Evaluation of zinc metabolism with use of stable-isotope techniques: implications for the assessment of zinc status
K Michael Hambidge, Nancy F Krebs, and Leland Miller
ABSTRACT: Zinc stable isotopes can be applied to the identification of populations at risk for zinc deficiency and to monitoring the effects of zinc intervention studies designed to improve zinc nutriture. Techniques using these isotopes can provide information on how effectively the intestine is absorbing exogenous dietary zinc and conserving endogenous zinc. They can also yield estimates of the quantity of readily exchangeable zinc in the body. Data derived from stable-isotope studies can provide extensive information on zinc status and the bioavailability of dietary zinc, allowing researchers to relate zinc intake to physiologic and pathologic conditions. Application of these techniques in longitudinal studies can provide quantitative data on the effectiveness of prevention programs such as simple community measures aimed at reducing dietary phytate and zinc fortification and supplementation programs. Further, judicious application of zinc stable-isotope techniques could make an important contribution to progress toward the eradication of zinc deficiency in infants and young children in the developing world. Am J Clin Nutr 1998;68(suppl):410S-13S.
Plasma zinc as a predictor of diarrheal and respiratory morbidity in children in an urban slum setting
Rajiv Bahl, Nita Bhandari, K Michael Hambidge, and Maharaj K Bhan
ABSTRACT: The association between low initial plasma zinc concentration and risk of morbidity over the subsequent 3 mo was examined in a cohort of 116 children aged 1259 mo recovering from acute diarrhea. Children with low initial plasma zinc (£ 8.4 mmol/L) had more episodes of diarrhea [risk ratio (RR): 1.47; 95% CI: 1.03, 2.49) and severe diarrhea, defined as passage of ³ 5 liquid stools in a 24-h period, (RR: 1.70; 95% CI: 1.06, 2.72) than did children with normal plasma zinc (> 8.4 mmol/L). mean prevalence rate of diarrhea associated with fever was 4 times higher in the zinc-deficient group (P = 0.01). Overall, the difference in the number of episodes of acute lower respiratory tract infections (ALRIs) between the two groups was not statistically significant (RR: 1.76; 95% CI: 0.883.53) but the mean prevalence rate of ALRIs was 3.5 times higher in children with low plasma zinc (P = 0.05). The increased risk of diarrhea and ALRIs episodes in zinc-deficient children was larger in boys than in girls. These results show that children with low plasma zinc concentrations are at risk for increased diarrheal and respiratory morbidity. Am J Clin Nutr 1998;68(suppl):414S-17S.
Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil
Pedro IC Lira, Ann Ashworth, and Saul S Morris
ABSTRACT: In Brazil, the highest incidence of low birth weight (LBW) occurs in the northeast, and diarrhea and respiratory infections are the main causes of infant mortality and morbidity. We hypothesized that LBW infants may be zinc deficient, and that this might be adversely affecting their immune function, morbidity, and postnatal growth. We therefore examined the effect of zinc supplementation on these outcomes during the first 6 mo of life. LBW full-term infants (mean birth weight 2337 g) were given daily for 8 wk either 5 mg Zn (n = 71), 1 mg Zn (n = 68), or a placebo (n = 66). Morbidity was determined prospectively through daily home visits (except on Sunday) during weeks 08, then twice weekly in weeks 926. Anthropometric measurements were made at 0, 4, 8, 17, and 26 wk. Immune function was assessed at 8 wk by the phytohemagglutinin skin test. Supplementation (5 mg Zn) was associated with a 28% reduction in diarrhea prevalence over the 6-mo period [after adjustment for confounders (P = 0.043)], and a 33% reduction in the prevalence of cough (NS, adjusted prevalence P = 0.073). All infants had a positive immune response at 8 wk. Although supplementation had no significant effect on weight and length gains from 0 to 26 wk, infants given 5 mg Zn gained more weight than infants given placebo during weeks 1726 (P = 0.024, analysis of variance). There was no effect on any outcome with 1 mg Zn. We conclude that 5 mg Zn/d is of benefit to LBW, full-term infants who only have a modest weight deficit. Am J Clin Nutr 1998;68(suppl):418S-24S.
