Zinc – an essential micronutrient for health and development

28 Zinc – an essential micronutrient for health and development Sunil Sazawal and Pratibha Dhingra

Sunil Sazawal, MD, MPH, PhD, is an Associate Professor, Johns Hopkins Bloomberg School of Public Health; Visiting Professor, Annamalai University, India; and the Director, Center for Micronutrient Research, New Delhi, India. Dr Sazawal is a physician by profession and has more than 20 years of research experience in conducting clinical and community-based trials of micronutrient interventions, especially in role of zinc and iron in reducing infectious diseases and mortality in children. Pratibha Dhingra, PhD, is a Senior Research Scientist at the Center for Micronutrient Research, New Delhi, India. Dr Dhingra has more than 16 years of research experience in community-based health projects, with a special focus on role of micronutrients in preventing and improving the health, growth and development of children.

&.1

Introduction

Zinc is an essential micronutrient for all forms of life and plays a critical structural and functional role in multiple enzyme systems involved in gene expression, cell division and growth, immunologic and reproductive functions. Clinical zinc deficiency in humans was first described in Iran in 1961, when the consumption of diets with low zinc bioavailability due to high phytic acid content was associated with delayed sexual development and “adolescent nutritional dwarfism” [1] and later recognized in a group of patients from Egypt with hypogonadism, anemia and hepatosplenomegaly [2]. Since then, zinc insufficiency has been recognized as an important public health issue, especially in developing countries [3].

&.

Biological functions of zinc

Zinc occurs in divalent state (Zn++) and is a bluish white metallic element (atomic number 30, atomic weight 65.4), which makes up about 0.002%

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of the earth’s crust and is the 23rd most abundant element. Zinc is associated with more than 200 distinct metalloenzymes, which have a diverse range of functions, including the synthesis of nucleic acids and specific proteins, such as hormones and their receptors [4]. Zinc also chelates with the amino acids cysteine and histidine, forming ‘zinc fingers’ that are important for protein transcription. Additional processes that are regulated by zinc include expression of the metallothionein gene, apoptosis and synaptic signaling. Zinc plays an important role in human metabolism and in the perpetuation of genetic material, including transcription of DNA, translation of RNA, and ultimately cellular division. Zinc deficiency at the gene regulatory level probably provides the common mechanism for many of the clinical signs of zinc deficiency such as growth failure, skin abnormalities and other signs that occur in various organs and organ systems. Of auxiliary interest is the absence of redox properties in zinc, which allows it to be transported in biological systems without inducing oxidant damage, as can occur with other trace elements, such as iron and copper.

28.3

Public health significance

Zinc Investigators’ Collaborative Group, 2000 [5] has emphasized the significance of zinc in human nutrition and public health due to its role in normal growth/tissue repair; neural, cognitive and sexual development; immune function, resistance to disease and stress. Estimates indicate that approximately 20.5% of the world’s population might be at risk of zinc deficiency [6]. Zinc affects health, mental/physical function, and survival of more than two billion people worldwide and ranks fifth in the leading risk factors for illness and disease in developing countries with high mortality [7]. Zinc deficiency is estimated to be responsible for 453,207 deaths globally [8]. Of these, 260,502 occur in Africa, 182,546 in Asia and 10,159 in Latin America. Zinc deficiency is considered responsible for 14.4% of diarrhea deaths, 10.4% of malaria deaths and 6.7% of pneumonia deaths among children between 6 months and 5 years of age [8]. A loss of nearly 16 million global disability-adjusted life years (DALYs) is attributed to zinc deficiency [9]. In India, estimated population at risk of inadequate zinc intake is as much as 25.9 % which is considered to be high risk category [7].

28.4

Zinc epidemiology

The epidemiological data on zinc deficiency has lagged behind that for other more well known vitamin and mineral deficiencies because of lack of scientific, practical, and accepted indicators for zinc deficiency. Population-based surveys have not been undertaken, marginal zinc

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deficiency is not characterized by a highly specific deficiency syndrome and severe clinical deficiency in humans is rare. Importance of mild zinc deficiency has been documented in the last decade in clinical trials of zinc supplementation. Risk of zinc deficiency is highest among infants, young children, pregnant and lactating women, when there is an extra demand due to multiplicative cell growth. Risk factors include insufficient dietary intake due to poverty, food taboos, and special diets (i.e. vegetarian diets that are high in phytate and fiber). Dietary zinc intake of young children appears to be inadequate in many developing countries [10, 11]. Women of childbearing age have inadequate dietary zinc intake in many populations [12, 13]. Eighty percent of women globally, and 100% women in developing countries, have inadequate zinc intake during pregnancy [14]. Individuals with malabsorption syndromes, diarrhea and parasitic diseases, acrodermatitis enteropathica, sickle cell disease, and cystic fibrosis are also at higher risk of zinc deficiency.

28.5

Clinical manifestations of zinc deficiency

Clinical manifestations of zinc deficiency are generally non-specific, vary widely, and depend on the severity of deficiency. The clinical manifestations in severe cases of zinc deficiency include bullous-pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males and are fatal if unrecognized and untreated. Moderate zinc deficiency is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, the symptoms include oligospermia, slight weight loss, and hyperammonemia [15].

28.6

Dietary sources, intake, absorption and bioavailability

Zinc content in foods is closely related to their protein content. Richest sources of dietary zinc are animal products such as shellfish, poultry, beef, and other red meats. Nuts and legumes are relatively good plant sources of zinc. Foods from plant sources such as beans, lentils, chickpeas, and peas are relatively rich in zinc. Little zinc is found in white rice or wheat breads, as zinc is contained in the bran and germ portions of whole cereal grains, which are normally lost through milling. Dairy products contain only moderate amounts of zinc. Zinc content of some common foods is shown in Table 28.1. Zinc intake in developing

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countries is commonly sub-optimal due to usual consumption of foods with very poor sources of zinc. Table 28.1 Zinc content of some of the commonly consumed foods Zinc category (mg/1000 kcal)

Foods

Very poor (0-2)

Fats, oils, butter, cream, cheese, sweets, chocolates, soft drinks, alcoholic drinks, preserves Fish, fruits, refined cereal products, pastries, biscuits, cakes, puddings, tubers, plantains, sausages, chips Whole grains, pork, poultry, milk, low fat cheese, yoghurt, eggs, nuts Lamb, leaf, and root vegetables, crustacea, beef, kidney, liver, heart, mollusks

Poor (1-5) Rich (4-12) Very rich (12-882)

Zinc in flesh foods is more bioavailable than the zinc in plant foods because during their digestion certain L-amino acids and cysteine containing peptides are released, which form soluble ligands with zinc. Plant based diets often contain high levels of phytic acid (myoinositol hexaphosphate), dietary fiber, oxalate, tannin and lignin, the components known to inhibit absorption of dietary zinc. Of these, phytic acid, the major storage form of phosphorus in whole grains, legumes, oleaginous seeds and leafy vegetables, is the most potent inhibitor of zinc absorption as it forms insoluble chelates at alkaline pH [16]. However, lower inositol phosphates (i.e. tetra-, tri-, di-, and mono-inositol phosphates), formed by enzymatic or non-enzymatic hydrolysis of phytic acid, do not form insoluble complexes with zinc. The bioavailability of dietary zinc can be predicted from the ratio of phytic acid (Phy) to zinc (Zn) in the diets. The critical (Phy): (Zn) molar ratios associated with the risk of zinc deficiency are equivocal; ratios above 15 having been associated with biochemical, and in some cases, even the clinical signs of zinc deficiency in humans [17]. Soaking and fermentation of plant foods are among some strategies that can be used to reduce intake of phytic acid, as phytate is partially hydrolyzed to other analogous metabolites that have a lower capacity to bind zinc. The enzymatic action of yeast reduces the level of phytic acid in foods. Therefore, leavened whole grain breads have more bioavailable zinc than unleavened whole grain breads.

28.7

Physiology of zinc

28.7.1 Physiology and metabolism of zinc The total body content of zinc is approximately 2 g and it is present in all the tissues/fluids of the body [18]. The skeletal muscle accounts for about 60%, bone for 30% and plasma 0.1% of the total body content of zinc. But

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plasma zinc has a rapid turnover rate, and its level appears to be under close homeostatic control. High concentration of zinc is found in the choroid of the eye as well as in prostatic fluids, semen ejaculates up to 1 mg and losses in menstruation are small (0.01 mg) [19, 20], other losses like normal daily zinc loss of hair are probably insignificant. Zinc is not stored in the conventional sense. Under conditions of bone resorption and tissue catabolism, it can be released and to some extent reutilized. Experimental studies in humans showed that in low zinc-containing diets (2.6–3.6 mg/day), plasma zinc and the activities of zinc-containing enzymes can be maintained within a normal range over several months indicating some zinc availability from tissues [21]. Zinc is lost from the body via kidneys, skin and the intestine; the endogenous intestinal losses can range between 0.5 and 3.0 mg/day depending on the zinc intake but exercise, diarrhea and fever could lead to large losses [22].

28.7.2 Zinc absorption Zinc is absorbed mainly in the small intestine. Under normal circumstances the gastrointestinal tract adapts effectively to changes in zinc intake and/or nutriture with compensatory changes in the fractional absorption and excretion of endogenous zinc [23]. Pancreatic secretions deliver zinc into the duodenum equivalent to that provided by most meals. The intestine reabsorbs appropriate amounts of zinc from both dietary and endogenous sources to maintain favorable zinc balance. Zinc is absorbed both by passive diffusion and through a carrier-mediated process on the brush border of enterocytes. Zinc absorbed from the intestinal lumen is bound to many different molecules within the enterocytes, and metallothionein and cysteine-rich intestinal protein play a role in transmucosal transport.

