**5. Thyroid dysfunction**

*Human Blood Group Systems and Haemoglobinopathies*

there is a family history of diabetes [30]. Screening is carried out with the oral glucose tolerance test (OGTT) [30]. However, OGTT compliance is often poor. This makes the development of adjunct or alternative screening tests of particular interest, as detecting pre-clinical diabetes is crucial because the development of clinical diabetes can possibly be slowed down or halted. Pancreatic iron overload can be assessed by MRI [62] but does not seem to correlate with siderosis in other organs. Currently, the relationship between MRI detectable iron and pancreatic beta cell dysfunction is not well characterised and MRI of the pancreas for iron deposition monitoring is not used clinically [30, 63]. However, there may be scope to use cardiac and liver MRI which already have established protocols, for the purpose of screening for impaired glucose tolerance or diabetes. Ang et al. found that abnormal myocardial T2 signal may indicate the development of diabetes mellitus and other prediabetic states [54]. Li et al. showed similar findings whereby Cardiac T2 MRI values were higher in patients with normal fasting glucose levels (P = 0.03) [58]. Kanbour et al. found that patients with very high liver iron concentration (LIC) (>30 mg Fe/gm dry liver) were more likely to have a higher prevalence of impaired fasting glucose when compared to those with lower LIC (p = 0.044) [55]. The use of continuous glucose monitoring (CGMS) in detecting glucose intolerance and diabetes mellitus has also been studied, with CGMS found to be superior when compared to OGTT (p = 0.012) [64]. El-Samahy et al. studied 20 beta thalassaemia patients with random blood glucose >7.8 mmol, who then had OGTT and CGMS. OGTT detected 6/20 patients (30%) who had impaired glucose tolerance and 7/20 (35%) patients who were in the diabetic range, while CGMS found that 7/20 (35%) patients had IGT and 13/20 (65%) had frank diabetes mel-

In terms of determining overall glycaemic control, UK guidelines recommend that serum fructosamine should be used. Fructosamine is a circulating glycated protein which measures overall glucose control in the previous 2–3 weeks. HbA1c or glycated haemoglobin should be avoided in thalassaemia as it is unreliable in any

Although inadequate insulin release has been reported by several groups [60, 65, 66]. Other aetiologies identified include hyperinsulinemia, reduced insulin sensitivity [67] and reduction of hepatic insulin release. A study by Siklar et al. suggested that development of insulin impairment occurs prior to insulin resistance [68]. Furthermore, autoimmunity results in selective oxidative damage to beta cells of the pancreas [68]. Beta cells retain their function up to the later stages of the disease [9], however insulin sensitivity was found to be inversely related to iron overload and age [69]. Fasting pro-insulin and pro-insulin to insulin ratios was found to be considerably elevated and have a positive correlation with hepatic iron [70], however C-peptide levels were found to be inconsistent, thus reflecting fluctuating beta cell function [71, 72]. A reduction in serum trypsin and lipase levels were found, alongside regular alpha amylase activity. It was also found that the development of other endocrine and cardiac complications were followed by the onset of diabetes mellitus [73]. A 50% decline beta cell function was found to be correlated with glucose intolerance, and beta cell function was not entirely recovered even after intensive iron chelation. Moreover, high transfusion regimes that were not paired with appropriate iron chelation

The prevalence of abnormal glucose metabolism has gradually increased over the last 20 years [55]. Therefore, the topic of glucose intolerance and diabetes mellitus in patients with thalassaemia major continues to be of significant clinical

haemoglobinopathy and also after transfusion [30].

could advance the prevalence of diabetes mellitus further.

**66**

importance.

litus [64].

Thyroid dysfunction is a frequently occurring endocrine complication in thalassaemia major [39]. Hypothyroidism occurs either as a results of primary gland failure, or insufficient thyroid gland stimulation [74]. Hypothyroidism is thought to be a graded phenomenon and many types of hypothyroidism have been described: (1) sub-biochemical hypothyroidism: which consists of an exaggerated TSH response to TRH test in the presence of normal TSH and FT4; (2) sub-clinical hypothyroidism: elevated serum TSH with normal serum FT4 levels; (3) overt (clinical) hypothyroidism: High TSH with low FT4 level and (4) central Hypothyrodism: an inappropriately low or normal TSH with a low free T4 level [74]. The lack of autoimmune thyroiditis in thalassaemia patients continues to be supported by multiple studies [75, 76].

Subclinical hypothyroidisim was found to be the most prevalent thyroid dysfunction in many studies [77, 78]. In a study of 144 thalassaemia patients by by Saleem et al., hypothyroidism was found in 31.2% of patients. Subclinical hypothyroidism was found to be the most prevalent thyroid dysfunction (31.2%; 45 patients), whilst only 6.7% [3] patients were found to have overt hypothyroidism. Interestingly, 76% of the patients with subclinical hypothyroidism were in the first decade of life [77].

The study conducted by Yassouf et al. demonstrated that out of the 82 cases of thalassaemia studied, subclinical hypothyroidism was once again found to be the most prevalent thyroid disorder - 29.27% of patients [24] had subclinical hypothyroidism while only one patient (1.22%) had overt hypothyroidism. In contrast to other studies, no case of central hypothyroidism was found [78].

There is a general consensus that central hypothyroidism is underestimated as there are only a handful of studies on the topic currently. The diagnosis of central hypothyroidism remains difficult from a clinical perspective, as its non-specific symptoms means that symptoms are usually attributed to another cause. From a biochemical perspective, central hypothyroidism is diagnosed based on a low to normal TSH level, in the presence of low levels of free T4 [74].

De Sanctis et al. explored the prevalence of central hypothyroidism in their thalassaemia population (339 patients). They found that central hypothyroidism was present in 6% of patients aged less than 21 years old, and 7.9% in patients above 21 years of age. Delaporta et al. showed that 16% of 114 studied patients (mean age 20.9 ± 7.8 years) had central hypothyroidism [79].

A prospective study carried out by Soliman et al. followed a total of 48 patients over a period of 12 years. In this duration, hypothyroidism was diagnosed in 35% [17] of patients - central hypothyrodisim was found in 13/17 (76%) patients [75]. Unexpectedly, this paper also found that the mean serum ferritin level did not differ significantly between patients with or without central hypothyroidism. This in turn did not support the hypothesis that iron overload of the HPA axis had resulted in central hypothyroidism thus concluding that the precise underlying aetiology of central hypothyroidism was unclear. However, due to the susceptibility of the pituitary gland to excess iron, central hypothyroidism due to iron overload of the HPA axis still remains a possibility [74].

Belhoul et al. found an increase in prevalence of hypothyroidism in splenectomised patients [80]. In non-splenectomised thalassemic patients, the spleen was thought to have a scavenging effect on free iron fractions. However, further studies are needed to evaluate this hypothesis [74].

Thyroid failure was found to correlate with age at which iron chelation therapy started. When iron chelation therapy was started late, thyroid dysfunction was

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 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].

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 progression towards the endpoint of thyroid dysfunction [81].

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 over-appreciated [76].

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 suggestive symptoms of thyroid deficiency between times [30].
