|Year : 2013 | Volume
| Issue : 3 | Page : 91-95
Thyroid status in Egyptian primary school children with iron deficiency anemia: Relationship to intellectual function
Kotb Abbass Metwalley1, Hekma Saad Farghaly1, Asmaa Farghaly Hassan2
1 Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt
2 Department of Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt
|Date of Web Publication||6-Aug-2013|
Kotb Abbass Metwalley
Pediatric Endocrinology Unit, Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut
Source of Support: None, Conflict of Interest: None
Background: Only few studies concerning thyroid status and intellectual evaluation in iron deficiency anemia, which is frequently seen in primary school children in Egypt. Aim: The present study was planned to investigate the effect of iron deficiency anemia on the thyroid functions and intellectual activity of young children in a primary school. Settings and Design: Cross-sectional controlled study. Patients and Methods: This study was carried out on 60 primary school children aged 6-12 year with iron deficiency anemia (Group 1) and 20 children as control (Group 2). Complete blood count, iron, total iron binding capacityferritin, thyroid stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), free thyroid hormones (FT4 and FT3), and intelligence quotient (IQ) were determined in all the children included in the study. Results: TT3 and TT4 values were statistically lower while TSH is significantly higher in the study group as compared to control (P < 0.001 for each). Patients with hemoglobin (HB) level < 10 > 7 g/dl had significantly lower levels of serum FT3 and FT4 (P < 0.01 for both) and significantly higher levels of serum TSH (P < 0.05) as compared to patients with HB level <7 g/dl. Serum ferritin was correlated negatively with TSH levels (r = −0.76, P < 0.001) while positively with TT4 (r = 0.69, P < 0.001) and TT3 (r = 0.84, P < 0.001) levels. A significant positive correlation was found between serum level of TT3 and transferrin saturation% (r = 0.78, P < 0.001). Total, as well as performance IQ were significantly lower in patients than controls with P <0.05 for each. Significant positive correlations were observed between both total and performance IQ and thyroid hormone levels and iron status parameters. Conclusion: Egyptian primary school children with iron deficiency anemia especially severe type are liable to develop subclinical hypothyroidism and intellectual dysfunction. A randomized, double-blind, controlled study is needed to address the question of whether subclinical hypothyroidism associated with iron deficiency anemia should be treated with oral iron only or iron and levothyroxine combination aiming to prevent the combined effects of both conditions on cognitive function of the brain. Moreover, more comprehensive studies are needed to elucidate if the effect of iron deficiency anemia on thyroid status is reversible or not.
Keywords: Anemia, iron deficiency, thyroid hormone
|How to cite this article:|
Metwalley KA, Farghaly HS, Hassan AF. Thyroid status in Egyptian primary school children with iron deficiency anemia: Relationship to intellectual function. Thyroid Res Pract 2013;10:91-5
|How to cite this URL:|
Metwalley KA, Farghaly HS, Hassan AF. Thyroid status in Egyptian primary school children with iron deficiency anemia: Relationship to intellectual function. Thyroid Res Pract [serial online] 2013 [cited 2019 Nov 18];10:91-5. Available from: http://www.thetrp.net/text.asp?2013/10/3/91/116131
| Introduction|| |
Children and adolescents differ from adults in many aspects especially, in that they continue to grow. The thyroid gland is one of the most important organs for optimal growth, development and metabolism. Normal thyroid status is dependent on the presence of many trace elements e.g., iron, iodine, selenium, and zinc for both the synthesis and metabolism of thyroid hormones. Deficiencies of these elements can impair thyroid functions.  Iron deficiency anemia is one of the world's most widespread health problems especially among children. In Egypt 27% of Egyptian children have iron-deficiency anemia.  Since iron is essential for all cells, many systems are affected in iron deficiency in addition to anemia. Psychomotor retardation in addition to growth and development retardation is observed in children with iron deficiency anemia. In some studies performed in animals and in humans, thyroid hormone metabolism has been reported to be disturbed in iron deficiency.  There was a limited number of studies investigating the relation of iron deficiency anemia and thyroid hormones as well as intellectual activity in children The aim of the present study was to investigate the effect of iron deficiency anemia on the thyroid function and intellectual activity of young Egyptian children in a primary school.
