Journal of the American College of Nutrition, Vol. 17, No. 4, 388-391 (1998)
Published by the American College of Nutrition
Studies to Determine the Usefulness of the Zinc Clearance Test to Diagnose Marginal Zinc Deficiency and the Effects of Oral Zinc Supplementation for Short Children
Masayuki Kaji, MD, PhD,
Mikio Gotoh, MD,
Yasuko Takagi, MD,
Hiroyuki Masuda, MD, PhD,
Yujiro Kimura, MD and
Yasushi Uenoyama, MD, PhD
Division of Endocrinology and Metabolism, Shizuoka Children’s Hospital (M.K.), JAPAN
Department of Pediatrics, Shizuoka General Hospital (M.G., Y.T., H.M., Y.K., Y.U.), JAPAN
Address reprint requests to: Masayuki Kaji, MD, Division of Endocrinology and Metabolism, Shizuoka Children’s Hospital, 860 Urushiyama, Shizuoka, 420, Japan
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ABSTRACT
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Objective: To evaluate the usefulness of the body zinc clearance test in the diagnosis of marginal zinc deficiency and to estimate the efficacy of oral zinc supplementation on growth in short children.
Methods: Zinc status was evaluated in 30 (19 boys and 11 girls) Japanese children with short stature using the body zinc clearance test. Changes in growth after oral zinc supplementation (ZnSO4 · 7H2O; 5 mg/kg/day in two divided doses) were studied.
Results: Basal serum zinc concentrations were 75.0±12.7 µg/dl and zinc clearance values were 19.1±5.8 ml/kg/hour in the 30 subjects. The correlation coefficient between serum zinc concentrations and zinc clearance values was as small as -0.36. There were nine cases whose body zinc clearance values were high and serum zinc concentrations were low, indicating definite zinc deficiency. There were nine cases whose body zinc clearance values were high, despite normal serum zinc concentrations, indicating marginal zinc deficiency. The mean height velocity for males was 5.3 cm/year before zinc supplementation and 7.8 cm/year after the therapy; and the mean SD score for height for age improved from -1.85 to -1.53. The mean height velocity for females was 5.1 cm/year before zinc supplementation and 5.9 cm/year after the therapy, and the mean SD score for height for age changed from -2.02 to -2.03.
Conclusion: The body zinc clearance test was much more useful than serum zinc concentrations in diagnosing marginal zinc deficiency. Oral zinc supplementation improved the height velocity in short males, but not in short females.
Key words: marginal zinc deficiency, zinc clearance test, zinc supplementation, short stature
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INTRODUCTION
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Zinc is very important for human growth and zinc deficiency causes growth disturbance in children [1–3]. There have been some reports on the positive effects of oral zinc supplementation on height velocity in children with definite zinc deficiency [4,5], but in 1993, Nakamura et al conducted the first age-matched control study which showed that oral zinc supplementation was effective in improving the growth rate in short children [6]. The results of another study by Nakamura and his colleagues to evaluate zinc status of short children showed that measurements of serum zinc concentrations were not very useful in estimating the marginal status of zinc nutrition. They recommended the body zinc clearance test to detect marginal zinc deficiency [7].
The purpose of the study reported here was to evaluate the usefulness of the body zinc clearance test in diagnosing marginal zinc deficiency and to determine the effects of oral zinc supplementation on the growth rate in short children.
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SUBJECTS AND METHODS
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A total of 30 Japanese children (19 boys and 11 girls) with short stature were studied. The boys ranged in age from 6.1 to 15.5 years (mean; 10.0 years) and in pubertal stage from Tanner I to Tanner V (14 subjects of Tanner I, three of Tanner II, one of Tanner III and one of Tanner V). The girls ranged in age from 4.7 to 15.7 years (mean; 11.2 years) and in pubertal stage from Tanner I to Tanner V (eight subjects of Tanner I, one of Tanner III, one of Tanner IV and one of Tanner V).
