Skip to main content
Device Global Header

Subscribe
or Renew

Advanced Search

Original Article

Zinc Supplementation in Young Children with Acute Diarrhea in India

List of authors.
  • Sunil Sazawal, M.B., B.S., M.P.H., Ph.D.,
  • Robert E. Black, M.D., M.P.H.,
  • Maharaj K. Bhan, M.D.,
  • Nita Bhandari, M.B., B.S., Ph.D.,
  • Anju Sinha, M.B., B.S.,
  • and Sanju Jalla, Ph.D.

Abstract

Background

In developing countries the duration and severity of diarrheal illnesses are greatest among infants and young children with malnutrition and impaired immune status, both factors that may be associated with zinc deficiency. In children with severe zinc deficiency, diarrhea is common and responds quickly to zinc supplementation.

Methods

To evaluate the effects of daily supplementation with 20 mg of elemental zinc on the duration and severity of acute diarrhea, we conducted a double-blind, randomized, controlled trial involving 937 children, 6 to 35 months of age, in New Delhi, India. All the children also received oral rehydration therapy and vitamin supplements.

Results

Among the children who received zinc supplementation, there was a 23 percent reduction (95 percent confidence interval, 12 percent to 32 percent) in the risk of continued diarrhea. Estimates of the likelihood of recovery according to the day of zinc supplementation revealed a reduction of 7 percent (95 percent confidence interval, -9 percent to +22 percent) in the risk of continued diarrhea during days 1 through 3 and a reduction of 38 percent (95 percent confidence interval, 27 percent to 48 percent) after day 3. When zinc supplementation was initiated within three days of the onset of diarrhea, there was a 39 percent reduction (95 percent confidence interval, 7 percent to 61 percent) in the proportion of episodes lasting more than seven days. In the zinc-supplementation group there was a decrease of 39 percent (95 percent confidence interval, 6 percent to 70 percent) in the mean number of watery stools per day (P = 0.02) and a decrease of 21 percent (95 percent confidence interval, 10 percent to 31 percent) in the number of days with watery diarrhea. The reductions in the duration and severity of diarrhea were greater in children with stunted growth than in those with normal growth.

Conclusions

For infants and young children with acute diarrhea, zinc supplementation results in clinically important reductions in the duration and severity of diarrhea.

Introduction

Among children in developing countries, diarrheal illnesses, especially those of prolonged duration, are important causes of growth retardation and death.1-5 Episodes of diarrhea, which usually resolve within a few days in a healthy child, persist longer in children with malnutrition,6,7 impaired cellular immunity,7-9 or recurrent diarrhea.10

We hypothesized that zinc deficiency is a link between these risk factors and the duration of diarrhea. Diarrhea is consistently found in children with severe zinc deficiency,11,12 as well as in animals with zinc depletion13; it responds quickly to zinc supplementation.14 Zinc deficiency can result in growth retardation, especially stunting,15 and impairment of immune function.16,17 Finally, diarrhea leads to excess zinc losses and could contribute to zinc deficiency,18-21 especially if the zinc content of the diet is limited.22,23 To evaluate this hypothesis, we investigated the effect of zinc supplementation on the duration and severity of diarrhea in a community-based, double-blind, controlled trial.

Methods

The trial was conducted in the Kalkaji neighborhood of New Delhi, India, an urban population of low socioeconomic status, between September 1992 and November 1994. The incidence of diarrhea in this population is nine episodes per year for children up to 11 months of age and five episodes per year for children 12 to 36 months of age.24

Screening and Selection of Patients

All patients with diarrhea who presented to the dispensary at Kalkaji, where a special diarrhea clinic was operated by research physicians, were screened for enrollment in the trial. Children 6 to 35 months of age who were reported to have passed at least four unformed stools in the previous 24 hours, who had had diarrhea for less than seven days, and who were permanent residents of Kalkaji were selected for inclusion. Children who presented to the clinic a second time, those who were judged by the physician to have malnutrition requiring hospitalization, and those whose parents did not provide consent were excluded. The parents of children without dehydration or with mild dehydration were advised to give them 50 ml of oral rehydration solution per kilogram of body weight at home and were given packets of oral rehydration salts. Parents were advised to continue feeding the child his or her usual diet. Children who presented with dehydration of more than 7 percent as assessed clinically were enrolled, supplementation was started, and the children were referred to the All India Institute of Medical Sciences for rehydration.

