Zinc deficiency in low- and middle-income countries: prevalence and approaches for mitigation.

This review addresses the prevalence of zinc deficiency in Low- and Middle-income Countries (LMICs) and assesses the available strategies for its alleviation. The paucity of national-level data on the zinc deficiency in LMICs is partially a result of the lack of a reliable biomarker. Zinc deficiency appears to be a public health problem in almost all the LMICs, irrespective of the recommended indicators (plasma zinc concentration, dietary zinc adequacy and stunting prevalence) used. Based on plasma/serum zinc concentration (PZC), which is the most appropriate indicator at present, the prevalence of zinc deficiency in LMICs is of concern. Among the 25 countries for which national PZC data were available, 23 had a zinc deficiency prevalence of >20% for at least one physiological group. Zinc supplementation is largely restricted as an adjunct therapy for diarrhoea management in children, and the best platform and the most effective way of preventive zinc supplementation delivery remains to be established. Impact assessment for current zinc fortification programmes in LMICs and the effectiveness of zinc supplementation as part of a multi-micronutrient powder is to be determined. Dietary diversification, though promising for LMICs, is in the nascent stages of development at present. Inclusion of meat and animal products can be an important way of improving zinc status. Programmatic experience with the promotion of home processing techniques to increase absorbable zinc in the diet is lacking. Conventional biofortification techniques are gaining recognition in LMICs; however, transgenic biofortification as a strategy remains controversial.

Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis.

In developing countries, deficiencies of micronutrients are thought to have a major impact on child development; however, a consensus on the specific relationship between dietary zinc intake and cognitive function remains elusive. The aim of this systematic review was to examine the relationship between zinc intake, status and indices of cognitive function in children and adults. A systematic literature search was conducted using EMBASE, MEDLINE and Cochrane Library databases from inception to March 2014. Included studies were those that supplied zinc as supplements or measured dietary zinc intake. A meta-analysis of the extracted data was performed where sufficient data were available. Of all of the potentially relevant papers, 18 studies met the inclusion criteria, 12 of which were randomised controlled trials (RCTs; 11 in children and 1 in adults) and 6 were observational studies (2 in children and 4 in adults). Nine of the 18 studies reported a positive association between zinc intake or status with one or more measure of cognitive function. Meta-analysis of data from the adult's studies was not possible because of limited number of studies. A meta-analysis of data from the six RCTs conducted in children revealed that there was no significant overall effect of zinc intake on any indices of cognitive function: intelligence, standard mean difference of <0.001 (95% confidence interval (CI) -0.12, 0.13) P=0.95; executive function, standard mean difference of 0.08 (95% CI, -0.06, 022) P=0.26; and motor skills standard mean difference of 0.11 (95% CI -0.17, 0.39) P=0.43. Heterogeneity in the study designs was a major limitation, hence only a small number (n=6) of studies could be included in the meta-analyses. Meta-analysis failed to show a significant effect of zinc supplementation on cognitive functioning in children though, taken as a whole, there were some small indicators of improvement on aspects of executive function and motor development following supplementation but high-quality RCTs are necessary to investigate this further.

The relationship between zinc intake and growth in children aged 1-8 years: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: It is estimated that zinc deficiency affects 17% of the world's population, and because of periods of rapid growth children are at an increased risk of deficiency, which may lead to stunting. This paper presents a systematic review and meta-analysis of the randomised controlled trials (RCTs) that assess zinc intake and growth in children aged 1-8 years. This review is part of a larger systematic review by the European Micronutrient Recommendations Aligned Network of Excellence that aims to harmonise the approach to setting micronutrient requirements for optimal health in European populations (www.eurreca.org). SUBJECT/METHODS: Searches were performed of literature published up to and including December 2013 using MEDLINE, Embase and the Cochrane Library databases. Included studies were RCTs in apparently healthy child populations aged from 1 to 8 years that supplied zinc supplements either as capsules or as part of a fortified meal. Pooled meta-analyses were performed when appropriate. RESULTS: Nine studies met the inclusion criteria. We found no significant effect of zinc supplementation of between 2 weeks and 12 months duration on weight gain, height for age, weight for age, length for age, weight for height (WHZ) or WHZ scores in children aged 1-8 years. CONCLUSIONS: Many of the children in the included studies were already stunted and may have been suffering from multiple micronutrient deficiencies, and therefore zinc supplementation alone may have only a limited effect on growth.

Effect of acute zinc depletion on zinc homeostasis and plasma zinc kinetics in men.

