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 Table of Contents  
Year : 2019  |  Volume : 17  |  Issue : 3  |  Page : 215-221

Thyroid functions and levels of some trace elements in children with beta-thalassemia major

1 Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
2 Department of Pediatric, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
3 Department of Tropical Medicine, Faculty of Medicine, Al-Azhar University, Assiut, Egypt

Date of Submission10-Sep-2017
Date of Decision23-Apr-2019
Date of Acceptance02-Jun-2019
Date of Web Publication26-Nov-2019

Correspondence Address:
Mohamed S Zaghlol

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AZMJ.AZMJ_48_17

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Background High plasma iron in β-thalassemia major (BTM) leads to enhanced generation of reactive oxygen species, oxidative stress, and endocrine disorders. We aimed to assess thyroid function and trace elements [copper (Cu) and zinc (Zn)] in patients of BTM and to evaluate the relation, if any, of thyroid function with iron store in the form of ferritin levels.
Patients and methods A total of 30 children with BTM and 30 healthy controls were enrolled and interviewed at the Al-Azhar University. Complete blood count, random blood sugar, liver enzymes, and creatinine were measured in all participants. Iron level, total iron-binding capacity, ferritin level, Zn level, and Cu level in sera were determined. Thyroid function was also assessed by evaluating free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels.
Results There were significantly increased serum iron, ferritin, Cu, and Zn levels, whereas total iron-binding capacity was depleted in patients with BTM as compared with healthy controls. There were significant positive correlations between ferritin level and both serum Cu and Zn (r=0.536 and 0.513, respectively), with P value less than 0.05. Moreover, there were significant positive correlations between TSH level and both serum Cu and Zn (r=0.416 and 0.355, respectively), with P value less than 0.05. Thyroid function represented by FT3, FT4, and TSH did not correlate with serum ferritin level.
Conclusion Careful monitoring of ferritin, Cu, Zn, TSH, FT4, and FT3 levels at regular intervals is recommended for early diagnosis of thyroid dysfunctions in patients with BTM.

Keywords: beta-thalassemia, copper, ferritin, iron, thyroid, total iron-binding capacity, zinc

How to cite this article:
Zaghlol MS, Al-Sayed MT, Yonis MM, Mohamed AQ. Thyroid functions and levels of some trace elements in children with beta-thalassemia major. Al-Azhar Assiut Med J 2019;17:215-21

How to cite this URL:
Zaghlol MS, Al-Sayed MT, Yonis MM, Mohamed AQ. Thyroid functions and levels of some trace elements in children with beta-thalassemia major. Al-Azhar Assiut Med J [serial online] 2019 [cited 2020 Dec 3];17:215-21. Available from: http://www.azmj.eg.net/text.asp?2019/17/3/215/271680

  Introduction Top

Beta-thalassemia is the commonest single-gene inherited disease in the world owing to no or reduced production of beta globin chains, while the alpha chain production will continue to occur, developing erythrocytes that are more fragile, leading to early damage, ineffective erythropoiesis, and anemia. Beta-thalassemia exists in different forms depending upon the beta globin chain deficit [1]. β-thalassemia major (BTM) is the most severe form among them, which is caused by mutations in the HBB gene in chromosome 11 (β), leading to defective synthesis of β-globin subunits of hemoglobin HbA (α2β2) [2].

BTM is a common health problem in the Middle East, Africa, and Southeast Asia [3]. It is a major public health problem in Egypt. It has been estimated that 1000 children of 1.5 million live births are born annually with BTM [4]. In multicenter studies, the carrier rate in Egypt has been reported to be in the range of 9–10% [5].

The released iron during repeated blood transfusions in BTM could play an essential role in the oxidation of membrane cells and senescent cell antigen formation of the major pathways for erythrocyte removal [6]. Iron overload is responsible for peroxidative damage by increased production of reactive oxygen species within the erythrocytes leading to oxidative stress with endocrine complications [7]. The reported thyroid dysfunctions seen in patients with BTM include primary hypothyroidism-caused abnormalities of the thyroid gland, subclinical hypothyroidism as well as secondary hypothyroidism [8],[9]. The frequency of hypothyroidism shows a discrepancy depending on the region, quality of management, and treatment protocols ranges between 13 and 60% [10],[11].

Copper (Cu) and zinc (Zn) are important antioxidant elements that are required in trace amount as cofactors for some metalloenzymes to be functional such as Zn–Cu superoxide dismutase, and thus play key roles in maintaining cellular homeostasis [12],[13]. Zn is also required for thyroid metabolism and structure and may play a role in conversion of T4 to T3 in humans. Zn deficiency may lead to reduction in concentrations of T3 in plasma [14],[15].