Body zinc clearance test was performed using the method described by Nakamura et al [7] as follows: zinc sulfate solution (1.0 µmol/kg) was injected in a single dose into a midcubital vein and blood specimens were obtained from the vein of the contralateral arm before the injection and at 30, 60, 90 and 120 minutes after the injection. Serum zinc concentrations were measured by atomic absorption spectrophotometry. The serum zinc level declined exponentially for up to 120 minutes after the injection of zinc. Body zinc clearance (ClZn) was calculated using the following equation [7]:
where Vd is volume of distribution and Kel is the elimination constant of serum zinc. Vd and Kel were calculated as follows:
where dose is the amount of zinc administered intravenously, Cp is the theoretical serum zinc concentration immediately after the injection as calculated from the serum concentration versus time profile, Co is the basal serum zinc concentration, and T1/2 is the biological half-life of serum zinc calculated directly from the serum concentration vs. time profile.
Fourteen of the boys and six of the girls in the study group, who consented to take zinc sulfate after information was given, were administered ZnSO4 · 7H2O; 5 mg/kg/day in two divided doses. Since 10 of the boys and two of the girls dropped out, the effectiveness of oral zinc administration was evaluated in four boys and four girls who had been taking zinc sulfate for more than 6 months (range; 6 to 23 months).
Statistical analyses of the data were performed by Student’s t test and regression analysis.
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RESULTS
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In 19 boys who underwent the body zinc clearance test, the mean SD score for height for age was -2.13 (range; -0.93 to -3.04). Their serum zinc concentrations were 73.9±10.6 µg/dl (mean±standard deviation) and ranged from 58 to 91 µg/dl. Eight of the 19 boys had low serum zinc levels (<70 µg/dl). The ClZn values were 19.6±5.9 ml/kg/hour and ranged from 11.0 to 32.1 ml/kg/hour (reference values; 15.1±0.6 ml/kg/hr [6]). Twelve of the 19 boys had high ClZn values (>18 ml/kg/hour) indicating a zinc deficiency.
In 11 girls who underwent the body zinc clearance test, the mean SD score for height for age was -2.25 (range; -1.12 to -3.20). Their serum zinc concentrations were 77.0±16.2 µg/dl and ranged from 49 to 100 µg/dl. Three of the 11 girls had low serum zinc levels. The ClZn values were 18.3±5.9 ml/kg/hour and ranged from 9.8 to 27.5 ml/kg/hour. Six of the 11 girls had high ClZn values.
There were nine cases (seven boys and two girls) where ClZn values were high and serum zinc concentrations were low, indicating definite zinc deficiency. There were nine cases (five boys and four girls) where ClZn values were high, in spite of normal serum zinc concentrations, indicating marginal zinc deficiency. There were no cases with obvious delay in pubertal development for their age in either group of zinc deficiency.
The relationship between serum zinc concentrations and ClZn values is shown in Fig. 1. The correlation coefficient between them was as small as -0.36. The changes in height velocity after oral zinc supplementation were studied in four boys and four girls who had taken oral zinc for more than six months (Table 1). For the four boys, the mean height velocity was 5.3 cm/year before oral zinc supplementation and 7.8 cm/year after the therapy (p<0.05), and the mean SD score for height for age improved from -1.85 to -1.53 SD. There was a significant correlation between the ClZn values and percent increases in the height velocity after oral zinc supplementation in the four boys (Fig. 2). Three of the four boys were at the prepubertal stage and there were not obvious changes in their testicular sizes during the course of zinc supplementation. One of the four boys was at the pubertal stage of Tanner III and there was not remarkable progress in his pubertal stage during the 6-month course of zinc supplementation. The growth curve of one of the prepubertal boys is shown in Fig. 3, showing evident increase in height gain after zinc supplementation. For the four girls, the mean height velocity was 5.1 cm/year before oral zinc supplementation and 5.9 cm/year after the therapy, and the mean SD scores for height for age were -2.02 and -2.03, respectively. There was not remarkable progress in their pubertal stage during the course of zinc supplementation.
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Fig. 2. Correlation between zinc clearance and percent increase in the height velocity after oral zinc supplementation in boys.
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No adverse effects were observed with oral zinc administration.