The study was approved by the human research review committees at the All India Institute of Medical Sciences, Johns Hopkins School of Hygiene and Public Health, and the World Health Organization (WHO). The consent form was read to a parent, and written informed consent was obtained for each child's enrollment.

Base-Line Assessment

A base-line assessment, including a detailed physical examination, was performed by a research physician at the time of enrollment. Weight was measured using an electronic scale with a sensitivity of ±10 g (SECA, Columbia, Md.) by two independent observers; length (for children less than 24 months old) or height (for children 24 to 35 months old) was measured using Shorr length boards (Shorr Productions, Olney, Md.) to within 0.1 cm. For dehydrated children the examination was repeated after hydration. Stunting was defined as a z score of less than -2 for length or height for age (indicating a value more than 2 SD below the median for the reference population) and wasting as a z score of less than -2 for weight for length; the reference population used was that of the National Center for Health Statistics.25

A venous blood sample for the estimation of zinc levels was collected with Monovette trace element–free heparinized syringes (Sarstedt, Newton, N.C.); plasma was separated within 15 minutes after collection of samples. Zinc was analyzed with standard methods.26

Randomization and Blinding

Randomization schedules with permuted blocks of 1027,28 were used for children with four combinations of characteristics: those with z scores of -2 or greater for weight for length who were partially or exclusively breast-fed (stratum A1); those with z scores below -2 who were breast-fed (A2); those with z scores of -2 or greater who were not breast-fed (A3); and those with z scores below -2 who were not breast-fed (A4). Within each stratum, enrolled children were assigned sequential serial numbers indicating whether they would receive the zinc preparation or placebo. The solutions were identical in appearance and taste. The code, which was kept by WHO personnel, was not available to the investigators until the end of the study.

Intervention

The liquid preparations given to the children in the two groups were made by Sandoz India (Bombay). Each daily 10-ml dose contained vitamins A (1600 units), B1 (1.2 mg), B2 (1.0 mg), B6 (1.0 mg), D3 (200 IU), and E (6 mg) and niacinamide (20 mg). The zinc preparation contained zinc gluconate (20 mg of elemental zinc). Bottles were given to each child's mother and kept at home. A separate team of field assistants dispensed the assigned preparation to the child in the home every day except Sundays and holidays, when they left a measured dose in a separate vial for the mother to give to the child. Compliance was checked by other workers who visited to assess the child's condition and by study supervisors. The supplement was actually fed by the field worker on 78 percent of the days in the zinc-supplementation group and 79 percent of the days in the control group; on 2 to 3 percent of the days in each group no supplement was consumed.

Follow-up Visits

Each enrolled child was visited at home by a trained field worker every fifth day, and information for each of the previous five days, including the number and consistency of stools, was recorded. Children who were unavailable were visited again the next day. Mothers were asked to contact the study physicians at the clinic if they felt that their children were sick between the visits. Packets of oral rehydration salts were provided by the field worker, and the mother was advised about treating the child's diarrhea. Parents were given a card to show to any non-study health worker stating that the child should not be given any additional vitamin or mineral preparation. Children who had dysentery or who had diarrhea for 10 days or more after enrollment were given antibiotics. None of the medications used contained zinc.

Study Groups

Of 960 children screened, 13 were excluded because their parents did not give consent; no child was excluded because of malnutrition. A total of 947 children were assigned to treatment groups: 462 to the zinc-supplementation group and 485 to the control group; 576 were from stratum A1, 177 from A2, 143 from A3, and 51 from A4. Ten children were excluded from analysis (six in the zinc group and four in the control group); in five cases consent was withdrawn at the first home visit, in two the diarrhea stopped before supplementation could be begun, and in three there was missing information for two or more consecutive visits. For six children, three in each group, the total duration of diarrhea was unknown; they were included in the survival analysis but not in analyses of the total duration of diarrhea. In eight cases, consent to collect a blood sample for the estimation of the zinc concentration was refused.

