**4. Glucose intolerance and diabetes mellitus**

Effective management of patients suffering from homozygous beta thalassaemia has led to improved life expectancy and hence manifestations of haemosiderosis related complications, notably, disturbances of the exocrine and endocrine function of the pancreas [53]. The prevalence of glucose intolerance and diabetes mellitus (DM) in patients with homozygous beta thalassaemia has been found to be variable. A retrospective analysis of 92 patients performed by Ang et al. showed that diabetes mellitus was one of the most common endocrinopathies with 41% of the study population affected [54] while a study conducted by Kanbour et al. reported a prevalence of 16.7% for impaired fasting glucose and 12.5% for diabetes mellitus [55]. Recently, a meta-analysis conducted by He et al. which included 44 studies with 16,605 cases showed that diabetes mellitus was present in 6.54%, impaired fasting glucose (IGF) in 17.21% and impaired glucose tolerance (IGT) in 12.46% [56]. While the prevalence of glucose intolerance and diabetes mellitus is undoubtedly high, many risk factors have also been identified. There was evidence of increased risk of diabetes mellitus with co-infection with hepatitis C [55–57], longer duration of disease [57–59] and with increased pancreatic iron deposition [58, 60].

Li et al. have found that in addition, patients with diabetes mellitus were characterised by higher ferritin levels, smaller pancreas volume, lower cardiac T2 magnetic resonance signal (MRI) than patients without diabetes, and higher prevalence of hypogonadism. Interestingly, patients with diabetes were found to be young (median age was 22 years [range of 10 to 34 years]) and non-obese (BMI of 20.1 ± 2.8 kg/m2 ) [58]. This may explain why the classical association between diabetes and increased prevalence of arteriosclerotic cardiovascular disease is not a feature in this population [30].

Poor compliance with desferrioxamine therapy (p < 0.05), older age commencing intensive chelation therapy, liver cirrhosis and severe fibrosis were found to be risk factors for glucose intolerance and diabetes mellitus. Risk factors for impaired glucose tolerance (IGT) also included male sex [61], poor compliance with desferrioxamine therapy and high hepatic iron concentration.

Current UK guidelines recommend annual monitoring for impaired glucose tolerance and diabetes from the onset of puberty, or from the age of 10 years if

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 mellitus [64].

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 haemoglobinopathy and also after transfusion [30].

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 could advance the prevalence of diabetes mellitus further.

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 importance.

**67**

*Investigation and Management of Endocrinopathies in Thalassaemia Major*

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

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

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

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

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

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

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

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

other studies, no case of central hypothyroidism was found [78].

normal TSH level, in the presence of low levels of free T4 [74].

20.9 ± 7.8 years) had central hypothyroidism [79].

HPA axis still remains a possibility [74].

are needed to evaluate this hypothesis [74].

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

**5. Thyroid dysfunction**

multiple studies [75, 76].

decade of life [77].
