Effects of Iron(II) Salts and Iron(III) Complexes on Trace Element Status in Children with Iron-Deficiency Anemia

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1 Copyright 2003 by Humana Press Inc. All rights of any nature, whatsoever, reserved /03/ $25.00 Short Communication Effects of Iron(II) Salts and Iron(III) Complexes on Trace Element Status in Children with Iron-Deficiency Anemia ESER YıLDıRıM SÖZMEN,* KAAN KAVAKLı, 2 BILIN ÇETINKAYA, 2 YASEMIN DELEN AKÇAY, 1 DENIZ YıLMAZ, 2 AND YEŞIM AYDıNOK 2 1 Department of Biochemistry, Ege University Faculty of Medicine 2 Department of Pediatry, Division of Haemotology, Ege University Faculty of Medicine, İzmir, Turkey Received August 12, 2002; Revised August 28, 2002; Accepted October 14, 2002 ABSTRACT Iron-deficiency anemia (IDA) is the most common nutritional deficiency in childhood throughout the world. Although it has been shown that IRA is associated with elevated plasma copper and depleted zinc levels in children, there are conflicting results on the effect of iron supplementation on the absorption of these elements. The aim of this study was to investigate the effects of ferrous and ferric iron supplementation on the trace element status in children (n=25, aged mo) with IDA. Fourteen of them were treated with ferric hydroxide polymaltose complex (Ferrum, Vifor, Switzerland) (6 mg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance); the others were treated with a ferrous sulfate complex (FerroSanol, Schwarz, Germany) (6 mg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance). Plasma copper, zinc, and ceruloplasmin levels as well as hematological parameters were determined at baseline and the first, third, and sixth month of the treatment period. The hemoglobin and iron levels of patients in both groups were higher in the first and sixth months compared to baseline. Although the ceruloplasmin levels were depleted (48.9 mg/dl vs 41.4 mg/dl, p=0.035) during ferrous iron treatment, the copper and zinc levels remained unchanged. On the other hand, ferric iron supplementation led to an increase in zinc levels in the sixth month of treatment (0.77 mg/l vs 1.0 mg/l, *Author to whom all correspondence and reprint requests should be addressed. Biological Trace Element Research 79 Vol. 94, 2003

2 80 Sözmen et al. p=0.021). The plasma copper levels were lower in the ferrous iron-treated group at the end of the first month of treatment than in the ferric irontreated group (1.06 mg/l vs 1.29 mg/l, p=0.008). In conclusion, our data showed that copper and ceruloplasmin metabolisms were affected by ferrous iron supplementation, whereas ferric iron kept them to normal levels of zinc, possibly by affecting their absorption. We conclude that the copper and zinc status of patients with IDA should be taken into consideration before and after iron therapy. Index Entries: Iron-deficiency anemia; copper; zinc. BACKGROUND AND AIM Iron-deficiency anemia (IDA) is the most common nutritional deficiency in childhood throughout the world. IDA was treated with mainly two preparations: ferrous (Fe 2+ ) sulfate and ferric (Fe 3+ ) hydroxide polymaltose complex. Although animal studies showed no significant difference in bioavailability or iron utilization between the two iron preparations following oral administration, there are two distinct mechanisms for the uptake of iron from the gut. Although the DCT-1 pathway is more efficient for uptake of ferrous iron, the mobilferrin integrin pathways is responsible for ferric iron uptake (1). Recently, it has been suggested that the mobilferin integrin pathway, which was not upregulated in iron-deficient animals (2,3), saturates with iron regarding to the status of iron repletion. DCT-1 (divalant cation transporter-1, Nramp-2), which was detected in duodenal brush border of iron-deficient mice, serves to enhance iron absorption (4,5). Recently, it has been shown that IDA is associated with elevated plasma copper and depleted zinc levels in children; however, there are conflicting results on the effect of iron supplementation on the absorption of these elements (6 9). It has been known that cations with similar valences can inhibit the absorption of other minerals and they would be antagonists to each other biologically (8). Yip et al. (7) demonstrated that iron administration had no effect on the zinc and copper levels in plasma in healthy infants. Ceruloplasmin (Cp), which has ferroxidase activity, has also played a main role in absorption of iron by oxidizing ferrous iron to the ferric state. The aim of this study was to investigate the effects of ferrous sulfate and ferric hydroxide polymaltose complex supplementation on the trace element status in children with IDA. SUBJECTS AND METHODS Thirty-seven children (aged mo, 22 boys and 15 girls) with IDA were taken into the study. They were diagnosed with IDA by an hematol-