Definitions of Primary Outcomes

A day of diarrhea was defined as the passage of four or more unformed stools in 24 hours, and an episode of diarrhea was considered terminated on the last day of diarrhea that was followed by a 72-hour diarrhea-free period. A day with watery stools was defined as the passage of three or more watery stools in 24 hours.

Statistical Analysis

Statistical analysis was performed using SPSSPC+ (version 6.0), Epi-Info (version 6.0), and SAS (version 6.08) software. Relative risks and 95 percent confidence intervals were estimated by the Taylor series method.29 The total duration of episodes was modeled with Cox survival regressions with a time-dependent covariate (PHREG in SAS 6.07 on a VMS mainframe had to be used to enable the use of the “exact option” for the handling of ties).30,31 The time-dependent covariate was assigned a value of 0 (for children in the control group) or 1 (for those in the zinc-supplementation group) on the day that supplementation began. In addition, a second model that allowed the effect of supplementation to change between days 1 through 3 and day 4 or later after the beginning of supplementation32 was fitted with two time-dependent variables. Finally, logistic-regression models used the duration of diarrhea (>7 days vs. <7 days) from the time of enrollment as the dependent variable; the treatment group, potential covariates, and interaction terms were the independent variables.27

Results

Table 1. Table 1. Base-Line Demographic Characteristics and Features of the Episodes of Diarrhea, According to Study Group.

The base-line characteristics of the children in the two groups were similar (Table 1). Identical proportions (0.4 percent) were exclusively breast-fed. One child in each group was initially hospitalized for the treatment of dehydration. Among socioeconomic indicators, the average annual incomes (about $532) and the rate of ownership of a number of household items (data not shown) were similar in the two groups.

Duration of Episodes of Diarrhea

Table 2. Table 2. Relative Risk of Continued Diarrhea in the Cox Regression Models, According to Study Group.

Of 931 episodes of diarrhea, 44.4 percent resolved within three days after enrollment, and 83.5 percent resolved by day 7. Supplementation with zinc was associated with a 23 percent reduction in the risk of continued diarrhea on a given day (model 1 in Table 2). For the subgroups of children who had stunted growth or low plasma zinc concentrations at enrollment, the reductions in risk were 25 percent and 27 percent, respectively (model 1). In a model including stunting, age group, and plasma zinc concentration as covariates (model 2 in Table 2), zinc supplementation was associated with a 21 percent reduction in the risk of continued diarrhea.

Kaplan–Meier curves (data not shown), although they did not take into account the duration of diarrhea before enrollment, indicated that the reduction in the duration of diarrhea became evident on the fourth day after the beginning of supplementation. Therefore, we used a model that included the effect of supplementation for days 1 through 3 and for day 4 and subsequent days; the resulting fit was better than with model 1.32 The estimated relative risk of continued diarrhea in the zinc-supplementation group as compared with the control group was 0.93 (95 percent confidence interval, 0.78 to 1.09) during days 1, 2, and 3 of supplementation and 0.62 (95 percent confidence interval, 0.52 to 0.73) after day 3.

Persistence and Severity of Diarrhea

Table 3. Table 3. Frequency of Diarrhea Lasting More than Seven Days and Severity of Episodes of Diarrhea, According to Study Group.

In the zinc-supplementation group there was a significant reduction (39 percent) in episodes of diarrhea lasting more than seven days after enrollment when supplementation was started within three days of the onset of diarrhea (Table 3). To evaluate the effect of supplementation in a multivariate analysis, we used a logistic-regression model in which the dependent variable was the duration of diarrhea (<7 vs. >7 days from the onset of treatment); sex, the use of a drug during the episode (yes or no), breast-feeding (yes or no), years of schooling of the child's mother, study group (zinc supplementation or control), z score for height for age (< -2.0 or ≥ -2.0), and the plasma zinc concentration (<60.0 or ≥60.0 μg per deciliter [<9.2 or ≥9.2 mmol per liter]) were entered as independent variables. In this model, the odds ratio for diarrhea lasting more than seven days was 0.79 with zinc supplementation (95 percent confidence interval, 0.64 to 0.96). The odds ratio was 0.74 (95 percent confidence interval, 0.57 to 0.95) when the model was restricted to the children enrolled by day 3 of the episode of diarrhea.

