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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 39  |  Issue : 3  |  Page : 103-108

Some endocrinal changes in children with β-thalassemia major


1 Department of Pediatrics, Assiut University, Assiut, Egypt
2 Department of Pediatrics, South Valley University, Cairo, Egypt
3 Department of Clinical Pathology, South Valley University, Cairo, Egypt

Date of Submission14-Jul-2014
Date of Acceptance20-Dec-2013
Date of Web Publication31-Dec-2014

Correspondence Address:
Ahlam M Ismail
Department of Pediatrics, South Valley University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.148228

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  Abstract 

Background Endocrinal disorders are well-described in patients with β-thalassemia major (BTM) and are among the most common consequences of the disease worldwide affecting patient's quality of life and causing considerable morbidity and mortality. Even with iron chelating agents, the rate of endocrinopathies remains high among thalassemia major patients.
Aims To study the thyroid & parathyroid glands functions in children with Beta- thalassemia and find out the influence of iron overload on them.
Patients and Methods This study was carried out on 35 children diagnosed as Beta-thalassemia major and 15 healthy children as a control group who attended the outpatient clinic as well as the inpatient Pediatric Department, Qena University Hospital. All patients were subjected to thorough medical history, clinical examination and abdominal ultrasound. Laboratory investigations were done to confirm diagnosis and severity of the disease and iron status. Calcium, phosphorus, TSH, T3 & T4 and Parathormone (PTH) levels were detected to find out the thyroid and parathyroid gland functions.
Results There were significant increase in TSH and decrease in T4 and PTH levels in cases than in control. There were also significant increase in TSH and significant decrease in T4 & PTH level regarding age but not significant with sex. Height was significantly lower in cases than control. According to the clinical data, the present study showed that TSH level was significantly higher and PTH was significantly lower among patients whose duration of illness was ≥6 years, those required frequent blood transfusion and with patients on irregular iron chelation therapy (poorly chelated) and splenectomized cases. There were significant and highly significant difference between TSH and PTH levels and serum ferritin, but there were no significant difference in relation to serum iron, TIBC, HB level, calcium and phosphorus. The present study detected correlations between TSH, PTH and serum ferritin.
Conclusion We concluded that there were thyroid and parathyroid endocrinal changes in thalasthemic patients and recommend careful follow up of them by assessments of thyroid and parathyroid hormones as early recognition and hence prevention of these complications might help improve the quality of life of these patients.

Keywords: children; parathyroid; thalassemia major; thyroid


How to cite this article:
Mohey El-Deen ZM, Ismail AM, Abdel Meguid MM, Harb MT. Some endocrinal changes in children with β-thalassemia major. Egypt J Haematol 2014;39:103-8

How to cite this URL:
Mohey El-Deen ZM, Ismail AM, Abdel Meguid MM, Harb MT. Some endocrinal changes in children with β-thalassemia major. Egypt J Haematol [serial online] 2014 [cited 2019 Dec 12];39:103-8. Available from: http://www.ehj.eg.net/text.asp?2014/39/3/103/148228


  Introduction Top


β-Thalassemias are a group of hereditary blood disorders first described by Cooley and Lee [1] . It is an autosomal recessive hereditary anemia, which is incurable, caused by defective synthesis of hemoglobin (Hb), ineffective erythropoiesis, and rapid erythrocyte breakdown [2],[3] . β-Thalassemias are characterized by anomalies in the synthesis of the β-chains of Hb, resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. Three main forms have been described: thalassemia major, thalassemia intermedia, and thalassemia minor [4] . Individuals with thalassemia major usually present within the first 2 years of life with severe anemia, requiring regular red blood cell transfusions [5] . If a regular transfusion program that maintains a minimum Hb concentration of 9.5-10.5 g/dl is initiated, growth and development tends to be normal up to 10-12 years [6] . However, unfortunately, transfused patients may develop complications related to iron overload, including endocrinal complications such as growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands [7] . Even with iron-chelating agents, the rate of endocrinopathies remains high among patients with thalassemia major [8],[9] . Little is known, however, about the current prevalence of various endocrinopathies and endocrinal changes among patients with thalassemia syndromes with today's therapy. One would expect better outcomes in patients with mild to moderate disease who do not require regular transfusions.