28.7.3 Zinc homeostasis Zinc homeostasis is affected by the liver and intestine at adequate and marginally adequate dietary zinc intakes [24]. When the body is at risk of zinc deprivation, intestinal absorption of exogenous zinc increases and there is a reduction in intestinal losses of endogenous zinc arising from intestinal conservation with an up regulation of carrier sites, and from a reduction in the pancreatico-biliary secretion of zinc, and to a lesser extent, increased renal conservation of the element [23]. These mechanisms are important because with the exception of the possible hepatic labile pool, there are no specific systemic stores of zinc and we are dependent on acquiring zinc from external sources [25]. Zinc transporters such as ZIP proteins (zinc importer proteins) and ZnT

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(zinc transporter proteins) have recently been recognized as two families of proteins involved in understanding the mechanisms of zinc-absorption and homeostasis. ZIP proteins transport zinc from the extracellular space and intracellular organelles into the cytoplasm [26]. ZnT proteins are primarily involved in the cellular efflux of zinc and in uptake of zinc by intracellular organelles. Thus, the net effect of these transporters is to decrease cytoplasmic zinc [27].

28.7.4 Zinc requirements Varied estimates of zinc requirements have been proposed by several expert committees [28–32]. In 2004, the International Zinc Consultative Group (IZiNCG) Steering Committee [7] reviewed the methods used by the World Health Organization and Food and Nutrition Board/Institute of Medicine (FNB/IOM) committees to estimate zinc requirements, taking into consideration the methodology used to measure absorption, the types of diets and subjects from whom the data were derived, as well as the models used to summarize these data. Based on the review, this Committee followed the factorial approach used by the FNB/IOM but decided to base intestinal losses of endogenous zinc on the estimates derived by IZiNCG [7], and to use the NCHS/CDC/WHO reference body weights for laying down the zinc requirements. Using this approach for computing the estimated average requirement (EAR) of zinc [EAR of zinc is the amount of zinc that must be absorbed to match the amount of endogenous zinc losses. Both intestinal and non-intestinal sources (urine, surface losses of skin/hair/nail/sweat) contribute to endogenous zinc losses], the requirements for different ages and physiologic groups are laid down (Table 28.2). Table 28.2 Recommended dietary intake of zinc [31] Children Population Age group

Adults

Males Females Population (mg/day) (mg/day) group

Age

Males Females (mg/ day) (mg/day)

Infants Infants

0-6 months 2 (AI) 7-12 months 3

2 (AI) 3

Adolescents 14-18 years Adults 19 years and

Children

1-3 years

3

Pregnancy

older 18 years and

-

12

Pregnancy

younger 19 years and

-

11

Lactation

older 18 years and

-

13

Lactation

younger 19 years and

-

12

Children Children -

4-8 years 9-13 years -

3 5 8 -

5 8 -

older

11 11

9 8

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28.7.5 Interaction of zinc with other trace elements A bi-directional interaction between copper and zinc has been postulated, one reducing the bioavailability of the other [33]. High levels of zinc (120– 240 mg/kg) in the diets of rats have been reported to result in lower copper levels in the serum and liver. Dietary zinc deficiency has also been reported to cause mild increase in tissue copper levels. Conversely copper deficiency has been reported to result in mild increase in zinc absorption. Experimental zinc deficiency in guinea pigs caused significant reductions in plasma sodium (Na), potassium (K) and zinc (Zn) and increase in copper (Cu) and iron (Fe) content(s) of liver and kidney. Conversely, zinc supplementation improved the serum and tissue mineral levels whereas levels of hepatic Cu and Fe remained unchanged [11]. Zinc and vitamin A interact in several ways. Zinc is a component of retinol-binding protein, a protein necessary for transporting vitamin A in the blood. Zinc is also required for the enzyme that converts retinol (vitamin A) to retinal. This latter form of vitamin A is necessary for the synthesis of rhodopsin, a protein in the eye that absorbs light and thus is involved in dark adaptation. Zinc deficiency is associated with decreased release of vitamin A from the liver, which may contribute to symptoms of night blindness that are seen with vitamin A deficiency [34, 35]. I n c h i l d r e n w i t h s e v e r e p r o t e i n e n e rg y m a l n u t r i t i o n , z i n c supplementation improved serum retinol binding protein and retinol concentration [36]. Combined zinc and vitamin A synergistically reduced the prevalence of persistent diarrhea and dysentery. Zinc was associated with a significant increase in acute lower respiratory infection, but this adverse effect was reduced by the interaction between zinc and vitamin A [37]. The zinc to iron ratio in the diet may be of importance for the absorption of the individual trace elements [38]. In thirty-one adult subjects, simultaneous administration of zinc sulphate and ferrous sulphate in a ratio of Fe/Zn of 1:1 slightly inhibited zinc absorption while Fe/Zn ratio 2:1 and 3:1 inhibited zinc uptake [39]. High iron concentrations that are present in some supplements can reduce zinc absorption. The effect of iron on zinc will only occur when the iron to zinc ratio is very high (such as 25:1) and both are administered in solutions. Similarly, iron fortification of food has no adverse effect on zinc absorption and long term use of iron supplements does not impair zinc absorption or status. Thus, under most dietary conditions, Zn–Fe interaction is not likely to have a major influence on zinc requirement. But there is now evidence to suggest that iron supplementation with zinc may increase morbidity of infectious diseases [40] and the risk of adverse events especially in malarious areas [41], and may reduce linear growth in iron replete infants [42, 43].

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There is also evidence that high calcium (2.0 g/d) reduced zinc absorption significantly whereas phosphorus (2.0 g/d) did not change the absorption. However, zinc balance was not significantly different with change in dietary calcium levels. Excess dietary calcium has been shown to decrease zinc absorption in animals, but such an effect is less conclusive in humans. While calcium phosphate decreases zinc absorption, calcium citrate-malate does not. The presence of phytate may also influence the effect of calcium on zinc absorption. Calcium may interact with zinc and phytate to form insoluble complexes, thus rendering zinc unavailable. Nonetheless, available data suggest that a calcium-rich diet has no significant inhibitory effect on zinc absorption, provided intake of zinc is adequate [44]. Studies on zinc-folate interaction have produced conflicting results. Some have shown low zinc intake decreases folate absorption, while others have not found such an adverse effect. Administration of 800 μg of folic acid daily for 2 weeks to a group of adults inhibited zinc absorption when the fractional rate of zinc absorption was higher than 30% [45]. This finding raises concern about pregnant women, who are often given supplemental folic acid to reduce the risk of birth defects. Otherwise, folate supplementation does not appear to have a deleterious effect on zinc status.

28.7.6 Zinc and immune response Zinc is known to play a central role in the immune system, and zincdeficient individuals experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. 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, Th1 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 provides a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation [46–48].

Zinc – an essential micronutrient for health and development

28.8

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Evidence from zinc supplementation studies on child health

28.8.1 Zinc supplementation and physical growth Zinc-responsive growth stunting has been identified in many studies from several regions worldwide. A meta-analysis of growth data from zinc intervention trials recently confirmed the widespread occurrence of growthlimiting zinc deficiency in young children, especially in developing countries [49]. The meta-analysis showed a significant positive effect of zinc supplementation (ranging from 0.9 to 21.4 mg of zinc/day) on growth among prepubertal children [50]. Zinc supplementation produced a highly significant, positive impact on children’s linear growth, with effect size of 0.170 (95% CI: 0.075 to 0.264, p = 0.001) and weight gain, with a mean effect size of 0.119 (95% CI: 0.048 to 0.190; p = 0.002). Although the exact mechanism for the growth-limiting effects of zinc deficiency is not known, research indicates that zinc availability affects cell-signaling systems that coordinate the response to the growth-regulating hormone, insulin-like growth factor-1 (IGF-1) [51].

28.8.2 Therapeutic effects of zinc supplementation and morbidity Effects of zinc on diarrhea Diarrhea is still the major cause of childhood mortality estimated to cause 2 million deaths and remains responsible for 18% of all child deaths [52, 53]. The adverse effects of zinc deficiency on immune system function are likely to increase the susceptibility of children to infectious diarrhea, and persistent diarrhea contributes to zinc deficiency and malnutrition. Zinc deficiency may also potentiate the effects of toxins produced by diarrheacausing bacteria like E. coli [54]. Two measures of the effects of zinc supplementation on diarrhea have been reported in the literature. First, the ‘therapeutic effect’ which describes the effect of giving zinc supplementation to the child during an episode of diarrhea. Second, the ‘preventive effect’ which describes the effect of zinc supplementation given over a prolonged period on the occurrence and severity of diarrhea morbidity to all children in a population where there is some indication of zinc deficiency. Therapeutic effects of zinc supplementation on acute and persistent diarrhea The role of zinc supplement (5–45 mg/day) in acute diarrhea (<7 days duration) has been recently updated in a meta-analysis which included 14 randomized controlled trials (Figure 28.1) [55].

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28.1 Impact of zinc supplementation on mean duration of acute diarrhea, all age groups, WMD, weighted mean difference [55]

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Current analysis of the adjunctive therapeutic benefit of zinc in acute diarrhea corroborates existing reviews [5] and provides evidence of reduction in duration of diarrhea by half a day. However, zinc supplementation was found to have no beneficial impact in infants under 6 months of age. Studies assessing the impact of zinc supplementation on the clinical outcome of the treated episode demonstrated 32% reduction in episodes of diarrhea lasting more than 7 days and a reduction in the frequency and/or volume of stools [56, 57]. Zinc supplementation given during a diarrheal episode and for a few days following the end of the episode (14 days) [58, 59] provides additional benefits, including decline in diarrheal incidence, and reduction in non-injury deaths. Boxes 28.1 and 28.2 present the experience with introduction of zinc supplementation in treating childhood diarrhea in India and other developing countries. Box 28.1 Experiences with introduction of zinc supplementation in treating childhood diarrhea in developing countries In recent years, three large-scale effectiveness trials using zinc for the treatment of diarrhea have been completed in India, Pakistan, and Bangladesh through both the public and the private sector health systems. Preliminary evidence suggests there was substantial reduction in diarrheal morbidity with zinc usage [60]. In these studies, the strategy was to give 20 mg elemental zinc daily in tablet/syrup form for 14 days along with ORS. In India [59], the study was conducted in rural Haryana and the strategy was to give 1 blister strip containing 14 dispersible zinc tablets (20 mg each) along with 2 ORS packets (to mix in 1 litre of water each) to all of the children aged 1 month to 4 years with diarrhea. Infants aged <6 months were to receive half a tablet in a teaspoonful of breast milk; older children were to receive 1 tablet dissolved in breast milk or clean water. The results demonstrated utilization of zinc supplements in 36.5% ( n = 1,571) and 59.8% ( n = 1,649) of diarrheal episodes occurring in the 4 weeks preceding interviews in the intervention areas [59]. The prevalence rates of diarrhea and pneumonia during the preceding 14 days were lower by 44% and 45% respectively in the intervention communities during the third quarterly survey. The numbers of hospitalizations for any cause, diarrhea, and pneumonia in the preceding 3 months were reduced in the intervention compared with the control areas (survey 3) (odds ratio for diarrhea hospitalizations, 0.69; 95% CI, 0.50 to 0.95; odds ratio for pneumonia hospitalizations, 0.29; 95% CI, 0.15 to 0.54). In a similar large-scale project in Matiari district in Pakistan, zinc supplements delivered by primary care government health workers to children with acute diarrhea produced a reduction in the subsequent incidence rates of diarrhea and mortality. These results have led to the incorporation of oral zinc sulfate for the treatment of diarrhea by the national primary health care programs and policies. In addition, the large effectiveness studies conducted in Bangladesh and in India [61, 62], have shown that when zinc and ORS are promoted together for the treatment of diarrhea, as part of a diarrhea control program, it led to increased ORS prescription rates, increased ORS use rates, decreased irrational antibiotic use rates, decreased anti-diarrheal use rates, and reduction in hospital rates.

