat and other sources of highly
bioavailable zinc are infrequently consumed. In Egypt, blood loss from hookworm and schistosomiasis infections causes further impairment of zinc nutriture. In Iran, geophagia is a common practice among village children. Clay forms insoluble complexes with iron.5 Presumably, it also binds zinc and inhibits its absorption. The discovery of dietary zinc deficiency in humans pro¬ vided substantial stimulation to study the role of zinc in metabolism, human physiology, and disease. Before that time, the essentiality of zinc for plants6 and experimen¬ tal7,8 and farm animals9,10 had been established, and the impairment of zinc utilization by dietary phytate had been described in chicks.11 The following and many other studies established the essentiality of zinc for cell growth and differentiation. Lieberman et al12 were among the first to show that zinc is essential for synthesis of DNA by mammalian cells. They found that the activity of DNA polymerase was reduced in zinc-deprived kidney cells in vitro. Subsequent in vivo research disclosed that the synthesis of DNA, RNA, and proteins was suppressed in zinc-deficient rats to a greater extent than in pair-fed control rats.13"17 Similarly, zinc de¬ ficiency was found to cause reductions in activities of some enzymes that mediate these processes. Examples include thymidine kinase,18 DNA-dependent RNA polymerase,16 and aminoacyl-tRNA synthetase.19 Other studies found fewer polysomes on sucrose-density gradients of brain and liver from zinc-deficient rats than control rats.20,21 More recently the binding of zinc to strategically located cysteines and histidines in the peptide chain of auxiliary of Xenopus transcription factors was reported. Factor laevis was the first of those "finger proteins" to be recog-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/05/2015
Table 1.—Zinc Content of Common Household Portions of Selected Foods Food
Portion
Fish (flounder, tuna, salmon)
Zinc, mg
Protein, g 22.89
3
oz
3 3
oz
0.58 77.51
oz
6.48
Dark meat
3
oz
Light meat
3
oz
3
oz
3 3
oz
2.20 0.87 4.60 4.40
oz
1.70
22.08 25.34 26.82 26.72 13.02
3
oz
4.90 0.70
23.48 6.07
0.95 0.93 0.88
7.70 8.03
1 slice 1 slice
0.15 0.47
2.07 2.69
% cup Vï cup Vi cup Vi cup
2.00 1.80 1.50 3.00 3.20 0.95
Oysters Crab
6.00 16.46
Poultry Beef Pork
Bologna Liver
(chicken, beef, pork)
Whole egg Dried beans and lentils Milk Cheese (cheddar) Bread White Wheat Rice White Brown
Sixteen-year-old zinc-deficient Egyptian boy with a prepubertà! physical appearance and growth stunting. This subject was studied at US Naval Medical Research Unit 3 in Cairo, Egypt, in 963.3
nized.22 Other findings suggest that zinc mediates
en¬
zymes that degrade nucleic acids. The activity of ribonuclease is increased in tissues from zinc-deficient animals,23 while the activity of nucleoside phosphorylase is de¬ pressed by zinc deficiency.24 Further information on zinc deficiency can be found in reviews.25"27 Factors in the pathogenesis of primary zinc deficiency include the zinc content of the diet, the consumption of dietary and other substances that affect zinc bioavailability, and the homeostatic capacity of the individual to retain zinc. The zinc content of foods varies widely, as does its bioavailability. The zinc content of commonly consumed food in the United States is indicated in Table l.28 Current data29 suggest that about 50% of zinc in US diets is pro¬ vided by meat, and that beef is the principle source.30 Dairy products provide about 20%, while cereals and le¬ gumes provide most of the remainder. In contrast to om¬ nivorous diets, most of the zinc in lacto-ovo-vegetarian diets is provided by cereal products (26%), beans and nuts (26%), and milk and eggs (18%).31 A variety of substances in the diet can affect the bio¬ availability of zinc. Inhibitors include phytate (hexaphosphate inositol), oxalate, certain components of dietary fi¬ ber, products of Maillard browning, phosphopeptide products of the digestion of casein, ferrous iron, calcium, copper, and cadmium.32"37 Facilitators include digestible
dietary proteins, histidine, cysteine, citrate, picolinate, ethylenediaminetetraacetic acid.38"41 Phytate is believed by many investigators to be the most important dietary inhibitor of zinc bioavailability. It is present in many food products that are derived from and
Cornmeal (cooked) Oatmeal (cooked) Bran flakes (40%) Corn flakes *Source: United States Handbooks, 1976-1988.