There are limited data available in our country concerning oxidative stress, antioxidant status, degree of peroxidase damage, and role of trace elements in patients with BTM. We therefore planned the present study with the aim to assess thyroid function and trace elements (iron, Cu, and Zn) in patients of BTM and to evaluate its relation, if any, with serum ferritin levels.

  Patients and methods Top

This study was done on 30 children presented with BTM [16 (53.3%) males and 14 (46.7%) females]. Their ages ranged from 5 to 10 years, with mean±SD of 7.46±1.45 years. They were blood transfusion dependent. This study was carried out in Pediatric Department, of Al-Azhar Assiut University Hospital, over a period from June 2014 to March 2015. The study protocol was approved by the local ethics committees, and all parents of children gave adequate informed consent.

The diagnoses of BTM were made based on the clinical, hematological, and hemoglobin electrophoresis profiles at Hematology Unit at Al-Azhar Assiut University Hospital. Hemoglobin electrophoresis shows decreased Hgb A, increased Hgb F, and variable Hgb A2.

In addition, 30 healthy children of matched age and sex were also included as controls. None of these children had history of anemia, abnormal complete blood counts (CBCs), and abnormal hemoglobin electrophoresis results.

Exclusion criteria

Any child with a history of cardiovascular diseases, hypertension, diabetes mellitus, and splenectomy was excluded from this study.

All children were subjected to the following:
  1. Full history taking.
  2. General examination and local thyroid examination.
  3. CBCs using automated cell counter Drew (Miami Lakes, Florida, USA).
  4. Biochemical assay of random blood sugar (RBS), liver enzymes [aspartate transaminase (AST) and alanine transaminase (ALT)], and serum creatinine was done by autoanalyzer Mindray BS-380 (Assuit).
  5. Serum iron and total iron-binding capacity (TIBC) (µg/dl) were assessed using a substrate method with Feren S (Thermo Fisher Scientific, Waltham, Massachusetts, USA). Cu and Zn were assessed directly (µg/dl) by Abnova Cu and Zn assay kit (Neihu District, Taipei City, Taiwan) using Photometer 5010 system (Robert Riele, Berlin, Germany).
  6. Free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and ferritin were measured using immunoassay based on immunofluorescence on the Tosoh AIA-600II System (Tosoh, Tokyo, Japan).

Specimen collection and preparation

Blood samples were taken from the patients using wide-bore needle and withdrawn slowly from antecubital vein to avoid hemolysis of RBCs by careful venipuncture. These samples were divided into three aliquots: the first aliquot was added to florid tube for RBS measurements, the second aliquot was added to an EDTA tube for CBC measurements, and the third aliquot was added to a tube with no anticoagulant and then allowed to be clotted for 30 min, and then the serum was separated by centrifugation at 4000 rpm for 5 min. The serum was used for routine laboratory investigation (AST, ALT, and serum creatinine) and measurement of iron, TIBC, ferritin, Cu, Zn, and thyroid function tests (FT3, FT4, and TSH).

Statistical analysis

Data were described as mean±SD/SE and percentages. Least significant difference for intergroup variance was measured at 95% confidence interval. The metric data were analyzed by Student’s t test, whereas Pearson’s coefficient of linear correlation was used to describe the level of correlation between the studied parameters. All statistical analyses were performed using SPSS (Statistics Products Solutions Services, New York, New York, USA), version 20 software for Windows (Redmond, Washington, USA). The results were expressed in mean±SD. P values less than 0.001 and less than 0.005 were considered as highly significant.

  Results Top

Comparative data of age, sex, and routine investigation between patient and control groups are illustrated in [Table 1]. There were statistically significant differences between BTM and control groups regarding hemoglobin, hematocrit, RBS, AST, ALT, and serum creatinine (with P<0.05). However, there were no significant differences between them regarding age and sex differences (with P>0.05).
Table 1 Parameters for patients with β-thalassemia major and controls

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Regarding parameters of iron status, mean iron levels were 188.30±67.29 versus 90.36±29.20 mg/dl and mean ferritin levels were 2782.6±2075.4 versus 86.66±19.37 ng/ml for patients with BMT and control group, respectively (P<0.01). However, there were no significant differences between them regarding TIBC (P>0.05).

Regarding thyroid function tests, serum TSH was significantly higher in patients with BTM compared with the controls (7.53±6.29 vs. 3.98±1.47 µIU/ml, respectively). However, the mean level of serum FT3 and FT4 were significantly lower in patients with BTM compared with the controls (2.87±0.77 vs. 3.37±0.84 pg/ml, respectively, for FT3 and 0.90±0.39 versus 1.13±0.29 ng/dl, respectively, for FT4) (P<0.01).

