【关键词】 commentary
zinc is an essential nutrient, which is required to maintain the normal structure and/or function of multiple enzymes, including those that are involved in transcription and translation of genetic material and ultimately, therefore, in cell division.1 early research in experimental animals demonstrated the critical importance of zinc for normal dietary intake and physical growth.2 these results suggested that zinc nutriture might also influence the growth of young children, particularly in resource-poor countries where dietary intake or absorption of zinc may be inadequate3 and/or excessive zinc losses may occur due to frequent enteric infections.4 nevertheless, the lack of simple, objective biomarkers of zinc status has hindered the ability to implicate zinc nutriture unequivocally as a cause of growth failure in humans.
in an attempt to shed more light on this topic, we recently prepared a quantitative review of 33 previously completed studies of the effect of zinc supplementation on children’s growth.5 according to the results of this meta-analysis, zinc supplementation produced a small, but highly significant, positive impact on children’s weight gain and linear growth. notably, the growth-promoting effect of zinc was restricted to those studies that enrolled children with low mean initial weight-for-age or height-for-age. when the analysis was restricted to studies of malnourished subjects, as evidenced by mean initial anthropometric z-scores (<2.0 z), the effect of zinc on growth was moderately large (effect size of ~0.5 sd units).
in this issue of the international journal of epidemiology, müller et al. report the results of a zinc intervention trial conducted in rural burkina faso,6 from which they concluded that there was no effect of supplemental zinc on the children’s growth. because this finding is at odds with the above-mentioned meta-analysis, it is instructive to examine the details of the current report in relation to the findings of that review. possible explanations for the discrepant results include: (1) methodological issues, such as differences in the dose, form, and means of delivering the zinc supplement, or the anthropometric techniques used to assess growth, and (2) specific characteristics of the study population that may have affected their ability to respond to supplemental zinc. each of these points will be discussed briefly, as follows.
in the study by müller et al., 12.5 mg zinc was provided daily as zinc sulphate to children 631 months of age. this level of supplementation is within the range of doses provided in the previously reviewed studies of young children and slightly greater than the mean level offered, so it is unlikely that the dose of the supplement was inadequate. the supplements were dissolved in water and fed to the children without regard for consumption of other foods. although it is conceivable that other components of the diet may have interfered with absorption of the supplemental zinc, in previous studies included in the meta-analysis the authors rarely reported that they attempted to provide the zinc supplements apart from meals. thus, there is little reason to believe that insufficient absorption of the supplement was the reason for a lack of response in the current study, although future research should probably address this issue specifically.
it is generally assumed that a functional response to nutrient supplementation will occur only if the particular nutrient was consumed previously in amounts that were not adequate to satisfy physiological requirements. moreover, for a particular response (in this case, growth) to be detectable, that function must have been occurring sub-maximally prior to initiation of the intervention. what, then, is the evidence that the subjects in the current study were, indeed, zinc deficient and growing less than their physiological potential prior to the start of the study? with regard to zinc status, we can rely on just two types of data: (1) ecological information, such as the nature of the local diet and the rate of enteric infections, and (2) biochemical indicators, namely the serum zinc concentrations. information on the adequacy of dietary zinc intake is not available for the study subjects, although we know from earlier reports, based on national food balance sheets, that the food supply in most sub-saharan african countries is moderately or severely limited in absorbable zinc content.7 thus, the study subjects may have had an elevated risk of inadequate zinc intake, although this was not documented in the study subjects.
despite known limitations in the interpretation of serum zinc concentration as a marker of individual zinc status, there is some evidence that this is a useful indicator for assessing populations.8 statistical cut-offs for adequate serum zinc concentration have been developed recently, based on the distribution of serum zinc values in presumably healthy, zinc-replete individuals in the us.9 this latter analysis showed that the distribution of serum zinc values differs by age group, fasting status, time of day, and presence of illness. the suggested lower cut-offs for serum zinc concentrations of young children are 9.9 µmol/l (65 µg/dl), if they are examined in the morning while non-fasting, and 8.7 µmol/l (57 µg/dl), if studied in the afternoon. in the current study, the mean serum zinc levels were 11.7 µmol/l, and 72% of the values were <13.0 µmol/l; but the time of the blood sampling was not stated. assuming that the samples were collected from non-fasting individuals in the morning, and that the values were reasonably normally distributed, it is likely that about 20% of the values were less than the proposed cut-off. this suggests that zinc deficiency may, in fact, be a problem of public health importance in this population.