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Box 28.2 Experiences with introduction of zinc supplementation in treating childhood diarrhea in Mali [63] Zinc for the treatment of childhood diarrhea was introduced in a pilot area in southern Mali to prepare for a cluster-randomized effectiveness study and to inform policies on how to best introduce and promote zinc at the community level. Dispersible zinc tablets in 14-tablet blister packs were provided through community health centres and drug kits managed by community health workers (CHWs) in two health zones in Bougouni district, Mali. Population-based household surveys with caretakers of children sick in the previous two weeks were carried out before and four months after the introduction of zinc supplementation. Household follow-up visits with children receiving zinc from the health centres and CHWs were conducted on days 3 and 14 after treatment for a subsample of children. A qualitative process evaluation also was conducted to investigate operational issues. Preliminary evidence from this study suggests that the introduction of zinc does not reduce the use of ORS and may reduce inappropriate antibiotic use for childhood diarrhea. Financial access to treatments, management of concurrent diarrhea and fever, and high use of unauthorized drug vendors were identified as factors affecting the effectiveness of the intervention in this setting.

In five studies that evaluated the effect of zinc supplementation on persistent diarrhea (episode that lasts 14 days or more) in children under 5 years of age, zinc-supplementation resulted in a significant reduction of duration of persistent diarrhea by 0.68 day and 21% lower probability of continuation of diarrhea on a given day. The meta-analysis showed a significant mean reduction of 42% (range, 10–63%) in the rate of treatment failure or death in children (<5 years of age) [55]. The benefit appeared to be more marked in children who were aged <12 months, were male, and had wasting or lowered baseline plasma zinc levels. Therapeutic effects of zinc supplementation on other illnesses Evidence of the benefit of zinc supplementation on pneumonia, malaria and tuberculosis in children under 5 years of age is insufficient and needs further evaluation [55].

28.8.3 Preventive effects of zinc supplementation Brown et al [50] recently conducted a series of meta-analyses of the randomized controlled trials to quantify the impact of preventive zinc supplementation on morbidity, mortality and physical growth. A total of 55 individual trials i.e. 7 from Africa, 23 from Asia, 12 from South America, 11 from North America, 1 from Australia, and 1 from Europe were included in the analyses which enrolled 202,692 children. Preventive effects of zinc on diarrhea morbidity Zinc supplementation has been shown to reduce the incidence of diarrhea in several community and hospital based studies. The preventive effects

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of zinc supplementation on diarrhea have recently been updated by Brown et al [50] from 24 randomized controlled trials (Figure 28.2).

28.2 Effect of zinc supplementation on diarrhea incidence from 24 intervention trials with 33 groupwise comparisons in which the supplements differed only bythe presence or absence of zinc [50].

Data from these studies which enrolled 16,339 children aged <4 years were pooled by using random-effect models with significant heterogeneity among

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children. The supplementation periods ranged from 2 weeks to 15 months and the dosage ranged from 1 to 70 mg per dose (median, 10 mg) mainly in the form of zinc sulfate. There was a significant 20% lower incidence of diarrhea among children who received zinc supplementation. The data indicated that the mean initial age of the study subjects was highly significantly associated with the magnitude of the effect of zinc supplementation. Among the subset of studies that enrolled children with the mean initial age greater than 12 months, the relative risk of diarrhea incidence was reduced by 27%. Data on duration of diarrhea from 9 studies which enrolled 1,692 children in the age group of 6 to 29 months indicated no significant effect of preventive zinc supplementation on duration of diarrhea. Preventive effects of zinc on pneumonia Zinc supplementation may also reduce the incidence of lower respiratory infections, such as pneumonia. Recently, Brown et al [50] have updated the meta-analysis, which included 12 randomized controlled trials with 16 group-wise comparisons, to evaluate the efficacy of zinc supplementation in respiratory illnesses among children between the mean initial ages of 0.9 and 49 months (Figure 28.3). Pooled data indicated that children who received a zinc supplement had significantly 15% reduction in lower respiratory tract infection or pneumonia than did those who received a placebo. Zinc supplementation and malarial morbidity In Gambia, using a twice-weekly 70 mg zinc supplementation, Bates et al [64] reported a 32% reduction in clinic visits due to malaria. In Papua New Guinea using daily 10 mg zinc supplementation, Shankar et al [65] reported a reduction of 38% in health center-based episodes of Plasmodium falciparum. Using a 12.5 mg daily zinc supplementation in Burkina Faso, Muller et al [66] found no effect in the incidence of P. falciparum malaria (relative risk of 0.98). Additionally, a randomized controlled trial reported that zinc supplementation did not benefit preschool-aged children with acute, uncomplicated P. falciparum malaria [67]. In a study in the Peruvian Amazon, children who received zinc or zinc plus iron had 15% fewer episodes of Plasmodium vivax infections though the results were not statistically significant [68]. A randomized controlled trial in over 42,000 children aged 1 to 48 months found that zinc supplementation did not significantly reduce mortality associated with malaria and other infections [69]. In a recently completed study in Burkina Faso, children who received zinc daily plus a single dose of vitamin A had 22% lower rate of fever and 30% reduction in malaria incidence [70]. In summary, there is still insufficient evidence to allow definitive conclusions to be drawn regarding the effect of zinc supplementation on

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28.3 Effect of zinc supplementation on the incidence of acute lower respiratory tract infection (ALRI) a from 12 intervention trials with 16 groupwise comparisons in which the supplements differed only by the presence or absence of zinc. (a)

Gray circles indicate studies in which ALRI was diagnosed by fieldworkers or physicians by using objective clinical signs: black circles indicate studies in which the diagnoise was based on caregiver reports of elevated respiratory rate or difficulty breathing [50].

the risk of malaria, although the weight of currently available information suggests that zinc may reduce the incidence of malaria, especially that of more severe cases that result in clinic attendance. Zinc supplementation and mortality Given the effects of zinc supplementation on diarrhea and pneumonia morbidity, which are the main causes of mortality in preschool children, there is a strong case for the impact of zinc supplementation on mortality. To date there are ten studies with information on impact of zinc supplementation, given alone or with iron folic acid, on mortality. However, these studies are heterogeneous in terms of the study population. Seven studies measured the impact on unselected populations of young children (Burkina Faso,

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Bangladesh, India, Nepal, Tanzania and Papua New Guinea) [65, 66, 69, 71–74]. Zinc supplementation had a marginal 6% impact on overall child mortality (Figure 28.4), there was an 18% reduction in deaths among zincsupplemented children older than 12 months of age but it had no effect on younger children. Two studies which measured the impact of zinc supplementation on selected population, low birth weight (LBW) and small for gestational age (SGA) infants (Brazil, India) [75, 76], found 52–68% lower mortality rates among children who received zinc and showed a pooled RR for reducing mortality of 0.35. In these studies the children were followed up for <1 year, therefore the impact of zinc supplementation is not available beyond 1 year. These results are consistent with the analyses by birth weight in Nepal (2006), wherein they reported the relative risk of mortality was reduced by 44% [74]. One study carried out in Bangladesh enrolled ill children with diarrhea, with subsequent home based zinc supplementation for 14 days [61]. There was 51% lower rate of non-injury deaths in the group of children receiving zinc in addition to ORS as a part of diarrhea management than the group of children that was just receiving ORS.

=

a

28.4 Effect of zinc supplementation on childhood mortality from 10 intervention trials (a) is with 13 groupwise comparisons in which the supplements differed only by the presence or absence of zinc. (a)

The figure does not include the study by Bhandari et al. [73] (India, 2002; n = 2,482) because this study had no deaths in the zinc-supplemented group.

These combined sets of results indicate that providing preventive zinc supplementation in settings where there is an increased risk of zinc deficiency would reduce mortality among children greater than 1year of age and possibly among LBW infants. However, additional studies are needed to confirm the results.

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28.8.4 Zinc supplementation and neurological/behavioral, mental and motor development of children Low maternal zinc nutritional status has been associated with diminished attention in newborn infants and poorer motor function at six months of age. Zinc supplementation has been associated with improved motor development in very low-birth-weight infants, more vigorous activity in Indian infants and toddlers, and more functional activity in Guatemalan infants and toddlers [14, 77]. Additionally, zinc supplementation was associated with better neuropsychologic functioning (e.g. attention) in Chinese first grade students, but this was observed only when zinc was provided with other micronutrients [78]. Two other studies failed to find an association between zinc supplementation and measures of attention in children diagnosed with growth retardation. Investigations of zinc supplementation on infants’ development and behavior have yielded inconsistent findings [79]. There are 7 studies (provided nine groupwise comparisons) that reported on children’s developmental outcomes in relation to zinc supplementation [50]. The study duration ranged from 1.9 to 12 months, and just two studies lasted more than 6 months. Two comparisons evaluated the impact of zinc supplementation versus placebo [80, 81], and the others provided additional micronutrients, such as iron [82, 84] or vitamin A [84, 85], to both groups. None of the studies found a significant positive effect of zinc on Mental Development Index (MDI). As with MDI, there was no significant overall impact of zinc supplementation on PDI (Psychomotor Development Index).