The mean levels of serum Cu and Zn were significantly higher in patients with BTM than the controls (193.56±31.03 vs. 105.63±16.42 µg /dl, respectively) for Cu and 241.93±54.41 versus 118.40±15.32 µg/dl, respectively for Zn; P value less than 0.01) ([Table 1]).

There were significant positive correlations between ferritin level and both serum Cu and Zn (r=0.536 and 0.513, respectively), with P value less than 0.05, whereas there was no significant correlation between ferritin and TSH levels (r=0.184, P>0.05). On the contrary, there were significant positive correlations between TSH level and both serum Cu and Zn (r=0.416 and 0.355, respectively) with P value less than 0.05 ([Figure 1]).
Figure 1 Correlation between ferritin, copper, zinc, and TSH. r=correlation coefficient; P=significance level. TSH, thyroid-stimulating hormone.

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  Discussion Top

Patients with BTM are known to have poor growth, altered puberty and immune function, as well as reduced bone mineral formation. The etiology of these comorbidities is typically ascribed to the toxic effects of transfusion-related iron overload. These patients also have iron overload independent of blood transfusions [16].

Studies on trace elements like iron, Cu, and Zn reveal significant changes in plasma concentration of these trace elements in patients with BTM. In our study, there were significantly increased serum iron and depleted TIBC levels in patients with BTM as compared with healthy controls. Our findings are in accordance with series of reports [2],[17],[18],[19].

Against our study results, the study by Huang et al. [20] revealed that TIBC level decreased significantly in the beta-thalassemia group compared with those in the other control group and even other types of thalassemia. Furthermore, they found that serum iron and TIBC are better indices for monitoring iron loading in children with thalassemia in comparison with transferrin level. They used increase in serum iron level and decrease in TIBC in the diagnosis of beta-thalassemia in children with anemia.

Cu and Zn were found to be significantly increased in patients with BTM as compared with controls. This increased level of Cu may be owing to acute or chronic infections and hemochromatosis that occur as complications in thalassemia major [21],[22],[23].

Our findings are in concurrence with several studies reported from Jordan, Turkey, Tunisia, Tehran, and Thailand [24],[25],[26],[27],[28],[29].

Against our study, Kwan et al. [30] reported only three of 68 patients with thalassemia to have Zn deficiency. Furthermore, Kajanachumpol et al. [26] and Rashidi et al. [31] reported plasma and hair Zn levels to be much lower but erythrocytes’ Zn was higher in patients with thalassemia than controls. They concluded that the regularity of blood transfusion appears to somehow prevent such deficiency because of receiving healthy blood donation, and it may clarify the normal or even elevated serum Zn levels. The mechanism of increased erythrocytic Zn was not clear but may be affected by impaired Zn metabolism.

In contrast to our results, Al-Samarrai et al. [23] from Iraq demonstrated Zn deficiency among patients with thalassemia and attributed it to hyperzincuria. Shamshirsaz et al. [22] have reported 79.6% of their patients with thalassemia to have Zn deficiency and subsequent delayed sexual activity, retarded growth, and significant association with lumbar BMD. The authors emphasized that the cause of Zn deficiency was insufficient Zn intake which could be attributed to a high prevalence of deficiency of this trace mineral in general Iranian population. In Egypt, Nasr et al. [21] in their series of 64 patients with BTM reported that the mean Zn level was significantly lower in patients versus the control group. They also analyzed association of Zn insufficiency with duration of transfusion and chelation therapy but no correlation were established, with suboptimal chelation. A report by Dehshal et al. [32] showed that 37% of patients with thalassemia had Zn deficiency, and the authors proposed that serum Zn levels be routinely monitored in these patients. Likewise, Ferdaus et al. [33] from Bangladesh also found that desferrioxamine treatment was associated with Zn loss in 60% of their patients with thalassemia. Another regional study by Ghone et al. [34] reported from India showed diminished levels of serum Zn in their series of 72 patients. Another study by Moafi et al. [35] has identified a reverse correlation of Zn deficiency with blood transfusion rate (P<0.05). Moreover, Bekheirnia et al. [36] from Iran found 84.8% of patients with thalassemia to be Zn deficient.