| Materials and Methods|| |
This study was conducted on 60 primary school children aged 6-12 year with iron deficiency anemia (Group 1):32 boys and 28 girls. In addition, 20 apparently healthy age and sex matched children were studied as a control (Group 2). They were 12 boys and 8 girls. Both patients and controls were recruited from Pediatric Outpatients Clinics in Assiut University Children Hospital, in cooperation with Physiology Department Assiut University, Egypt. Iron deficiency anemia was defined as anemia with a serum ferritin concentration <15 μg/dl, decreased iron <50.43 μg/dl and increased total iron binding capacity (TIBC > 413.89 μg/dl. The cut-off values for the diagnosis of microcytic hypochromic anemia were: hemoglobin (HB) <10.9 g/dl, mean cell volume<68.5 fl (famtoliter) and mean cell HB concentration <25.5 g/dl. 
The inclusion criteria of the patients were
0absence of any systemic diseases except for iron deficiency, serum albumin within the normal range: 3.5-5.5 g/dl, urinary iodine >100 μg/l and body mass index (BMI) >19 kg/m 2 .
Exclusion criteria were
Iron therapy, acute illness, hormonal therapy, family history of hypothyroidism, children with autoimmune thyroditis or syndromic children. The study protocol was approved by the ethical committees of Assiut University Children Hospital, Egypt. Written informed consents were obtained from the parents of both patients and controls. Clinical examination of all cases was done including vital signs, anthropometric measurements (weight, height, head circumference, and BMI), signs of iron deficiency and thyroid examination. For intellectual evaluation, intelligence quotient (IQ) was performed in all subjects (patients and controls) using Weschler Intelligence Scale for children 3 rd edition. (Egyptian Standardization). This scale measures IQ as total, verbal and performance. The evaluation was performed by a qualified clinical psychologist in a calm room with no parental interference. The psychologist was unaware of other study methods. Grades of IQ scores were interpreted according the classification of the American Psychiatric Association  as follow [Table 1]:
Ten milliliter fasting venous blood samples were drawn from the arm. Blood was collected in two tubes; for evaluation of hematologic variables, approximately 2 ml venous blood was placed in a hemogram tube with EDTA for measurement of HB and hematocrit. The 8 ml in another tube for estimation of serum iron by using atomic absorption/flame spectrophotometer (Model AA-630-02). Serum TIBC by colorimetric method using COBAZ integra 800 device using commercial available kits and serum ferritin by enzyme-linked immunosorbent assay using DRG commercial kit. Transferrin saturation% (TFS%) was determined by dividing the serum iron concentration by the TIBC and multiplying by 100.  Serum thyroid stimulating hormone (TSH), TT4, TT3, FT4, FT3 levels were measured by immunoassay, according to kit instructions (Siemens Healthcare Diagnostics, Deerfield, IL). In addition, a morning urine sample was obtained from each child and stored at −20°C until assay of urinary iodine by Sandell-Kolthoff reaction according to Ohashi method. 
Data were expressed as mean ± standard error (SEM) for all parameters. The data were analyzed by using GraphPad Prism data analysis program (Graph Pad Software, Inc., San Diego, CA, USA). For the comparison of statistical significance between cases and control, Student Newman-Keuls t-test for unpaired data was used. Correlations analysis between variable were assessed using Spearman's non-parametric correlation coefficient. P value is considered significant if < 0.05.
| Results|| |
Physical characteristics of the studied groups were shown in [Table 2]. The mean BMI of the patients was within the normal reference range. Anthropometric data indicated normal values. Hematological and biochemical parameters of the studied groups were shown in [Table 3]. Hematological indices for iron status were indicative that all patients were iron-deficient where serum levels of iron, ferritin and TFS% were significantly decreased (P < 0.001 for each) while TIBC was significantly increased (P < 0.01) as compared to control. Serum levels of TSH were significantly higher (P < 0.001) whereas TT4 and TT3 values were significantly lower in patients group (P < 0.001 for each) as compared to control group. There was no significant difference between the groups in terms of FT4 and FT3 levels. In order to evaluate thyroid dysfunction in relation to the severity of iron deficiency anemia, the patients were grouped according to HB level. Patients with HB level <10 >7 g/dl had significantly lower levels of serum FT3 and FT4 (P < 0.01 for both) and significantly higher levels of serum TSH (P < 0.05) as compared to patients with HB level < 7 g/dl [Figure 1].
