|Year : 2018 | Volume
| Issue : 2 | Page : 63-68
Hypoparathyroidism in children with β-thalassemia major and its relation to iron chelation therapy
Lerine Bahy El-Din, Fatma S.E Ebeid, Nadin N Toaima, Walaa W Ibrahim
Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||27-Sep-2017|
|Date of Acceptance||02-Oct-2017|
|Date of Web Publication||7-Aug-2018|
Fatma S.E Ebeid
2 Lotfy Elsayed St. Ain Shams University Staff’s Campus
Source of Support: None, Conflict of Interest: None
Background β-Thalassemia major (BTM) constitutes a major public health problem in Egypt. Early diagnosis of hypoparathyroidism (HPT) could prevent other severe disorders such as seizures, osteopenia, and osteoporosis.
Objective The aim of this study was to determine the prevalence of HPT in patients with BTM and its relation to iron chelation therapy.
Patients and methods This is a cross-sectional study that included 60 patients with transfusion-dependent BTM who were regularly attending the Pediatrics Hematology Clinic, Ain Shams University. The male–female ratio was 1 : 1.2. Their mean age was 12.47±3.63 years. The recruited patients were subjected to thorough clinical assessment with special emphasis on demographic characteristics, chelation and transfusion therapy, calcium consumption, age of onset of HPT, any symptoms of hypocalcemia, and presence of other complications. Laboratory investigations included hemoglobin electrophoresis, serum ferritin, serum calcium, serum phosphate, and serum parathyroid hormone levels.
Results A total of 26 patients were on single iron chelation therapy, whereas 34 patients were on combination therapy. The prevalence of HPT was relatively high, as 20% were diagnosed as having HPT. There was a high prevalence of asymptomatic hypocalcemia (51.6%), including 12 patients who had HPT and 19 patients who had hypocalcemia without HPT. Moreover, 14 patients had hyperphosphatemia without HPT. Although HPT was less common in those treated with single-agent desferrioxamine, asymptomatic hypocalcemia was more prevalent in those who were treated with desferrioxamine iron chelation. In contract, hyperphosphatemia was more common in those on combination therapy.
Conclusion HPT is not an uncommon complication of BTM, as well as the asymptomatic hypocalcemia, which necessitates early diagnosis and management.
Keywords: β-thalassemia, endocrinal complications, hypoparathyroidism, iron chelation
|How to cite this article:|
El-Din LB, Ebeid FS, Toaima NN, Ibrahim WW. Hypoparathyroidism in children with β-thalassemia major and its relation to iron chelation therapy. Egypt J Haematol 2018;43:63-8
|How to cite this URL:|
El-Din LB, Ebeid FS, Toaima NN, Ibrahim WW. Hypoparathyroidism in children with β-thalassemia major and its relation to iron chelation therapy. Egypt J Haematol [serial online] 2018 [cited 2019 May 22];43:63-8. Available from: http://www.ehj.eg.net/text.asp?2018/43/2/63/238765
| Introduction|| |
β-Thalassemia represents a group of recessively inherited hemoglobin disorders characterized by reduced synthesis of β-globin chains leading to the synthesis of hemoglobin with an impaired oxygen-binding capacity . The advent of safe transfusions with adjuvant chelation therapy has dramatically improved the life expectancy of patients with β-thalassemia major (BTM), who can now survive into their fourth and fifth decades of life . However, frequent blood transfusions have been associated with iron overload, which may result in endocrine abnormalities mainly hypogonadism, diabetes mellitus, and hypoparathyroidism (HPT) .
HPT is one of the most important endocrine complications of BTM. The most important factors attributed to this complication are the deposition of iron in parathyroid gland leading to gland dysfunction and the possible suppression of parathyroid secretion induced by bone resorption resulting from increased hematopoiesis secondary to chronic anemia . HPT may be presented by neurological abnormalities that include latent and manifest tetany, seizures, laryngeal stridor, and paresthesia in the hands or in the region of the lips . Osteoporosis represents an important cause of morbidity in the thalassemic population. Even well-transfused patients with normal gonadal function who are supplemented with calcium show low bone mass by dual-energy x-ray absorptiometry , suggesting other factors are also involved.
The objective of iron chelation is to avoid the complications of iron overload such as cardiac complications, hepatic dysfunction, and endocrinal complications . Currently, the main iron chelators available for clinical use are desferrioxamine (DFO) , deferiprone , and deferasirox (DFX) . The aim of the current study was to determine the prevalence of HPT in a group of patients with BTM in relation to iron chelation therapy received.
| Patients and methods|| |
This cross-sectional study was conducted at Hematology Clinic, Children Hospital, Ain Shams University. A total of 60 regularly attending patients for transfusion, aged from 6 to 18 years, were recruited. There were 27 males and 33 females, with male–female ratio of 1 : 1.2, and their mean age was 12.47±3.63 years (6–18 years). They were subdivided according to the type of the main iron chelation therapy received, either single (DFO, DFP, or DFX) or combined therapy. Patients with any known pre-existing medical condition other than BTM or patients on drug therapy (steroid therapy) and pregnant adolescent females were excluded.