Effect of infections on plasma zinc concentration and implications for zinc status assessment in low-income countries
Kenneth H Brown
ABSTRACT: The development of intervention programs to control zinc deficiency is hampered by the lack of sensitive, specific, low-cost indicators of zinc status. The mean plasma zinc concentration of groups of individuals has been suggested as a possible indicator of a populations zinc status because the plasma zinc concentration seems to predict whether growth will increase in response to zinc supplementation. However, experimental studies in both animal models and adult human volunteers as well as clinical studies of infected and noninfected adults indicate that systemic infections that produce an acute phase response also cause the plasma zinc concentration to fall. Therefore, concerns have been raised about the usefulness of plasma zinc concentration as an indicator of zinc status in populations with high prevalences of infections. By contrast with the aforementioned studies in adults, cross-sectional, community-based surveys of children with and without common infections have not found any association between the presence of infection and plasma zinc concentration, possibly because the severity of those infections observed in children in field settings was less than that of the infections studied in adults. Thus, it appears that the mean plasma zinc concentration may be a useful indicator of population zinc status for children in low-income countries despite the high prevalence of common childhood infections encountered in these settings. Am J Clin Nutr 1998;68(suppl):425-9S.
Assessment of dietary zinc in a population
RS Gibson and EL Ferguson
ABSTRACT: Assessment of dietary zinc status in a population requires several steps, consisting of the measurement of food intake distributions in the population; the analysis of local staple foods, from which zinc intake distributions can be determined, and the comparison of zinc intakes with requirement estimates to determine the risk of inadequate intakes. In low-income countries, these steps may be complicated by the lack of preexisting food-composition data, variations in food preparation methods, inhibition of absorption by other compounds in the diet, and variations in intake among seasons, individuals, and populations. Different techniques for determining the adequacy of zinc intake are compared. Whereas the techniques described in this paper allow for the determination of probability estimates for risk of zinc inadequacy, they do not allow for the identification of actual individuals in a population who are zinc deficient, or define the severity of zinc inadequacy. This information is vital, especially in areas where zinc deficiency is but one of many health problems, and can be obtained only from more detailed biochemical and physiologic studies of zinc status. Am J Clin Nutr 1998;68(suppl):430S-4S.
Interactions between zinc and vitamin A: an update
Parul Christian and Keith P West Jr
ABSTRACT: Zinc status influences several aspects of vitamin A metabolism, including its absorption, transport, and utilization. Two common mechanisms postulated to explain this dependence relate to 1) the regulatory role of zinc in vitamin A transport mediated through protein synthesis, and 2) the oxidative conversion of retinol to retinal that requires the action of a zinc-dependent retinol dehydrogenase enzyme. However, evidence of an effect of zinc intake on vitamin A status from animal experiments is inconclusive, mainly because of the use of inadequate control groups. The higher weight gain of control animals as compared with the zinc-deficient ones in these experiments, even though pair fed, makes it difficult to isolate effects of zinc deficiency per se from those of generalized protein-energy malnutrition. A curvilinear relation has been suggested to describe an effect of plasma zinc on vitamin A transport. In humans, cross-sectional studies have more often than not shown a weak linkage between vitamin A and zinc status. Randomized trials have failed to show a consistent effect of zinc supplementation on vitamin A status. In disease states in which liver function is severely compromised and both zinc and vitamin A metabolism and transport are impaired, serum zinc and vitamin A concentrations tend to be positively correlated. In conclusion, clear evidence of synergy between these 2 micronutrients and its public health significance in humans is lacking. Research should focus on understanding this interaction in the context of coexisting moderate-to-severe zinc and vitamin A deficiencies in the population. Am J Clin Nutr 1998;68(suppl):435S-41S.
Iron and zinc interactions in humans
ABSTRACT: Iron deficiency is the most common nutritional deficiency in the world; zinc deficiency is associated with poor growth and development and impaired immune response. Several Third World countries are taking measures to increase the dietary intake of iron and zinc with fortification of foods or dietary supplements. Several studies showed that high iron concentrations can negatively affect zinc absorption in adults when these trace minerals are given in solution. However, when iron and zinc are given in a meal, this effect is not observed. Solomons (J Nutr 1986;116:92735) postulated that the total amount of ionic species affects the absorption of zinc and that a total dose of > 25 mg Fe may produce a measurable effect on zinc absorption. This could occur if iron supplements are taken with a meal, and iron experts recommend that iron supplements be taken between meals. Recent studies using stable isotopes showed that fortifying foods with iron at current fortification amounts has no adverse effect on zinc absorption. There are 5 zinc salts listed as generally recommended as safe (GRAS) by the US Food and Drug Administration for food fortification. From 1970 to 1987, the total poundage of zinc salts used in food continually increased, with zinc oxide and zinc sulfate showing the largest increases. Twelve iron sources are listed as GRAS; elemental iron has become the source of choice because it is less expensive to produce and has fewer organoleptic problems. Use of ferrous fumarate is also increasing. Am J Clin Nutr 1998;68(suppl):442S-6S.
Zinc and immune function: the biological basis of altered resistance to infection
Anuraj H Shankar and Ananda S Prasad
ABSTRACT Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th 1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation. Am J Clin Nutr 1998; 68(suppl):447S-63S.
