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ORIGINAL ARTICLE
Year : 2020  |  Volume : 17  |  Issue : 2  |  Page : 70-75

Thyroid dysfunction in beta thalassemia major patients


1 Department of Biochemistry, G B Pant Hospital Attached to Maulana Azad Medical College, New Delhi, India
2 Department of Pathology, St.Stephen's Hospital, New Delhi, India

Date of Submission22-Jan-2020
Date of Acceptance28-Apr-2020
Date of Web Publication17-Jul-2020

Correspondence Address:
Dr. Ankush Singhal
Department of Biochemistry, G B Pant Hospital Attached to Maulana Azad Medical College, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_4_20

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  Abstract 


Background: Endocrinopathies are now amongst the common complications of thalassemia but determining the exact prevalence is difficult because of differences in age of first exposure to chelation therapy and the continuing improvement in survival in well-chelated patients. Hypothyroidism is the second most common endocrine disorder after hypogonadism, having been reported in 5.6% to 17% of patients.
Material and Methods: The present study was conducted in Umaid hospital attached to Dr S.N. Medical College, Jodhpur. 112 children were enrolled in the study and thyroid function tests along with serum Ferritin levels were done for all the subjects.
Results: Out of a total of 112 children, 82 were Euthyroid (73.2%) and 30 were Hypothyroid (26.8%). The mean serum Ferritin, serum TSH, serum Free T4 and serum Free T3 in Euthyroid children were 1975.4 ± 706.2(ng/ml), 3.23 ± 0.93(μIU/ml), 12.8 ± 2.3(pmol/l) and 6.12 ± 1.4(pmol/l) respectively. Whereas in Hypothyroid children the mean serum Ferritin, serum TSH, serum Free T4 and serum Free T3 were 2842.9 ± 1095.2(ng/ml), 7.05 ± 1.91(μIU/ml), 10.55 ± 2.0(pmol/l) and 4.49 ± 1.2(pmol/l) respectively.
Conclusion: Prevalence , severity of thyroid dysfunction in thalassemics is variable and regular follow up is the key. Assessment of thyroid function should be done annually from the age of 9 or earlier if patient is clinically symptomatic.

Keywords: Beta thalassemia major, endocrinopathies, thyroid dysfunction


How to cite this article:
Singhal A, Goyal H. Thyroid dysfunction in beta thalassemia major patients. Thyroid Res Pract 2020;17:70-5

How to cite this URL:
Singhal A, Goyal H. Thyroid dysfunction in beta thalassemia major patients. Thyroid Res Pract [serial online] 2020 [cited 2020 Oct 27];17:70-5. Available from: https://www.thetrp.net/text.asp?2020/17/2/70/290001




  Introduction Top


Thalassemia is the most common inherited monogenic disorder in the world. It is an autosomal recessive disorder of two major types – alpha and beta – depending on the affected gene for globin chain.[1]

The average prevalence of beta thalassemia carriers is 3%–4%, which translates to 35–45 million carriers in our multi-ethnic and culturally and linguistically diverse population of 1.21 billion people, which also includes around 8% of tribal groups according to the Census of India 2011. Several ethnic groups have a much higher prevalence (4%–17%) with an estimated 100,000 patients with thalassemia.[2],[3]

Endocrinopathies are now among the common complications of thalassemia, but determining the exact prevalence is difficult because of differences in age of first exposure to chelation therapy and the continuing improvement in survival in well-chelated patients.[4] The causes of endocrine complications in the general population are multiple, while in Thalassemia major, the endocrine complications are because of iron deposition in the endocrine glands due to transfusion dependency.[5]

Hypothyroidism is the second most common endocrine disorder after hypogonadism, having been reported in 5.6%–17% of patients.[6],[7],[8] Iron deposition is the main cause of damage to the endocrine glands, directly or through the hypothalamic–pituitary axis. High ferritin levels, poor compliance with chelation, and splenectomy increase the risk of endocrinopathies in thalassemics.[7],[9]