28.9

Zinc supplementation in pregnancy

Poor maternal zinc nutritional status has been associated with a number of adverse outcomes of pregnancy, including low birth weight, premature delivery, labor and delivery complications, fetal growth retardation, congenital anomalies and early postnatal infant immune dysfunction [86]. However, the results of maternal zinc supplementation trials in the U.S. and developing countries have been mixed [14]. Although some studies have found maternal zinc supplementation increases birth weight and decreases the likelihood of premature delivery, two placebo-controlled studies in Peruvian and Bangladeshi women found that zinc supplementation did not affect the incidence of low birth weight or premature delivery [87, 88]. Supplementation studies designed to examine the effect of zinc supplementation on labor and delivery complications have also generated mixed results, though few have been conducted in

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zinc-deficient populations [14]. A recent systematic review of 17 randomized controlled trials found that zinc supplementation during pregnancy was associated with a 14% reduction in premature deliveries; the lower incidence of preterm births was observed mainly in low-income women [89]. This analysis, however, did not find zinc supplementation to benefit other indicators of maternal or infant health. However, these results are quite limited, and more studies are needed to confirm these observations.

28.10 Effect of zinc on immune response in the elderly Age-related declines in immune function are similar to those associated with zinc deficiency, and the elderly are vulnerable to mild zinc deficiency. However, the results of zinc supplementation trials on immune function in the elderly have been mixed. A randomized placebocontrolled study in men and women over 65 years of age found that a zinc supplement of 25 mg/day for three months increased levels of some circulating immune cells (i.e., CD4 T-cells and cytotoxic Tlymphocytes) compared to placebo [90]. However, other studies have reported zinc supplementation does not improve parameters of immune function, indicating that more research is required before any recommendations can be made regarding zinc and immune system response in the elderly.

28.11 Zinc toxicity Zinc toxicity can occur in both acute and chronic forms. Acute adverse effects of high zinc intake include nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches [31]. One case report cited severe nausea and vomiting within 30 minutes of ingesting 4 g of zinc gluconate (570 mg elemental zinc) [91]. Relatively speaking, zinc is nontoxic, non-accumulative compared to other trace elements such as lead, cadmium or arsenic and the proportion absorbed is inversely related to the amount ingested [92, 93]. Intakes of 150–450 mg of zinc per day have been associated with such chronic effects as low copper status, altered iron function, reduced immune function, and reduced levels of high-density lipoproteins [94]. Reductions in a copper-containing enzyme, a marker of copper status, have been reported with even moderately high zinc intakes of approximately 60 mg/day for up to 10 weeks [19]. The doses of zinc used in the Age-Related Eye Disease Study (80 mg per day of zinc in the form of zinc oxide for 6.3 years, on an average) have been associated with a significant increase in

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hospitalizations for genitourinary causes, raising the possibility that chronically high intakes of zinc adversely affect some aspects of urinary physiology [95].

28.12 Assessment of zinc status The diagnosis of zinc deficiency is hampered by the lack of a single, sensitive, and specific low-cost indicator of zinc status. There are no generally accepted methods. Zinc status can be assessed by measurement of zinc in plasma, erythrocytes, leucocytes (lymphocytes/ neutrophils), platelets, urine, skin, sweat, saliva, and/or hair [96, 97].

28.12.1 Plasma/serum zinc concentrations Plasma or serum zinc concentrations are the most widely used indicator for zinc status. In general, during zinc deficiency, plasma or serum zinc concentrations will decrease. The amount of zinc circulating in plasma is <0.2% of the total body zinc content, as most of the total body content of zinc is contained in muscle and liver. There are several confounding factors that may limit the use of plasma or serum zinc concentrations such as infection, inflammation, chronic disease, pregnancy and malnutrition. The cut off for plasma or serum zinc concentrations generally used to assess the risk of zinc deficiency is <10.71 μmol/L (<70 μg/dL) for pre-prandial samples and <9.95 μmol/L (<65 μg/dL) for post prandial samples. Zinc plasma or serum concentrations can be measured by flame atomic absorption spectroscopy and most recent methods include flameless atomic absorption spectroscopy or inductively coupled plasma mass spectrometry. Plasma or serum should be separated as quickly as possible, as zinc concentrations may change if the plasma or serum has not separated from the blood within 1 hour. Hemolyzed samples should not be used, as zinc concentrations are higher in erythrocytes than in plasma. As zinc contamination may occur with use of regular blood-drawing equipments and supplies, trace element-free syringes, pipette tips and storage tubes should be used for the collection of plasma or serum for zinc determination.

28.12.2 Leucocyte and Erythrocyte Zinc Content Leucocyte zinc content may be a useful indicator as leuocytes turnover is rapid but requires large quantity of blood sample (~10 ml), subject to contamination and is difficult to obtain from young children. Polymorphonuclear leucocytes can be collected relatively free from

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contamination with platelets but monocytes which are in themselves a very mixed population are difficult to collect free of contamination with platelets. Leucocyte subsets have different zinc contents e.g. mean (SD): neutrophils 1.26 (0.27); monocytes 2.58 (0.65); lymphocytes 1.85 (0.32) μmol zinc/mg protein. Each has a different biological half-life (e.g. neutrophils 6 hours; monocytes 1–3 days; T lymphocytes 30 hours – 200 days). Pathophysiological changes in the relative proportions of the leucocyte subsets would lead to significant changes in the zinc content of the entire population. These phenomena could seriously limit the interpretation of mixed white cell analyses and the use of selected white cell subsets may seem to be more valuable. Analyses on selected separated subsets may prove to be more useful but are for the moment too impractical for routine or emergency use. In a systematic study of zinc supplemented children, leucocyte zinc concentrations were found to be a useful indicator of zinc deprivation [98]. Though, erythrocytes have a long shelf life (approximately 40 days), their zinc contents cannot be regarded as reliable indicators of recent or acute changes in zinc supply, unless zinc toxicity is suspected, but even so there are no adequate reference ranges to enable data to be evaluated.

28.12.3 Hair zinc concentrations Although hair zinc has been used in literature due to ease of obtaining a sample, the limitations of determining hair zinc concentrations to detect severe zinc deprivation have been shown in animal models in which there is a paradoxical increase in zinc content of hair with severe zinc deprivation. This has been noted in malnourished children. A possible explanation for this is that as zinc supply becomes limiting, hair synthesis in the follicle is reduced such that despite the reduced supply of zinc, it accumulates in the hair root at a normal or increased rate.

28.12.4 Functional indices of zinc Proxy indicators, such as activity of zinc metalloenzymes (alkaline phosphatase, carbonic anhydrase etc.), have been shown to be useful [99]. Serum alkaline phosphatase is low in severe zinc deficiency and returns to normal and a rise in serum alkaline phosphatase after zinc supplementation has been considered as a supportive indicator for the diagnosis of zinc deficiency. Increase in the plasma alkaline phosphatase following zinc supplementation to zinc deficient subjects has been frequently reported [100, 101]. Alkaline phosphatase level in serum responds to zinc depletion through a significant reduction in activity. Since

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the activity of this enzyme decreased before any sign of a lower food intake or reduced growth, it can be considered that the activity of serum alkaline phosphatase returns to the level of the control animals within 3 days of supplementation with zinc [100]. Improvement in serum alkaline phosphatase level was associated with corresponding improvement of clinical signs of zinc deficiency [99]. The metalloenzymes which responded with reduced activities in experimental zinc deficiency are alkaline phosphatase, pancreatic carboxy-peptidase, carbonic anhydrase, glutamic dehydrogenase, lactic and malic dehydrogenate, aldolase, NADH Diaphorase and pyridoxal phosphokinase. Metallothionein, a cytoplasmic metalloprotein, has been implicated in metabolism of zinc [102]. Experiments in rats indicated that metallothionein in hepatic and intestinal mucosal cells responded to altered dietary zinc content and serum zinc was directly related to metallothionein. To assess an acute zinc deficiency state, measurement of zinc metalloenzymes or tissue, which has a rapid turnover rate, may be more practical. Labeled isotopes such as 69zn and 70zn have been used in absorption studies [103]. A good correlation between zinc status and the activity of the ribonuclease (RNase) has been observed.

28.12.5 Zinc pool – size and turnover rates The exchangeable zinc pool (EZP) is the sum of the combined pools that exchange with zinc in the plasma within 48–72 hours and is thought to be critical for zinc dependent biological processes. The estimates of the size of the EZP have been found to be positively related to dietary zinc intake, especially the amount of absorbed zinc and fecal excretion of endogenous zinc. Once links to clinical, biochemical, or molecular effects of zinc deficiency have been achieved, the pool size and turnover measurements may be of value in evaluating the zinc status and zinc homeostasis [104, 105].

28.12.6 Growth faltering Although growth faltering alone is not diagnostic of zinc deficiency, it is along with other factors a possible cause. A falling of height and weight measurements compared with normal standards or previous records of growth velocity may be one of the first clinical observations that suggest zinc deficiency. Growth faltering is a hall mark of severe zinc deficiency, and a rapid decline in growth velocity is the most striking clinical feature of mild zinc deficiency. Both linear and ponderal growth are negatively affected by inadequate zinc intake [106]. In populations where stunting is

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prevalent, growth of stunted children is most often significantly improved following zinc supplementation. Zinc supplementation had a positive impact on linear growth (effect size = 0.46) as well as, though small, but a highly significant impact on weight increments (effect size = 0.26 SD units) among those studies that enrolled stunted children (HAZ <-2SD). Thus the prevalence of growth stunting may be a useful indicator of poor zinc status in the population [107].

28.12.7 Dietary zinc estimates Dietary zinc intake can be assessed quantitatively by a number of different methods, the simplest of which for population assessment is a modified interactive 24-hour dietary recall [108, 109]. Once the daily food intake is known, the total zinc intake can be estimated by multiplying the amount of each of the foods that are consumed by its zinc content, as recorded in local food composition tables or in databases available internationally, such as the US Department of Agriculture (USDA) food composition database [110]. For developing countries the World Food Dietary Assessment Program can be used [111]. The nutrient database associated with this system contains food composition values for 1800 foods from six countries (Egypt, Kenya, Mexico, Senegal, India, and Indonesia) and provides data for 53 nutrients and antinutritional factors that interfere with the absorption of nutrients including zinc, iron, dietary fiber, and phytate. Local databases are theoretically advantageous because the zinc content of foods can vary according to soil conditions, agronomic practices, and local food-processing techniques, although in many cases local food composition tables contain fewer food items and fewer replicate analyses per item. Moreover, these local tables frequently omit analyses of zinc and phytate. To estimate the amount of zinc available for absorption from the diet, the diet can be categorized according to its phytate–zinc molar ratio.

