Introduction

Endocrine abnormalities are the most common complications of transfusion-dependent β thalassaemia (TM). Prevalence varies because of the different levels of treatment followed by centres across the world, particularly the severity of the defective genetic background, the haemoglobin concentration and the degree of iron load in various patient groups (Figure 1). Another contributing factor is that of the increased survival to adulthood (De Sanctis et al., 2016a).

Figure 1

Aetiopathogenesis of endocrine complications in thalassaemia. [LTTCs, L-type Ca 2+ channels].

Aims of blood transfusion

The prevalence of different endocrine-related complications:

1. Delayed puberty and hypogonadism: the prevalence of hypogonadotropic hypogonadism in both sexes varies considerably between countries and between different centres. It ranges from 50% to 100 %. The reported prevalence of adult-onset hypogonadism (AOH) in TM patients ranges between 8.3% and 12%.
2. Hypothyroidism: the prevalence varies from 6 to 35% in different studies.
3. Impaired glucose tolerance and diabetes mellitus: the prevalence increases with age and varies from 10 to 24% in different studies.
4. Hypoparathyroidism: the prevalence varies from 1% to 19%.
5. Adrenal insufficiency: prevalence of ‘biochemical adrenal insufficiency’ varies up to 45%, but clinical adrenal insufficiency is rare (De Sanctis et al., 2016b).

Genetic factors influence the susceptibility to hypogonadism in patients with thalassaemia, possibly because of differences in transfusional iron input and/or the vulnerability to free radical damage. Patients with the β0/β0 genotype have a significantly higher prevalence of growth retardation, hypogonadism, hypothyroidism and hypoparathyroidism compared to those with the β0 /β+ and β+ /β+ genotypes.

Delayed Puberty and Hypogonadism

Delayed puberty and hypogonadism are the most obvious clinical consequences of iron overload. Delayed puberty is defined as the complete lack of pubertal development in girls by the age of 13, and in boys by the age of 14. Hypogonadism is defined in boys as the absence of testicular enlargement (less than 4 ml) and in girls as the absence of breast development by the age of 16 (De Sanctis et al., 2013). Arrested puberty is a relatively common complication in moderately or grossly iron overloaded patients with TM and is characterised by a lack of pubertal progression over a year or more. In such cases, the testicular size remains 6-8 ml, and breast size at B3. In such cases annual growth velocity is either markedly reduced or completely absent (De Sanctis et al., 2013). Hypogonadism in adolescents and adults with TM has a prevalence of 38% in females and 43% in males (Figure 2).

Figure 2

The prevalence of endocrine-related complications in thalassaemia major. [Short stature (< 3rd centile) ] (De et al. Sanctis 2004).

• Routine investigations include biochemical analysis, thyroid function tests (thyroid stimulation hormone (TSH) and free thyroxine (FT4), bone age (X-ray of wrist and hand) and bone mineral density (BMD).
• Testing the hypothalamic-pituitary gonadal axis (hypogonadotropic hypogonadism) – patients with TM and delayed puberty/hypogonadism have:

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  Lower basal follicle stimulating hormone (FSH) and luteinising hormone (LH) secretion.

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  Low LH/FSH response to gonadotropin releasing hormone (GnRH) and variable disturbance of the spontaneous pulsatile pattern of LH and FSH secretion.

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  Low basal sex steroid levels (estradiol and testosterone).

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  In some cases, low testosterone secretion in response to human chorionic gonadotropin (HCG).

• Pelvic ultrasound to assess ovarian and uterine size in females.

Treatment

The treatment of delayed or arrested puberty and of hypogonadotropic hypogonadism depends on factors such as age, severity of iron overload, damage to the hypothalamic-pituitary-gonadal axis, chronic liver disease and the presence of psychological problems resulting from hypogonadism. Collaboration between endocrinologists and other doctors is critical.

For girls, therapy may begin with the oral administration of ethinyl estradiol (2.5-5 μg daily) for six months, followed by hormonal reassessment. If spontaneous puberty does not occur within six months from the end of treatment, oral oestrogen is re-introduced in gradually increasing dosages (ethinyl estradiol from 5-10 μg daily) for another 12 months. If breakthrough uterine bleeding does not occur, low oestrogen-progesterone hormone replacement is the recommended treatment (De Sanctis et al., 2013).

For delayed puberty in males, low dosages of intramuscular depot-testosterone esters (30-50 mg) are given monthly for six months, followed by hormonal re-assessment. In patients with hypogonadotropic hypogonadism, treatment at a dose of 50 mg per month can be continued until growth rates wane. The fully virilising dose is 75-100 mg of depot-testosterone esters every 10 days, administered intramuscularly after growth is almost completed and afterwards. The same effects can be achieved with topical testosterone gel (De Sanctis et al., 2013).

For pubertal arrest, the treatment consists of testosterone esters or topical testosterone gel, administered as for the treatment of delayed puberty and hypogonadotropic hypogonadism.

It is important that the treatment of pubertal disorders is considered on a patient-by-patient basis, taking account of the complexity of the issues involved and the many associated complications (De Sanctis et al., 2013).