There was a 39 percent reduction (95 percent confidence interval, 6 percent to 70 percent) in the mean number of watery stools per day in the zinc-supplementation group (P = 0.02) and a 21 percent reduction (95 percent confidence interval, 10 percent to 31 percent) in the number of days with watery stools. In the zinc-supplementation group the mean (±SD) number of watery stools per day was 3.1±9.9, as compared with 5.1±14.9 in the control group. Fewer children in the zinc-supplementation group were taken to a physician at least once during follow-up because their parents were concerned about their health, but this difference was not significant (P = 0.12).

Analyses of Subgroups

Table 4. Table 4. Duration and Severity of Episodes of Diarrhea among Children with Stunted Growth and Children with Plasma Zinc Levels ,60 mg/dl at Enrollment, According to Study Group.

The reduction in the likelihood of diarrhea lasting more than seven days was 65 percent in the subgroup of children with stunted growth who had had diarrhea for less than four days before enrollment (Table 4). The effect of zinc on the number of days with watery stools was greater in children with stunted growth than in those with normal growth (relative risk in the zinc-supplementation group as compared with the controls, 0.59 [95 percent confidence interval, 0.48 to 0.73] and 0.95 [95 percent confidence interval, 0.79 to 1.15], respectively). In children with wasting (z score for weight for length < -2), there was an even greater reduction in the number of days of watery diarrhea (relative risk in the zinc-supplementation group, 0.48; 95 percent confidence interval, 0.39 to 0.68). There was no clear trend with respect to the effect within subgroups defined according to the plasma zinc levels.

Adverse Reactions

Four children, two in each group, reported vomiting immediately after consuming the supplement on one or two occasions.

Discussion

This study, conducted in New Delhi, documents the effectiveness of zinc supplementation as an adjunct to oral rehydration therapy and early continued feeding among preschool children with acute diarrhea. Zinc supplementation was associated with a clinically important and statistically significant overall reduction of 23 percent in the risk of continued diarrhea and a 39 percent reduction in the frequency of episodes persisting more than seven days after treatment began. It also resulted in a 21 percent reduction in the number of days with watery stools and a 39 percent reduction in the mean number of watery stools per day. Reductions in the frequency of prolonged diarrhea and the number of days with watery stools may decrease the risk of dehydration and the need for fluid and electrolyte replacement. We could not measure the effect of zinc supplementation on dehydration because oral-rehydration solution was provided from the day of enrollment. Reductions in the frequency of diarrhea may also improve growth.33

Because the study was conducted with the children at home rather than in the hospital, they were able to continue their usual diets. We made relatively few visits to assess morbidity, so that the natural history of the illness could be evaluated without intensive medical intervention, although this practice might have limited the precision of the information on daily outcomes.

In a previous trial of supplementation with 20 mg of zinc daily in children with acute diarrhea, there were no differences in outcomes overall, but the children with low zinc concentrations in the rectal mucosa had shorter episodes of diarrhea and less frequent stools.34 In a small study of children with persistent diarrhea, the administration of a 20-mg zinc supplement was associated with a 20 percent reduction in the duration of diarrhea and the frequency of stools, although these differences were not statistically significant.35

The finding of a sizable effect of supplementation and the observation that 37 percent of the children with diarrhea had plasma zinc levels below 60 μg per deciliter suggest a high prevalence of zinc deficiency in this population. Since the plasma zinc level was measured during the episode of diarrhea, a transient effect of the episode on plasma zinc levels cannot be eliminated36-42; however, similar plasma zinc levels were found in the study children who did not receive the supplement 120 days after episodes of diarrhea (unpublished data). Studies from other developing countries suggest that dietary zinc deficiency can be highly prevalent among preschool-age children.22,23 The diets of young children in our Indian study population share two characteristics with other zinc-deficient populations: a low intake of meat or dairy products, which contain zinc, and a high intake of phytates, which interfere with the bioavailability of zinc.