28.13 Scaling up programs to improve zinc nutrition Despite the promising effects of zinc supplementation, public health programs have been slow to embrace zinc-related interventions. Reasons for the lack of large-scale programs to prevent zinc deficiency may include the limited information available on the prevalence of zinc deficiency and need for practical intervention strategies that could be incorporated into ongoing health programs. This section presents an abstracted overview of current public health programs and possible gaps in information needed to design large scale programs which has been reviewed in detail by Brown et al [112].

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28.13.1 Assessment of population zinc status Very few countries have systematically collected information on population zinc status, so the global prevalence of zinc deficiency remains unknown. To address this issue on an interim basis, IZiNCG has proposed using suggestive evidence of zinc deficiency, based on the rates of stunting of under-five children and information on the absorbable zinc content of the national food supply using FAO’s food balance sheets [6]. National surveys of representative samples of the population are needed in high risk areas. Studies are also needed to validate the suggested cutoffs of zinc status indicators in relation to the functional effects of zinc deficiency. Additional field-applicable biomarkers of zinc status need to be developed. Finally, the suggestive evidence for classifying the population risk of zinc deficiency needs to be validated against objective biomarkers of zinc status.

28.13.2 Zinc intervention strategies Three major nutrition-related strategies proposed to control zinc deficiency include supplementation, fortification, and dietary diversification/ modification. The supplementation can further be divided into therapeutic and preventive supplementation. Therapeutic zinc supplementation for treatment of diarrhea This is by and large the most advanced component programmatically. Programs have begun in several countries, testing various approaches to training both health facility staff and community health workers, developing and delivering behavior change communication messages and consumer educational materials, and monitoring program progress. Private sector zinc programs are testing the feasibility of marketing zinc tablets and ORS as standalone products or packaging them together as a Diarrhea Treatment Kit (DTK). Box 28.3 presents the WHO/UNICEF Zinc recommendations for treatment for diarrhea. Box 28.3 Zinc as a treatment for diarrhea – WHO/UNICEF recommendations Based on the updated meta-analyses of randomized, controlled intervention trials on children, the WHO/UNICEF recommended 20 mg zinc/day for 10–14 days for children with acute diarrhea and 10 mg/day for infants under 6 months of age in the form of sulfate, gluconate, or acetate. These updated recommendations take into account new research findings showing the beneficial effects of oral rehydration salts (ORS) containing lower concentrations of glucose and salts as well as of zinc

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supplementation. In combination with prevention and treatment of dehydration with appropriate fluids, breastfeeding, continued feeding and selective use of antibiotics, these two scientific advances – regarding ORS and zinc supplementation can drastically diminish the number of child deaths by reducing the duration and severity of diarrheal episodes and lowering their incidence [113, 114].

Subsequent to global recommendations upon review Indian Academy of Pediatrics (IAP) and Government of India also have revised guidelines for the use of zinc in diarrhea as given below (see Boxes 28.4 and 28.5): Box 28.4 Revised recommendations of the IAP National Task Force for use of zinc in diarrhea, May 2006 1. All cases of diarrhea should receive zinc in addition to ORS. A uniform dose of 20 mg of elemental zinc should be given to all children older than 6 months and should be started as soon as diarrhea starts and continued for a total period of 14 days. Children aged 2 months to 6 months should be advised 10 mg per day of elemental zinc for a total period of 14 days. 2. Based on all the studies the group proposed that zinc salts e.g. sulphate, gluconate or acetate may be recommended. 3. The industry should be encouraged to prepare dispersible tablets that are reasonably priced, can be stored and transported easily. They can be dissolved in breast milk or water before use.

Box 28.5 Recommendations by the Government of India, 2007 Based on the WHO/UNICEF and the IAP recommendations and the data available on the evaluation of addition of zinc to current case management strategy in primary health setting [59] and personal communication of a larger study by Bhandari, et al. The Ministry of Health, Government of India has recommended that 20 mg of elemental zinc should be given to all children with diarrhea, older than 6 months, and should be started as soon as diarrhea starts and continued for a total period of 14 days. Children aged 2 months to 6 months should be advised 10 mg per day of elemental zinc for a total period of 14 days.

As part of global leadership mandate, USAID’s Social Marketing Plus for Diarrheal Disease Control: Point-of-Use Water Disinfection and Zinc Treatment (POUZN) Project, has been implemented in 20 countries [115]. Box 28.6 presents the scaling up efforts of zinc supplementation programme in Nepal. These efforts have focused on involving private companies to produce appropriate preparation for the diarrhea treatment and use social marketing approach to help scaling up its implementation. It is also recommended as part of standard case management in persistent diarrhea and in those with severe malnutrition.

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Box 28.6 Successful zinc supplementation scale-up in Nepal In 2005, the Ministry of Health and Population requested assistance from the United States Agency for International Development (USAID) to support the integration of zinc into the government’s diarrhea management programme. In 2005, the Government of Nepal, through the Ministry of Health and Population’s (MOHP) Child Health Division, is one of the first health ministries in the world to create a Zinc Task Force and prepare stakeholders for the introduction of zinc in line with the new World Health Organization (WHO)/UNICEF recommendations for standard management of childhood diarrhea, which includes ORS/ORT along with a 10–14 day regimen of pediatric zinc. USAID’s Nepal Family Health Project and UNICEF took the lead in providing commodities, training, and technical assistance to strengthen the skills of public sector health care providers in treating childhood diarrheas with both ORS/ ORT and zinc. At the same time, USAID/ Nepal funded the global Social Marketing Plus for Diarrheal Disease Control: Point-of-Use Water Disinfection and Zinc Treatment (POUZN) Project , implemented by Abt Associates in partnership with Population Services International, to introduce pediatric zinc in Nepal through the private sector as a companion piece to the introduction of zinc as the standard pediatric diarrhea treatment at public sector health facilities. Both public and private sector programs have now been implemented in 30 targeted districts encompassing 65% of the population. The POUZN programme in Nepal, although active nationwide for only six months, has already successfully contributed to an increase in zinc use from 0.4% in 2005 to nearly 16% in 2008. Of users, 85% correctly took zinc and ORS together, and 67% correctly took zinc for the full 10 days, demonstrating the positive impact of the communications messages.

Box 28.7 presents the Scaling Up Zinc for Young Children (SUZY) project in Bangladesh. Box 28.7 Scaling Up Zinc for Young Children (SUZY) Project in Bangladesh The Scaling Up of Zinc for Young Children (SUZY) Project was established in 2003 with the aim of setting Bangladesh on the path to covering all under-five children with zinc treatment of any diarrheal illness episode. ICDDR, B is the implementing and coordinating agency of the SUZY Project. Ministry of Health and Family Welfare (MoHFW) in collaboration with the SUZY team has developed two committees: (1) a National Advisory Committee, headed by the Health Secretary and (2) a Planning and Implementation Committee, headed by the Joint Secretary, Public Health and WHO. These two committees have been formed to have effective effort on policy decision. The National Advisory Committee of MoHFW approved the policy on using zinc in addition to ORS for under-five children suffering from diarrhea on 13 September 2006 and revised the National Diarrhea Treatment Guideline to incorporate zinc treatment in it. A partnership was also created that included public, private, nongovernmental organization, and multinational sector agencies. Over a period of 3 years activities in support of preparing for the national scale up included formative and operational research, product registration and technology transfer, awareness building and orientation of health professionals, and preparation of mass media messages. In December, 2006 a national mass media campaign to promote a dispersible tablet zinc formulation, “Baby Zinc,” for the treatment of childhood diarrhea was launched. All media messages linked zinc treatment to the continued use of oral rehydration salts (ORS). The scale-up of zinc treatment of childhood diarrhea rapidly attained widespread awareness, but actual use has lagged behind. Disparities in zinc coverage favoring higher income, urban households were

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identified, but these were gradually diminished over the two years of follow-up monitoring. The scale up campaign has not had any adverse effect on the use of ORS.

Preventive zinc supplementation The evidence for preventive zinc supplementation on the functional outcomes of morbidity and mortality and physical growth, have been presented earlier. There has not been progress in scaling up preventive zinc supplementation. For scale up information is needed on the optimal safe and effective dose of preventive zinc supplements for children of different ages and the appropriate frequency and duration of supplementation, with and without other micronutrients. Information from effectiveness studies combining zinc supplementation with other routine health/nutrition contacts, such as growth monitoring, EPI, or periodic vitamin A supplementation activities is needed. Finally, the best way of integrating preventive and therapeutic supplementation programs would contribute a big step. Zinc fortification Several studies have evaluated the effects of fortifying different food products with multiple micronutrients, including zinc. Serum zinc concentrations of older infants did not respond to zinc-containing, multimicronutrient fortified, cereal-based complementary foods in the four studies that measured this outcome [116–120]. Also there were no effects of the interventions on growth. In contrast serum zinc concentrations increased significantly among school children who received a multimicronutrient fortified beverage between meals [121] or a multimicronutrient fortified seasoning powder with meals [122]. Very little information is available from large-scale, programmatic interventions. Studies investigating the impact of home-based fortification using a mixture of vitamins and minerals packaged in small sachets containing a daily dose of micronutrients have focused mainly on the prevention of anemia and iron deficiency [123, 124]. Little is known about the impact of other micronutrients included in the multi-micronutrients mixture. In particular, there is limited information regarding their impact on zinc status. In general the health benefits of zinc included in “Sprinkles” have not yet been proven. Information is needed on the efficacy of zinc fortification programs (with and without other micronutrients), including their impact on biochemical indicators of zinc status and related functional outcomes. Similar information is needed for home fortification programs with zinc-containing micronutrient mixtures.