1
large
1/2 cup 1 cup 1
oz
1
oz
0.35 0.60 0.15 0.58 1.16
1
oz
0.03
7.05
Department of Agriculture; Agricultural
plants.
Whole grain cereals and legumes are the major of phytate for humans. The inhibitory effects of phytate and calcium on zinc nutriture were first described in chicks and rats.11,42 It is now known that phytate com¬ plexes with zinc and calcium together at alkaline pH to form highly insoluble compounds.35 The inhibition of hu¬ man zinc absorption by phytate was suggested by the find¬ ings of Reinhold et al, in which diets rich in phytate low¬ ered zinc retention. Subsequent zinc tolerance tests in humans confirmed that foods rich in phytate reduce zinc absorption.44 More recently, Turnland et al45 showed that sodium-phytate suppresses the retention of stable isotopie tracers of zinc by humans. Semiquantitative studies by Sandström et al46 indicate that retention of zinc is inversely related to the level of dietary phytate. They fed subjects 80-g meals of rye, barley, oatmeal, triticale, or whole wheat that were labeled with zinc 65 and measured retention of the isotope 14 days later using wholebody counting technology. The retention of zinc was in¬ versely proportional to the amount of phytate present in the meal. For example, an intake of 600 µ of phytate was associated with a retention of 8%, while a phytate intake of 100 µ was associated with a retention of 25%. These in¬ vestigators had previously shown that 16 hours of leavening caused a substantial reduction in phytate in whole-wheat bread and a doubling of zinc 65 retention from a standard meal.47 Sandström et al48 also found that the impact of phytate from beans on zinc retention was less than that of sources
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/05/2015
Table 2.—Factorial Basis of Provisional
Requirements of Dietary Zinc in Assumed
Losses and
Availability*
Daily Dietary Requirement as a Available
Peak
Age Infants,
1-10 11-17 3=18
Urinary
Sweat
Total
Function of
'
Required, mg_10%
Retention, mg
Excretion, mg
Excretion, mg
0.35
0.2
0.4 0.4
0.5 0.5
1.25 1.1
12.5 11.0
0.2 0.8 0.2
0.4 0.5 0.5
1.0 1.5
1.6 2.8 2.2
0.15 0.65 0.2 0.2
0.4
0.5 0.5 0.5
1.0 1.5 1.5 1.5
1.55 2.65 2.2 2.2
15.5 26.5 22.0 22.0
0.5 0.5 0.5 0.5
1.5 1.5 1.5 1.5
20%
40%
6.3
3.1
5.5
2.8
16.0
8.0
4.0
28.0 22.0
14.0
7.0
11.0
5.5
7.8
3.9
13.3
6.6 5.5 5.5
mo
0-4 5-12
Boys,
Daily
Zinc, mg
y
Girls, y 1-9
10-13 14-16 3=17
Pregnant women, wk of gestation
1.5
11.0 11.0
2.55 25.5 12.8 6.4 2.9 29.0 14.5 7.3 30-40 3.0 30.0 15.0 7.5 5.45 54.5 27.3 13.7 Lactating women "The above estimates are based on the assumption that the fat-free tissue concentration of zinc in man is approximately 30 µg/g. This figure is equivalent to 2.0 g of zinc in the soft tissues of an adult male and 1.2 gin the softintissues of an adult female, as determined from lean body mass. The zinc requirement at various ages was determined from the change lean body mass with age. Bone zinc was not included in these calculations, because it is relatively sequestered from the metabolically active pool of body zinc. The excretion of zinc 1 in sweat is based on an assumed zinc content in sweat of mg/L. The estimated requirement for lactation is based on a zinc content in milk of 5 mg/L and a daily milk secretion of 650 mL. The urinary excretions or zinc are based on levels reported.43
0-20
0.55
20-30
0.9 1.0 3.45
phytate from cereal products. The effects of relatively small intakes of wheat bran on zinc retention were shown by balance studies in which 20 normal men were fed 26 g of wheat bran daily as part of a mixed diet
of conventional North American foods. Zinc retention was measured in intervals of 26 to 30 days. The phytate content of the control diet was 0.29 mmol daily compared with 1.42 mmol daily in the experimental diets. Analysis of covariance, with dietary zinc as the covariate, revealed that zinc retention was reduced substantially (P
