|Year : 2019 | Volume
| Issue : 2 | Page : 206-211
Does Thyroid dysfunction correlates with iron overload in Eβ thalassemia patients? A study from a tertiary care thalassemia center in India
Shuvraneel Baul1, Tuphan Kanti Dolai1, Pranab Kumar Sahana2, Rajib De1, Prakas Kumar Mandal1, Prantar Chakrabarti1
1 Department of Hematology, NRS Medical College, Kolkata, West Bengal, India
2 Department of Endocrinology, NRS Medical College, Kolkata, West Bengal, India
|Date of Submission||05-Jul-2019|
|Date of Decision||15-Jun-2019|
|Date of Acceptance||26-Aug-2019|
|Date of Web Publication||16-Dec-2019|
Dr. Prakas Kumar Mandal
8C/1/N, Roy Para Road, Kolkata - 700 050, West Bengal
Source of Support: None, Conflict of Interest: None
Background and Aim: Large number of Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) patients show iron overloads and related end-organ damage irrespective of transfusion requirements. The prevalence of hypothyroidism in Indian population is approximately 11%. We studied the relationship between thyroid dysfunction and iron overload in Hb E/β-thalassaemia. Materials and Methods: The study included Eβ-thalassemia patients above the age of 10 years. Patient's serum ferritin level evaluated for the evaluation of iron status and thyroid-stimulating hormone, FT4, T3 for thyroid function status. Results: The study was conducted from January 2016 to December 2017. Of 50 Eβ-thalassemia patients, there were 22 females; the mean age was 19 years (range: 12–47 years). A total of 22 (44%) patients showed thyroid dysfunction; overt hypothyroidism seen in 6 (12%) patients with mean ferritin level of 1077 ng/ml and subclinical hypothyroidism seen in 16 (32%) patients with mean ferritin level of 1200 ng/ml. Normal thyroid function seen in 28 (56%) of patients with mean ferritin level of 1155 ng/ml. Conclusion: The prevalence of thyroid dysfunction was found to be higher in Hb E/β-thalassaemia patients, but a definite correlation with the serum ferritin level could not be established.
Keywords: Hb E/β-thalassaemia, serum ferritin, thyroid function
|How to cite this article:|
Baul S, Dolai TK, Sahana PK, De R, Mandal PK, Chakrabarti P. Does Thyroid dysfunction correlates with iron overload in Eβ thalassemia patients? A study from a tertiary care thalassemia center in India. Arch Med Health Sci 2019;7:206-11
|How to cite this URL:|
Baul S, Dolai TK, Sahana PK, De R, Mandal PK, Chakrabarti P. Does Thyroid dysfunction correlates with iron overload in Eβ thalassemia patients? A study from a tertiary care thalassemia center in India. Arch Med Health Sci [serial online] 2019 [cited 2020 Apr 2];7:206-11. Available from: http://www.amhsjournal.org/text.asp?2019/7/2/206/273074
| Introduction|| |
Hb E/β-thalassemia is a heterogeneous disease. In the state of West Bengal from India, Hb E/β-thalassemia accounts for more than 50% of thalassemia disease burden.
There are various factors indicating the disease severity of Hb E/β-thalassemia patients such as age at onset of symptoms, age of the first transfusion, steady-state hemoglobin concentration, transfusion requirement, spleen size, and growth retardation. It is probable that these factors along with iron overload may be related with endocrine dysfunction.
Majority of studies in endocrine dysfunction are predominantly seen in patients of beta-thalassemia major. Iron overload in beta-thalassemia intermedia is multifactorial and attributed primarily to increase gastrointestinal iron absorption. It can also result from chronic hemolysis and occasional blood transfusions.,
To date, there are few studies regarding the exact nature of thyroid dysfunction in patients of Hb E/β-thalassemia. Henceforth, this study was undertaken to evaluate the thyroid dysfunction in patients of Hb E/β-thalassemia, and its correlation to serum ferritin level.
| Materials and Methods|| |
Study participants and period
This prospective cross-sectional study included patients suffering from E/β thalassemia attending thalassemia clinic and thalassemia daycare center. The study was done over 2 years from January 2016 to December 2017. The inclusion criteria for the study were age more than 10 years and included only those who had agreed to participate in the present study after valid consent. The exclusion criteria for the study were pregnancy, co-inheritance with other thalassemia, critically ill patients.