3 Trace Elements in Fe-Deficient Children 81 ogist according to their clinical and laboratory data (Hb<11.5 g/dl, Htc <35%, MCV<75, ferritin<20 mg/dl). Seventeen, who were chosen randomly, were treated with the ferric hydroxide polymaltose complex (Ferrum, Vifor, Switzerland) (6 mg/kg/d in the first 3 mo for initial therapy and then 3 mg/kg for 3 mo as maintenance); the others (n=20) were treated with a ferrous sulfate complex (FerroSanol, Schwarz, Germany) (6 mg/kg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance). Fasting blood samples of patients were obtained at baseline, the first, the third, and six month of treatment period. Written consent forms obtained from parents of children prior to study. Hemoglobin and hematocrit levels were determined by an automatic hemocounter (Abbott-Cell-Dyne 3700 hemocounter), and serum iron and iron-binding capacity were measured by an autoanalyzer using a commercially available kit. Plasma copper and zinc levels were analyzed using a JV24 inductively coupled plasma atomic emission spectrometer (ICP- AES). The ICP-AES was operated according to the manufacturer s recommendations. The wavelengths were nm for zinc and nm for copper (10). Stock standard solutions (1000 ppm) for Zn and Cu were diluted with 0.1 M HCl to prepare working standards (1, 10, and 100 ppm). Ceruloplasmin levels were analyzed according to the method of Ravin. Statistical Analyses All statistical analyses of relations among copper, zinc, and ceruloplasmin levels were performed by the statistical package SPSS for Windows, version 10.0 (SPSS, Chicago, IL). Correlation was calculated as Spearman correlation coefficients. Analysis of variance followed by the Newman Keuls multiple range tests; Mann Whitney U-test, and the Student s t-test for intergroup comparisons were used to analyse the results. For the analysis of paired samples, the Wilcoxon signed rank tests and paired Student s t-tests were used. RESULTS Hemoglobin and iron levels of patients in both groups were higher in the first, third, and sixth months compared to baseline (see Table 1). We observed a significant positive correlation between the serum zinc levels with hemoglobin (p=0.003, r=0.482) and iron (p=0.006, r=0.465) levels for the baseline data. However, there was a significant inverse correlation between the iron and copper levels (p=0.023, r= 0.388). Although ceruloplasmin levels depleted during ferrous iron treatment (see Fig. 3), copper levels decreased only in the first month (p=0.054) of treatment (see Fig. 2). In accordance with these data, there was a strong negative correlation (p=0.000, r= 0.767) between the copper and iron levels of

4 82 Sözmen et al. Table 1 Effect of Ferrous and Ferric Iron Supplementation on Hematological Parameters Fig. 1. Serum copper levels (mg/l) during the treatment period.

5 Trace Elements in Fe-Deficient Children 83 Fig. 2. Serum zinc levels (mg/l) during the treatment period. Fig. 3. Plasma ceruloplasmin levels (mg/dl) during the treatment period. patients treated with ferrous iron at the end of the first month. As seen in Fig. 2, zinc levels of patients treated with ferrous iron increased in the third month (p=0.024). Although ferric iron supplementation also led an increase in zinc levels in the sixth month of treatment (p=0.041), copper and ceruloplasmin levels remained unchanged. Interestingly, there was a positive correlation between the zinc levels with iron (p=0.041, r=0.573) and copper (p=0.003, r=0.682) in patients treated with ferric iron in the third month. Plasma copper levels at the end of the first month (1.06 mg/l vs 1.18 mg/l, p=0.088) and zinc levels at the end of the sixth month (0.83 mg/l vs 0.99 mg/l, p=0.083) were insignificantly lower in the ferrous irontreated group than the ferric iron-treated group.

6 84 Sözmen et al. CONCLUSION We aimed to compare the effects of different iron preparates on the zinc and copper status in children with IDA. Hemoglobin and iron levels of patients in both groups were higher in the first, third, and sixth months compared to baseline (see Table 1). Serum iron levels were higher in patients treated with ferrous iron compared to those of ferric iron. This difference may be explained with two mechanism. Because DCT-1 (a divalent cation transporter), which is responsible for ferrous iron absorption, is upregulated in iron deficiency, the amount of ferrous iron that may be absorbed is higher. The other mechanism may be related to the availability of absorbed iron, whereas ferrous iron incorporate into compounds such as ferritin and heme as soon as absorption, ferric iron can incorporate after reduction by reducing agents (such as ascorbic acid). Cp has also a main role in iron metabolism by its ferroxidase activity. Recently, Mukhopadhyay et al. (11) reported that plasma Cp increases in IDA and iron chelators induce the mrna expression and protein synthesis in human hepatocarcinoma HepG2 cells. We determined a decrease in plazma Cp levels upon ferrous iron administration, as plasma iron levels increase. However, ferric iron did not affect the Cp levels because of its role in the reduction of ferric iron. We suggested that the elevation in plazma Cp levels in IDA patients is not only related with elevated levels of copper but also with the increase in the availability of iron in a different form, coming from different sources. Ece et al. (6) showed a significant depletion in serum zinc levels and a significant elevation in serum copper levels in children with IDA when compared to the controls. They suggested that zinc and iron deficiency is closely related with the high phytate diets (especially grain products) that inhibit zinc and iron absorption rather than inadequate dietary intake. Hastka et al. (12) also determined that zinc instead of iron incorporated into protoporphyrin, which results in a decrease in serum zinc levels in patients with IDA. In accordance with this observation, we found a significant positive correlation between the serum zinc levels with hemoglobin (p=0.003, r=0.482) and iron (p=0.006, r=0.465) levels in the baseline data. However, there was a significant inverse correlation between the iron and copper levels (p=0.023, r= 0.388), possibly the result of excessive copper absorption from grain products. Although copper levels (first month, p=0.054) depleted during ferrous iron treatment (see Figs. 1 and 2), zinc levels increased in the third month (p=0.024). Additionally, there was a strong negative correlation (p=0.000, r= 0.767) between the copper and iron levels of patients treated with ferrous iron at the end of the first month. It has been shown that DCT-1 is upregulated in iron deficiency and it is responsible for the transport of ferrous iron as well as other divalent cations such as copper and zinc into the cells. Conrad et al. (1) described that zinc enters the cell independently of either ferrous and ferric iron in rats. Our data suggested that copper and ferrous iron share the same pathway for transport into cells and also that there may