BACKGROUND: Zinc homeostasis and normal plasma zinc concentrations are maintained over a wide range of intakes. OBJECTIVE: The objective was to identify the homeostatic response to severe zinc depletion by using compartmental analysis. DESIGN: Stable zinc isotope tracers were administered intravenously to 5 men at baseline (12.2 mg dietary Zn/d) and after 5 wk of acute zinc depletion (0.23 mg/d). Compartmental modeling of zinc metabolism was performed by using tracer and mass data in plasma, urine, and feces collected over 6-14 d. RESULTS: The plasma zinc concentration fell 65% on average after 5 wk of zinc depletion. The model predicted that fractional zinc absorption increased from 26% to essentially 100%. The rate constants for zinc excretion in the urine and gastrointestinal tract decreased 96% and 74%, respectively. The rate constants describing the distribution kinetics of plasma zinc did not change significantly. When zinc depletion was simulated by using an average mass model of zinc metabolism at baseline, the only change that accounted for the observed fall in plasma zinc concentration was a 60% reduction in the rate constant for zinc release from the most slowly turning over zinc pool. The large changes in zinc intake, excretion, and absorption-even when considered together-only explained modest reductions in plasma zinc mass. CONCLUSION: The kinetic analysis with a compartmental model suggests that the profound decrease in plasma zinc concentrations after 5 wk of severe zinc depletion was mainly due to a decrease in the rate of zinc release from the most slowly turning over body zinc pool.

Accuracy of simple techniques for estimating fractional zinc absorption in humans.

The theoretical basis of the accuracy of a number of simple techniques for estimating fractional zinc absorption (FZA) in humans using stable isotopic tracers has not been evaluated. These techniques include fecal monitoring (FM), deconvolution analysis (DA), double isotopic tracer ratio (DITR) and indicator dilution methods. Using a compartmental model, we investigated the accuracy and logic of each of these techniques. Time-dependent estimates of FZA based on the simple techniques were simulated using the compartmental model and compared with the known FZA derived from the model. The analysis elucidated logical errors in some of the FM techniques, and even when these problems were corrected, the FM technique was still prone to errors due to incomplete fecal tracer recovery and variable gastrointestinal (GI) transit time. Although logically correct, the indicator dilution techniques were also highly sensitive to incomplete fecal tracer recovery and variable GI transit time. The DA and DITR techniques were the most robust in that they were logically correct and were insensitive to incomplete fecal tracer recovery and variable GI transit time. Although all of the DA and DITR methods provided similarly good estimates of FZA relative to the compartmental model, the DITR technique performed on a spot urine specimen obtained several days after tracer administration was the preferred choice because of its simplicity and minimal requirements for patient compliance.

Comparison of estimates of zinc absorption in humans by using 4 stable isotopic tracer methods and compartmental analysis.

BACKGROUND: Adjustment of gastrointestinal absorption is the primary means of maintaining zinc homeostasis; however, a precise, accurate method for measuring zinc absorption in humans has not been identified. OBJECTIVE: The purpose of this study was to compare the estimates of the fraction of dietary zinc absorbed (FZA) by using 4 stable isotopic tracer methods: mass balance (MB) corrected for endogenous secretion, fecal monitoring (FM), deconvolution analysis (DA), and the double isotopic tracer ratio (DITR) method. DESIGN: All 4 methods were applied to a single data set for each of 6 women. FZA was also determined for each subject by using a detailed compartmental model of zinc metabolism, and that value was used as the reference with which the simpler methods were compared. RESULTS: The estimates of FZA (&xmacr; +/- SD) determined by DA (0.27 +/- 0. 08) and the DITR technique in plasma (0.30 +/- 0.10), 24-h urine samples (0.29 +/- 0.09), and spot urine samples (0.291 +/- 0.089) all compared well with the FZA reference value from the compartmental model (0.30 +/- 0.10). The MB and FM methods tended to overestimate FZA compared with the reference value. CONCLUSIONS: The determination of FZA by MB or FM is laborious, is sensitive to subject compliance, and may result in an overestimate. DA, although relatively accurate, has the disadvantage of requiring multiple blood drawings over several days. In contrast, the DITR technique applied to a spot urine specimen obtained >/=3 d after tracer administration provides an accurate measure of FZA and is easy to implement; therefore, it is the recommended method for determination of FZA.

The effects of zinc depletion on peak force and total work of knee and shoulder extensor and flexor muscles.