In all patients, detail clinical history was taken pertaining to thyroid disorders as per established clinical studies, besides history related to details of thalassemia was also taken along with it following investigation was performed-complete hemogram, high-performance liquid chromatography (HPLC) and free T4, T3, thyroid-stimulating hormone (TSH), serum ferritin assay. The serum ferritin was done at the time of entry into the study and subsequently as per standard guidelines and mean serum ferritin was taken into consideration during data analysis.
High-performance liquid chromatography
HPLC was done by BioRad Variant Haemoglobin Testing system (BioRad Labs, Hercules, CA, USA) as per standard protocol.
Serum ferritin assay
For the present study, ferritin was done by ELIZA method using ferritin Accubind VAST ELISA kit, (Monobind Inc., Lake Forest, CA, USA) with the sensitivity of 1.0 ng/ml.
Hypersensitive thyroid-stimulating hormone assay
In the present study, HYPERsensitive TSH (hTSH) assay was done by Access 2 Immunoassay System (Beckman Coulter). The Access hTSH Assay is a two-site immunoenzymatic (“sandwich”) assay, for the quantitative determination of TSH in human serum, using the access immunoassay system. A sample is added to a reaction vessel with goat anti-hTSH-alkaline phosphatase conjugate, buffered protein solution, and paramagnetic particles coated with immobilized mouse monoclonal anti-hTSH antibody. Goat anti-mouse antibody is used to immobilize the mouse anti-hTSH antibody. The serum hTSH binds to the immobilized monoclonal anti-hTSH on the solid phase while the goat anti-hTSH-alkaline phosphatase conjugate reacts with a different antigenic site on the serum hTSH. Separation in a magnetic field and washing removes materials not bound to the solid phase. A chemiluminescent substrate, Lumi-Phos 530, is added to the reaction vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of human thyroid-stimulating hormone in the sample. The amount of analyte in the sample is determined by means of a stored, multipoint calibration curve.
Specimen collection, storage, and handling procedures
Samples collected as per standard protocol.
Normal range of the test assay
- TSH is 0.34–4.20 μIU/ml
- FT4 is 0.58–1.64 ng/dl
- T3 is 2.39–6.78 pg/ml.
For frank hypothyroidism, serum TSH level more than 20 μIU/ml, is considered the cutoff value or TSH is >4.20 μIU/ml, for free T4, cutoff value for hypothyroid disorder is <0.58 ng/dl. T3 level lower than 2.39 pg/ml or within normal range was considered. Subclinical hypothyroidism is a combination of high TSH with normal FT4 levels. Patients with normal FT4 and TSH >4.20 μIU/ml were defined as subclinical hypothyroidism. When FT4 is <0.58 ng/dl and TSH is low or normal central hypothyroidism is diagnosed.
All recorded data were analyzed using standard statistical methods, and the findings were discussed in detail to draw an appropriate conclusion. Descriptive statistics were first used to record data and were presented as mean ± standard deviation (SD). The MedCalc (Version 15.11.4, MedCalc Software, Acacialaan 22, Belgium) software were used for statistical analysis. Fisher's exact test was used for dichotomous variables. Statistical significance was assumed at a P < 0.05. Linear regression was used to test correlation among variables TSH, FT4, T3 with serum ferritin.
