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Editorial

Indian Pediatrics 1999; 35:1173-1176 

Recent Advances in Research on Zinc and Child Health in Developing Countries


Since the role of zinc (Zn) in correcting growth retardation was first described in 1961(1) several studies have categorized the role of Zn in human nutrition, quantified the effects of Zn and have defined the interactions between Zn and other micronutrients that are also known to be important to human health.

The interest in Zn has, in no small mea- sure, been spurred by the recognition that not only is it essential to human health, but a relative Zn deficiency may be a global problem, affecting people in both developing and industrialized countries. Dietary factors place children from developing countries at particular risk. The amount of Zn necessary for both positive balance and homeostasis is related to physiological demand(2). The greater the demand for Zn such as in states of growth and stress (infection or trauma), the greater the need for zinc supply. The most common source of Zn in times of increased demand is food, since body stores are at best modest. In order to be a significant Zn source, a food must not only contain Zn but the Zn must be bioavailable. Animal protein is a rich source of Zn, but most people in the developing world do not consume it in adequate quantities. Foods that comprise the major part of the diet in most developing countries are low in Zn content and contain high amounts of fiber as well as phytic acid, substances that inhibit Zn absorption(3). Phytates in particular are potent inhibitors of Zn absorption through the formation of insoluble complexes with the metal.

Zn is lnvolved in a variety of essential functions, including the initiation of DNA synthesis, bone formation, cell-mediated immunity and tissue growth. Most of these effects are mediated through Zn-dependent metalloenzymes(4). Zn is also an acute phase reactant and thus assists the body to respond to acute stresses, such as infection, trauma, and burns. Since the requirement of Zn is dependent on physiological demand, these responses may be blunted if the tissue availability of Zn is low, exposing an infected and/or growing child to an increased risk of adverse outcome.

Over the last decade, there has been an increase in the number of intervention studies to determine the effect of Zn on physiological states and dynamic functions. Generally speaking, there have been two types of intervention studies: those on acute treatment effects, which lower the prevalence of disease, and those on primary preventive effects which lower the incidence of disease. In the former group, acute treatment effects on growth, the recovery phase of severe malnutrition, and acute and persistent diarrheal disease have been the most widely studied. In the latter, attention has focussed primarily on the prevention of diarrheal disease and acute lower respiratory tract infection (ALRI).

The essential clinical role of Zn was first demonstrated(1) by increasing the rate of linear growth in Iranian and Egyptian dwarfs (the Prasad-Halstead syndrome). We now know that this syndrome is due to Zn deficiency, but what of growth deficits due to other etiologies, specifically protein-energy malnutrition (PEM) which is common in developing countries? Zn supplementation during the recovery phase of PEM enhances weight gain and linear growth, independent of caloric intake(5-7). These gain are due primarily to the synthesis of lean tissue, not fat. There seems to be little debate that children recovering from severe malnutrition should be given zinc.

Children suffering from either acute watery or persistent diarrhea (watery diarrhea lasting for 14 days or longer) experience reductions in both duration and severity of illness (measured as either frequency or volume of stool) with Zn supplementation(8-10). The exact mechanism by which Zn mediates this improvement remains to be worked out, but it probably involves a Zn-mediated improvement in both intestinal integrity and immune function(11). Again, the response is most notable in children with either documented Zn deficiency or with chronic or acute malnutrition. Primary prevention has been reported against both diarrhea and ALRI(5,8,12,13). The evidence to date strongly suggests that children with acute watery or persistent diarrheal disease, or children with a relative Zn deficiency benefit from supplementation.

Concerns have been raised about the possibility of safety issues of zinc supplementation, particularly in children with marginal stores of other micronutrients(14). There are two distinct but related aspects to the question of the safety of Zn supplementation. The first is the potential for direct toxic effects of Zn and the other is the effect of Zn on the status of other clinical micro- nutrients, particularly copper. The primary concern in the latter is the effect of Zn administration in excess of the daily requirement in severely malnourished children or the long-term supplementation in undernourished children with marginal copper status. Acutely toxic effects of Zn have been reported from isolated cases of poisonings in which extreme amounts were ingested. Doses of Zn higher than those used in present experimental trials have resulted in disturbances of hematological parameters (anemia, neutropenia), but only after prolonged periods of use. Investigators have also noted derangements of immunological indices, 'such as macrophage bactericidal activity, but without apparent systemic illness(15-17). Thus far, there does not appear to be compelling evidence that Zn in the doses presently used in intervention trials is either directly toxic or causes clinical copper deficiency in children with relative Zn deficiency, however the effects of long-term supplementation have not been adequately studied.

Several gaps in our zinc knowledge base need to the filled before programmatic implementation can be confidently pursued. These relate primarily to questions of optimal dosing, effectiveness and safety. A few important efficacy questions remain, particularly acute treatment effects against.

ALRI (pneumonia, specifically). Such studies are warranted, not only because preventive effects of zinc against ALRI have been observed, but also because ALRI accounts for an extreme burden of morbidity and mortality among young children in the developing world (4 million deaths/year world-wide)(18). Further, a meta-analysis has shown that early intervention in general with appropriate management is an important determinant of outcome of ALRI(19). Since the causative pathogen is seldom confirmed in a given case of pneumonia, the availability of an effective adjuvant that improves outcome and lessens the severity of illness would be important, especially among the most vulnerable age group of under two years old children.