  Aim Top


The aim of this work was to study thyroid and parathyroid gland functions in children with β-thalassemia, and find out the endocrinal changes that could develop in transfusion-dependent and transfusion nondependent patients, and the influence of iron overload on thyroid and parathyroid glands.


  Patients and methods Top


This study was carried out on 35 children diagnosed with β-thalassemia major (BTM), in addition to 15 apparently healthy children of matching age and sex as a control group, who attended the outpatient clinic as well as the inpatient Pediatric Department, Qena University Hospital. All patients were subjected to thorough medical history taking to detect the duration of the disease, the frequency of blood transfusion, treatment with iron-chelating agents (types and frequency), and any symptoms suggestive of thyroid and parathyroid gland dysfunctions. Clinical examination and abdominal ultrasound were performed to detect anthropometric measurements, vital signs, cardiac examination, chest examination, organomegaly, skeletal changes and signs of thyroid and parathyroid dysfunctions. Laboratory investigations were carried out to confirm the diagnosis and the severity of the disease and the iron status. Seven milliliter of blood were drawn from each patient and control and divided as follows:



  1. Two milliliter were placed on EDTA anticoagulant for blood count (using Sysmex KX21 autoanalyzer; Roche), reticulocytic count, and Hb electrophoresis (using HPLC; Biorad).
  2. Five milliliter were placed in a plain vacutainer: the serum was separated and aliquoted into Eppendorf tubes and stored in the freezer at -80°C till analysis for the following:

    1. Iron, ferritin, and total iron-binding capacity (TIBC) (using Cobas C311 chemistry autoanalyzer; Roche).
    2. Calcium and phosphorus (using Cobas C311 autoanalyzer; Roche).
    3. Thyroid-stimulating hormone (TSH), T3, and T4 (using Architect i2000; Abbott).
    4. Parathyroid hormone (PTH) assay by ELISA (using hPTH ELISA kit; DIAsource ImmunoAssays S.A., Louvain-la-Neuve, Belgium).




Statistical analysis

Data were statistically analyzed using Student's unpaired t-test, one-way analysis of variance and χ2 (linear-by-linear correlation) tests to compare qualitative variables between groups, as applicable (with a preset probability of P < 0.05). The results were presented as arithmetic mean±SD. Statistical tests were conducted using the SPSS (version 16; SPSS Inc., Chicago, Illinois, USA) software package on a personal computer.


  Results Top


The study included 35 children with BTM (cases), and 15 other healthy children of matching and sex were considered as controls.

BTM patients included 22 (63%) male and 13 (37%) female patients, and their ages ranged from 1 to 12 years with a mean ± SD of 7.43 ± 3.42 years, whereas the control group included seven (46.7%) male and eight (53.3%) female participants, and their ages ranged from 3 to 14 years with a mean ± SD of 8.05 ± 3.12 years.

Regarding anthropometric measurements, weight of the patients ranged from 7 to 24 kg (mean ± SD 17.74 ± 4.71 kg), their height ranged from 69 to 137 cm (mean ± SD 110.6 ± 18.19 cm), and their BMI ranged from 10.19 to 26.22 kg/mm 2 (mean ± SD 18.15 ± 2.640 kg/mm 2 ). The weight of the controls ranged from 11 to 36 kg (mean±SD 19.50 ± 5.14 kg), their height ranged from 94 to 161 cm (mean ± SD 125.5 ± 19.72 cm), and their BMI ranged from 12.45 to 23.34 kg/mm 2 (mean ± SD 18.23 ± 2.63 kg/mm 2 ).

The comparison between patients and controls with regard to anthropometric measurements revealed no significant difference in all parameters except height, as it was lower in cases with a mean ± SD of 92 ± 17 cm compared with the control group with a mean±SD of 104.8 ± 7.53 cm in both age groups of patients (P = 0.012), as illustrated in [Table 1].
Table 1 Anthropometric measurements of cases and controls with regard to age

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Regarding clinical data, we found that 13 (37%) cases had a duration of illness less than 6 years, whereas 22 (63%) cases had a duration of illness more than 6 years; also, 18 (51%) cases were exposed to frequent blood transfusion (frequency, every 2 weeks), whereas 17 (49%) cases were not transfused frequently. Regarding iron-chelating therapy, 22 (63%) cases showed good compliance to treatment with good chelation, whereas 13 (37%) cases showed poor compliance to treatment and were poorly chelated. All BTM patients presented with hepatomegaly: among them, 21 (60%) cases presented with splenomegaly, whereas the remaining 14 (40%) cases were splenectomized. Also, 21 (60%) cases presented with skeletal changes and thalassemic facies, whereas the remaining 14 (40%) cases did not have any skeletal changes.