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Dietary diversification Diets in low income countries are predominantly plant-based and consumption of animal-source foods, such as meat, poultry, and fish, is often limited because of economic, cultural, and/or religious constraints. As a result, the zinc content of such diets is low and the efficiency of absorption is limited. Dietary inadequacy is probably the primary cause of zinc deficiency. To increase the zinc content in the diets, promotion of small-livestock husbandry, aquaculture, and production of other indigenous zinc-rich food has been proposed. At the household level, reduction of phytate content of the diet by using simple techniques to activate phytase, which is present naturally in cereals and legumes has been suggested. Such strategies have the added advantage of simultaneously improving the content and bioavailability of iron, vitamin B12, vitamin A, and calcium while enhancing protein quality and digestibility [125]. However there is little experience from large-scale programs to promote increased intake of zinc-rich foods. Practical information is needed on how best to identify locally available, low-cost, culturally acceptable zinc-rich foods and promote their consumption by those at risk of zinc deficiency. Information is also needed on best ways of implementing both large-scale and homebased food processing interventions to enhance zinc absorption from the usual diet [126, 127]. Agricultural interventions to increase dietary zinc content through improved agronomic practices and/or plant breeding need to be implemented and assessed.

28.14 Conclusion Zinc is a crucial micronutrient because it affects few hundred enzyme systems, DNA replication and various immune mechanisms and modulates host resistance to several pathogens. Zinc nutrition is necessary for optimal child health, physical growth, and normal pregnancy outcomes. In recent years, global recognition of the importance of zinc nutrition in public health has been recognized and there is some understanding for the design and implementation of zinc intervention programs. Zinc supplementation reduces morbidity from diarrhea and pneumonia in high risk populations. A large body of evidence shows important therapeutic benefits with zinc administration during and after diarrhea and some studies also reported reduction in diarrhea morbidity in the subsequent 2–3 months without further supplementation. Zinc supplementation is also shown to have positive impact on growth in terms of height and weight gain in pre-pubertal children. In the interim, the present WHO strategy to focus on introduction of zinc for treatment of diarrhea is an important step forward. The administration of zinc with oral rehydration salts for diarrhea in the program

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settings resulted in increased use of these salts, decreased use of antimicrobials and harmful anti-diarrheal drugs, and also reduced hospital admissions. Further evidence is required for qualifying its use in treatment of other infectious diseases like pneumonia. In view of the available data on effect of zinc supplementation in reducing the diarrheal and pneumonia morbidity and child mortality, preventive zinc supplementation has a potential to contribute to achievement of the MDG 4 (reduction in child mortality) by 2015 [128]. In the long-term, measures to improve zinc intake of children, improvement of the overall diet, supplementation, food fortification, and sub-selection of crops with improved zinc content need to be explored and assessed. However, the challenges of delivery of zinc as a preventive intervention in a population like India where centralized food processing is not existent need to be sorted out before any program recommendation can be made. Effectiveness studies for novel ways to deliver zinc need to be undertaken to inform policy. More data and may be studies starting in pre-conception period are needed to make any firm conclusion about maternal supplementation during pregnancy.

References 1.

2.

3. 4. 5.

6.

7.

8.

9.

PRASAD AS , HALSTED JA , NADIMI M (1961). Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism, and geophagia. Am J Med, 31, pp. 532–546. PRASAD AS , MIALE A , FARID Z , SCHULER A , SANDSTEAD HH (1963). Zinc metabolism in patients with the syndrome of Iron deficiency anemia, hepatosplenomegaly, dwarfism and hypogonadism. J Lab Clin Med, 61, pp. 573–549. PRASAD AS (1988). Zinc in growth and development and spectrum of human zinc deficiency. J Am Coll Nutr, 7(5), pp. 377–384. HAMBIDGE M (2000). Human zinc deficiency. J Nutr., 130, pp. 1344S–1349S. BHUTTA ZA , BIRD SM , BLACK RE , BROWN KH , GARDNER JM , HIDAYAT A , KHATUN F , MARTORELL R, NINH NX , PENNY ME , ROSADO JL , ROY SK, RUEL M, SAZAWAL S , SHANKAR A (2000). Zinc Investigators’ Collaborative Group. Therapeutic effects of oral zinc in acute and persistent diarrhoea in children in developing countries: Pooled analysis of randomized controlled trials. Am J Clin Nutr, 72, pp. 1516–1522. WUEHLER SE , PEERSON JM, BROWN KH (2005). Estimation of the global prevalence of Zinc (Zn) deficiency using national food balance data. http://www zinc-health org/Health/Ab-s1p-ws cfm 2005. International Zinc Nutrition Consultative Group (IZiNCG) Technical Document #1(2004). Assessment of the Risk of Zinc Deficiency in Populations and Options for Its Control. The United Nations University. Food and Nutrition Bulletin, 25(1), pp. S94–S203. FISCHER WALKER CL , EZZATI M, BLACK RE (2008). Global and regional child mortality and burden of disease attributable to zinc deficiency. Eur J Clin Nutr., 63(5), pp. 591–597. BLACK RE , ALLEN LH , BHUTTA ZA , CAULFIELD LE , DE ONIS M , EZZATI M , MATHERS C, RIVERA J (2008). For the Maternal and Child Undernutrition Study Group.

Zinc – an essential micronutrient for health and development

10.

11.

12.

13. 14.

15. 16. 17.

18. 19. 20. 21.

22.

23. 24.

25. 26. 27. 28. 29.

765

Maternal and child undernutrition: Global and regional exposures and health consequences. Lancet, 371, pp. 243–260. MURPHY SP, BEATON GH, CALLOWAY DH (1992). Estimated mineral intakes of toddlers: predicted prevalence of inadequacy in village populations in Egypt, Kenya, and Mexico. Am J Clin Nutr., 56(3), pp. 565–572. GUPTA RP , VERMA PC , SADANA JR , GUPTA VK (1989). Effect of experimental zinc deficiency and repletion on sodium, potassium, copper and iron concentrations in guinea-pigs. Br J Nutr, 62, pp. 407–414. MUÑOZ EC , ROSADO J L , LÓPEZ P , FURR HC , ALLEN LH (2000). Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers. Am. J Clin. Nutr, 71(3), pp. 789–794. TAMURA T and GOLDENBERG RL (1996). Zinc nutriture and pregnancy outcome. Nutrition Research, 16, pp. 139–181. CAULFIELD LE , ZAVALETA N , SHANKAR AH , MERIALDI M (1998). Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival. Am J Clin Nutr., 68(2), pp. 499S–508S. PRASAD AS (1985). Clinical manifestations of zinc deficiency. Annu Rev Nutr., 5, pp. 341–363. SANDSTROM B and LONNERDAL B (1989). Promoters and Antagonists of Zinc Absorption. C Mills (ed), Springer-Verlag, London. FERGUSON EL , GIBSON RS , THOMPSON LU , OUNPUU S (1989). Dietary calcium, phytate and zinc intakes and the calcium, phytate, and zinc molar ratios of the diets of a selected group of East African children. Am J Clin Nutr, 50, pp. 1450–1456. JACKSON MJ (1984). Physiology of zinc: general aspects. Zinc in human biology, pp. 1–14. BAER MT and KING JC (1984). Tissue zinc levels and zinc excretion during experimental zinc depletion in young men. Am J Clin Nutr, 39, pp. 556–570. HAMBIDGE KM and MERTZ W (1987). Trace elements in human and animal nutrition. In: San Diego FL AP, (ed). pp. 1–137. LUKASKI HC , BOLONCHUK W , KLEVAY LM , MILNE DB , SANDSTEAD HH (1984). Changes in plasma zinc content after exercise in men fed a low-zinc diet. Am J Physiol, 247, pp. E88–E93. MILNE DB , CANFIELD WK , GALLAGHER SK , HUNT JR , KLEVAY LM (1987). Ethanol metabolism in postmenopausal women fed a diet marginal in zinc. Am J Clin Nutr, 46, pp. 688–693. LEE HH , PRASAD AS, BREWER GJ , OWYANG C (1989). Zinc absorption in human small intestine. Am J Physiol, 256, pp. G87–G91. TAYLOR CM , BACON JR, AGGETT PJ , BREMMER I (1991). Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men. Am J Clin Nutr, 53, pp. 755–763. LOWE NN , BREMNER I , JACKSON NJ (1991). Plasma Zinc kinetics in the rat. Br. Nutr., 65, pp. 445–455. EIDE DJ (2006). Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta, 17(63), pp. 711–722. MCMAHON RJ and COUSINS RJ (1998). Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc Natl Acad Sci U S A , 95, pp. 4841–4846. WORLD HEALTH ORGANIZATION ( WHO) (1996). Trace elements in human health and nutrition. World Health Organization, Geneva. NATIONAL RESEARCH COUNCIL ( NRC ) (2001). Institute of Medicine, Food and Nutrition Board. Dietary reference intakes for vitamin A, vitamin K, arsenic,

766

30.

31.

32. 33. 34. 35. 36.

37.

38. 39.

40. 41.

42.

43.

44. 45. 46. 47.