The details of the study design and laboratory investigations were explained to all individuals and/or their parents, and informed consent was obtained from each patient or their legal guardians before enrolment in the study. The study was approved by the institutional regulatory board of Pediatric Hospital, Faculty of Medicine, Ain Shams University, and it was conducted in accordance with Declaration of Helsinki for working with human with the code of Ethics of the World Medical Association.
Medical history was obtained by reviewing the patients filing system and/or by directly interviewing the patients and/or their legal guardians and included demographic characteristics, transfusion history, iron chelation therapy, and medical history of iron overload complication, complication of therapy, and endocrinal manifestations such as diabetes, hypogonadism, hypothyroidism, and HPT. Furthermore, the mean ferritin level in past 6 months and pretransfusion hemoglobin level in the past 3 months before the study were assessed.
Anthropometric measurements for every patient were done by two trained investigators. Height was measured to the nearest 0.1 cm with a portable stadiometer (Seca, Marsden, UK) with children standing in bare feet. Weight in kilograms with minimal clothing was measured by using digital electronic weight standing scale. BMI values were calculated using measured height and weight values [weight (kg)/height (m2)]. Anthropometric Z-scores were calculated relative to age-specific and sex-specific norms produced by the Center for Disease Control from National Health and Nutrition Examination Survey III data .
Five milliliters of blood was collected under complete aseptic condition and allowed to clot, and then centrifuged for separation of serum, which was stored and frozen till assessment of the following laboratory investigations were done:
- Serum calcium was assessed using the synchron CX-7 autoanalyzer (Bechman Instrument Incorporation). Normal local reference value was from 8.8 to 10.8 mg/dl.
- Serum phosphorus was assessed using the synchron CX-7 autoanalyzer (Bechman Instrument Incorporation). Normal local reference value was from 3.7 to 5.7 mg/dl.
- Serum alkaline phosphatase was measured by enzymatic diethanolamine buffer method. Normal local reference value was up to 750 U/l.
- Serum level of parathyroid hormone (PTH) was assessed using fully automated chemiluminescent immunoassay. Normal local reference value was from 40 to 65 pg/ml.
Analysis of data was done using IBM Statistical Program for Social Science (IBM SPSS) for Windows, Version 20 (2011; IBM Corp., Armonk, New York, USA). Qualitative data were presented as number and percentages, whereas quantitative data were presented as mean, SDs, and ranges. χ2-Test and Fisher’s exact test were used to compare between qualitative data, whereas the comparison between two independent groups regarding quantitative data with parametric distribution was done by using independent t-test. Moreover, the comparison between two paired groups regarding quantitative data with parametric distribution was done by using the paired t-test. The confidence interval was set to 95%, and the margin of error accepted was set to 5%.
| Results|| |
The transfusion history of the studied patients
The median (interquartile range) age at first blood transfusion (age at diagnosis) was 0.8 (0.6–1.6) years. They were transfused on a monthly basis [34 (56.7%)] or biweekly [26 (43.3%)], and their mean pretransfusion hemoglobin level in the past 3 months before the study was 7.58±0.66 g/dl (5.93–8.77 g/dl).
The chelation history of the studied patients
The age of the patients at the start of chelation ranged from 1 to 7.9 years, with a mean of 3.17±1.55 years and the mean duration on regular chelation was 9.53±3.74 years. Their mean ferritin level in the past year ranged from 195.33–7287.33 ng/ml, with mean of 2567.09±1353.48 ng/ml.
There were 26 patients who were on single iron chelation therapy, whereas10 patients were on a combination of DFO+DFX, 10 patients on DFP+DFX, and 14 patients were on DFP+DFO. The clinical and biochemical characteristics of patients on combination chelation therapy and those not on combination chelation therapy are illustrated in [Table 1].
|Table 1 Clinical and biochemical characteristics of patients on single and combined chelation therapy|
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DFP was the most common iron chelation agent used in the current study either as a single agent, with 12 out of 60 (20%) studied patients, or as combined, 24 out of 34 (70%) patients on combined therapy.
A total of 42 patients shifted their chelation to another chelation therapy or shifted from single to combined therapy. The most common shift was in DFO group, with 21 patients, whereas 17 patients who started with DFP shifted to other chelators. There were 18 patients who did not shift their iron chelation therapy. The main adverse effects of DFO were irritation at the injection site and difficulty to get injection pump, whereas regarding the adverse effects of DFP, they were gastrointestinal upset, neutropenia, and arthralgia.
The anthropometric characteristic of the studied patients
Standard deviation scores (SDS) of weight for height ranged from −4.45 to 1.71, with a mean±SD of −1.18±1.30, and SDS of height for age ranged from −6.69 to 1.93, with a mean±SD of −1.75±1.75. Sixteen out of the 60 studied patients had short stature (SDS of height ≤3 for age and sex). Comparison between patients on single iron chelation therapy and those on combination therapy regarding anthropometric and biochemical characteristics is illustrated in [Table 2].
|Table 2 Comparison between patients on single and combined chelation therapy regarding anthropometric and biochemical characteristics|
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A total of 17 patients were prepubertal, and 43 were at pubertal age. Overall, 83.7% of the patients at pubertal age (36 out of 43) had delayed puberty, with no statistical difference regarding chelation therapy, either single or combined.