Clinically overt manifestations of hypothyroidism occur late in life, and therefore most of the available studies have been done in adults. Only a very few pediatric studies are available. In India, the cost of chelation precludes ideal therapy for majority of the patients, and the compliance with transfusion is often not optimal. Therefore, there is a possibility that there might be a high prevalence of thyroid dysfunction in such patients, and there are high chances of it manifesting at an age earlier than that projected in Western studies.[10] In view of the nonavailability of pediatric studies in the Indian population and the increasing prevalence of thyroid dysfunction, there is a need to look into the burden of endocrine complications among thalassemic children.


  Materials and Methods Top


The present study was conducted jointly in the Thalassemia Day Care Centre, Department of Pediatrics, Umaid Hospital and Department of Biochemistry, Dr. S. N. Medical College, Jodhpur, Rajasthan. All the children were registered under Marwar Thalassemia society. It was a cross-sectional study.

Inclusion criteria

  1. Children between 6 and 18 years of age
  2. Children who had received blood transfusion for at least 5 years
  3. Children diagnosed as beta thalassemia major on the basis of family history, high-performance liquid chromatography report, and complete transfusion dependence
  4. Those whose parents signed informed written consent.


Exclusion criteria

  1. Children diagnosed as thalassemia minor and intermedia
  2. Children with a family history of any thyroid disorder
  3. Children on any hormonal therapy
  4. Children with any acute illness.


Out of a total of 137 children, 112 thalassemic children of either sex were included in the present study on the basis of the inclusion/exclusion criteria as shown in [Flowchart 1].



The selected children were further subdivided into two major groups:

  1. According to age:


    1. Group I: Children <10 years of age
    2. Group II: Children aged 10 years or more.


  2. According to serum ferritin level:


    1. Group A: Children having ferritin level up to 2000 ng/ml
    2. Group B: Children having ferritin level more than 2000 ng/ml.


History regarding (age at diagnosis/ first blood transfusion, average pretransfusion hemoglobin (Hb) in the last 6 months, and blood requirement per year) was also taken.

Collection and analysis of blood samples

Five milliliter venous sample was drawn under aseptic conditions from the median cubital vein of selected children and transferred in a plain vial, and the sample was allowed to clot. Serum was separated from the clotted sample by centrifugation at 3000 rpm for 10 min, and the following biochemical parameters were estimated in the separated serum: free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) by enzyme-linked fluorescent assay method on VIDAS system from Biomerieux (Biomerieux – French multinational biotechnology company founded & headquartered in Marcy – I'Etoile, France) and ferritin by direct chemiluminometric technology on ADVIA Centaur system (ADVIA Centaur System from Seimens – headquartered in Munich, Germany). The thyroid function TEST assay were of 3rd generation with Coefficient of Variation (CV) <5%. The normal values of FT3, FT4, and TSH were 4–8.3 pmol/L, 9–20 pmol/L, and 0.25–5.0 μIU/ml, respectively. Euthyroid was defined as a patient with FT3, FT4, and TSH within the above-mentioned normal limits. Subclinical hypothyroid was defined as a patient with high TSH and normal FT3 and FT4. Overt hypothyroid was diagnosed with low FT3 and FT4 with high TSH.

Statistical analysis

The data obtained for different biochemical parameters were subjected to suitable statistical analysis using SPSS 16 (SPSS 16 – By SPSS Inc. based in Chicago, IL) to compute mean and standard deviation for all the groups. The magnitude of intergroup differences for each of the parameters was quantified by using Student's t-test. On the basis of t-values, P values (probability) were calculated to determine the significance of variation between the mean values of individual parameters among the groups of patients studied.