Deficiency
A Public Health Problem? Harold H. Sandstead, MD
deficiency occurs in individuals and populations whose diets are low in sources of readily bioavailable zinc such as red meat, and high in unrefined cereals that are rich in phytate and dietary fibers. Dietary zinc deficiency was described nearly three decades ago among the poor of the Middle East. It is now known to occur in children and adolescents from widely diverse areas including Egypt, Iran, Turkey, China, Yugoslavia, Canada, and the United States; and among pregnant women from Iran, Turkey, the United Kingdom, Australia, and the United States. Major manifestations include retarded growth and development and an increased incidence of pregnancy complications. Other manifestations may include suppressed immunity, poor \s=b\ Zinc
healing, dermatitis, and impairments in neuropsychological functions. Precise information as to the numbers of people affected by dietary zinc deficiency is not available. Even so the nature of diets associated with zinc deficiency suggests that mild deficiency is common in some populations. (AJDC. 1991;145:853-859)
evidence of primary human zinc Prasad et al,1,2 who stud¬ ied Egyptian village boys. Subsequently, in 1967, the growth and sexual maturation of the zinc treatment were described.3 Coinci¬ boys following dent with the studies in Egypt, Halsted et al4 investigated the syndrome in growth-stunted adolescents from Iranian farm villages. They found that both boys and girls were affected. They also conducted controlled therapeutic trials of zinc in village schoolboys and showed that their growth improved subsequent to zinc repletion.
first unequivocal Theadolescent deficiency reported by was
improved
See also pp 860, 865, 871 and 877.
Adolescents with the Prasad-Halsted syndrome display growth retardation, delayed sexual maturation, and in most instances, iron deficiency (Figure). Plasma zinc levels are generally reduced. Measurements of zinc kinetics are severe
publication February 11, 1991. Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston. Presented at the Jack Metcoff Festschrift, Chicago, Ill, June 11,1990. Reprint requests to Department of Preventive Medicine, University of Texas Medical Branch, Ewing Hall J-09, Galveston, TX 77550\x=req-\ Accepted
for
From the
2774
(Dr Sandstead).
consistent with zinc deficiency in that isotopie tracers of zinc given intravenously rapidly disappear from the plasma, and their retention in the is Treatment with zinc and an adequate intake of other nutrients stimulated linear growth, maturation of the skeleton, and development of the genitalia and secondary sex organs to a greater extent than treatment with diet alone or diet and iron.3,4 From an examination of the settings in which the Prasad-Halsted syndrome occurs, it appears that the af¬ fected individuals represent index cases of a common problem among the poor. The syndrome is associated with poverty and the consumption of diets that include large
body prolonged.2
amounts of unleavened whole-meal wheat bread, a rich source of phytate. Red meat and other sources of highly
bioavailable zinc are infrequently consumed. In Egypt, blood loss from hookworm and schistosomiasis infections causes further impairment of zinc nutriture. In Iran, geophagia is a common practice among village children. Clay forms insoluble complexes with iron.5 Presumably, it also binds zinc and inhibits its absorption. The discovery of dietary zinc deficiency in humans pro¬ vided substantial stimulation to study the role of zinc in metabolism, human physiology, and disease. Before that time, the essentiality of zinc for plants6 and experimen¬ tal7,8 and farm animals9,10 had been established, and the impairment of zinc utilization by dietary phytate had been described in chicks.11 The