|Table 3: Hematological and biochemical parameters of the studied groups |
Click here to view
|Figure 1: Thyroid stimulating hormone, FT4 and FT3 levels in iron deficient anemic patients in relation to hemoglobin level|
Click here to view
Using correlation analysis and stepwise regression procedure, it was found that serum ferritin was correlated negatively with TSH levels (r = −0.76, P < 0.001) while positively with TT4 (r = 0.69, P < 0.001) and TT3 (r = 0.84, P < 0.001) levels. A significant positive correlation was found between serum level of TT3 and TFS% (r = 0.78, P < 0.001) [Figure 2]. Urinary iodine was non-significantly varied in patients group in comparison with control. All our studied cases were clinically euothyroid with no goiter.
|Figure 2: (a) Correlations between serum ferritin levels and each of thyroid stimulating hormone. (b) Correlations between serum ferritin levels and TT4. (c) Correlation between serum ferritin levels and TT3. (d) Correlation between TT3 and transferrin saturation%|
Click here to view
Regarding intellectual activity, [Figure 3]: showed that the total as well as performance IQ were significantly lower in patients than controls with P <0.05 for each, whereas verbal IQ was non-significantly varied. Correlations analysis between IQ and thyroid hormone levels as well as iron status were shown in [Table 4] where significant positive correlations were observed between both total and performance IQ and thyroid hormone levels and iron status parameters.
|Table 4: Correlations between intellectual activity and thyroid hormones levels as well as iron status in iron deficient anemic patients |
Click here to view
|Figure 3: Total, verbal and performance intelligence quotient in patients and controls|
Click here to view
| Discussion|| |
Iron is an essential element for many living organisms and has a vital importance. Since, it is necessary for structure and function of many enzymes and is used widely in the human body, all systems are affected in its deficiency and many systemic symptoms and clinical findings occur. If iron deficiency anemia is not treated in the childhood, it results in physical, intellectual and cognitive retardation. Iron deficiency was reported to decrease intellectual and motor development test scores in children even if anemia was not present.  The relation between thyroid function and intellectual function is also well known. 
Our result revealed that TT4, TT3 levels were significantly lower, FT4 and FT3 were non-significantly varied while TSH level is significantly higher compared with the control. Patients with HB level < 10 > 7 g/dl had significantly lower levels of serum FT3 and FT4 and significantly higher levels of serum TSH (P < 0.05) as compared to patients with HB level <7 g/dl [Figure 1]. In addition, serum ferritin was correlated negatively with TSH levels, while positively with TT4 and TT3 levels. These results are similar to results of studies reported in animal and human studies. , The two initial steps of thyroid hormone synthesis are catalyzed by heme-containing thyroid peroxidase.  Severe iron deficiency may lower thyroperoxidase activity and interfere with the synthesis of thyroid hormones.  Hess et al. have shown that thyroid peroxidase activity is significantly reduced in iron deficiency anemia. In addition, iron deficiency may alter central nervous system control of thyroid metabolism  and modify nuclear triiodothyronine binding.  Iron-deficiency anemia decreases plasma concentrations of thyroxine and triiodothyronine, reduces the peripheral conversion of thyroxine to triiodothyronine, and increases circulating concentrations of thyrotropin.  The fact that total hormone levels were decreased, while levels of free hormones which are biologically active were within normal limits may be an adjustment developing against iron deficiency anemia. In contrast to our results, Tienboon and Unachak,  found no difference in TT4, TT3, FT4, FT3, TSH levels in children with iron deficiency anemia before and after iron treatment, these difference can be attributed to difference of number of cases enrolled, difference in the age and inclusion criteria. The known effects of thyroid hormones on functions of the central nervous system include effects on intelligence, emotional status, behavior and cognitive functions. ,
Subclinical hypothyroidism or compensated hypothyroidism is defined as a normal total or free T4 and T3 levels, a slightly elevated TSH, and absence of clinical features of hypothyroidism.  In the present study, the interpretation of the thyroid function test implies that studied cases with iron deficiency anemia had subclinical hypothyroidism. In addition, the total as well as performance IQ were significantly lower in patients than controls with P < 0.05 for each and significant positive correlations were observed between both total and performance IQ and thyroid hormone levels. This is in agreement with Salerno et al.  who reported that subclinical hypothyrodism in children has been associated with lower intellectual performance and decreased visual-spatial ability. Either iron deficiency anemia or subclinical hypothyroidism can cause intellectual dysfunction. The additive effects of both co-morbid conditions lead to further amplification of intellectual dysfunction.