Regarding routine laboratory findings among the studied cases, we found that patients' Hb levels ranged from 6.9 to 10.2 g/dl (mean ± SD 7.6 ± 1.99 g/dl): 33 (94%) cases presented with Hb levels below 10 g/dl at the time of sampling, whereas two (6%) cases presented with Hb levels above 10 g/dl. The serum level of ferritin ranged from 1350 to 3370 mg/dl (mean ± SD 1824 ± 955 μg/dl): 12 (34%) cases presented with serum ferritin levels below 2000 mg/dl, whereas 23 (66%) cases presented with serum ferritin higher than 2000 mg/dl. The serum iron level ranged from 189 to 497 mg/dl (mean ± SD 210.6±18.19 mg/dl): 33 (94%) cases presented with high serum iron levels and two (6%) cases presented with normal serum iron, and 32 (92%) cases presented with low TIBC levels, whereas three (8%) cases presented with normal TIBC levels. The serum calcium level ranged from 7.5 to 11 mg/dl (mean ± SD 8.9 ± 1.8 mg/dl), and it was within the normal range for 27 (77%) cases and below the normal level in eight (23%) cases. The serum phosphorus level ranged from 4.1 to 7.3 mg/dl (mean ± SD 5.6 ± 1.8 mg/dl), and was normal in 11 (31%) cases and higher than normal in 24 (69%) cases.

[Table 2] and [Figure 1]a and b show that on comparison between the patient and the control groups regarding the serum level of thyroid hormone and PTH, there was a significant difference between them regarding TSH (P = 0.03) and T4 (P = 0.02). Also, there was a highly significant difference between both groups regarding PTH (P 0≤ 0.001), whereas there was no significant difference between both groups regarding the serum level of T3.
Figure 1 (a, b) Comparison between patient and control groups with regard to the serum level of thyroid and parathyroid hormones. PTH, parathyroid hormone; TSH, thy roid-stimulating hormone.

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Table 2 Comparative study of thyroid and parathyroid hormones between β-thalassemia major patients and controls

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[Table 3] shows serum levels of thyroid hormone and PTHs in cases and controls regarding age and sex: TSH was significantly increased in patients above 6 years old (P
= 0.02); also, the serum T4 was significantly lower in patients below 6 years old (P = 0.04), but not reaching significant levels in controls. We also found a significant difference between both age groups regarding the PTH level (P = 0.02), but there was no significant difference with the control group regarding TSH, T4, and PTH in relation to sex.
Table 3 Serum levels of thyroid hormones and parathyroid hormone in cases with regard to age and sex

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As shown in [Table 4], we found that TSH was significantly higher among patients whose duration of illness was 6 years or more (P = 0.03), in patients on irregular iron-chelation therapy (P = 0.02) and also significantly higher among splenectomized cases (P = 0.04). However, the frequency of blood transfusion had no significant effect on the serum level of TSH (P = 0.32). However, PTH (pg/ml) was significantly lower among patients whose duration of illness was 6 years or more (P = 0.03), in those who required frequent blood transfusion (P = 0.027), those on irregular iron-chelation therapy (P = 0.24), and those who underwent splenectomy (P = 0.04).
Table 4 Thyroid-stimulating hormone level and parathyroid hormone in relation to clinical data in the studied case

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[Table 5] shows TSH (μIU/ml) and parathyroid hormone (PTH) (pg/ml) in relation to laboratory data among cases; there was also a highly significant difference between the PTH level and serum ferritin when less than 2000 mg/dl (mean ± SD 19.44 ± 4.7 mg/dl) and 2000 mg/dl or more (mean ± SD=24.56±3.9 mg/dl) (P ≤ 0.001). However, regarding TSH and PTH, there were no significant differences in relation to the levels of serum iron, TIBC, Hb, calcium, and phosphorus.
Table 5 Serum thyroid-stimulating hormone level and parathyroid hormone in relation to laboratory data of the studied cases

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There was a positive correlation between TSH and serum ferritin (r = 0.457, P < 0.05) as illustrated in [Figure 2].
Figure 2 Correlation between thyroid-stimulating hormone (TSH) and serum ferritin. S, serum.