The comparison of the effects of supplementation among subgroups indicates that stunting, wasting, or both can be used to select the children most likely to benefit from treatment with zinc. The initial plasma zinc level did not differentiate those who would derive greater benefit from supplementation from those who would benefit less.

The possible mechanisms for the effect of zinc supplementation on diarrhea include improved absorption of water and electrolytes by the intestines,43-49 regeneration of gut epithelium or the restoration of its function,50-58 increased levels of enterocyte brush-border enzymes,59-65 and enhanced immunologic mechanisms for the clearance of infection, including cellular immunity and higher levels of secretory antibodies.66-68 It is also possible that improved appetite and dietary intake resulted in shorter episodes of diarrhea, as a result of the effect of staple foods on stool consistency.69

In conclusion, a dietary supplement of zinc, along with selected vitamins, resulted in clinically important reductions in the duration and severity of diarrhea among preschool-age children. Because these findings may have important implications for the reduction of morbidity and mortality due to diarrhea in children, they need to be confirmed in other developing countries.

Funding and Disclosures

Supported by the World Health Organization, Diarrheal Disease Control Program, the Thrasher Research Fund, and the Indian Council for Medical Research. Dr. Sazawal is the recipient of a fellowship from the Rockefeller Foundation.

We are indebted to Dr. Michael Hambidge and Jaime Westcott for help with the estimation of plasma zinc levels; to Dr. Larry Moulton for statistical advice; to Dharminder Kashyap and Usha Dhingra for data management; to the field staff of the project and the parents of the participating children for their assistance; to Sandoz India, Ltd., for the supplements; and especially to Dr. Ashok Agarwal for preparing the supplements, maintaining their quality, and ensuring delivery.

Author Affiliations

From the Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore (S.S., R.E.B.), and the Indian Council for Medical Research Advanced Center for Diarrheal Disease Research, Division of Pediatric Gastroenterology, All India Institute of Medical Sciences, New Delhi, India (S.S., M.K.B., N.B., A.S., S.J.).

Address reprint requests to Dr. Black at 615 N. Wolfe St., Baltimore, MD 21205.

References (69)

  1. 1. Fauveau V, Yunus M, Zaman K, Chakraborty J, Sarder AM. Diarrhea mortality in rural Bangladeshi children. J Trop Pediatr 1991;37:31-36

  2. 2. Puffer RR, Serrano CV. Patterns of mortality in childhood: report of the Inter-American Investigation of Mortality in Childhood. Washington, D.C.: Pan American Health Organization, 1973. (PAHO scientific publication no. 262.)

  3. 3. Bhandari N, Bhan MK, Sazawal S. Mortality associated with acute watery diarrhea, dysentery and persistent diarrhea in rural north India. Acta Paediatr Suppl 1992;381:3-6

  4. 4. Bhan MK, Arora NK, Ghai OP, Ramachandran K, Khoshoo V, Bhandari N. Major factors in diarrhea related mortality among rural children. Indian J Med Res 1986;83:9-12

  5. 5. Black RE. Would control of childhood infectious diseases reduce malnutrition? Acta Paediatr Scand Suppl 1991;374:133-140

  6. 6. Black RE, Brown KH, Becker S. Malnutrition is a determining factor of diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh. Am J Clin Nutr 1984;39:87-94

  7. 7. Baqui AH, Sack RB, Black RE, Chowdhury HR, Yunus M, Siddique AK. Cell-mediated immune deficiency and malnutrition are independent risk factors for persistent diarrhea in Bangladeshi children. Am J Clin Nutr 1993;58:543-548

  8. 8. Black RE, Lanata CF, Lazo F. Delayed cutaneous hypersensitivity: epidemiologic factors affecting and usefulness in predicting diarrheal incidence in young Peruvian children. Pediatr Infect Dis J 1989;8:210-215

  9. 9. Baqui AH, Black RE, Sack RB, Chowdhury HR, Yunus M, Siddique AK. Malnutrition, cell-mediated immune deficiency, and diarrhea: a community-based longitudinal study in rural Bangladeshi children. Am J Epidemiol 1993;137:355-365

  10. 10. Sazawal S, Bhan MK, Bhandari N, Clemens J, Bhatnagar S. Evidence for recent diarrhoeal morbidity as a risk factor for persistent diarrhoea: a case-control study. Int J Epidemiol 1991;20:540-545