In this study we tested the effect of zinc (Zn) on muscle function in human. After receiving 12 mg Zn/day for 17 days, 8 male subjects received 0.3 mg Zn/day for either 33 or 41 days. Subjects were divided into two groups for repletion. Group A subjects received overnight infusions of 66 mg Zn on Days 1 and 10 and then were fed 12 mg Zn/day for another 16 days. Group B subjects were fed 12 mg Zn/day for 3 weeks. Peak force and total work capacity of the knee and shoulder extensor and flexor muscle groups were assessed using an isokinetic dynamometer at baseline, at two points during depletion, and at repletion. Plasma Zn declined significantly during depletion and remained below baseline levels after repletion. The peak force of the muscle groups tested was not affected by acute Zn depletion, however, total work capacity for the knee extensor muscles and shoulder extensor and flexor muscles declined significantly. The data suggest that acute Zn depletion alters the total work capacity of skeletal muscle.

Short-term zinc kinetics in pregnant rats fed marginal zinc diets.

The effect of pregnancy and a chronic, marginal intake of zinc on zinc kinetics was studied in rats. Weanling female rats were fed either a zinc-adequate diet, containing 30 microg Zn/g, (30Zn) (n = 16) or a marginally zinc-deficient diet, containing 6 microg Zn/g, (6Zn) (n = 16). After 6 wk, half of each group was mated (30ZnPG, 6ZnPG). A third group of pregnant rats was pair-fed (PFPG) (n = 6) to the 6ZnPG group. On d 20 of gestation, or at the end of the 9-wk study, 65Zn was injected intravenously. The plasma 65Zn disappearance curve over the next 105 min was used to study the size and fractional turnover rates of two rapidly exchanging zinc metabolic pools (pool a and pool b). Plasma zinc concentrations on d 20 of gestation were significantly lower in the 6ZnPG group compared with the 30ZnPG and PFPG controls, (P < 0.05). The exchangeable pools were also smaller in the 6ZnPG group compared with the 30ZnPg and PFPG groups, (P < 0.02); this reduction was accompanied by a 60% greater fractional turnover rate of pool a, (P < 0.02). Pregnancy outcomes did not differ among the three groups. We conclude that there is an increase in the turnover rate of the exchangeable plasma zinc pool when dietary zinc intake is marginal during pregnancy. This response may help maintain a supply of zinc to the growing fetus when plasma zinc concentrations are reduced.

A comparison of the short-term kinetics of zinc metabolism in women during fasting and following a breakfast meal.

The physiological importance and mechanism of the postprandial fall in plasma Zn concentration is not well understood. In order to gain further information on this apparent redistribution of plasma Zn, a stable isotope, 70Zn, was used to study the effect of a breakfast meal on plasma Zn kinetics. Nine women participated in two trials, a fasting trial and a breakfast-meal trial; five of the women participated in a third trial in which the energy content of the breakfast meal was doubled. At each trial, 0.1 mg of 70Zn was infused intravenously, and the plasma disappearance of the isotope was analysed using a two-compartment model of Zn kinetics. Plasma Zn concentration fell significantly following the two trials in which the subjects were given meals, reaching low points that were 13 and 19%, respectively, below concentrations at comparable times during the fasting trial. Kinetic analysis revealed that after the doubled breakfast meal there was a significant fall (P < 0.007) in the size of the most rapidly turning over Zn pool (pool (a)) from 2.90 (SE 0.13) mg in the fasting state to 2.47 (SE 0.14) mg postprandially. The fractional turnover rate of pool (a) to other extravascular Zn pools, i.e. outside the two-compartment system, was also significantly elevated after the doubled breakfast meal (P < 0.05). These results suggest that the decline in plasma Zn concentration following a meal is due to a redistribution of Zn from the plasma to other more slowly turning over extravascular pools that may be involved in the assimilation and metabolism of fuels following food intake.

A compartmental model of zinc metabolism in healthy women using oral and intravenous stable isotope tracers.

A mathematical model of zinc metabolism in six healthy women (average age: 30 +/- 11 y) was developed by using stable isotopes of zinc. After equilibration on a constant diet containing 7.0 mg Zn/d, an oral tracer highly enriched in 67Zn and an intravenous tracer highly enriched in 70Zn were administered simultaneously. Multiple plasma and 24-h urine samples were collected for the next 7 d with complete fecal collections for 11 d. Tracer-trace ratios in plasma, urine, and feces were calculated from isotope ratios of 67Zn to 66Zn and 70Zn to 66Zn measured by using inductively coupled plasma-mass spectrometry. An a priori identifiable model composed of seven compartments was developed to describe the kinetics of both tracers as well as that of naturally occurring zinc. The parameters of the model were fitted to the data by using the SAAM-CONSAM modeling software and were estimated with good precision. Several important, not directly measurable zinc variables were estimated (mean +/- SEM) from the model including the fractional absorption from the gastrointestinal tract (0.279 +/- 0.043), the rates of endogenous secretion (2.79 +/- 0.49 mg/d) and excretion (2.01 +/- 0.35 mg/d), the fractional turnover rate of the plasma pool (131 +/- 20/d), and the sizes (7.2 +/- 1.2 and 77.1 +/- 6.4 mg) and fractional turnover rates (22.3 +/- 7.1 and 1.49 +/- 0.18/d) of the fast and slow tissue pools equilibrating with the plasma, respectively.

