Zinc in the Treatment of Diarrhea (1997)

Zinc supplementation in young children with acute diarrhea in India. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S.N Engl J Med 1995;333:839-44. Summary: Sazawal et al. examined the effect of zinc supplementation in children with acute diarrhea in a community-based, double-blind, controlled trial. Children aged 6 to 35 months with acute diarrhea (at least four unformed stools in the previous 24 hours and diarrhea for less than 7 days), who visited the Kalkaji dispensary in New Delhi, India, were enrolled. Children with severe malnutrition requiring hospital admission were excluded. A total of 947 children were randomly assigned either to a group to receive zinc supplementation or to a control group. In both groups, oral rehydration therapy was prescribed, and parents were advised to continue the child's usual diet. At home children were given a 10-ml dose suspended in solution containing vitamins A, B1, B2, B6, D3, and E and niacinamide by field assistants or mothers every day. In the zinc-supplement group, the preparation also contained zinc gluconate (20 mg elemental zinc). Zinc supplementation was associated with a significant overall reduction of 23% in the risk of continued diarrhea on a given day. When supplementation was initiated within 3 days of the onset of diarrhea (in 60% of children), there was a significant reduction of 39% in the frequency of episodes lasting more than 7 days after the beginning of the treatment. When a multivariate analysis of the totality of the data (including children enrolled after day 3) was performed, the reduction of the persistence of diarrhea dropped to 21% but remained significant. Zinc also decreased the severity of diarrhea: There was a significant reduction of 21% in the number of days with watery stools in the zinc-supplement group. At enrollment, 37% of children had plasma zinc levels less than 60 μg/dl, 40% were stunted (z score for length or height appropriate for age was less than -2), and 8% were wasted (z score for weight appropriate for length was less than -2). Subgroups defined by the plasma zinc levels did not respond differently to zinc supplementation. By contrast, there was a marked reduction in the duration and severity of diarrhea in the subgroup of children with stunted growth: Among them, the reduction in the frequency of episodes lasting more than 7 days was 65% (when supplementation was initiated before the fourth day of diarrhea). Similarly, the reduction in the number of days with watery stools was 41% in children with stunted growth and 52% in children with wasting. The authors point out that a high prevalence of zinc deficiency is likely among preschool children in developing countries. Although they propose that stunting, wasting, or both, but not initial plasma zinc level, can be used to select the children most likely to benefit from supplementation, they did not provide any practical advice on supplementation. Rather, they stressed that these findings must be confirmed in other developing countries. Comment The link between diarrhea and zinc is well established. Diarrhea leads to zinc loss and abnormalities of zinc metabolism; and, conversely, zinc deficiency is associated with diarrhea (Acta Paediatr 1992;381:S82-6). Previous studies have looked at the impact of zinc supplementation in children with acute diarrhea. This one is the first conducted in a large number of children, in their community, with children consuming their usual diet. It is also the first to show at the same time a clinically important and a statistically significant limitation of diarrhea with zinc supplementation. In results of two studies from Bangladesh, zinc supplementation provided significant improvement in intestinal permeability, but direct clinical evidence of an effect on the duration or severity of diarrhea was lacking (J Pediatr Gastroenterol Nutr 1992;15:289-96; Gut 1994;35:1707-11). In results of a study from India, zinc did not significantly affect the duration and frequency of diarrhea, except in children with low rectal zinc concentration (J Pediatr Gastroenterol Nutr 1988;7:877-81). Although oral rehydration solutions treat dehydration efficiently, the need for a symptomatic treatment of diarrhea still persists (Bull World Health Organ 1994;72:945-55). The study by Sazawal et al. evaluates the capacity of zinc to reduce the duration and severity of diarrhea, in contrast to studies looking for new compounds capable of improving rehydration in oral rehydration solutions (Annu Rev Nutr 1994;14:321-42), and in contrast to studies of zinc supplementation with nutritional objectives (Nutr Res Rev 1994;7:151-173). The impact of zinc on nutritional or rehydration parameters, such as weight gain, food intake, or rehydration requirements, has not been examined. Rather, zinc is proposed as a new candidate to add to the existing list of drugs with possible antidiarrheal activity. In that respect, the capacity of zinc in reducing the volume, frequency, and duration of diarrhea has not been evaluated with criteria comparable with those generally used for such drugs-that is, the total duration of diarrhea (in hours), the number of incidences (per 24 hours), and the weight or volume (per kilogram of body weight) of diarrheal stools (J Pediatr Gastroenterol Nutr 1994;19:251-4). Before zinc can be recommended on a large scale, possible mechanisms to explain the effect of zinc on diarrhea must be considered. Acute diarrheas among children in developing countries are likely to be infectious diarrheas (Gut 1994;35:1687-9). Zinc may have a preferential effect on enterocytes and immune cells that interact with infectious agents during diarrhea. Zinc primarily acts on tissues with a high turnover rate as in those of the gastrointestinal tract and the immune system, in which