**6. Hypoparathyroidism**

Hypoparathyroidism, resulting in hypocalcaemia, is a late complication of iron overload, typically manifesting after the age of 10 years and with a higher incidence in men [46]. The first sign of incipient hypoparathyroidism is loss of the diurnal pattern of parathyroid hormone (PTH) secretion [9]. The typical biochemical profile is low serum calcium, low serum PTH, low serum vitamin D and elevated serum phosphate levels [82]. Clinical signs of the disorder are most frequently noted from the second decade of life onwards [15].

A recent survey of clinicians by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) published in 2018 reported a prevalence of 6.8% among 3023 thalassaemia major patients from 17 centres [83]. 42.2% of hypoparathyroid patients in this study were described as asymptomatic at diagnosis. The most common presenting symptom was paraesthesia and/or cramping seen in 37.6% patients [83]. In the ICET-A study, 49.8% of [83] hypoparathryoid individuals were also noted to have serum ferritin level > 2.500 ng/ml8 . Chirico and colleagues also noted a significant association between elevated ferritin and incidence of hypoparathyroidism in thalassaemia major, proposing its use a prognostic marker for development of endocrinopathy [84].

**69**

*Investigation and Management of Endocrinopathies in Thalassaemia Major*

Inconsistencies in case definition of hypoparathyroidism have complicated estimates of prevalence. In a cohort of transfusion-dependent thalassaemia major patients, 13.5% were shown to have hypoparathyroidism, characterised by low serum PTH, total and ionised calcium levels [85]. In contrast, a multicentre study in Italy, encompassing 25 units, showed the prevalence to be 3.6% [46]. A French study from 1993 showed the prevalence of hyperparathyroidism to be as high as 22.5% [86]; similarly Aleem and colleagues reported a prevalence of 20% [87]. Shamshirsaz and colleagues showed a prevalence of 7.6% [1] with male:female ratio of 4:1, a higher ratio than has been described elsewhere [46, 83]. Further studies in Iran by Bordbar et al. and Bazi et al. reported prevalences of 13.2% [88] and 18% [89] respectively among their thalassaemia patient cohorts. Interestingly, Tangngam and colleagues reported a prevalence of asymptomatic hypoparathyroidism of 38% in their cohort of 66 transfusion-dependent thalassaemia patients, with significantly lower serum FGF-23, a major regulator of phosphate, detected in

A small study by Even and colleagues suggests loss of normal diurnal variation in PTH secretion in thalassaemia patients, even in individuals with normal daytime

In the UK, annual screening of parathyroid function and bone profile is recommended in thalassaemia patients [30]. Limited data [92, 93] shows that early supplementation with Vitamin D or calcitriol treatment for three months is sufficient to normalise plasma calcium and phosphate levels. 2016 UKTS guidelines recommend treatment with activated vitamin D preparations in the case of primary hypoparathyroidism secondary to iron overload. In order to avoid nephrocalcinosis, adjusted calcium levels should be targeted towards the lower reference range [30]. With regard to other complications, tetany, seizures or cardiac failure due to severe hypocalcaemia is rare and requires immediate correction with intravenous administration of calcium. Koutsis and colleagues report a rare case of Fahr's syndrome—striatopallidodentate calcinosis—in a 42 year-old woman with thalassaemia major with erratic compliance with oral vitamin D/calcium supplementation. Her hyperkinetic symptoms resolved with resumption of adequate oral

Histological and imaging studies have shown that iron deposits in the adrenal cortex of thalassaemic patients are mainly confined to the zona glomerulosa with rare involvement of the zona fascicularis [95]. Most studies have revealed intact pituitary adrenal axis in thalassaemia patients [35, 60, 65, 66, 96]. Prevalence of adrenal insufficiency is variable and depends both on the degree of iron overload,

Poggi et al. used a low dose synacthen test with adrenal insufficiency determined by cortisol <500 nmol/L and found a prevalence of 13.7% in the study population [97]. Huang et al. used a glucagon stimulation test, followed by cortico-

Raised ACTH levels were found by McIntosh which suggests primary adrenal failure [66], however Costin et al. found suppressed ACTH levels and reduced adrenal reserve despite the lack of clinical signs [5]. The diminished ability of the adrenal cortex to react to further pulses of ACTH may be reflected in the fact that

Low serum Dihydroepiandrostenedione (DHEA), Dihydroepiandrostenedione

Sulphate (DHEAS), androstenedione and testosterone levels were found to be

cut off values for cortisol measurement and diagnostic test used [97, 98].

trophin-releasing hormone and found a prevalence of 61% [98].

baseline serum and urinary cortisol levels are usually normal [99].

*DOI: http://dx.doi.org/10.5772/intechopen.93861*

hypoparathyroid patients [90].

calcium levels [91].

supplementation [94].

**7. Adrenal dysfunction**

#### *Investigation and Management of Endocrinopathies in Thalassaemia Major DOI: http://dx.doi.org/10.5772/intechopen.93861*

*Human Blood Group Systems and Haemoglobinopathies*

found to occur earlier [74]. A study published in 2018 by Upadya et al. showed that of a population of 83 children with thalassaemia, 4.8% had evidence of subclinical hypothyroidism. In this study, the mean ferritin level was 3983.0 ± 169,830 ng/ml. However, while the severity of thyroid dysfunction was statistically significantly associated with higher serum TSH value in children in the second decade of life (p = 0.001), it is important to note that no significant correlation was found between the severity of thyroid dysfunction and serum ferritin levels [76].