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DISCUSSION
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It has been reported recently that serum zinc measurement is not useful for estimating marginal zinc status, and that the measurement of leukocyte zinc content or of ClZn seems more reliable [7,8]. Nishiyama et al reported that the mean serum zinc concentration was 86.2 µg/dl in seven Japanese female athletes with anemia whose ClZn values were high (>25 ml/kg/hour) and 86.6 µg/dl in 14 Japanese female athletes whose ClZn values were not high [9]. There was no difference in serum zinc levels between the two groups, despite the significant difference in ClZn values. Therefore, it is obvious that zinc deficiency can not be easily excluded based on the measurement of serum zinc levels. In the study reported here, there were nine cases (30% of the total 30) whose ClZn values were high, despite normal serum zinc concentrations. The diagnosis of marginal zinc deficiency could be made only after the body zinc clearance test was conducted. The correlation coefficient between basal serum zinc levels and ClZn values is small (Fig. 1), meaning that the serum zinc level may not reflect precisely the status of zinc nutrition. The authors suggest the reason for this is that in comparison to total body zinc content (2 to 3 g in adults [10]), only a small part exists in serum (<0.1%), and the regulatory mechanisms for serum zinc homeostasis may not be as strict as those for electrolytes such as calcium. This study revealed a remarkable correlation between the ClZn values and the change in growth rate after oral zinc supplementation in boys with short stature (Fig. 2), suggesting that the higher the ClZn values, the more effective oral zinc supplementation is on height gain. These results support the significance of the body zinc clearance test in diagnosing marginal zinc deficiency and the appropriateness of oral zinc supplementation for height gain in short children.
The results of this study indicated that 60% of short children had zinc deficiency. The authors suggest that this is due to the prevalence of precooked foods, snacks and convenience foods in their diets. These foods are typically processed and, in general, lack trace minerals.
Although the mechanisms of the effects of zinc on height gain have not been fully made clear, it may be easily supposed that a zinc deficiency causes growth disturbance, because zinc is essential for the activity of many important enzymes for DNA and RNA synthesis and cell proliferation [10]. In addition, a reduction in circulating IGF-I concentrations has been proposed as a possible reason for growth retardation in subjects with zinc deficiency [3]. Kurtogu et al observed that zinc-deficient rats had narrower epiphyseal growth plates than those of a control group, and the number of hypertrophied cells was also lower in the zinc-deficient group [11]. Yamaguchi and Inamoto reported that zinc synergistically enhanced 1,25-dihydroxyvitamin D3-stimulated bone metabolism in weanling rats [12]. Nakamura et al reported that oral zinc supplementation induced increases of serum IGF-I, osteocalcin and alkaline phosphatase activity in short children with marginal zinc deficiency [6]. It is not clear whether zinc supplementation promotes pubertal development. In this study, there was not remarkable progress in the pubertal stages during the course of zinc supplementation both in boys and girls, probably because no subject had severe delay in pubertal development due to zinc deficiency.
In this study, oral zinc supplementation was effective on height gain in boys, but not in girls. Although the reasons for the difference in the effects between the sexes are not clear, a study by Castillo-Duran et al showed similar results [13]. They reported that oral zinc supplementation improved the height gain of both pre-adolescent and adolescent males, but the therapy had no effect on the growth of either pre-adolescent or adolescent females in Chile. They hypothesized that the predominance of the X chromosome in females of Indian origin was the cause of the reduced height gain for the females in their study [13]. There is no conclusive evidence, however, that oral zinc supplementation has no effect on height gain in girls.
The authors believe that oral zinc supplementation should be considered as the growth-promoting therapy for children with short stature once the status of their zinc nutrition is established. Further study is required to determine the mechanisms of the effects of zinc supplementation on growth and the causes of the gender differences.
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ACKNOWLEDGMENTS
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The authors are grateful to Mr. Hiroaki Aoshima and Miss Setsuko Ihara of the Department of Pharmacy, Shizuoka General Hospital for preparation of sterilized zinc sulfate solution for intravenous injection.
Received January 1, 1997.
Accepted December 1, 1997.
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ABSTRACT
INTRODUCTION