Limitations of the study
First; the number of children with T4 and TSH values beyond the reference ranges was rather small in this study. Thus, the study might have insufficient power to detect the differences between the groups. Second; it is possible that those parents who agreed to enter their children in the study had doubts about neurodevelopment of their off-spring thus, introducing a selection bias. Third; an absence of follow-up results after treatment.
| Conclusion|| |
Egyptian primary school children with iron deficiency anemia especially, severe type is liable to develop subclinical hypothyroidism and intellectual dysfunction. A randomized, double-blind, controlled study is needed to address the question of whether subclinical hypothyroidism associated with iron deficiency anemia should be treated with oral iron only or iron and levothyroxine combination aiming to prevent the combined effects of both conditions on cognitive function of the brain. Moreover, more comprehensive studies are needed to elucidate if the effect of iron deficiency anemia on thyroid status is reversible or not.
| References|| |
|1.||Eftekhari MH, Eshraghian MR, Mozaffari-Khosravi H, Saadat N, Shidfar F. Effect of iron repletion and correction of iron deficiency on thyroid function in iron-deficient Iranian adolescent girls. Pak J Biol Sci 2007;10:255-60. |
|2.||El-Beshlawy A, Emara A, Hanna T, Moustafa A, Ragab L, Youssry I, et al. Microcytic hypochromic anemia in Egyptian children. Egypt J Haematol 2000;25:585-96. |
|3.||Beard J, Tobin B, Green W. Evidence for thyroid hormone deficiency in iron-deficient anemic rats. J Nutr 1989;119:772-8. |
|4.||Batra J, Sood A. Iron deficiency anaemia: Effect on congnitive development in children: A review. Indian J Clin Biochem 2005;20:119-25. |
|5.||American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4 th ed (DSM-IV, text revision) Washington, 2000. |
|6.||Ohashi T, Yamaki M, Pandav CS, Karmarkar MG, Irie M. Simple microplate method for determination of urinary iodine. Clin Chem 2000;46:529-36. |
|7.||Azizi F, Mirmiran P, Sheikholeslam R, Hedayati M, Rastmanesh R. The relation between serum ferritin and goiter, urinary iodine and thyroid hormone concentration. Int J Vitam Nutr Res 2002;72:296-9. |
|8.||Brigham DE, Beard JL. Effect of thyroid hormone replacement in iron-deficient rats. Am J Physiol 1995;269:R1140-7. |
|9.||Beard JL, Borel MJ, Derr J. Impaired thermoregulation and thyroid function in iron-deficiency anemia. Am J Clin Nutr 1990;52:813-9. |
|10.||Dillman E, Gale C, Green W, Johnson DG, Mackler B, Finch C. Hypothermia in iron deficiency due to altered triiodothyronine metabolism. Am J Physiol 1980;239:R377-81. |
|11.||Hurrell RF. Bioavailability of iodine. Eur J Clin Nutr 1999;51:S9-12. |
|12.||Hess SY, Zimmermann MB, Arnold M, Langhans W, Hurrell RF. Iron deficiency anemia reduces thyroid peroxidase activity in rats. J Nutr 2002;132:1951-5. |
|13.||Beard JL, Brigham DE, Kelley SK, Green MH. Plasma thyroid hormone kinetics are altered in iron-deficient rats. J Nutr 1998;128:1401-8. |
|14.||Smith SM, Finley J, Johnson LK, Lukaski HC. Indices of in vivo and in vitro thyroid hormone metabolism in iron-deficient rats. Nutr Res 1994;14:729-39. |
|15.||Tienboon P, Unachak K. Iron deficiency anaemia in childhood and thyroid function. Asia Pac J Clin Nutr 2003;12:198-202. |
|16.||Dugbartey AT. Neurocognitive aspects of hypothyroidism. Arch Intern Med 1998;158:1413-8. |
|17.||Wu T, Flowers JW, Tudiver F, Wilson JL, Punyasavatsut N. Subclinical thyroid disorders and cognitive performance among adolescents in the United States. BMC Pediatr 2006;6:12. |
|18.||Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: A joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab 2005;90:581-5. |
|19.||Salerno M, Militerni R, Di Maio S, Bravaccio C, Gasparini N, Tenore A. Intellectual outcome at 12 years of age in congenital hypothyroidism. Eur J Endocrinol 1999;141:105-10. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]