Zinc deficiency and child development
Maureen M Black
ABSTRACT Zinc is a trace metal that is present in the brain and contributes to its structure and function. Limited evidence from both animal and human studies suggests that zinc deficiency may lead to delays in cognitive development. Although the mechanisms linking zinc deficiency with cognitive development are unclear, it appears that zinc deficiency may lead to deficits in childrens neuropsychologic functioning, activity, or motor development, and thus interfere with cognitive performance. In this article a model is presented that incorporates the influence of social context and the caregiving environment and suggests that the relation between zinc deficiency and cognitive development may vary by age in children and may be mediated by neuropsychologic functioning, activity, and motor development. Suggestions for further research are provided. Am J Clin Nutr 1998;68(suppl):464S-9S.
Effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of Chinese children
Harold H Sandstead, James G Penland, Nancy W Alcock, Hari H Dayal, Xue C Chen, Jui S Li, Faji Zhao, and Jia J Yang
ABSTRACT The knowledge that zinc is essential for growth and neuropsychologic performance and a report of zinc-responsive stunting in Chinese children prompted this project. This article summarizes findings from a 10-wk, double-blind, controlled trial of zinc repletion in 740 urban, 69-y-old first graders from low-income families in Chongqing, Qingdao, and Shanghai, Peoples Republic of China. Treatments were 20 mg Zn alone (Z), 20 mg Zn with micronutrients (ZM), and micronutrients alone (M). The M mixture was based on National Academy of Sciences guidelines. Nutrients that might interfere with zinc retention were excluded or given in lower amounts. Main outcomes were changes in neuropsychologic performance and knee height. Hemoglobin, serum ferritin, plasma and hair zinc, and whole blood and hair lead were also measured. Anemia was not common, and serum ferritin concentrations were usually within the range of normal. Mean baseline plasma zinc concentrations were marginal in children from Chongqing and Qingdao and normal in children from Shanghai. After treatment with ZM or M plasma zinc increased. Hair zinc tended to decrease after all treatments. Mean baseline whole blood lead concentrations were slightly below the limit considered excessive for children by the US Centers for Disease Control and Prevention. Neuropsychologic performance and growth were most improved after treatment with ZM. These findings were consistent with the presence of micronutrient deficiencies. Am J Clin Nutr 1998;68(suppl):470S-5S.
Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries
Robert E Black
ABSTRACT In children in developing countries, zinc deficiency may be common and associated with immune impairment and increased risk of serious infectious diseases such as diarrhea, pneumonia, and malaria. Studies have evaluated the therapeutic effects of zinc supplementation during acute or persistent diarrhea. In studies of acute diarrhea, the illness duration has been found to be 923% shorter in zinc-supplemented than in control children. Diarrhea was also less severe in zinc-supplemented children. In studies of persistent diarrhea, the effect sizes were similar but were often not statistically significant, perhaps because of the small number of children participating in these studies. Trials that provided continuous daily zinc supplementation for 515 mo evaluated effects on the incidence of diarrhea and in some studies acute lower respiratory infections and malaria. The reduction in the incidence of diarrhea in the zinc-supplemented group in these studies ranged from 8% to 45%. A study that gave 2 wk of zinc supplementation found preventive effects against diarrhea for the 3 mo of surveillance. More limited data also suggest that the incidence of acute lower respiratory infection and clinical attacks of malaria may also be reduced by zinc supplementation. If these results are confirmed by meta-analysis of the existing trials and additional research, improvement of zinc nutriture should become a priority intervention to reduce the high burden of serious infectious disease in children in developing countries. Am J Clin Nutr 1998;68(suppl):476S-9S.
Possibilities for zinc in the treatment of acute diarrhea
George J Fuchs
ABSTRACT Zinc therapy shows promise in the treatment of acute diarrhea. Several questions must be answered before it can be incorporated into diarrheal disease control programs, namely, whether it should be targeted at the groups of children in whom it has been shown to work and what the optimal dosing regimen should be, the amount of therapeutic zinc, optimal duration of therapy, and the interaction of zinc and copper absorption. The evidence supporting inclusion of zinc in treatment programs is strong and may become more so when these questions are answered. Am J Clin Nutr 1998;68(suppl):480S-3S.