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  Discussion Top


Endocrinal disorders are well-described in patients with BTM and are among the most common consequences of the disease worldwide, affecting patients' quality of life and causing considerable morbidity and mortality [10] . The present study was undertaken to determine thyroid and parathyroid gland functions in children with β-thalassemia.

In this study, our data show that the height in BTM patients was significantly decreased compared with normal controls (P = 0.012). This finding is consistent with observations of other studies reported by many authors, wherein growth retardation and short stature were found in thalassemic patients [11],[12] . Overt hypothyroidism in patients with thalassemia represents the final stage of thyroid dysfunction, and it is not yet known as to how long it takes to develop [13] . In our study, the TSH level was significantly higher in patients than in controls (P = 0.03). We also found that the serum T4 level was significantly lower in patients than in controls (P = 0.02). These findings were consistent with findings of the study conducted by Zervas et al. [14] .

In our study, we found that the TSH level in relation to age was significantly higher in cases aged 6 or more years (P = 0.02); the serum T4 level was also significantly lower in the same age group (P = 0.04). This suggests that thyroid hypofunction is likely to be found in older patients. A similar finding was reported by other authors [14] . In contrast, Gulati et al. [10] mentioned the possibility of endocrine dysfunction in patients with thalassemia in earlier periods of age.

Hypoparathyroidism has generally been considered as a typical complication of the second decade of life in transfusion-dependent patients with BTM [15] . Our results showed a highly significant difference between patients and controls regarding PTH (P ≤ 0.001). This was reported in previous study that investigated the incidence of hypoparathyroid dysfunction in thalassemic patients, and the incidence was up to 22.5% of the patients [16] . Our study pointed out that there is no significant difference in the PTH level with regard to the sex of the patient (22 male and 13 female) and the same was reported by Angelopoulos et al. [15] . Regarding the age of the patients in our study, we found that the PTH level was significantly lower in patients 6 or more years old than in patients less than 6 years old (P = 0.39), which could be explained by more blood transfusions and subsequently a greater iron overload. This is in accordance with Hamidieh et al. [17] who found that the mean age of thalassemic patients with HPT was significantly higher than that of patients without hypoparathyrodism (HPT). Lala et al. [18] found that TSH was significantly higher with patients on irregular iron-chelation therapy as the use of iron-chelation therapy has been known to delay or reverse the development of iron-induced tissue damage. This is consistent with our research, which proved the significantly higher TSH level in patients on irregular iron-chelation therapy compared with controls (P = 0.02). The same finding was noticed in splenectomized cases (P = 0.04). There was no significant relation between TSH levels with regard to the frequency of blood transfusion.

Our study demonstrated a positive correlation between increasing serum ferritin and TSH levels. Other study reported a significant difference in the mean serum ferritin level between thalassemic patients with primary amenorrhea, irregular menses, hypogonadism and those without endocrinopathies. These findings highlight the importance of iron overload in the development of endocrine disorders [19] .

In contrast, Zervas et al. [14] and Pirinççioğlu et al. [14],[20] suggested no relation between the level of ferritin and some endocrinopathies. Therefore, it is possible that there are other factors responsible for organ damage. These factors include liver damage due to viral infections, increased activity of the iron-dependent protocollagen proline hydroxylase enzyme, chronic anemia, and individual susceptibility to damage from iron overload.

Hypoparathyroidism is usually, but not always, accompanied by hypocalcemia. In our study, we found no significant difference in the PTH level with regard to the serum calcium level (P = 0.46) and the serum phosphorus level (P = 0.12), which is in agreement with Gulati et al. [10] who stated that hypocalcemia is less likely to occur in hypoparathyroidism. In contrast, Mostafavi et al. [21] reported hypocalcemia among 22.7% of thalassemic patients and hyperphosphatemia among 70% of them. This can be attributed in our study to the daily calcium and vitamin D intake of our patients in addition to nutritional supplementation, and hence no symptomatic hypocalcemia was noted in our patients.