  11. 11. Moynahan EJ. Acrodermatitis enteropathica: a lethal inherited human zinc-deficiency disorder. Lancet 1974;1:399-400

  12. 12. Kay RG, Tasman-Jones C. Zinc deficiency and intravenous feeding. Lancet 1975;2:605-606

  13. 13. Tomkins A, Behrens R, Roy S. The role of zinc and vitamin A deficiency in diarrhoeal syndromes in developing countries. Proc Nutr Soc 1993;52:131-142

  14. 14. Hambidge KM. Zinc and diarrhea. Acta Paediatr 1992;381:82-86

  15. 15. Allen LH. Nutritional influences on linear growth: a general review. Eur J Clin Nutr 1994;48:Suppl 1:S75-S89

  16. 16. Beisel WR. Single nutrients and immunity. Am J Clin Nutr 1982;35:Suppl:417-468

  17. 17. Golden MHN, Golden BE. Zinc and delayed hypersensitivity responses. Nutr Res 1985;5:Suppl I:S-700

  18. 18. Wolman SL, Anderson GH, Marliss EB, Jeejeebhoy KN. Zinc in total parenteral nutrition: requirements and metabolic effects. Gastroenterology 1979;76:458-467

  19. 19. Castillo-Duran C, Vial P, Uauy R. Trace mineral balance during acute diarrhea in infants. J Pediatr 1988;113:452-457

  20. 20. Zinc and copper wastage during acute diarrheaNutr Rev 1990;48:19-22

  21. 21. Ruz M, Solomons N. Fecal zinc excretion during oral rehydration therapy for acute infectious diarrhea. Fed Proc 1987;46:748-748 abstract.

  22. 22. Prasad AS. Discovery of human zinc deficiency and studies in an experimental human model. Am J Clin Nutr 1991;53:403-412

  23. 23. Murphy SP, Beaton GH, Calloway DH. Estimated mineral intakes of toddlers: predicted prevalence of inadequacy in village populations in Egypt, Kenya, and Mexico. Am J Clin Nutr 1992;56:565-572

  24. 24. Bhandari N, Bhan MK, Sazawal S. Impact of massive dose of vitamin A given to preschool children with acute diarrhoea on subsequent respiratory and diarrhoeal morbidity. BMJ 1994;309:7404-7407

  25. 25. National Center for Health Statistics. Growth curves for children birth–18 years, United States. Vital and health statistics. Series 11. Washington, D.C.: Government Printing Office, 1977. No. 165. (DHEW publication no. (PHS) 78-1650.)

  26. 26. Hambidge KM, King JC, Kern DL, English-Westcott JL, Stall C. Pre-breakfast plasma zinc concentrations: the effect of previous meals. J Trace Elem Electrolytes Health Dis 1990;4:229-231

  27. 27. Matthews DE, Farewell VT. Using and understanding medical statistics. 2nd ed. Basel, Switzerland: Karger, 1988:164-6.

  28. 28. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 2nd ed. Littleton, Mass.: PSG Publishing, 1985:54-5.

  29. 29. Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data. Biometrics 1985;41:55-68

  30. 30. The PHREG procedure. In: SAS/STAT software: changes and enhancements, release 6.07. SAS technical report P-229. Cary, N.C.: SAS Institute, 1992:435-79.

  31. 31. Cox DR, Oakes D. Analysis of survival data. London: Chapman & Hall, 1984.

  32. 32. Wax Y, Galai N, Carey V, Simchen E. Cox regression models for intermediate events, with discharge from hospital as an example. Epidemiology 1993;4:120-127

  33. 33. Black RE, Brown KH, Becker S. Effects of diarrhea associated with specific enteropathogens on the growth of children in rural Bangladesh. Pediatrics 1984;73:799-805

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

  35. 35. Sachdev HPS, Mittal NK, Yadav HS. Oral zinc supplementation in persistent diarrhoea in infants. Ann Trop Paediatr 1990;10:63-69

  36. 36. Guerrieri A, Catassi C, Pasquini E, Coppa GV, Benetti E, Giorgi PL. Plasma zinc levels in children with chronic diarrhoea. Eur J Pediatr 1986;145:563-564