following and many other studies established the essentiality of zinc for cell growth and differentiation. Lieberman et al12 were among the first to show that zinc is essential for synthesis of DNA by mammalian cells. They found that the activity of DNA polymerase was reduced in zinc-deprived kidney cells in vitro. Subsequent in vivo research disclosed that the synthesis of DNA, RNA, and proteins was suppressed in zinc-deficient rats to a greater extent than in pair-fed control rats.13"17 Similarly, zinc de¬ ficiency was found to cause reductions in activities of some enzymes that mediate these processes. Examples include thymidine kinase,18 DNA-dependent RNA polymerase,16 and aminoacyl-tRNA synthetase.19 Other studies found fewer polysomes on sucrose-density gradients of brain and liver from zinc-deficient rats than control rats.20,21 More recently the binding of zinc to strategically located cysteines and histidines in the peptide chain of auxiliary of Xenopus transcription factors was reported. Factor laevis was the first of those "finger proteins" to be recog-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/05/2015
Table 1.—Zinc Content of Common Household Portions of Selected Foods Food
Portion
Fish (flounder, tuna, salmon)
Zinc, mg
Protein, g 22.89
3
oz
3 3
oz
0.58 77.51
oz
6.48
Dark meat
3
oz
Light meat
3
oz
3
oz
3 3
oz
2.20 0.87 4.60 4.40
oz
1.70
22.08 25.34 26.82 26.72 13.02
3
oz
4.90 0.70
23.48 6.07
0.95 0.93 0.88
7.70 8.03
1 slice 1 slice
0.15 0.47
2.07 2.69
% cup Vï cup Vi cup Vi cup
2.00 1.80 1.50 3.00 3.20 0.95
Oysters Crab
6.00 16.46
Poultry Beef Pork
Bologna Liver
(chicken, beef, pork)
Whole egg Dried beans and lentils Milk Cheese (cheddar) Bread White Wheat Rice White Brown
Sixteen-year-old zinc-deficient Egyptian boy with a prepubertà! physical appearance and growth stunting. This subject was studied at US Naval Medical Research Unit 3 in Cairo, Egypt, in 963.3
nized.22 Other findings suggest that zinc mediates
en¬
zymes that degrade nucleic acids. The activity of ribonuclease is increased in tissues from zinc-deficient animals,23 while the activity of nucleoside phosphorylase is de¬ pressed by zinc deficiency.24 Further information on zinc deficiency can be found in reviews.25"27 Factors in the pathogenesis of primary zinc deficiency include the zinc content of the diet, the consumption of dietary and other substances that affect zinc bioavailability, and the homeostatic capacity of the individual to retain zinc. The zinc content of foods varies widely, as does its bioavailability. The zinc content of commonly consumed food in the United States is indicated in Table l.28 Current data29 suggest that about 50% of zinc in US diets is pro¬ vided by meat, and that beef is the principle source.30 Dairy products provide about 20%, while cereals and le¬ gumes provide most of the remainder. In contrast to om¬ nivorous diets, most of the zinc in lacto-ovo-vegetarian diets is provided by cereal products (26%), beans and nuts (26%), and milk and eggs (18%).31 A variety of substances in the diet can affect the bio¬ availability of zinc. Inhibitors include phytate (hexaphosphate inositol), oxalate, certain components of dietary fi¬ ber, products of Maillard browning, phosphopeptide products of the digestion of casein, ferrous iron, calcium, copper, and cadmium.32"37 Facilitators include digestible
dietary proteins, histidine, cysteine, citrate, picolinate, ethylenediaminetetraacetic acid.38"41 Phytate is believed by many investigators to be the most important dietary inhibitor of zinc bioavailability. It is present in many food products that are derived from and
Cornmeal (cooked) Oatmeal (cooked) Bran flakes (40%) Corn flakes *Source: United States Handbooks, 1976-1988.
1
large
1/2 cup 1 cup 1
oz
1
oz
0.35 0.60 0.15 0.58 1.16
1
oz
0.03
7.05
Department of Agriculture; Agricultural
plants.