  Results Top


Out of a total of 112 children, 82 were euthyroid (73.2%) and 30 were hypothyroid (26.8%). The mean age of euthyroid children and hypothyroid children was 11.25 ± 3.4 years and 11.84 ± 3.5 years, respectively. There were 51 boys and 31 girls in the euthyroid group compared to 23 boys and 7 girls in the hypothyroid group. The mean age at which transfusion was started was lesser in hypothyroid children (8.58 ± 2.04 months) than children who were euthyroid (14.23 ± 10.23 months). Comparing the average pretransfusion hemoglobin for the last 6 months, we found that it was low in hypothyroid children (7.83 ± 0.56 g/dl) compared to euthyroid ones (8.68 ± 0.45 g/dl). The amount of blood transfused (ml/kg/year) was more in children who were hypothyroid (273.9 ± 32.45) when compared to that of euthyroid children (228.8 ± 26.34) [Table 1].
Table 1: Comparison of demographic and biochemical parameters in euthyroid and hypothyroid children

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The mean serum ferritin, serum TSH, serum FT4, and serum FT3 in euthyroid children were 1975.4 ± 706.2 ng/ml, 3.23 ± 0.93 μIU/ml, 12.8 ± 2.3 pmol/l, and 6.12 ± 1.4 pmol/l, respectively, whereas in hypothyroid children, the mean serum ferritin, serum TSH, serum FT4, and serum FT3 were 2842.9 ± 1095.2 ng/ml, 7.05 ± 1.91 μIU/ml, 10.55 ± 2.0 pmol/l, and 4.49 ± 1.2 pmol/l, respectively [Table 1].

Overall 26.8% of children had hypothyroidism, out of which 18.8% had subclinical hypothyroidism and 8% had overt hypothyroidism.

We also compared the thyroid profile according to age and the mean ferritin levels. The serum ferritin cutoff was set at 2000 ng/ml and the age cutoff was at 10 years.

In children <10 years of age with ferritin level ≤2000 ng/ml, the mean serum TSH was 3.1 ± 1.3 μIU/ml with a range of 1.5–5.6 μIU/ml, the Mean serum FT4 level was 14.9 ± 2.6 pmol/L with a range of 11.4–18.6 pmol/L, and the mean serum FT3was 6.3 ± 1.1 pmol/L with a range of 4.8–7.5 pmol/L [Table 2].
Table 2: Statistical analysis of serum thyroid indices in relation to serum ferritin levels in different age groups of patients studied

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In children <10 years of age with ferritin level >2000 ng/ml, the mean serum TSH was 4.7 ± 2.2 μIU/ml with a range of 2.3–11.5 μIU/ml, the mean serum FT4 level was 12.4 ± 2.2 pmol/L with a range of 7.8–16.5 pmol/L, and the mean serum FT3 was 5.7 ± 1.4 pmol/L with a range of 2.8–8.1 pmol/L [Table 2].

For children ≥10 years, the level of serum TSH was 3.3 ± 1.3 μIU/ml in a range of 1.1–7.4 μIU/ml, serum FT4 was 12.8 ± 2.1 pmol/L in a range of 7.9–17.2 pmol/L, and serum FT3 was 6.2 ± 1.3 pmol/L in a range of 2.4–8.2 pmol/L with ferritin level ≤2000 ng/ml [Table 2].

For children ≥10 years, the level of serum TSH was 5.2 ± 2.4 μIU/ml with a range of 1.76–12.65 μIU/ml, serum FT4 was 11.2 ± 1.9 pmol/L with a range of 6.5–15.2 pmol/L, and serum FT3 was 5.5 ± 1.5 pmol/L with a range of 2.5–8.2 pmol/L with ferritin >2000 ng/ml [Table 2].

We found that there was a statistical significance between TSH and FT4 levels when compared on the basis of serum ferritin levels in both the age groups. However, for FT3, the significance was found only in age group ≥10 years. The level of TSH was more and FT4 and FT3 were less in children with serum ferritin level >2000 ng/ml in both the age groups.