Public health nutrition in developing countries boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, zinc. Washington, DC: National Academy Press. Panel on dietary reference values of the committee on medical aspects of food policy (1991). Dietary reference values for food energy and nutrients for the United Kingdom. Her Majesty’s Stationery Office, London, p. 210. INSTITUTE OF MEDICINE , FOOD AND NUTRITION BOARD (2001). Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. FAO / WHO (2002). Human Vitamin and Mineral Requirements. Report of a joint FAO/WHO expert consultation. Rome. OESTREICHER P and COUSINS RJ (1985). Copper and Zinc Absorption in the Rat: mechanism of Mutual Antagonism. J Nutr, 115, pp. 159–166. BORON B et al (1988). Effect of zinc deficiency on hepatic enzymes regulating vitamin A status. J Nutr., 118(8), pp. 995–1001. CHRISTIAN P and WEST KP , JR (1998). Interactions between zinc and vitamin A: an update. Am J Clin Nutr., 68(2), pp. 435S–441S. SHINGWEKAR AG , MOHANRAM M, REDDY V (1979). Effect of zinc supplementation on plasma levels of vitamin A and retinol-binding protein in malnourished children. Clin Chim Acta. 93, pp. 97–100. RAHMAN MM , VERMUND SH , WAHED MA , FUCHS GJ , BAQUI AH , ALVAREZ JO (2001). Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. BMJ. 323(7308), pp. 314–318. OLIVARES M , PIZARRO F , RUZ M (2007). New insights about iron bioavailability inhibition by zinc. Nutrition 2007, 23(4), pp.292–295. SOLOMONS NW and JACOB RA (1981). Studies on bioavailability of zinc in humans: effects of heme and nonheme iron on the absorption of zinc. Am J Clin Nutr, 34, pp. 475–482. OPPENHEIMER SJ (2001). Iron and its relation to immunity and infectious disease. J Nutr, 131, pp. 616S–635S. SAZAWAL S , BLACK RE, RAMSAN M, CHWAYA HM , STOLTZFUS RJ , DUTTA A , DHINGRA U , KABOLE I , DEB S , OTHMAN MK , KABOLE FM (2006). Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: Community-based, randomised, placebo-controlled trial. Lancet, 367, pp. 133–143. DEWEY KG , DOMELLOF M, COHEN RJ , LANDA RIVERA L, HERNELL O, LONNERDAL B (2002). Iron supplementation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras. J Nut., 132(3), pp.249–255. LIND T , SESWANDHANA R, PERSSON LA , LÖNNERDAL B (2008). Iron supplementation of iron-replete Indonesian infants is associated with reduced weight-for-age. Acta Paediatr. 97(6), pp. 770–775. SPENCER H , KRAMER L , NORRIS C , OSIS D (1984). Effect of calcium and phosphorus on zinc metabolism in man. Am J Clin Nutr, 40, pp. 1213–1218. MILNE D B (1989). Effects of folic acid supplements on zinc-65 absorption and retention. J. Trace Elements Exp. Med., 2, pp. 297–304. PRASAD AS (2008). Zinc in human health: effect of zinc on immune cells. Mol Med. 14(5–6), pp. 353–357. SHANKAR AH and PRASAD AS (1998). Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr., 68(2), pp. 447S–463S.

Zinc – an essential micronutrient for health and development 48.

49.

50.

51. 52.

53.

54. 55.

56.

57.

58.

59.

60.

61.

62. 63.

SAZAWAL S, JALLA S , MAZUMDER S , SINHA A , BLACK RE, BHAN MK

767

(1997). Effect of zinc supplementation on cell-mediated immunity and lymphocyte subsets in preschool children. Indian Pediatr., 34(7), pp. 589–597. HAMBIDGE M and KREBS N (2000). Zinc and growth. In: Roussel AM, (ed.) Trace elements in man and animals 10: Proceedings of the tenth international symposium on trace elements in man and animals. New York: Plenum Press, pp. 977–980. BROWN KH, PEERSON JM , BAKER SK , HESS SY (2009). Preventive zinc supplementation among infants, preschoolers, and older prepubertal children. Systematic Reviews of Zinc Intervention Strategies. International Zinc Nutrition Consultative Group Technical Document #2. Food and Nutrition Bulletin, 30 (1), pp. S12–S40. MACDONALD RS (2000). The role of zinc in growth and cell proliferation. J Nutr., 130(5S), pp. 1500S–1508S. BRYCE J , BOSCHI - PINTO C , SHIBUYA K , BLACK RE (2005). WHO Child Health Epidemiology Reference Group (2005) WHO estimates of the causes of death in children. Lancet, 365, pp. 1147–1152. MURRAY CJ , LAAKSO T , SHIBUYA K , HILL K , LOPEZ AD (2007). Can we achieve Millennium Development Goal 4? New analysis of country trends and forecasts of under-5 mortality to 2015. Lancet, 370, pp. 1040–1054. WAPNIR RA (2000). Zinc deficiency, malnutrition and the gastrointestinal tract. J Nutr. 130(5S), pp. 1388S–1392S. HAIDER BA and BHUTTA ZA (2009). The effect of therapeutic zinc supplementation among young children with selected infections: A review of the evidence. Systematic Reviews of Zinc Intervention Strategies. International Zinc Nutrition Consultative Group Technical Document #2. Food and Nutrition Bulletin, 30 (1), pp. S41–S59. DUTTA P, MITRA U , DATTA A , NIYOGI SK, DUTTA S , MANNA B , BASAK M, MAHAPATRA TS , BHATTACHARYA SK (2000). Impact of zinc supplementation in malnourished children with acute watery diarrhoea. J Trop Pediatr, 46, pp. 259–263. A L - S O N B O L I N , G U R G E L RQ , S H E N K I N A , H A RT CA , C U E VAS L E (2003). Zinc supplementation in Brazilian children with acute diarrhoea. Ann Trop Paediatr, 23, pp. 3–8. WINCH PJ, GILROY KE , DOUMBIA S , PATTERSON AE , DAOU Z , COULIBALY S , SWEDBERG E , BLACK RE , FONTAINE O (2006). Prescription and administration of a 14-day regimen of zinc treatment for childhood diarrhoea in Mali. Am J Trop Med Hyg., 74(5), pp. 880–883. BHANDARI N , MAZUMDER S, TANEJA S, DUBE B , BLACK RE , FONTAINE O, MAHALANABIS D , BHAN MK (2005). A pilot test of the addition of zinc to the current case management package of diarrhoea in a primary health care setting. J Pediatr Gastroenterol Nutr. 41(5), pp. 685–687. WHO / CAH and JHSPH (2008). Consultation to review the results of the large effectiveness studies examining the addition of zinc to the current case management of diarrhoea (India, Mali and Pakistan), New Delhi. BAQUI AH , BLACK RE , EL ARIFEEN S , YUNUS M, CHAKRABORTY J , AHMED S, VAUGHAN JP (2002). Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ., 325(7372), p. 1059. BHAN MK (2006). Personnel communication. WINCH PJ , GILROY KE , DOUMBIA S , PATTERSON AE , DAOU Z , DIAWARA A , SWEDBERG E , BLACK RE , FONTAINE O (2008). Mali Zinc Pilot Intervention Study Group.

768

64. 65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

Public health nutrition in developing countries Operational issues and trends associated with the pilot introduction of zinc for childhood diarrhoea in Bougouni district, Mali. J Health Popul Nutr., 26(2), pp. 151–162. BATES CJ et al (1993). A trial of zinc supplementation in young rural Gambian children. Br J Nutr, 69, pp. 243–255. SHANKAR AH et al (2000). The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg, 62, pp. 663–669. MULLER O et al (2001). Effect of zinc supplementation on malaria and other causes of morbidity in West African children: randomized double blind placebo controlled trial. BMJ, 32(2), p. 1567. Zinc Against Plasmodium Study Group (2002). Effect of zinc on the treatment of Plasmodium falciparum malaria in children: a randomized controlled trial. Am J Clin Nutr., 76(4), pp. 805–812. RICHARD SA , ZAVALETA N , CAULFIELD LE , BLACK RE, WITZIG RS , SHANKAR AH (2006). Zinc and iron supplementation and malaria, diarrhoea, and respiratory infections in children in the Peruvian Amazon. Am J Trop Med Hyg, 75, pp. 126–132. SAZAWAL S et al (2007). Effect of zinc supplementation on mortality in children aged 1-48 months: a community-based randomised placebo-controlled trial. Lancet. 369(9565), pp. 927–934. ZEBA AN , SORGHO H , ROUAMBA N , ZONGO I , ROUAMBA J , GUIGUEMDE RT , HAMER DH , MOKHTAR N , OUEDRAOGO JB (2008). Major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children in Burkina Faso: A randomized double blind trial. Nutr J, 7, pp. 7–13. BROOKS WA , SANTOSHAM M , NAHEED A , GOSWAMI D , WAHED MA , DIENER - WEST M , FARUQUE AS , BLACK RE (2005). Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, lowincome population in Bangladesh: randomised controlled trial. Lancet. 366(9490), pp. 999–1004. BHANDARI N , BAHL R , TANEJA S , STRAND T , MOLBAK K , ULVIK RJ, SOMMERFELT H , BHAN MK (2002). Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: Randomised controlled trial in an urban slum. BMJ, 32(4), p. 1358. BHANDARI N , TANEJA S , MAZUMDER S , BAHL R , FONTAINE O , BHAN MK (2007). Adding zinc to supplemental iron and folic acid does not affect mortality and severe morbidity in young children. J Nutr, 13(7), pp. 112–117. TIELSCH JM , KHATRY SK , STOLTZFUS RJ, KATZ J , LECLERQ SC , ADHIKARI R , MULLANY LC, BLACK R, SHRESTA S (2007). Effect of daily zinc supplementation on child mortality in southern Nepal: a community-based, cluster randomised, placebo-controlled trial. Lancet. 370(9594), pp. 1230–1239. SAZAWAL S, BLACK RE , MENON VP , DHINGRA P , CAULFIELD LE , DHINGRA U and BAGATI A (2001). Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. Pediatrics, 10(8), pp. 1280–1286. LIRA P , ASHWORTH A , MORRIS S (1998). Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil. Am J Clin Nutr., 68(1), pp. 418S–424S. SAZAWAL S , BENTLEY M, BLACK RE , DHINGRA P , GEORGE S , BHAN MK (1996). Effect of zinc supplementation on observed activity in low socioeconomic Indian preschool children. Pediatrics., 98(6), pp. 1132–1137.

Zinc – an essential micronutrient for health and development 78.

79. 80.

81.

82.

83.

84.

85.

86. 87.

88.

89. 90. 91. 92. 93. 94. 95.

96.