Dietary interventions to prevent zinc deficiency
Rosalind S Gibson, Fiona Yeudall, Nancy Drost, B Mtitimuni, and T Cullinan
ABSTRACT This review describes household dietary strategies to improve the content and bioavailability of zinc in predominantly plant-based diets and the implementation of these strategies in a community-based dietary intervention study in rural southern Malawi. The strategies involve increasing intakes of foods with high bioavailable-zinc contents, absorption enhancers, or both and using germination, fermentation, and soaking to reduce intake of phytic acid, a potent inhibitor of zinc absorption. The strategies were implemented at the household level in Malawi through a participatory research process that focused on building relationships with the community and involving them in the design, implementation, and monitoring and evaluation processes. In this way, community participation and awareness of zinc deficiency might be enhanced and the dietary strategies planned will be appropriate and sustainable. Am J Clin Nutr 1998;68(suppl):484S-7S.
Plant breeding: a long-term strategy for the control of zinc deficiency in vulnerable populations
Marie T Ruel and Howarth E Bouis
ABSTRACT Because trace minerals are important not only for human nutrition but for plant nutrition as well, plant breeding holds great promise for making a significant, sustainable, low-cost contribution to the reduction of micronutrient deficiencies in humans. It may also have important spinoff effects for increasing farm productivity in developing countries in an environmentally beneficial way. This article describes ongoing plant breeding research that could increase the intake of bioavailable zinc from food staple crops in vulnerable populations in developing countries. The three most promising plant breeding strategies toward this goal are as follows: 1) increasing the concentration of zinc, 2) reducing the amount of phytic acid (a strong inhibitor of zinc absorption), and 3) raising the concentrations of sulfur-containing amino acids (thought to promote zinc absorption) in the plant. The agronomic advantages and disadvantages as well as the potential benefits and limitations of each approach for human nutrition are described. Research is currently underway to identify the optimal combination of these approaches that will maximize the effect on human zinc nutrition. Am J Clin Nutr 1998;68(suppl):488S-94S.
Zinc and micronutrient supplements for children
Lindsay H Allen
ABSTRACT Provision of zinc supplements to children should be considered in the presence of a diet low in absorbable zinc; severe stunting, low plasma zinc, or both; or persistent diarrhea. Inadequate zinc intakes are highly prevalent in developing countries, especially during the period of complementary feeding when zinc requirements are high and breast milk con-tributes little. To date, systematic evaluation of the acceptability of different zinc salts used as supplements is lacking. Some zinc salts are unpalatable and cause problems, such as nausea, at higher doses. Zinc carbonate and oxide are insoluble and poorly absorbed. Little information on the bioavailability of different zinc supplements in the presence of dietary inhibitors of zinc absorption exists. More information is needed on the quantity and frequency of dosing. Consideration should be given to the routine inclusion of zinc in iron supplements provided to children and to the simultaneous inclusion of other micronutrients in zinc supplements. Am J Clin Nutr 1998;68(suppl):495S-8S.
Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival
Laura E Caulfield, Nelly Zavaleta, Anuraj H Shankar, and Mario Merialdi
ABSTRACT Mild-to-moderate zinc deficiency may be relatively common worldwide, but the public health importance of this zinc deficiency is not well defined. The purpose of this review was to provide a conceptual framework for evaluating the public health importance of maternal zinc deficiency as it relates to fetal growth and development, complications of pregnancy, labor and delivery, and maternal and infant health. The mechanisms through which zinc deficiency could influence health out-comes are well described. The results of experimental studies conducted in animal models have motivated concern about the potential health effects of mild-to-moderate maternal zinc deficiency. Observational studies in human populations have produced strong associations between poor maternal zinc status and various indicators of poor pregnancy outcome, but supplementation trials have not produced strong, or even consistent results. Supplementation trials are needed to define the public health importance of maternal zinc deficiency worldwide. Am J Clin Nutr 1998;68(suppl):499S-508S.
Zinc supplementation during lactation
Nancy F Krebs
ABSTRACT The requirements for zinc during lactation are greater than those during pregnancy, especially during the early weeks postpartum. Therefore, lactation poses a significant threat to maternal zinc homeostasis, particularly in populations with chronically low dietary zinc intakes. The current knowledge of maternal zinc status in lactation, particularly in developing countries, is reviewed herein with emphasis on the effects of zinc supplementation trials. The studies that have examined the zinc status of breast-fed infants are also reviewed. Am J Clin Nutr 1998;68(suppl):509S-12S.
Moving from science to public health programs: lessons from vitamin A
ABSTRACT The transition from research to the applications of its results is a difficult one. Several stages must be passed through before a discovery can be put to practical use. The development of the current standards for vitamin A is a good example of both a successful and a difficult transition. The importance of the public media and of international organizations, especially the World Health Organization, in any transition is noted. Movement from research to practical applications requires that scientists take an active, sensible leadership role, that mechanisms for disseminating information and for bringing about scientific consensus are used effectively, and that international funding and support agencies take a role. Am J Clin Nutr 1998;68(suppl):513S-6S.