  Discussion Top


The thyroid gland has a critical role in the maintenance of thermogenic and metabolic homeostasis.[11] It secretes two important hormones namely thyroxine (T4) and triiodothyronine (T3). These hormones play a very important role in controlling metabolic activity in children and adults, and affect the function of all organs.[12]

After approximately 1 year of transfusion, iron starts to accumulate in parenchymal tissues, where it leads to substantial toxicity as compared with iron stored in reticulo-endothelial cells.[13] Hypothyroidism may be partly related to the accumulation of iron in the gland. Other factors such as chronic hypoxic damage may also play a role in the development of hypothyroidism.[14]

A wide spectrum of pathogenic mechanisms is involved. Chronic tissue hypoxia and iron overload have a direct toxic effect on the thyroid gland.[15] High concentrations of labile plasma iron and labile cell iron which are considered to be responsible in the formation of free radicals and the production of reactive oxygen species may lead to cell and organ damage.[16] Organ siderosis (liver, cardiac and skeletal muscle, kidney) may affect specific receptors which regulate thyroid hormone action and convert T4 to the bioactive T3.[17]

The prevalence of hypothyroidism in thalassemia major patients ranges from 3.3% to 24.4% in various countries [Table 3]. The prevalence in our study was in accordance with studies done by Gamberini et al.[22] and Khider and Hussein,[26] while other studies showed a lower prevalence rate of hypothyroidism in beta thalassemia major patients.
Table 3: Various national and international studies showing the prevalence of hypothyroidism in beta thalassemia major patients

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Some studies have reported a high prevalence of primary hypothyroidism reaching up to 17%–18%,[15],[32] whereas others have reported a low prevalence of 0%–9%.[33],[34] A very high prevalence of hypothyroidism is due to iron overload.

Hypothyroidism in our study was prevalent in patients where transfusion was started at an early stage, in whom the blood requirement/year was more and the average pretransfusion Hb for the last 6 months was low.

The mean TSH, FT4, and FT3 in various studies is shown in [Table 4].
Table 4: Comparison of mean serum thyroid-stimulating hormone, FT4 and FT3 in different studies

Click here to view


Thyroid dysfunction has been reported in 13%–60% of thalassemia patients.[39] However, the overall prevalence of hypothyroidism is low.[15],[33],[40] These differences can be explained by therapeutic protocols (blood transfusion and deferoxamine administration) comparing to the patient's age.[41]

Autoimmunity has no role in the pathogenesis of hypothyroidism associated with thalassemia.[42] Up to 5% of thalassaemic patients develop overt clinical hypothyroidism which requires treatment,[18] whereas a much greater percentage have subclinical compensated hypothyroidism with normal T4 and T3 but high TSH levels. Overt clinical hypothyroidism usually occurs in severely anemic and/or iron overload thalassaemics but is uncommon in optimally treated patients.[32],[43] The pathogenesis is again unclear but thought to be related to lipid peroxidation, free radical release, and oxidative stress.[43]

De et al.[44] noticed that the incidence of hypothyroidism is directly related to the degree of iron overload and most patients have ferritin levels close to 2000 ng/ml, which is similar to the findings in our study.


  Conclusion Top


In patients with thalassemia major, uncontrolled iron overload has serious clinical consequences with considerable morbidity and mortality. Thyroid dysfunction is a frequent complication in thalassemic patients who are on regular transfusions. A significant association is present between the serum ferritin levels and the presence of thyroid dysfunction, emphasizing the important role of iron overload in the development.

An extensive endocrinological follow-up including annual screening is mandatory to prevent these complications. Monitoring of growth and endocrine functions is essential to achieve a good quality of life in beta thalassemia major patients. A collaborative research is necessary in this regard to educate and train endocrinologists and other pediatricians/physicians to combat the morbidity caused by iron overload in thalassemia major patients.

The prevalence and severity of thyroid dysfunction in thalassemics is variable, and regular follow-up is the key. Assessment of thyroid function should be done annually from the age of 9 or earlier if patient is clinically symptomatic.

Majority of patients have subclinical or mild form, while approximately one-third have the overt form of hypothyroidism. Regular assessment of FT4 and TSH is recommended after the first decade of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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