the children had a mean height-for-age z-score of approximately -1.5 z at baseline, which is just about the mean level of stunting where a positive impact of zinc supplementation was first observed in the previously cited meta-analysis.5 thus, it is possible that either the children in the current study were not stunted enough to respond to zinc or that the magnitude of any possible growth response was not large enough to be detectable with the available sample size and the measurement techniques that were employed. with regard to the measurement techniques, it is worth noting that length was measured with a precision of just 1 cm, whereas most studies of children’s growth attempt to measure to a precision of 1 mm. although this choice of measurement techniques would not have biased the study results, it may have reduced the investigators’ ability to detect fairly small differences in growth. interestingly, the observed sd in growth increments of ~2 cm/month is considerably greater than seen in most of the other 6-month studies of similarly aged children that were included in the meta-analysis. because müller et al. did not report intra- and inter-observer measurement errors, it is not certain if the greater variability observed in their study was due to measurement error or to greater heterogeneity of their study population.
a final possible explanation for the lack of growth response in the burkina faso children is that other nutritional deficiencies or infections may have limited their ability to respond to zinc alone. notably, the children had low initial weights-for-length. thus, it conceivable that the presence of wasting may have modified the effect of zinc, although specific interactions between weight-for-length and treatment group were not tested. it is also possible that deficiencies of other micronutrients may have prevented a functional response to zinc. in a recent study of chinese children, for example, the growth response to zinc was greatest when other nutrients were also supplemented.10
in summary, although a number of possible explanations have been proposed, it is still not clear why growth responses to supplemental zinc are inconsistent in different studies, and future research will be required to solve this mystery. nevertheless, it is worth emphasizing that decisions regarding the need for nutrition intervention programmes designed to enhance zinc status should be based on: (1) the likelihood that zinc deficiency is a public health problem in the particular population, and (2) the likely cost-benefit of the intervention relative to other possible health-promoting activities. in the case of zinc intervention programmes, it is important to recognize that growth is only one of several possible beneficial outcomes in high-risk populations. studies have consistently demonstrated a reduced incidence and severity of common childhood infections, like diarrhoea and acute lower respiratory tract infection, following zinc supplementation;11,12 and one study found that zinc supplementation reduced mortality among high-risk indian children.13 indeed, according to earlier results in the same study population in burkina faso,14 diarrhoea rates were significantly reduced by zinc supplementation and mortality fell by more than half, although the latter results were not statistically significant. thus, even if growth is not affected by supplemental zinc, there are other important reasons to consider intervening to enhance zinc status in this population.
references
1 cousins rj. zinc. in: ziegler ee, filer jr lj (eds). present knowledge in nutrition. 7th edn. washington, dc: ilsi press, 1996.
2 chesters jk. biochemistry of zinc in cell division and tissue growth. in: mills cf (ed.). zinc in human biology. london: springer-verlag, 1989.
3 gibson rs, ferguson el. nutrition intervention strategies to combat zinc deficiency in developing countries. nutr res rev 1998;10:118.
4 castillo-duran c, vial p, uauy r. trace mineral balance during acute diarrhea in infants. j pediatr 1988;113:45257.
5 brown kh, peerson jm, allen lh, rivera j. effect of supplemental zinc on the growth and serum zinc concentrations of pre-pubertal children: a meta-analysis of randomized, controlled trials. am j clin nutr 2002;75:106271.
6 müller o, garenne m, reitmaier p, baltussen van zweeden a, kouyate b, becher h. effect of zinc supplementation on growth in west african children: a randomised double-blind placebo-controlled trial in rural burkina faso. int j epidemiol 2003;32:1098102.
7 brown kh, wuehler se, peerson jm. the importance of zinc in human nutrition and estimation of the global prevalence of zinc deficiency. food nutr bull 2001;22:11325.
8 brown kh. effect of infections on plasma zinc concentration and implications for zinc status assessment in low-income countries. am j clin nutr 1999;68:425s29s.
9 hotz c, peerson jm, brown kh. suggested lower cutoffs of serum zinc concentration for assessing population zinc status: a reanalysis of the second us national health and nutrition examination survey data (nhanes ii: 19761980). am j clin nutr
10 sandstead hh, penland jg, alcock nw et al. effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of chinese children. am j clin nutr 1998;68:470s75s.[abstract]
11 zinc investigators’ collaborative group (bhutta za, black re, brown kh et al.). prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. j pediatr 1999;135:68997.
12 zinc investigators’ collaborative group (bhutta za, bird sm, black re et al.). therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. am j clin nutr 2000;72:151622.
13 sazawal s, black re, menon vp et al. zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. pediatrics 2001;108:128086.
14 müller o, becher h, baltussen van zweeden a et al. effect of zinc supplementation on malaria and other causes of morbidity in west african children: randomised double blind placebo controlled trial. bmj 2001;322:156770.