In relation to the serum PTH level, it was significantly lower in poorly chelated patients than in well-chelated patients, which is in accordance with other study. Chern and Lin [22] found that overt hypoparathyroidism is rare in well-chelated thalassemic patients, whereas the presence of subtle abnormalities in PTH secretion is not well established.

Regarding the serum TSH level, it was higher in poorly chelated than in well-chelated patients, but not reaching a significant difference (P = 0.06). This low level of TSH found in our well-chelated patients could indicate a well-functioning thyroid gland; yet they must be followed up because they might have subclinical hypothyroidism as shown in the study conducted by Zervas et al. [14] who found that one out of five thalassemic patients with normal thyroid functions developed an increase in TSH level after thyrotropin-releasing hormone (TRH) stimulation test. These well-chelated patients with normal TSH levels could have secondary hypothyroidism due to pituitary failure, which is common in thalassemia due to iron overload in the pituitary gland [23] . Therefore, they should be followed up regularly by monitoring either their thyroid hormones level or thyroid echogenicity by thyroid ultrasound examination.


  Conclusion Top


We conclude that there was a significant increase in TSH and a decrease in T4 and PTH levels in cases compared with controls. There was also a significant increase in TSH and a significant decrease in T4 and PTH levels with regard to age and sex. The height was significantly lower in cases than in controls. According to the clinical data, the present study showed that the TSH level was significantly higher and PTH was significantly lower among patients whose duration of illness was 6 or more years, in those who required frequent blood transfusion and in patients on irregular iron-chelation therapy (poorly chelated) and splenectomized cases. The present study detected a positive correlation between TSH and serum ferritin (r = 0.457, P < 0.05), but there were no significant correlations in relation to serum iron, TIBC and Hb levels. Serum calcium and phosphorus showed no significant correlation with either TSH or PTH. We recommend careful follow-up of thalassemic patients for thyroid and parathyroid dysfunction by assessment of thyroid hormone and PTHs, as early recognition and hence prevention of these complications might help improve the quality of life of these patients, and also replacement of thyroid hormone and oral calcium and vitamin D supplementation, as it is easy and does not have side effects. Advanced protocols for the treatment and optimization of transfusion and chelation therapy are needed for thalassemic patients.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Cooley, GB, Lee, P. A series of cases of splenomegaly in children with anemia and peculiar bone changes. Trans Am Pediatr Soc 1925;29-30.  Back to cited text no. 1
    
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De Sanctis V, Eleftheriou A, Malaventura C, Thalassemia International Federation Study Group on Growth and Endocrine Complications in Thalassemia. Prevalence of endocrine complications and short stature in patients with thalassemia major: a multicenter study by the Thalassemia International Federation (TIF). Pediatr Endocrinol Rev 2004; Suppl 2 :249-255.  Back to cited text no. 8
    
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Filosa A, Di Maio S, Aloj G, Acampora C. Longitudinal study on thyroid function in patients with thalassemia major. J Pediatr Endocrinol Metab 2006; 19 :1397-1404.  Back to cited text no. 13
    
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Angelopoulos NG, Goula A, Rombopoulos G, Kaltzidou V, Katounda E, Kaltsas D, Tolis G. Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. J Bone Miner Metab 2006; 24 :138-145.  Back to cited text no. 15
    
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Hamidieh AA, Moradbeag B, Pasha F, Jalili M, Hadjibabaie M, Keshavarznia M. High prevalence of hypoparathyroidism in patients with beta-thalassemia major. Int J Hematol Oncol Stem Cell Res 2009; 3 :17-20.  Back to cited text no. 17
    
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Lala R, Chiabotto P, Di Stefano M, Isaia GC, Garofalo F, Piga A. Bone density and metabolism in thalassemia. J Pediatr Endocrinol Metab 2005; 11 :785-790.  Back to cited text no. 18
    
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De Sanctis V, De Sanctis E, Ricchieri P, et al. Mild subclinical hypothyroidism in thalassemia major: prevalence, multigated radionuclide test, clinical and laboratory long-term follow-up study. Pediatr Endocrinol Rev 2008; 6 (Suppl 1):174-180.  Back to cited text no. 23
    


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