Zinc Supplementation in Children and Adolescents with Acute Leukemia

ORIGINAL ARTICLE Zinc supplementation in children and adolescents with acute leukemia

LZZ Consolo, P Melnikov, FZ Coˆ nsolo, VA Nascimento and JCDV Pontes

BACKGROUND/OBJECTIVES: Zinc is known as an essential micronutrient for human health because of its structural and biochemical functions, influencing growth and affecting multiple aspects of the immune system. Zinc has been extensively studied in neoplastic processes but its role in children with leukemia still remains to be elucidated in several aspects. The aim of this study was to evaluate the effects of oral zinc supplementation on weight gain and infectious episodes in children and adolescents with acute leukemia. SUBJECTS/METHODS: This study included 38 patients, and was carried out as a randomized, double-blind, placebo-controlled investigation. The dosage of plasma zinc levels and the evaluation of nutritional status were performed during a period of 60 days. Zinc was supplemented orally, 2 mg/kg/day, in the form of amino acid salt. RESULTS: The results showed that plasma zinc concentrations did not increase significantly with the addition of the micronutrient. However, from a clinical point of view, it has become evident that supplementary zinc exerts a positive effect on nutritional status as positive weight gain. Moreover, the number of infection episodes was significantly reduced, possibly because of the immune stimuli. CONCLUSIONS: In conclusion, zinc supplementation can prevent some of the chemotherapy adverse effects in children with leukemia, improving their quality of life.

European Journal of Clinical Nutrition (2013) 67, 1056–1059; doi:10.1038/ejcn.2013.146; published online 21 August 2013 Keywords: zinc supplementation; leukemia; children; adolescents

INTRODUCTION SUBJECTS AND METHODS Zinc is known as an essential micronutrient for human health A double-blind, placebo-controlled study was conducted in children within because of its structural and biochemical functions at cellular the age interval of 1–18 years, of both genders, who had a previously and subcellular levels, influencing growth and affecting multiple established clinical and laboratorial diagnosis either of lymphocytic or aspects of the immune system.1–3 It is known that even a marginal myeloid leukemia. They were undergoing chemotherapy, according to the established protocols for this disease, at the Regional Hospital ‘Rosa Maria zinc deficiency may be accompanied by an imbalance of T helper Pedrossian’, in Campo Grande, MS, Brazil, from March 2010 through type 1 and 2 cells. The beneficial effects of its supplementation in February 2012. The following exclusion criteria were applied in order to children in the management of infantile diarrhea, acute respiratory select the participants: acute infectious disease, renal failure, postsurgery infections and pneumonia are evidenced by decreased morbidity status or usage of any zinc-containing drug. An informed written consent and mortality.4,5 was obtained from the parents or person responsible before enrollment. Zinc supplementation manifests significant positive effects The project has been duly approved by the Ethical Committee of Federal on linear growth, especially when administered alone, and hence University of Mato Grosso do Sul. it was strongly recommended in the National Health Service Data on anthropometric parameters, nutritional status and plasma zinc 6 concentration were collected at the beginning of supplementation (T ), 30 strategies in order to reduce stunting in children o5 years of age. 0 days later (T30) and 60 days later (T60). The classification of the nutritional It was logical to believe that zinc might also be useful in status was based on the body weight, stature, arm circumference-for-age patients undergoing chemotherapy for acute leukemia and its and triceps skinfold-for-age.9–11 consecutive complications. So far, at least two zinc compounds In addition, xerostomy, taste dysfunction, nausea and vomiting were were shown to have the activity of their own in acute myeloid registered weekly for a period of 60 days. These data were taken from leukemia. The former is pyrithione zinc, which appears to possess medical records or provided by parents. As for the episodes of mucositis or the potential to directly suppress neoplastic activity,7 and clinically diagnosed infections, these were referred up to a broader period the latter is zinc ascorbate, proposed to diminish deleterious of 120 days (T120). effects of chemotherapy in children.8 As for the chemotherapy A total of 38 patients were randomized into two groups: one was given complications, infections and mucosal damage can be mentioned. orally placebo syrup containing no zinc (group A, n ¼ 18) and the other group (group B, n ¼ 20) received syrup containing zinc in the form of a The purpose of the present investigation was to evaluate the chelate solution (10 mg/ml). In total, group B was given 2 mg/kg/day of effects of oral zinc supplementation on weight gain and infectious zinc (maximum 60 mg/day) in two divided doses. The packages were episodes in children and adolescents with acute leukemia. Special identical in color, taste, odor and appearance. Both syrups were attention was given to the simultaneous nutritional assessment of manufactured by a single pharmacy. Zinc chelate was purchased from the patients. the Pharmanostra Laboratory (Ana´polis, Brazil). The bottles were randomly

Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil. Correspondence: Professor LZZ Consolo, Federal University of Mato Grosso do Sul, Rua Alexandre 378, Giocondo Orsi, Campo Grande, Mato Grosso do Sul CEP-79022-080, Brazil. E-mail: [email protected] Received 6 March 2013; revised 8 July 2013; accepted 11 July 2013; published online 21 August 2013 Zinc supplementation in leukemia LZZ Consolo et al 1057 labeled as A for placebo group and B for zinc group by a pharmacist not involved in the study. Neither the researchers nor the participants had any Table 1. Initial assessment (%) of nutritional status previous knowledge regarding the content of the bottles. All the children who participated in the study took the syrup for 60 days. Nutritional status All participants Group A Group B For plasma zinc analysis, blood samples were collected in polypropylene Mild malnutrition 18.4 (n 7) 16.7 (n 3) 20 (n 4) syringes and immediately transferred to vacuum tubes free of trace ¼ ¼ ¼ Nutritional risk 10.5 (n 4) 5.6 (n 1) 15 (n 3) elements (BD Vacutainer Systems–Becton, Dickinson and Company, ¼ ¼ ¼ Normal nutrition 52.6 (n 20) 61.1 (n 11) 45 (n 9) Sa˜o Paulo, Brazil). The plasma was separated by centrifugation and stored ¼ ¼ ¼ Overweight risk 5.3 (n ¼ 2) 0 10 (n ¼ 2) at À 18 1C for later analytical determinations. Overweight 10.5 (n 4) 11.1 (n 2) 10 (n 2) All materials, plastic or glass were previously treated for decontamina- ¼ ¼ ¼ Obesity 2.6 (n 1) 5.6 (n 1) 0 tion of any possible contaminant. The calibration curves were constructed ¼ ¼ Total 100 (n 38) 100 (n 18) 100 (n 20) using four different zinc concentrations with values in the range of ¼ ¼ ¼ 0.25–2.0 mg/l. Atomic absorption analyses for plasma zinc were performed with a PerkinElmer AA100 spectrometer (Waltham, MA, USA). The statistical analysis was carried out using mean±s.d., Student’s t-test, Pearson’s correlation, Fisher’s test, w2 test and analysis of variance. Data Table 2. Ranges of zinc concentrations (mg/l) and their averages at were analyzed using BioEstat, Version 5.0 statistical package (Minneapolis, different periods MN, USA). The value of ‘P’ adopted was p0.05. Group T0 T30 T60