it is needed for DNA and protein synthesis. Animal studies showed that white blood cells are involved in intestinal secretion during diarrheas associated with intestinal infection by protozoa, toxigenic bacteria, or nematode (Gastroenterology 1994;106:1705-7). Electron microscopy of the intestinal mucosa in patients with cholera showed degranulation of mucosal mast cells and eosinophils, an increase in neutrophils, and changes in the enteric nerve fibers (Gastroenterology 1995;109:422-30). Hence, inflammation and inflammatory mediators could be involved in the secretion associated with infectious diarrhea. Zinc stabilizes membrane structure and may modify membrane functions by interacting with by interacting with the oxygen, nitrogen and sulfur ligands of hydrophilic macromolecules, and by providing antioxidant activity (Free Radic Biol Med 1990;8:281-91; J Nutr Biochem 1993;4:194-207). Zinc protects membranes from the effects of infectious agents (Am J Pathol 1990;163:513-20) and from lipid peroxidation (Eur Biophys J 1991;19:317-22). In the rat intestine, zinc deficiency is associated with a significant reduction of sodium and water absorption (J Pediatr Gastroenterol Nutr 1984;3:608-12) and may affect intestinal disaccharidase activity (Pediatr Res 1985;19:1333-6), although this is controversial (J Lab Clin Med 1985;106:708-11). A recent study also suggests that zinc might act at the tight-junction level to prevent the increase of intestinal permeability associated with malnutrition (Gut 1996;39:416-22). Zinc also inhibits histamine release by mast cells (Agents Actions 1986;18:103-106) and both the contractile (J Pharm Pharmacol 1991;43:294-6) and secretory (Darmon et al. Proc Nutr Soc; in press) responses to histamine and serotonin in the intestine. Finally, zinc seems to prevent the increase in endothelial permeability initiated by tumor necrosis factor α (J Nutr 1993;123:1003-9), which also induces a permeability defect in the intestinal epithelial layer (Cytokines 1995;7:441-8). Hence, zinc may stimulate immune defenses (Proc Natl Acad Sci USA 1978;75:5660-4; Immunology 1995;85:69-73) while minimizing the adverse effect of immune cells activation on the epithelial layer. In the current study, as previously shown in Bangladesh (J Pediatr Gastroenterol Nutr 1992;15:289-96), the beneficial effects of zinc were particularly marked within the subgroup of malnourished children, suggesting that zinc also played a role as a nutrient. In fact, a biologic response to zinc supplements is often the best way to demonstrate a zinc deficiency (Nutr Res Rev 1994;7:151-73). Unfortunately, neither of these studies examined the subgroup of well-nourished children in a separate analysis. One might argue that zinc may be useful in the treatment of the diarrhea associated with malnutrition but not in the treatment of diarrhea in general. Indeed, there is a strong association between zinc and malnutrition. Stunting is frequently associated with poor zinc status (Am J Clin Nutr 1979;32:2490-4) and zinc supplementation improves the growth of malnourished children (Am J Clin Nutr 1981;34:898-908). Zinc could be a limiting nutrient in the children's diet, resulting in a reduction of dietary intake and growth failure. Sazawal et al. stressed that diets in their study population had low zinc and high phytate contents. Providing zinc to children who are eating such diets may increase their appetites (Nutr Res Rev 1994;7:151-173) and improve their nutritional status. Experimental studies showed that malnutrition severely impairs mucosal growth and function of the small intestine (Biol Neonate 1988;54:151-9) and that even a brief period of nutritional rehabilitation leads to a rapid recovery of these parameters (Pediatr Res 1990;27:245-51). Nutrient-nutrient interactions could also be involved. Vitamin A mobilization from the liver is zinc dependent (Science 1973;181:954-5). An analysis of vitamin A status would be warranted in a further study. A separate analysis of the subgroup of children that were not breast fed at all would be interesting (25% of them), in that the bioavailability of zinc is higher in human milk than it is in cow's milk (Analyst 1995;1020:905-9). The study of Sazawal et al. suggests that zinc can be used as an adjunct of vitamin supplementation, oral rehydration therapy, and early continual feeding, to diminish the duration and severity of acute diarrhea in preschool children, provided that treatment begins before the fourth day of diarrhea. However, before a generalization of its use might be achieved, questions must be answered: First, what is the key mechanism involved in its action? Second, does zinc have deleterious side effects? Although zinc is generally considered nontoxic, even at high doses, (Environ Health Perspect 1994;102:5-46), it inhibits the intestinal absorption of glucose (Pflugers Arch 1989;415:165-71), suggesting that it might diminish rehydration by glucose-based oral rehydration solutions, particularly in patients not deficient in zinc. Third, is the effect of zinc restricted to zincdeficient and malnourished children, or is it also present in well-nourished children with diarrhea? In fact, the high prevalence of zinc-deficiency in developing countries, the low cost and availability of zinc, together with its capacity to improve immune function and growth of malnourished children have already warranted its adjunction, as a nutrient, in the oral rehydration solution recommended by the World Health Organization for severely malnourished children (Manual for the treatment of diarrhea, CDD, WHO, Genéve 1995;26-7) and in the diets used for nutritional rehabilitation of severely malnourished children in refugee camps (Eur J Clin Nutr 1993;47:750-4). Nicole Darmon; André Briend; Jehan-François Desjeux U290 INSERM; Hôpital Saint-Lazare; Paris, France