These findings were also echoed in the study conducted by Yassouf et al. They

In another study a total of 72 thalassaemia patients were followed for 8 years. The study endpoint was defined as the incidence of thyroid dysfunction, and aim of the study was to analyse ferritin as a prognostic maker. It found that that patients with thyroid dysfunction had higher ferritin levels in contrast to those with normal thyroid function (1500 (872–2336)) vs. (513 (370–698) ug/l; P < 0.0001). The study also found patients with ferritin values above 1800ug/L had a more rapid progres-

However, as a single value, ferritin may not always be reliable. Ferritin, as an acute phase protein, is subject to fluctuations caused by other variables such as inflammation and malignancy. However, ferritin may still be the most convenient way to assess iron overload, especially when used as part of a serial measurement [81]. Ferritin may be of value as a prognostic maker and may be used to identify patients at risk of developing thyroid dysfunction [81]. This begs the question as to whether the value of ferritin in determining the severity of thyroid dysfunction is

Currently, the UK Thalassaemia Society Standards for the clinical care of children and adults with thalassaemia in the UK (2016) recommend thyroid functions tests annually in patients with thalassaemia from age of 12 years, or if there are any

Hypoparathyroidism, resulting in hypocalcaemia, is a late complication of iron overload, typically manifesting after the age of 10 years and with a higher incidence in men [46]. The first sign of incipient hypoparathyroidism is loss of the diurnal pattern of parathyroid hormone (PTH) secretion [9]. The typical biochemical profile is low serum calcium, low serum PTH, low serum vitamin D and elevated serum phosphate levels [82]. Clinical signs of the disorder are most frequently noted from

A recent survey of clinicians by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) published in 2018 reported a prevalence of 6.8% among 3023 thalassaemia major patients from 17 centres [83]. 42.2% of hypoparathyroid patients in this study were described as asymptomatic at diagnosis. The most common presenting symptom was paraesthesia and/or cramping seen in 37.6% patients [83]. In the ICET-A study, 49.8% of [83] hypoparath-

ryoid individuals were also noted to have serum ferritin level > 2.500 ng/ml8

and colleagues also noted a significant association between elevated ferritin and incidence of hypoparathyroidism in thalassaemia major, proposing its use a prognostic

. Chirico

found that serum ferritin was directly correlated with TSH levels (r = 0.414; p < 0.001). However, there was no correlation between serum ferritin and FT4 levels (r = 0.027; p > 0.05) [78]. This study also demonstrated that the risk of thyroid dysfunction was increased by non-compliance of chelation therapy by 6.38 fold as

compared with compliant patients (RR = 6.385 l 95% CI, 2.40–16.95) [78].

sion towards the endpoint of thyroid dysfunction [81].

suggestive symptoms of thyroid deficiency between times [30].

over-appreciated [76].

**6. Hypoparathyroidism**

the second decade of life onwards [15].

marker for development of endocrinopathy [84].

**68**

Inconsistencies in case definition of hypoparathyroidism have complicated estimates of prevalence. In a cohort of transfusion-dependent thalassaemia major patients, 13.5% were shown to have hypoparathyroidism, characterised by low serum PTH, total and ionised calcium levels [85]. In contrast, a multicentre study in Italy, encompassing 25 units, showed the prevalence to be 3.6% [46]. A French study from 1993 showed the prevalence of hyperparathyroidism to be as high as 22.5% [86]; similarly Aleem and colleagues reported a prevalence of 20% [87]. Shamshirsaz and colleagues showed a prevalence of 7.6% [1] with male:female ratio of 4:1, a higher ratio than has been described elsewhere [46, 83]. Further studies in Iran by Bordbar et al. and Bazi et al. reported prevalences of 13.2% [88] and 18% [89] respectively among their thalassaemia patient cohorts. Interestingly, Tangngam and colleagues reported a prevalence of asymptomatic hypoparathyroidism of 38% in their cohort of 66 transfusion-dependent thalassaemia patients, with significantly lower serum FGF-23, a major regulator of phosphate, detected in hypoparathyroid patients [90].

A small study by Even and colleagues suggests loss of normal diurnal variation in PTH secretion in thalassaemia patients, even in individuals with normal daytime calcium levels [91].

In the UK, annual screening of parathyroid function and bone profile is recommended in thalassaemia patients [30]. Limited data [92, 93] shows that early supplementation with Vitamin D or calcitriol treatment for three months is sufficient to normalise plasma calcium and phosphate levels. 2016 UKTS guidelines recommend treatment with activated vitamin D preparations in the case of primary hypoparathyroidism secondary to iron overload. In order to avoid nephrocalcinosis, adjusted calcium levels should be targeted towards the lower reference range [30].

With regard to other complications, tetany, seizures or cardiac failure due to severe hypocalcaemia is rare and requires immediate correction with intravenous administration of calcium. Koutsis and colleagues report a rare case of Fahr's syndrome—striatopallidodentate calcinosis—in a 42 year-old woman with thalassaemia major with erratic compliance with oral vitamin D/calcium supplementation. Her hyperkinetic symptoms resolved with resumption of adequate oral supplementation [94].