| Results|| |
Characteristics of patient groups
In this study, 50 patients of Hb E/β thalassemia were included among which 41 (82%) patients were transfusion-dependent and rest 9 (18%) patients were transfusion independent. There was slight male preponderance with 28 (56%) patients being male, mean ± SD age of patients was 19.74 ± 7.52 years (range: 12–28 years). The age of first transfusion (Mean ± SD) was 7.5 years' ±9.5 and hemoglobin (Mean ± SD) was 6.4 ± 1.13 g/L. The annual blood transfusion rate among transfusion-dependent patients was 11.7 ± 6.69 units and 40 (80%) were on oral iron chelation therapy. Splenectomy was done on 14 (28%) patients. Patients were further classified based on Mahidol score into mild (<4), moderate (4–7), and severe (>7) and there were 9 (18%), 24 (48%), and 17 (34%), respectively [Table 1].
|Table 1: Demographic profile, clinical features, and laboratory parameters of the patients under study (n = 50)|
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Hb E/β-thalassemia patients with thyroid dysfunction
Of 50 patients of Hb E/β thalassemia patients, 6 (12%) patients were overt hypothyroid, 16 (32%) patients were subclinical hypothyroid, and 28 (56%) patients were euthyroid. Thyroid dysfunction was observed in 22 (44%) patients of Hb Eβ-thalassemia patients.
Distribution of thyroid dysfunction in Hb E/β-thalassemia patients classified as per Mahidol score
In patients of Hb E/β-thalassemia with mild Mahidol score (<4), of 9 patients, there were 1 (12%), 4 (44%), and 4 (44%) were frank hypothyroid, subclinical hypothyroid, and euthyroid, respectively. In 24 patients of Hb E/β-thalassemia with moderate Mahidol score (4–7); there were 4 (17%), 2 (8%) and 18 (75%) cases of hypothyroid, subclinical hypothyroid, and euthyroid respectively. In patients of Hb E/β-thalassemia with severe Mahidol score (>7), of 17 patients, there were 1 (6%), 10 (59%), and 6 (35%) were frank hypothyroid, subclinical hypothyroid, and euthyroid, respectively [Figure 1].
Mean serum ferritin level of patients with thyroid dysfunction in patients of Hb E/β-thalassemia
Among six patients of Hb E/β-thalassemia with hypothyroidism mean ± SD serum ferritin level was 1077 ± 371.8 μg/L. Among 16 patients of Hb E/β-thalassemia with subclinical hypothyroidism mean ± SD serum ferritin level was 1422 ± 1361.0 μg/L. Among 28 patients of Hb E/β-thalassemia with euthyroidism Mean ± SD serum ferritin level is 1252 ± 664.4 μg/L. Serum ferritin levels do not predict thyroid dysfunction in patients of Hb E/β-thalassemia [Figure 2].
|Figure 2: Thyroid function status versus mean serum ferritin level (n = 50)|
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Correlation of serum thyroid-stimulating hormone and ferritin
There was no linear correlation between serum TSH and ferritin level as increased serum ferritin does not lead to linear increase in thyroid dysfunction [Figure 3].
|Figure 3: Correlation of serum ferritin and serum thyroid stimulating hormone (n = 50)|
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| Discussion|| |
Hemoglobin E/β-thalassemia is a heterogeneous disease, though majority 41 (82%) were transfusion-dependent in our study, 9 (18%) were transfusion independent, a study by Mandal et al. from eastern India has shown 44.7% of their E/beta thalassemic patients were regularly transfused compared to 82% in our study. However, their total study population comprised of 1380 patients, a much larger number, however, this was an epidemiological study.
In a study from Italy by Baldini et al., among 70 beta-thalassemia intermedia patients, endocrinopathies were found in 15 (21%) of patients among which 10 patients having hypothyroidism with 5 patients having subclinical hypothyroidism. Zekavat et al. from Iran among 75 patients of beta-thalassemia intermedia have found 10 (9.4%) with hypothyroidism. There was no clear distinction from the above studies about the exact disease entity among the spectrum of beta-thalassemia intermedia.