- The effect of different chelation therapy in patients with derangement in metabolic bone profile is illustrated in [Table 3], and it shows statistically significant higher level of serum phosphorus in those who were treated with DFP iron chelation.
|Table 3 Comparison of the effect of different chelation therapies in patients with derangement in metabolic bone profile|
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- Comparison between patients with HPT and normal parathyroid regarding clinical and laboratory characteristics is depicted in [Table 4], and it showed that there are significantly lower serum calcium and higher serum phosphorus levels in patients with HPT.
|Table 4 Comparison between patients with hypoparathyroidism and those with normal parathyroid regarding clinical and laboratory characteristics|
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| Discussion|| |
HPT is a well-known complicationin patients with BTM, but it is thought to be uncommon, and its incidence is considered to be decreasing with improvements in chelation therapy. A number of possible mechanisms have been described to be responsible for glandular damage through iron overload. These include free radical formation and lipid peroxidation, resulting in mitochondrial, lysosomal, and sarcolemmal membrane damage; a number of surface transferrin receptors in the cell; and the ability of the cell to protect itself against inorganic iron , but the reason why some patients develop HPT and others do not is not exactly known .
Thalassemia-related endocrinopathies have high incidence, and some of these endocrinopathies could develop in the first 10 years of life demonstrating that patients with BTM would benefit from endocrine screening well before puberty . Consequently, the objective of the current study was to assess the prevalence of HPT in patients with BTM and its relation to the type of chelation therapy. A total of 60 patients were recruited, and their mean age was 12.47±3.63 years. The selected patients were older than 6 years to better detect the effect of iron overload complications and chelation effects.
In the current study, the frequency of blood transfusions was significantly lower in patients who received single chelation therapy than those who received combined therapy. This could be explained by the fact that patients who received more blood transfusion per month had more iron overload and more complications that necessitate combination therapy.
Growth retardation is frequent in patients with BTM and becomes more evident at puberty because of the lack of growth spurt .This occurs because of many factors, including chronic anemia, folate deficiency, direct iron toxicity, and endocrine disorders . In the current study, there was a high prevalence of delayed puberty (83.7%) and short stature (27%), but there were nonsignificant differences between single and combination therapy groups regarding frequency of delayed puberty or the frequency of short stature.
PTH levels are very useful tools for diagnosing HPT, and the maintenance of a normal serum calcium concentration depends on the balanced actions of PTH, vitamin D, and to a lesser extent, calcitonin . In our study, the bone turnover markers including calcium, phosphorus, and PTH were used to diagnose HPT and were not statistically influenced by the type of chelation therapy. In contrast, a statistically significant higher serum alkaline phosphatase level was seen in patients who received combined therapy than those treated with single chelation therapy.
In this study, a high prevalence (53%) of asymptomatic hypocalcemia was detected. Consequently, as a routine procedure, in patients with BTM, screening for hypocalcemia should be done in the second decade of life, and as a preventive measure, they should be supplemented with calcium to prevent hypocalcemic tetany, to facilitate bone growth, and to prevent fractures . Although in the present study, HPT was less common in those treated with single-agent DFO, asymptomatic hypocalcemia was more prevalent in those who were treated with DFO iron chelation. In contrast, hyperphosphatemia was more common in those on combination therapy. Moreover, 13 (20%) patients showed biochemical diagnosis of HPT.
In line with our result, Basha et al.  studied 40 patients with BTM and 15 controls, and their age ranged from 2–18 years. They observed a significant decrease in PTH and serum calcium levels and a significant increase in both serum phosphorus and alkaline phosphatase levels in patients with β-thalassemia , and this goes with our study.
In our study, there were nonsignificant differences between those who had HPT and those who did not regarding transfusion and chelation therapy, serum ferritin, or hemoglobin level, which may suggest either an individual sensitivity to iron toxicity or early damage of the parathyroid gland before chelation had reduced the iron overload.
De Satictis et al.  observed 24 cases of BTM and HPT of variable severity. Their mean age when HPT was diagnosed was 16.5 years (11–24 years). The onset of HPT was preceded or followed in most patients by other endocrine and/or cardiac complications. It has been shown that prognosis for survival is best for those patients with thalassemia in whom serum ferritin levels can be maintained below 2500 µg/l, but at the same time, some patients who receive ideal management in terms of present standards do develop significant endocrine damage . Moreover, Olivieri et al.  found that 22% of their patients with thalassemia had endocrine complications, with a serum ferritin level below 2000 µg/l.
Finally, from the preceding discussion, it is highlighted that although optimal chelation therapy does reduce the incidence of HPT and other endocrinal complications, nonetheless some patients will continue to develop HPT.
| Conclusion|| |
HPT is not an uncommon complication of BTM, as well as the asymptomatic hypocalcemia, which necessitates early diagnosis and management.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]