769

et al (1998). Effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of Chinese children. Am J Clin Nutr., 68(2), pp. 470S–475S. BLACK MM (1998). Zinc deficiency and child development. Am J Clin Nutr., 68(2), pp. 464S–469S. A S H W O RT H A , M O R R I S S S , L I R A P I , G R A N T H A M - M C G R E G O R S M (1998). Zinc supplementation, mental development and behaviour in low birth weight term infants in northeast Brazil. Eur J Clin Nutr, 52, pp. 223–227. HAMADANI JD , FUCHS GJ , OSENDARP SJ , KHATUN F , HUDA SN , GRANTHAM - MCGREGOR SM (2001). Randomized controlled trial of the effect of zinc supplementation on the mental development of Bangladeshi infants. Am J Clin Nutr, 74, pp. 381–386. CASTILLO -DURAN C, PERALES CG , HERTRAMPF ED, MARIN VB , RIVERA FA , ICAZA G (2001). Effect of zinc supplementation on development and growth of Chilean infants. J Pediatr, 13(8), pp. 229–235. LIND T , LÖNNERDAL B, STENLUND H , GAMAYANTI IL , ISMAIL D , SESWANDHANA R, PERSSON LA (2004). A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: Effects on growth and development. Am J Clin Nutr, 80, pp. 729–736. BLACK MM , BAQUI AH , ZAMAN K , AKE PERSSON L , EL ARIFEEN S , LE K , MCNARY SW , PARVEEN M, HAMADANI JD, BLACK RE (2004). Iron and zinc supplementation promote motor development and exploratory behaviour among Bangladeshi infants. Am J Clin Nutr, 80, pp. 903–910. TANEJA S , BHANDARI N , BAHL R , BHAN MK (2005). Impact of zinc supplementation on mental and psychomotor scores of children aged 12 to 18 months: A randomized, doubleblind trial. J Pediatr, 14(6), pp. 506–511. SHAH D and SACHDEV HP (2006). Zinc deficiency in pregnancy and fetal outcome. Nutr Rev., 64(1), pp. 15–30. C A U L F I E L D L E , Z AVA L E TA N , F I G U E R O A A , L E O N Z (1999) . Maternal zinc supplementation does not affect size at birth or pregnancy duration in Peru. J Nutr., 129(8), pp. 1563–1568. OSENDARP SJ , VAN RAAIJ JM , ARIFEEN SE , WAHED M, BAQUI AH , FUCHS GJ (2000). A randomized, placebo-controlled trial of the effect of zinc supplementation during pregnancy on pregnancy outcome in Bangladeshi urban poor. Am J Clin Nutr., 71(1), pp. 114–119. MAHOMED K , BHUTTA Z , MIDDLETON P (2007). Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev., 2, CD000230. FORTES C et al (1998). The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc., 46(1), pp. 19–26. LEWIS MR and KOKAN L (1998). Zinc gluconate: acute ingestion. J Toxicol Clin Toxicol, 36, pp. 99–101. GALLERY EDM , BLOMFIELD J , DIXON SR (1972). Acute zinc toxicity in hemodialysis. BMJ, 4 (5836), pp. 331–333. HELLER VG and BURKE AD (1972). TOXICITY OF ZINC . J Biol Chem., 74, pp. 85–91. HOOPER PL, VISCONTI L , GARRY PJ, JOHNSON GE (1980). Zinc lowers high-density lipoprotein-cholesterol levels. J Am Med Assoc, 24(4), pp. 1960–1961. JOHNSON AR , MUNOZ A , GOTTLIEB JL , JARRARD DF (2007). High dose zinc increases hospital admissions due to genitourinary complications. J Urol, 17(7), pp. 639–643. HAMBIDGE KM , CASEY CE, KREBS NF (1986). Trace Elements in Human and Animal Nutrition. Academic, Orlando. SANDSTEAD HH

770 97. 98. 99.

100.

101. 102. 103.

104.

105.

106. 107.

108. 109.

110. 111.

112.

113. 114. 115.

116.

Public health nutrition in developing countries SANDSTEAD HH (1982). Nutritional role of zinc and effects of deficiency. Curr Concepts Nutr, 11, pp. 97–124. SIMMER K , KHANUM S , CARLSSON L , THOMPSON RP (1988). Nutritional rehabilitation in Bangladesh-the importance of zinc. Am J Clin Nutr, 47, pp. 1036–1040. ROTHBAUM RJ , MAUR PR , FARELL MK (1982). Serum alkaline phosphatase and zinc undernutrition in infants with chronic diarrhoea. Am J Clin Nutr, 35, pp. 595–598. PRASAD AS , MIALE A , FARID Z, SANDSTEAD H , SCHULER A , DARBY W (1963). Biochemical studies on dwarfism, hypogonadism, and anemia. Arch Intern Med, 11(1), pp. 407–428. PRASAD AS (1966). Metabolism of zinc and its deficiency in human subjects. Illinois. RICHARD MP and COUSINS RJ (1976). Mammalian zinc homeostasis requirement for RNA and metallothionine synthesis. J Nutr, 106(5), pp. 1591–1597. AUGUST D , JANGHORBANI M, YOUNG VR (1989). Determination of zinc and copper absorption at three dietary zinc-copper ratios by using stable isotope methods in young adults and elderly subjects. Am J Clin Nutr., 50, pp. 1457–1463. MILLER LV, KREBS NF , HAMBIDGE KM (2000). Development of a compartmental model of human zinc metabolism: identifiability and multiple studies analyses. Am J Physiol Regul Integr Comp Physiol, p. 279. SIAN L , MINGYAN X , MILLER LV , NG LI , EBS NF, MBIDGE KM (1996). Zinc absorption and intestinal losses of endogenous zinc in young Chinese women with marginal zinc intakes. Am J Clin Nutr, 63, pp. 348–353. GIBSON R (1994). Zinc nutrition in developing countries. Nutr Res Rev, 7, pp. 151–173. BROWN KH , PEERSON JM, RIVERA J , ALLEN LH (2002). Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a metaanalysis of randomized controlled trials. Am J Clin Nutr, 75, pp. 1062–1071. GIBSON RS (1990). Principles of Nutritional Assessment. Oxford University Press, New York. GIBSON RS (1999). An interactive 24-hour recall for assessing the adequacy of iron and zinc intakes in developing countries. International Life Sciences Institute Press. USDA WEBSITE (1999). BUNCH S and MURPHY SP (1994). User’s guide to the operation of the world food dietary assessment program. Office of Technology Licensing. University of California, Berkeley, p. 21. Brown KH information gaps for scaling-up programs to improve Zinc Nutrition 2007; 1-8 web site link: www a2z profect.org pdf Gap-Analysis-Zinc-Final.pdf. Accessed on 3rd September 2010. FONTAINE O (2006). Zinc and treatment of diarrhoea. Med Trop (Mars)., 66(3), pp. 306–309. WHO/ UNICEF (2004). Clinical management of acute diarrhoea. WHO/FCH/CAH/ 04.7. Geneva: WHO/UNICEF. POUZN - AED PSP - One Private Sector partnerships for better health. Web site link: http:/www.psp - ones.com/section/task orders/pouzn/pouzn acd. Accessed on 3rd September 2010. LARTEY A , MANU A , BROWN KH , PEERSON JM and DEWEY KG (1999). A randomized, community-based trial of the effects of improved, centrally processed

Zinc – an essential micronutrient for health and development

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

771

complementary foods on growth and micronutrient status of Ghanaian infants from 6 to 12 mo of age. Am J Clin Nutr, 70, pp. 391–404. OELOFSE A , VAN RAAIJ JM, BENADE AJ , DHANSAY MA , TOLBOOM JJ and HAUTVAST JG (2003). The effect of a micronutrient fortified complementary food on micronutrient status, growth and development of 6- to 12-month-old disadvantaged urban South African infants. Internatl J Food Sci Nutr, 54, pp. 399–407. FABER M, KVALSVIG JD , LOMBARD CJ and BENADE AJ (2005). Effect of a fortified maize-meal porridge on anemia, micronutrient status, and motor development of infants. Am J Clin Nutr, 82, pp. 1032–1039. LUTTER CK , SEMPERTEGUI F, RODRIGUEZ A , FUENMAYOR G , AVILA L and MADERO J (2006). Evaluacion e impacto del programa nacional de alimentacion nutricion PANN 2000. Washington DC: Organizacion Panamericana de la Salud. BROWN KH , LÓPEZ DE ROMAÑA G , ARSENAULT JE , PEERSON JM and PENNY ME . Effect of mode of delivery of zinc (provided in a fortified food or as a liquid supplement) on the growth, morbidity and plasma zinc concentration of young Peruvian children. Am J Clin Nutr, in press. ABRAMS SA , MUSHI A , HILMERS DC , GRIFFIN IJ , AVILA P and ALLEN L (2003). A multinutrient-fortified beverage enhances the nutritional status of children in Botswana. J Nutr, 13(3), pp. 1834–1840. WINICHAGOON P , MCKENZIE JE , CHAVASIT V , PONGCHAROEN T , GOWACHIRAPANT S , BOONPRADERM A , MANGER MS , BAILEY KB , WASANTWISUT E and GIBSON RS (2006). A multimicronutrient-fortified seasoning powder enhances the hemoglobin, zinc, and iodine status of primary school children in North East Thailand: a randomized controlled trial of efficacy. J Nutr, 13(6), pp. 1617–1623. ZLOTKIN S , ARTHUR P, SCHAUER C, ANTWI KY , YEUNG G and PIEKARZ A (2003). Homefortification with iron and zinc sprinkles or iron sprinkles alone successfully treats anemia in infants and young children. J Nutr, 13(3), pp. 1075–1080. GIOVANNINI M, SALA D , USUELLI M , LIVIO L , FRANCESCATO G , BRAGA M , RADAELLI F and RIVA E (2006). Double-blind, placebo-controlled trial comparing effects of supplementation with two different combinations of micronutrients delivered as sprinkles on growth, anemia, and iron deficiency in Cambodian infants. J Ped Gastroenterol Nutr, 42, pp. 306–312. GIBSON RS , YEUDALL F, DROST N , MTITIMUNI BM and CULLINAN TR (2003). Experiences of a community-based dietary intervention to enhance micronutrient adequacy of diets low in animal source foods and high in phytate: a case study in rural Malawian children. J Nutr, 13(3), pp. 3992S–3999S. BROWN KH , ENGLE -STONE R , KREBS NF, PEERSON JM (2009). Dietary intervention strategies to enhance zinc nutrition: promotion and support of breastfeeding for infants and young children. Food Nutr Bull. 30(1), pp. S144–171. GIBSON RS and ANDERSON VP (2009). A review of interventions based on dietary diversification or modification strategies with the potential to enhance intakes of total and absorbable zinc. Food Nutr Bull. 30(1), pp. S108–143. BRYCE J and VICTORIA CG (2005). Child survival: countdown to 2015. The Lancet, 365 (9478), pp. 2153–2154.