As shown in [Figure 3], the distribution of thyroid dysfunction in patients of Hb E/β-thalassemia shows 6 (12%) patients are frank hypothyroid, 16 (32%) patients are subclinical hypothyroid, and 28 (56%) patients were euthyroid. Overall, 22 (44%) patients showed thyroid dysfunction. Hypothyroidism was found to be a common form of thyroid dysfunction affecting 10.9% of the study population in India. Compared to general population, there is increased prevalence of thyroid dysfunction in patients of Hb E/β-thalassemia.
The age cutoff in this study was 10 years and above, a study by Filosa et al. reported progressive increase of hypothyroidism increased over a period of 12 years to 13.9% by the age of 25.7 ± 1.7 years. A considerable proportion of nontransfusion-dependent thalassemia (NTDT) patients eventually accumulate iron to liver iron concentration thresholds of clinical significance and can start experiencing iron-related morbidity beyond 10 years of age. The prevalence of hypothyroidism was the highest in the age group of 46–54 years (13.11%) and the lowest in that of 18–35 years (7.53%), in a study by Unnikrishnan et al. in the present study, we found thyroid dysfunction occurs at an earlier age in patients of Hb E/β-thalassemia patients compared to general population.
Our study showed 16 (32%) patients to have subclinical hypothyroid compared to frank hypothyroid status. Karamifar and et al. from Iran found among beta-thalassemia intermedia patients have primary hypothyroidism in 21% of patients. Ghosh et al. from eastern India have found in their study subclinical hypothyroidism present in 23.52% of patients. The study population patients however comprised of both beta thalassemia major and Hb E/β-thalassemia. The distinction between type of hypothyroidism and the thalassemia cohort varied from study to study.
The classical clinical signs and symptoms of hypothyroidism in TM patients are masked because most of the symptoms, especially in mild cases, are nonspecific and are frequently attributed to anemia or associated diseases.
The accumulation of iron in thalassemia intermedia patients has been shown to be age-related, reflecting increased iron accumulation over time, even in the absence of transfusion therapy. However, our study analysis showed that there was no correlation with high mean serum ferritin levels and thyroid dysfunction, and the following studies also have similar results with varied number of patients. A study by Mula-Abed et al., at Oman out of 30 patients of transfusion-dependent beta-thalassemia major, there was no significant difference (P > 0.050) in mean serum ferritin in patients with thalassemia with or without endocrinopathy, regardless of the number of endocrinopathy however study by Malik et al. in homozygous beta thalassemia major showed frequency of hypothyroidism was associated with increased serum ferritin levels. A study by Zervas et al., out of 200 β thalassemia major patients, mean ferritin levels in hypothyroid and euthyroid patients were 2707.66 ± 1990.5 μg/L and 2902.9 ± 1997.3 μg/L, respectively, with (P = 0.61), indicating no correlation between ferritin levels and thyroid functional status.
Sripichai et al. developed a scoring system (Mahidol score) for the classification of b-thalassemia/Hb E disease severity. As shown in [Figure 3], Mahidol score was used to classify the patients as mild, moderate, and severe and based on that thyroid dysfunction was observed, which showed more thyroid dysfunction in the severe group compared to mild and moderate group, the findings are not truly reflective in the sense that mild and moderate groups also had patients with subclinical hypothyroidism and frank hypothyroidism hence the straight forward mechanism of transfusion dependence and iron overload is not explained. Mahidol scoring system to classify the patients of Hb E/β-thalassemia and to assess endocrine dysfunction over time will provide a framework for future studies.