7 Trace Elements in Fe-Deficient Children 85 be a competency between these metals for absorption. On the other hand, zinc absorption is not significantly affected by ferrous iron supplementation. Although ferric iron supplementation also led to an increase in zinc levels in the sixth month of treatment (p=0.041), copper and ceruloplasmin levels remained unchanged. These data are also in agreement with the results of Conrad that showed two distinct pathways for iron absorption in the gut. They suggested that ferric iron enters the absorptive cells via β 3 integrin in combination with mobil ferrin, which is specific for ferric iron (1). Plasma copper levels at the end of the first month, (1.06 mg/l vs 1.18 mg/l, p=0.088) were insignificantly lower in the ferrous iron-treated group than in the ferric iron-treated group because of a possible competence for absorption with ferrous iron. In conclusion, our data showed that copper and ceruloplasmin metabolisms were affected by ferrous iron supplementation, possibly by a competition, whereas ferric iron maintained normal levels of zinc. We conclude that copper and zinc status of patients with IDA should be taken into consideration before and after iron therapy. REFERENCES 1. M. E. Conrad, J. N. Umbreit, and E. G. Moore, Iron absorbtion and transport, Am. J. Med. Sci. 318(4), (1999). 2. M. E. Conrad, J. N. Umbreit, and E. G. Moore, Regulation of iron absorption; proteins involved in duodenal mucosal uptake and transport, J. Am. Coll. Nutr. 12, (1993). 3. A. T. McKie, K. B. Raja, and T. J. Peters, Expression of genes involved in iron metabolism in mouse intestine, Am. J. Physiol. 271, G772 G779 (1996). 4. M. D. Fleming, C. C. Trevor, and M. A. Su, Microcytic anemia mice have a mutations in Nramp-2. A candidate iron transporter gene, Nat. Genet. 4, (1997). 5. H. Gunshin, B. Mackenzie, and U. V. Berger, Cloning and characterization of a mammalian proton-coupled metal iron transporter, Nature 388, (1997). 6. A. Ece, B. S. Uyanık, A. İşcan, et al., Increased serum copper and decreased serum zinc levels in children with iron deficiency anemia, Biol. Trace Element Res. 59, (1997). 7. R. Yip, J. D. Reeves, B. Lönnerdal, et al., Does iron supplementation compromise zinc nutrition in healthy infants? Am. J. Clin. Nutr. 42, (1985). 8. I. J. Newhouse, D. B. Clement, and C. Lai, Effects of iron supplementation and discontinuation on serum copper, zinc, calcium and magnesium levels in women, Med. Sci. Sports Exerc. 25(5), (1993). 9. A. E. Gomez-Ayala, F. Lisbona, I. Lopez-Aliaga, et al., The absorption of iron, calcium, phosphorus, magnesium, copper and zinc in the jejunum ileum of control and iron deficient rats, Lab Anim. 32(1), (1998). 10. E. S. Dipietro, M. M. Bashor, P. E. Stroud, et al., Comparison of an inductively coupled plasma emission spectrometry method for the determination of calcşum, magnesium, sodium, potassium, copper and zinc with atomic absorption spectroscopy and flame photometry methods, Sci. Total Environ. 74, (1988). 11. C. K. Mukhopadhyay, B. Mazmunder, and P. L. Fox, Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency, J. Biol. Chem. 275(28), 21,048 21,054 (2000). 12. J. Hastka, J. J. Lasserre, A. Schwarzbeck, et al., Central role of zinc protoporphyrin in staging iron deficiency, Clin. Chem. 40, (1994).