  37. 37. Castillo-Duran C, Vial P, Uauy R. Oral copper supplementation: effect on copper and zinc balance during acute gastroenteritis in infants. Am J Clin Nutr 1990;51:1088-1092

  38. 38. Rothbaum RJ, Maur PR, Farrell MK. Serum alkaline phosphatase and zinc undernutrition in infants with chronic diarrhea. Am J Clin Nutr 1982;35:595-598

  39. 39. Naveh Y, Lightman A, Zinder O. Effect of diarrhea on serum zinc concentrations in infants and children. J Pediatr 1982;101:730-732

  40. 40. Rodriguez A, Soto G, Torres S, Venegas G, Castillo-Duran C. Zinc and copper in hair and plasma of children with chronic diarrhea. Acta Pediatr Scand 1985;74:770-774

  41. 41. Sarker SA, Rahaman MM, Ali A, Hossain S, Alam AN. Prolonged depression of serum zinc concentrations in children following post-measles diarrhea. Hum Nutr Clin Nutr 1985;39:411-417

  42. 42. Brown KH, Lanata CF, Yuen ML, Peerson JM, Butron B, Lonnerdal B. Potential magnitude of the misclassification of a population's trace element status due to infection: example from a survey of young Peruvian children. Am J Clin Nutr 1993;58:549-554

  43. 43. Ghishan FK. Transport of electrolytes, water, and glucose in zinc deficiency. J Pediatr Gastroenterol Nutr 1984;3:608-612

  44. 44. Patrick J, Golden BE, Golden MHN. Leucocyte sodium transport and dietary zinc in protein energy malnutrition. Am J Clin Nutr 1980;33:617-620

  45. 45. Kasch P, Hook JB, Bond JT. Effects of zinc deficiency on carbonic anhydrase activity and renal function. Fed Proc 1979;39:605-605 abstract.

  46. 46. Patrick J, Michael J, Golden MN, Golden BE, Hilton PJ. Effect of zinc on leucocyte sodium transport in vivo. Clin Sci Mol Med 1978;54:585-587

  47. 47. Golden BE, Golden MHN. Zinc, sodium and potassium losses in the diarrheas of malnutrition and zinc deficiency. In: Mills CF, Bremner I, Chesters JK, eds. Trace elements in man and animals — TEMA 5. Aberdeen, United Kingdom: Rowett Research Institute, 1985:228-32.

  48. 48. Golden BE, Golden MHN. Dietary zinc and the output and composition of faeces. In: Gawthorne JM, Howell JM, White CL, eds. Trace element metabolism in man and animals. Berlin, Germany: Springer-Verlag, 1982:73-6.

  49. 49. Roy SK, Draser BS, Tomkins AM. The impact of zinc deficiency on the intestinal response to cholera toxin. Proc Nutr Soc 1986;45:39A-39A abstract.

  50. 50. Bettger WJ, O'Dell BL. A critical physiological role of zinc in the structure and function of biomembranes. Life Sci 1981;28:1425-1438

  51. 51. Elmes ME, Jones JG. Ultrastructural changes in the small intestine of zinc deficient rats. J Pathol 1980;130:37-43

  52. 52. Arcasoy A, Akar N, Ors U, Delilbasi L, Karayalcin S. Ultrastructural changes in the mucosa of the small intestine in patients with geophagia (Prasad's syndrome). J Pediatr Gastroenterol Nutr 1990;11:279-282

  53. 53. Koo SI, Turk DE. Effect of zinc deficiency on the ultrastructure of the pancreatic acinar cell and intestinal epithelium in the rat. J Nutr 1977;107:896-908

  54. 54. Moran JR, Lewis JC. The effects of severe zinc deficiency on intestinal permeability: an ultrastructural study. Pediatr Res 1985;19:968-973

  55. 55. Ford RPK, Menzies IS, Phillips AD, Walker-Smith JA, Turner MW. Intestinal sugar permeability: relationship to diarrheal disease and small bowel morphology. J Pediatr Gastroenterol Nutr 1985;4:568-574

  56. 56. Weaver LT, Chapman PD, Madeley CR, Laker MF, Nelson R. Intestinal permeability changes and excretion of micro-organisms in stools of infants with diarrhoea and vomiting. Arch Dis Child 1985;60:326-332

  57. 57. Evans PH, Bates CJ, Lunn PG, et al. Zinc supplementation in young Gambian children. Proc Nutr Soc 1993;52:25A-25A abstract.