Whole grain cereals and legumes are the major of phytate for humans. The inhibitory effects of phytate and calcium on zinc nutriture were first described in chicks and rats.11,42 It is now known that phytate com¬ plexes with zinc and calcium together at alkaline pH to form highly insoluble compounds.35 The inhibition of hu¬ man zinc absorption by phytate was suggested by the find¬ ings of Reinhold et al, in which diets rich in phytate low¬ ered zinc retention. Subsequent zinc tolerance tests in humans confirmed that foods rich in phytate reduce zinc absorption.44 More recently, Turnland et al45 showed that sodium-phytate suppresses the retention of stable isotopie tracers of zinc by humans. Semiquantitative studies by Sandström et al46 indicate that retention of zinc is inversely related to the level of dietary phytate. They fed subjects 80-g meals of rye, barley, oatmeal, triticale, or whole wheat that were labeled with zinc 65 and measured retention of the isotope 14 days later using wholebody counting technology. The retention of zinc was in¬ versely proportional to the amount of phytate present in the meal. For example, an intake of 600 µ of phytate was associated with a retention of 8%, while a phytate intake of 100 µ was associated with a retention of 25%. These in¬ vestigators had previously shown that 16 hours of leavening caused a substantial reduction in phytate in whole-wheat bread and a doubling of zinc 65 retention from a standard meal.47 Sandström et al48 also found that the impact of phytate from beans on zinc retention was less than that of sources
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/05/2015
Table 2.—Factorial Basis of Provisional
Requirements of Dietary Zinc in Assumed
Losses and
Availability*
Daily Dietary Requirement as a Available
Peak
Age Infants,
1-10 11-17 3=18
Urinary
Sweat
Total
Function of
'
Required, mg_10%
Retention, mg
Excretion, mg
Excretion, mg
0.35
0.2
0.4 0.4
0.5 0.5
1.25 1.1
12.5 11.0
0.2 0.8 0.2
0.4 0.5 0.5
1.0 1.5
1.6 2.8 2.2
0.15 0.65 0.2 0.2
0.4
0.5 0.5 0.5
1.0 1.5 1.5 1.5
1.55 2.65 2.2 2.2
15.5 26.5 22.0 22.0
0.5 0.5 0.5 0.5
1.5 1.5 1.5 1.5
20%
40%
6.3
3.1
5.5
2.8
16.0
8.0
4.0
28.0 22.0
14.0
7.0
11.0
5.5
7.8
3.9
13.3
6.6 5.5 5.5
mo
0-4 5-12
Boys,
Daily
Zinc, mg
y
Girls, y 1-9
10-13 14-16 3=17
Pregnant women, wk of gestation
1.5
11.0 11.0
2.55 25.5 12.8 6.4 2.9 29.0 14.5 7.3 30-40 3.0 30.0 15.0 7.5 5.45 54.5 27.3 13.7 Lactating women "The above estimates are based on the assumption that the fat-free tissue concentration of zinc in man is approximately 30 µg/g. This figure is equivalent to 2.0 g of zinc in the soft tissues of an adult male and 1.2 gin the softintissues of an adult female, as determined from lean body mass. The zinc requirement at various ages was determined from the change lean body mass with age. Bone zinc was not included in these calculations, because it is relatively sequestered from the metabolically active pool of body zinc. The excretion of zinc 1 in sweat is based on an assumed zinc content in sweat of mg/L. The estimated requirement for lactation is based on a zinc content in milk of 5 mg/L and a daily milk secretion of 650 mL. The urinary excretions or zinc are based on levels reported.43
0-20
0.55
20-30
0.9 1.0 3.45
phytate from cereal products. The effects of relatively small intakes of wheat bran on zinc retention were shown by balance studies in which 20 normal men were fed 26 g of wheat bran daily as part of a mixed diet
of conventional North American foods. Zinc retention was measured in intervals of 26 to 30 days. The phytate content of the control diet was 0.29 mmol daily compared with 1.42 mmol daily in the experimental diets. Analysis of covariance, with dietary zinc as the covariate, revealed that zinc retention was reduced substantially (P