Another important aspect of the study was therapeutic intervention in the form of oral iron chelation, transfusion support and replacement of thyroid hormone, patients with intermediate severity were given transfusion on-demand and mean serum ferritin above 800 μg/L were considered for oral chelation with deferasirox at dosage of 10 mg/kg. No thyroid hormone replacement was considered for subclinical hypothyroid patients, and they were biochemically followed with serial TSH estimation every 3 months' interval. Frank hypothyroid patients were given thyroid hormone replacement in standard prescribed dosage.,
In the severe category of patients, also patients with frank hypothyroidism were given replacement therapy, and subclinical hypothyroid patients were followed up as above. Oral iron chelation with deferasirox was given if mean serum ferritin estimation more than 1000 μg/L. In subsequent follow-up of these patients, there was no apparent change in signs and symptoms compared to the general population as predominantly the symptoms were due to anemia and iron overload.,
The prevalence of hypothyroidism and hyperthyroidism are similar in C282Y homozygote without previous hemochromatosis diagnoses and controls. It was concluded that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.
In patients with sickle cell anemia, endocrinopathy appears to be related to vaso-occlusive and ischemic events, rather than iron overload resulting from frequent transfusion as the sole mechanism. According to the various studies,,, the prevalence of endocrine and metabolic disorders in children with sickle cell disease varies in different populations depending on the literacy rate, socioeconomic status, and access to appropriate treatment.
In patients with thalassemia major and intermedia, iron deposition involves endocrine glands, and the hypothalamic-pituitary axis are due to repeated blood transfusion and increased gastrointestinal absorption, respectively. In developing countries, nonetheless, it is possible to have a high prevalence of endocrine complications at an early age due to suboptimal of transfusions and chelation therapy.
Thyroid function testing (TFT) in thalassemia patients are advised routinely, however, as per thalassemia international federation guidelines (TIF), endocrine evaluation should be done based on whether the patient is transfusion-dependent or independent, in situ ations of nontransfusion dependent, evaluation should be started at the age of 10 years; however in patients of transfusion dependence, there is no such specific age cutoff for TFT, but according to TIF guidelines, hypothyroidism should be suspected in patients, reported to exhibit stunted growth, delayed puberty, cardiac failure, and pericardial effusion. Screening for other endocrinopathies also differs by clinical behavior of patients whether TDT or NTDT needs regular monitoring for signs and symptoms of endocrine complications. When FT4 is <0.58 ng/dl and TSH is low or normal central hypothyroidism is diagnosed. In our study population, central hypothyroidism was not found in any of our patients.
As depicted in [Table 2], iron overload conditions and associated endocrinopathy in patients with thalassemia major and intermedia along with screening tests. Endocrine complications are highly prevalent in both patients with thalassemia major and intermedia and necessitate close monitoring. Early recognition of these complications, institution of appropriate treatment including transfusion regimen and chelation therapy, and specific treatment of each complication are the keys to successful management. The shortcomings of our study were that we did not do anti-thyroid peroxidase antibody and anti-thyroglobulin assay.
Thyroid dysfunction in the form of subclinical and frank hypothyroidism is seen in both intermedia and major patients with near about same ferritin level. For our study, as far as possible, we have adhered to TIF guidelines for nontransfusion-dependent thalassemia, where the iron overload and thyroid screening start at the age of 10 years. Although iron overload is the major cause of endocrinopathy in thalassemia major in thalassemia intermedia, iron overload is not the sole reason for thyroid dysfunction as other possible mechanisms such as chronic anemia, iron-free radical-mediated damage to thyroid gland, nutritional deficiency which needs to be studied further in future for definite answers.
We have specifically focused on patients with Hb E/β thalassemia and this is the major cohort of patients with thalassemia in the state of West Bengal, patients with Hb E/β thalassemia have a varied clinical presentation, we have also used the Mahidol scoring system of classification for severity, as a matter of fact Hb E/β thalassemia also clinically behaves such as thalassemia intermedia and also thalassemia major, our study is completely based on patients with outcomes of iron overload and thyroid dysfunction in patients with Hb E/β thalassemia. The sample size is another limitation factor in my study as larger cohorts needed with longer follow-up to know the exact pathogenesis behind thyroid dysfunction.
| Conclusion|| |
The prevalence of thyroid dysfunction was found to be higher (42%) in hemoglobin E/β-thalassemia patients compared to the general population. A definite correlation with the serum ferritin levels could not be established.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]