  58. 58. Roy SK, Behrens RH, Haider R, et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. J Pediatr Gastroenterol Nutr 1992;15:289-296

  59. 59. Gebhard RL, Karouani R, Prigge WF, McClain CJ. Effect of severe zinc deficiency on activity of intestinal disaccharidases and 3-hydroxy-3-methylglutaryl coenzyme A reductase in the rat. J Nutr 1983;113:855-859

  60. 60. Jones PE, Peters TJ. Oral zinc supplements in non-responsive coeliac syndrome: effect on jejunal morphology, enterocyte production, and brush border disaccharidase activities. Gut 1981;22:194-198

  61. 61. Suzuki I, Kushida H. Studies on mammalian glycosidases. V. Effects of metal ions upon acidic and neutral α-glucosidases, β-galactosidases, and α-mannosidases in liver extracts of rabbit. J Biochem (Tokyo) 1973;74:627-629

  62. 62. Peters TJ. Analytical subcellular fractionation of jejunal biopsy specimens: methodology and characterisation of the organelles in normal tissue. Clin Sci Mol Med 1976;51:557-574

  63. 63. Lisowski J, Rajkumar TV, Wolf DP, Stein EA. Evidence for tightly-bound zinc in leucine aminopeptidase from pig kidney. Acta Biochim Pol 1970;17:311-324

  64. 64. Warren L, Glick MC, Nass MK. Membranes of animal cells. I. Methods of isolation of the surface membranes. J Cell Physiol 1966;68:269-288

  65. 65. Truding R, Shelanski ML, Daniels MP, Morell P. Comparison of surface membranes isolated from cultured murine neuroblastoma cells in the differentiated or undifferentiated state. J Biol Chem 1974;249:3973-3982

  66. 66. Cunningham-Rundles C, Cunningham-Rundles S, Garofalo J. Increased T lymphocyte function and thymopoietin following zinc repletion in man. Fed Proc 1979;38:1222-1222 abstract.

  67. 67. Fenwick PK, Aggett PJ, Macdonald D, Huber C, Wakelin D. Zinc deficiency and zinc depletion: effect on the response of rats to infection with Trichinella spiralis. Am J Clin Nutr 1990;52:166-172

  68. 68. Schlesinger L, Arevalo M, Arredondo S, Diaz M, Lonnerdal B, Stekel A. Effect of a zinc-fortified formula on immunocompetence and growth of malnourished infants. Am J Clin Nutr 1992;56:491-498

  69. 69. Brown KH. Dietary management of acute diarrheal disease: contemporary scientific issues. J Nutr 1994;124:Suppl:1455S-1460S

Citing Articles (260)

    Figures/Media

    1. Table 1. Base-Line Demographic Characteristics and Features of the Episodes of Diarrhea, According to Study Group.
      Table 1. Base-Line Demographic Characteristics and Features of the Episodes of Diarrhea, According to Study Group.
    2. Table 2. Relative Risk of Continued Diarrhea in the Cox Regression Models, According to Study Group.
      Table 2. Relative Risk of Continued Diarrhea in the Cox Regression Models, According to Study Group.
    3. Table 3. Frequency of Diarrhea Lasting More than Seven Days and Severity of Episodes of Diarrhea, According to Study Group.
      Table 3. Frequency of Diarrhea Lasting More than Seven Days and Severity of Episodes of Diarrhea, According to Study Group.
    4. Table 4. Duration and Severity of Episodes of Diarrhea among Children with Stunted Growth and Children with Plasma Zinc Levels ,60 mg/dl at Enrollment, According to Study Group.
      Table 4. Duration and Severity of Episodes of Diarrhea among Children with Stunted Growth and Children with Plasma Zinc Levels ,60 mg/dl at Enrollment, According to Study Group.

      More Research