Like our results, Bashir [24] and Oktekin and Gokmen [37] reported that Zn and Cu levels are significantly increased in patient treated with chelation therapy. Similarly, a study done by Mehdizadeh et al. [29] showed that mean serum Zn level was significantly higher in the thalassemic group. Against our study, there is one prospective study indicating no change in serum Cu levels in patients with thalassemia major [18]. By contrast, low plasma Zn and Cu levels have been found in patients treated with iron chelators [38].

Zn, Cu, and ferritin are trace metals that play vital roles as cofactors for a variety of proteins. Besides iron, there is evidence that Zn and Cu abnormality can pose a significant threat to human health and well-being [29],[39],[40]. Abnormal levels and metabolism of Zn, Cu, and ferritin has been found to cause several chronic pathogenesis, such as endocrine dysfunctions, diabetes and diabetic complications, and others. Moreover, Cohen et al. [15] reported that chelation therapy can also act as chelator for both Zn and Cu. Thus, we anticipate that Zn and Cu levels could be closely similar to the controls.

However, our study reveals that there were significantly increases in mean levels of serum Zn and Cu in our patients compared with the controls. These findings indicate that Zn and Cu deficiencies in our patients with BTM are rare, and it appears that Zn and Cu supplementations are not required. These findings also support the aforementioned notion that chelation therapy appears to be not effective as evident by high Zn and Cu.

As the patients with thalassemia under current study have no obvious inflammatory diseases or infection, the increase in serum ferritin indicates iron overload owing to the frequent transfusions to the patients. In our study, mean ferritin levels in patients with BTM was 2782.6±2075.4 ng/ml, whereas in control group was 86.66±19.37 ng/ml, with more than 32 times elevated levels in patients with BTM than healthy controls. Our findings are in agreement with the other researchers [2],[41],[42],[43] that iron indices were markedly increased and the mean concentration of serum ferritin was elevated more than 20 times than controls.

Generally, serum ferritin represents only 1% of total iron pool, and inflammation (e.g. hepatitis) and liver damage usually induce an increase in serum ferritin level [44]. Thus, besides repeated blood transfusion, we cannot exclude the possibility that inflammation may contribute to such increase, because liver inflammation is more common in patients with BTM represented by significant elevation of AST and ALT in BTM compared with healthy controls.

In our study; there were significant positive correlations between ferritin level and both serum Cu and Zn (r=0.536 and 0.513, respectively), with P value less than 0.05. In contrast to our study, Mehdizadeh et al. [29] showed no relationship between serum Zn level and serum ferritin level. These results are compatible with our results.

Moreover, there were significant positive correlations between TSH level and both serum Cu and Zn (r=0.416 and 0.355, respectively) with P value less than 0.05. Against our study results, no significant correlation between Zn and thyroid gland functions was observed by Kontoghiorghes et al. [45]. These results might differ from ours probably because of differences in the manner, degree of compliance, doses, and/or type of chelation therapy. Based on these findings, there are wide discrepancies in existing studies regarding the status of Zn and Cu levels in patients with BTM treated with chelation therapy. Thus, the reasons for such increase in mean levels of serum Zn and Cu in our study are still unclear. However, a number of explanations can be proposed for such increase. High serum Zn and Cu levels are probably owing to the impairment of Zn and Cu metabolism and utilization in tissues in the pathogenesis of these patients. It is also possible that the decrease rate of glomerular filtration of Zn and Cu in chronic hemolysis may contribute to such increase in these two metals, which is explained by the significant increase of serum creatinine in patients with BTM compared with healthy controls ([Table 1]). Moreover, additional factors may also contribute to the increase in Cu and Zn, including an increase in Zn and Cu absorption via the gastrointestinal tract, different transfusion rates, types and doses of chelation therapies, age of patients, nutrition status, psychological and health problems, such as depression, and metabolic and endocrine complications.

We found that thyroid function represented by FT3, FT4, and TSH did not correlate with serum ferritin level. Similar observations have been made by others [46],[47]. The absence of the relationship between ferritin and hypothyroidism may be explained by suggesting that the damage of endocrine glands caused by chronic hypoxia is more pronounced than that caused by hemosiderosis as a consequence of the collapse of iron [48].

  Conclusion Top

There was a significant positive correlation between ferritin and both Cu and Zn levels on one side and between TSH and both Cu and Zn levels on other side in our patients with BTM even with no clinical signs of thyroid dysfunction, pointing to high serum levels of Cu and Zn might be seen as potential risk factors for future initiation and development of thyroid dysfunction as well as other organ dysfunctions in our patients. Thus, careful monitoring of ferritin, Cu, Zn, TSH, FT4, and FT3 levels at regular intervals is recommended.

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Conflicts of interest

There are no conflicts of interest.

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