One could make similar arguments for infectious diseases in general. However, two diseases assume special relevance for efficacy studies with Zn, malaria and tuberculosis, not merely for the high disease and mortality burden associated with each, but because drug resistance features prominently in both. Any agent that could lessen the severity and shorten the duration-in a word decrease the prevalence-of these two diseases would be of major benefit to world health. Likewise, one could envision specific treatment trials with measles, as well as follow-up morbidity studies.

Additional efficacy studies in Sub-Saharan Africa are needed. Results from a single study were disappointing, but given the. diversity of the peoples and environments of Africa(20) it is conceivable that host differences or host-environment inter- actions might affect responsiveness to Zn supplementation.

Among the most needed are large-scale mortality studies to determine whether or not there are significant reductions in disease-specific and total child mortality associated with Zn supplementation. This information will be essential to determine the cost-benefit of population-based supplementation programs. Other studies should address how best to supplement Zn. So far, most intervention trials in children have utilized daily administration of syrup, which is not likely to be feasible at the community level. Alternative methods and schedules should be explored, including food-based interventions with new foods and food preparations. Operations research to explore the possible incorporation of Zn supplementation to existing intervention programs should be pursued in order to enhance the cost-effectiveness of large-scale Zn supplementation. A stand-alone program would certainly be more costly and the addition of yet another single micronutrient programme might over-burden existing national health programs, perhaps prohibitively so.

Safety concerns are likely to remain until definitive data on toxicity and micronutrient interaction are obtained. Specifically, larger studies should assess functional outcomes associated with copper deficiency and other micronutrient interactions when zinc is administered over longer periods of time.

In summary, two clinical circumstances warrant Zn supplementation and a third might be added soon. First, Zn should be administered during the rehabilitative phase of malnutrition. Second, recent studies support its routine use in the treatment of both acute watery and persistent diarrheal diseases, especially among malnourished children. Third, existing data indicate that Zn may prevent a significant proportion of diarrheal disease and ALRI. However, we need additional information before we can advocate global programmatic implementation. Mortality studies, additional acute treatment and prevention trials, definition of the best and most-effective regimens for supplementation, studies on safety in long-term supplementation, and studies from other parts of the world-particularly Africa-should address this need.
 

W. Abdullah Brooks,
Clinical Sciences Division
George Fuchs,
Interim Director, ICDDR, B:
Centre for Health and Population Research,
GPO Box
128 Mohakhali,
Dhaka WOO, Bangladesh.
E-mail: [email protected]
 

References

1. Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency, hepatosplenomegaly, hypogonadism, dwarfism, and geophagia. AmJ Med 1961; 31: 532-546.

2. Sandstead HH. Is zinc deficiency a public health problem? Nutrition 1995; 11: (Suppl): 87-92.

3. Gibson RS, Yeudall F, Drost N, Mtitimuni B, Cullinan T. Dietary interventions to prevent zinc deficiency. Am J Clin Nutr 1998; 68 (Suppl): 484S-487S.

4. Cousins RJ. Absorption, transport, and hepatic metabolism of copper and zinc: Special reference to metallothionein and ceruloplasmin. Physiol Rev 1985; 56: 238- 309.

5. Ninh NX, Thissen JP, Collette L, Gerard G, Khoi HH, Ketelslegers JM. Zinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children. Am J Clin Nutr 1996; 63: 514- 519.

6. Castillo-Duran C, Heresi G, Fisberg M, Uauy R. Controlled trial of zinc supplementation during recovery form malnutrition: Effects of growth and immune function. Am J Clin Nutr 1987; 45: 602- 608.

7. Golden M, Golden B. Effect of zinc supplementation on the dietary intake, rate of weight gain, and energy cost of tissue deposition in children recovering . from severe malnutrition. Am J Clin Nutr 1981; 34: 900-908.

8. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A Jalla S. Zinc supplementation in young children with acute diarrhea in India. N Engl J Med 1995; 333: 839-844.

9. Sachdev HPS, Mittal NK Yadav HS, Mittal SK. A controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants. J Pediatr Gastroenterol Nutr 1988; 7: 877-881.

10. Roy SK, Tomkins SM, Akramuzzaman SM, Behrens RH, Haider R, Mahalanabis D, et al. Randomized controlled trial of zinc supplementation in malnourished Bangaldeshi children with acute diarrhea. Arch Dis Childhood 1997; 77: 196-200.

11. Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA, et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhea and persistent diarrhea syndrome. J Pediatr Gastroenterol Nutr 1992; 15: 289- 296.

12. Reul MT, Rivera JA Santizo MC, Lonnerdal B, Brown KH. Impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics 1997; 99: 808-813.

13. Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr 1997; 65: 13- 19.

14. Fuchs G. Possibilities for zinc in the treatment of acute diarrhea. Am J Clin Nutr 1998; 68 (Suppl): 480S-483S.

15. Chandra RK. Excessive intake of zinc im pairs immune responses. JAMA 1984; 252: 1443-1446.

16. Schlesinger L, Arevalo M, Arredondo S, Lonnerdal B, Stekel A. Zinc supplementation impairs monocyte function. Acta Paediatr 1993; 82: 734-738.

17. Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990; 51: 225-227.

18. Black RE, Brown KH, Becker S, Yunus M. Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh I. Patterns of morbidity. Am J Epidemiol 1982; 115: 305-314.

19. Selwyn BJ. The epidemiology of acute respiratory tract infection in young children: Comparison of findings from several de- veloping countries. Rev Infect Dis 1990; (Supp18): S870-S888.

20. Bates CJ, Evans PH, Dardenne M, Prentice A Lunn PGt Northrop-Clewes CA et al. A trial of zinc supplementation in young rural Gambian children. Br J Nutr 1993; 69: 243-255.
 

 

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