RESULTS Group A 0.22–1.45 0.6–1.55 0.75–1.30 (mean±s.d.) 0.99±0.08 1.0±0.07 0.99±0.04 In group A, 83.3% (n ¼ 15) had acute lymphocytic leukemia and Group B 0.6–1.9 0.8–1.9 0.6–1.55 16.7% (n ¼ 3) had acute myelocytic leukemia. In group B, 80% (mean±s.d.) 1.0±0.07 1.2±0.08 1.0±0.07 (n ¼ 16) had acute lymphocytic leukemia and 20% (n ¼ 4) had acute myelocytic leukemia. No difference was observed according Abbreviations: T0, time at the beginning of supplementation; T30, time after 30 days; T , time after 60 days. to diagnosis between the two groups (P ¼ 0.937). There were 53% 60 (n ¼ 20) male and 47% (n ¼ 18) female patients. The mean age in both groups was 9.9±5.5 years. There were no significant differences between both groups according to age (P ¼ 0.328), Zinc has been extensively studied in neoplastic processes but its gender (P ¼ 0.213), weight (P ¼ 0.609) and height (P ¼ 0.38) at T0. role in children with leukemia still remains to be elucidated in Table 1 shows the initial assessment of nutritional status of the several aspects. As a matter of fact, this study showed an participants. This status of the patients was found inadequate in improvement in the outcome of children with zinc supplementation, 28.9% of diagnosis. A significant difference was observed between regarding weight and episodes of infection. the groups according to weight gain at T30 and T60. The weight A mild to severe nutritional depletion can be present in gain of 2000 g for B group was higher than that observed B11–50% of children with leukemia before treatment, for group A. For group A, the weight gain was 100 g, showing a thus influencing the course and prospects for patients’ significant difference (P ¼ 0.032). As for height values, improvement.11–15 This large variation is because of several no significant differences were observed between the groups factors such as socioeconomic status and educational and cultural A and B. background of children’s family, beyond the disease itself.16 In The plasma zinc concentrations at different periods are shown malnourished children a decreased tolerance to chemotherapy is in Table 2. There were no significant differences for both groups A well known. It comprises an increased infection rate, which and B at T0 (P ¼ 0.16). Group A showed no differences between T0 contributes to a poor outcome of the disease.13,17 A meta-analysis and T30 and between T30 and T60 (P ¼ 0.22), whereas group B to assess the effects of zinc supplementation on physical growth showed significant differences between T0 and T30 (P ¼ 0.004), of children revealed a highly positive response in weight and but no changes occurred from T0 to T60 (P ¼ 0.217). There were no height increments.18 significant difference in zinc plasma concentrations between the This study showed that 28.9% of the patients needed a experimental and placebo groups (P ¼ 0.30). nutritional intervention at the moment of the first evaluation, As for the presence of xerostomy, taste dysfunction, nausea bearing in mind the malnourished status and the consumptive and vomiting, despite that children in group B showed these characteristic of leukemia. According to the ‘Laboratory Tests of symptoms to a lesser degree, it was not statistically different from Nutritional Status’,19 plasma zinc concentrations observed in these group A (P ¼ 0.812). children may be considered as low. They are close to those In group A, eight patients and in group B 6 patients developed recently found in pediatric acute lymphoblastic leukemia and mucositis, with no statistical difference between the groups non-Hodgkin’s lymphoma.20 (P ¼ 0.923). It was observed that with respect to T120, in 10 cases The children of zinc-supplemented group had a significant the children in group A developed the following infections: weight gain of B2 kg during the study. Weight gain in children gastroenteritis, sinusitis, perianal abscess, pneumonia, herpes without leukemia has been reported.21 In this work, it is an zoster, perineal moniliasis and sepsis. At the same time, four important achievement, taking into account the severity of their cases in group B corresponded to conjunctivitis, cellulites of the blood disorder. It means that despite an increase in plasma zinc leg, pneumonia and sepsis. There was a significant difference concentrations observed in group B for a shorter period (T0–T30), between group A and group B regarding infectious episodes clear clinical effects were evident for a longer time. (P ¼ 0.02). It has been reported for adults that age-related decline in taste acuity may be both a cause and an effect of depleted zinc.22 In this study the presence of xerostomy, taste dysfunction, nausea and DISCUSSION vomiting were observed in both groups, but with less intensity in This study was undertaken in order to evaluate the effects group B. All these symptoms may have affected food choices of zinc supplementation in children with acute leukemia. and are factors directly related to weight changes in children The strengths of this study include a randomized double-blind with leukemia. design and similarity of the patients’ characteristics in both groups In agreement with a previous trial,23 in cases of chemotherapy- considered, that is, gender, age and established diagnosis. induced mucositis, a significant difference in plasma zinc

& 2013 Macmillan Publishers Limited European Journal of Clinical Nutrition (2013) 1056 – 1059 Zinc supplementation in leukemia LZZ Consolo et al 1058 concentrations before and after supplementation could not be 3 Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered proved. In clinical practice with trace elements, medical personnel resistance to infection. Am J Clin Nutr 1998; 68: 447–463. and researches are inclined to make a logical connection between 4 Yakoob MY, Theodoratou E, Jabeen A, Imdad A, Eisele TP, Ferguson J et al. higher concentration of an ion and the consecutive effect. When this Preventive zinc supplementation in developing countries: impact on mortality does not happen, a larger number of observations are needed to and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health 2011; prove the fact. 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& 2013 Macmillan Publishers Limited European Journal of Clinical Nutrition (2013) 1056 – 1059