Dantrolene sodium protects against experimental ischemia and reperfusion damage to skeletal muscle.

The effect of 4 hours of ischemia followed by reperfusion for 1 hour has been studied in fully anesthetized rabbits. Muscles from the limb subjected to ischemia and reperfusion showed considerable ultrastructural damage, although the distribution of damage between muscles was not uniform (anterior tibialis > soleus > quadriceps). Damage to the muscle was associated with a significant increase in the concentration of some indicators of free radical-mediated processes (thiobarbituric acid-reactive substances and diene conjugates), although others (glutathione and protein sulfhydryl groups) were unchanged. Reperfused muscles also showed considerable changes in their calcium and sodium contents. Treatment of animals with dantrolene sodium (4 mg/hr) throughout the periods of ischemia and reperfusion was found to preserve the ultrastructural appearance of quadriceps, soleus and anterior tibialis muscles. No effect of dantrolene sodium on indicators of free radical activity or muscle cation content was seen.

A stable isotope study of zinc kinetics in Irish setters with gluten-sensitive enteropathy.

The short-term kinetics of Zn turnover were studied in Irish setters with gluten-sensitive enteropathy and control dogs following intravenous injection of 0.25 mg 96.5% enriched 70ZnCl2. The 70Zn enrichment of serum was found closely to obey two-compartment kinetics and the derived two-compartment decay equation was used to calculate the size and turnover of the two initial rapidly exchanging pools of body Zn. In normal Irish setters isotopic Zn initially equilibrates with a pool (a) of size 1.27 (SD 0.46) mumol/kg and then with a second pool (b) of size 6.83 (SD 1.72) mumol/kg. The fractional turnover of pool (b) was approximately one eighth that of pool (a). Enteropathic dogs showed no reduction in the size of either rapidly exchangeable Zn pool, reduction in serum Zn concentration or abnormality in Zn balance and hence these results do not support the possibility of an underlying Zn deficiency in this disorder.

Studies of human zinc kinetics using the stable isotope 70Zn.

1. The short-term (120 min) kinetics of Zn turnover has been studied in control subjects and patients with alcoholic liver disease after intravenous injection of 0.5 mg of 96.5% enriched 70ZnCl2. 2. The 70Zn enrichment of plasma was found closely to obey two-compartment kinetics and the derived two-component decay equation has been used to calculate the size and turnover of the initial two rapidly exchanging pools of body Zn. 3. In normal subjects isotopic Zn appears initially to equilibrate with the whole of the plasma Zn which comprises the first metabolic compartment, pool a. This has a size of 0.72 +/- 0.1 mumol/kg. 70Zn equilibration then occurs with a second compartment, pool b, consistent with a rapidly exchanging liver Zn pool of size 3.60 +/- 0.93 mumol/kg. The fractional turnover rate of pool b was found to be fivefold slower than that of pool a. 4. In the alcoholic group an expansion of pool a was observed (1.63 +/- 0.39 mumol/kg), but the size of the second pool was not significantly different from that of control subjects (5.55 +/- 1.0 mumol/kg), although its fractional turnover was significantly increased (Kab: control subjects, 0.018 +/- 0.002 min-1, alcoholic patients, 0.031 +/- 0.006 min-1). 5. These data therefore demonstrate that kinetic studies using stable isotopes of Zn can provide novel information on exchangeable Zn pools in man, but provide no support for the possibility of an underlying Zn depletion in patients with alcoholic liver disease.

Plasma 65Zn kinetics in the rat.

The amount of 65Zn in the plasma of rats after intravenous injection was found to decline following closely two-compartment kinetics over a period of 90 min. Comparative analysis of the amount of 65Zn present in the two kinetic pools at various time-intervals post-injection with the actual physiological location of the 65Zn, revealed that the initial pool (Qa) is primarily the blood plasma, while the second pool (Qb) is primarily within the liver. The plasma Zn concentration and Qa were both found to fall reproducibly during Zn depletion, whereas Qa and Qb increased following injection of Escherichia coli endotoxin in contrast to the decline in plasma Zn concentration. Further investigation of the nature of Qb indicates that it represents in part a metabolic pool within the liver which varies substantially in response to Zn status in a manner similar to metallothionein.