Hypothyroidism

This complication is mainly attributed to iron overload and is uncommon in optimally treated patients. Central hypothyroidism is uncommon (Soliman et al., 2013a). The frequency of hypothyroidism in TM patients ranges from 6 to 30%. A lower prevalence is found among patients with evidence of lower iron load as measured by ferritin levels. The wide variations in different reports can be attributed to differences in patient genotypes, differences in patients’ ages, ethnic variations and different treatment protocols, including differing transfusion rates and chelation therapies (De Sanctis et al., 2013).

Laboratory tests

Investigation of thyroid function should be performed annually, beginning at the age of nine years (unless symptomatic hypothyroidism is observed earlier) (Rindang et al., 2011). Free T4 and TSH are the key investigations. Additional tests may include the following:

• Thyroid autoantibodies: anti-thyroid peroxidase and antithyroglobulin autoantibodies. Thyroid antibodies to exclude autoimmunity are usually negative and are performed in selected cases. Ultrasonography, which may show different echo patterns, to evaluate structural thyroid abnormalities.
• Bone age, in selected cases.
• Biochemistry including lipid profile.
• Serum ferritin.
• Electrocardiogram (ECG) and echocardiogram (especially in severe cases).
• Hypothalamic-pituitary magnetic resonance imaging (MRI), in patients with central hypothyroidism

Assessment of thyroid function

The following grades of hypothyroidism have been identified (De Sanctis et al., 2012):

• Sub-clinical hypothyroidism is a combination of high TSH with normal FT4 levels. Two types of sub-clinical hypothyroidism have been reported:

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  Type A (normal FT4, TSH 5-10 μU/ml)

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  Type B (normal FT4, TSH > 10 μU/ml)

• Overt hypothyroidism is a combination of high TSH with low FT4
• Diagnosis of central hypothyroidism is usually made on a biochemical basis showing low circulating concentrations of thyroid hormone associated with inappropriately low TSH levels (Figure 3).

Figure 3

Flow chart for the assessment of thyroid function. [TSH, thyroid stimulating hormone; FT4, free thyroxine].

Clinical examination

The classical clinical signs of hypothyroidism in TM patients are not easy to identify because most of the symptoms, especially in mild cases, are nonspecific and are frequently attributed to anaemia or associated diseases (Sabato et al., 1983).

Thalassaemic patients with overt hypothyroidism have been reported to exhibit stunted growth, delayed puberty, cardiac failure, and pericardial effusion (De Sanctis et al., 2012). They are shorter with more delayed bone age than euthyroid TM patients.

Treatment

• Overt and central hypothyroidisms are treated with levothyroxine (L-thyroxine).
• If subclinical hypothyroidism is detected, chelation should be intensified and the patient carefully monitored (De Sanctis et al., 2012).
• Subclinical hypothyroidism is treated with L-thyroxine when TSH is equal to or above 8 mUI/ml (Figure 4).

Figure 4

Flow chart for the treatment of thyroid dysfunction in thalassaemia. [FT4, free thyroxine; RM of hypothalamic-pituitary region; TSH, thyroid stimulating hormone].

Treatment with amiodarone may result in the rapid progression from subclinical hypothyroidism to severe hypothyroidism, which in turn causes deterioration of cardiac function (Alexandrides et al., 2000).

Impaired Glucose Tolerance (IGT) and Insulin-dependent Diabetes Mellitus (IDDM)

IGT and IDDM are relatively common complications in patients who have been inadequately iron chelated, although these abnormalities have also been observed in well transfused and regularly chelated TM patients, suggesting that the development of diabetes might be caused by other factors such as: individual sensitivity to iron damage, chronic anaemia, zinc deficiency and increased collagen deposition secondary to increased activity of the iron-dependent protocollagen proline hydroxylase enzyme, with subsequent disturbed microcirculation in the pancreas (De Sanctis et al., 2004; Iancu, Ward & Peters, 1990).

The prevalence of IGT and IDDM in adolescents and young adults with TM treated mainly with deferoxamine (desferrioxamine) varies in different series from 0 to 17% (Skordis, 2012). IDDM is uncommon during the first years of life and rates progressively increase with age. Impaired glucose tolerance may start early in the second decade of life in parallel with puberty. The combined adverse effects of puberty and thalassaemia-associated risk factors on insulin action may partly explain the increase of insulin resistance in adolescent thalassaemics (Skordis, 2012).

Pathogenesis of IDDM in β thalassaemia patients

The initial abnormality appears to be iron-mediated insulin resistance rather than defective insulin production, but pancreatic β-cell damage and insulin deficiency subsequently develop as a result of direct toxic damage from iron deposition (Skordis, 2012).

Pancreatic β-cell function in thalassaemia is characterised by the following sequence (Figure 5):

Figure 5

Pathogenesis of abnormal glucose homeostasis in thalassaemia (Reproduced with permission from Soliman AT).

• Insulin - resistance with hyperinsulinaemia and normal glucose tolerance.
• Insulin-resistance with IGT and progressive impairment of β-cell function with reduction of insulin secretion, and
• Insulin dependent diabetes mellitus.

Both liver and pancreatic β-cell siderosis and glucose toxicity may impair glucose tolerance. The interplay between liver siderosis and hepatitis C facilitates and accelerates the progression to IDDM, at least in adulthood (De Sanctis et al., 2016c). Early recognition of glucose abnormalities is essential. The oral glucose tolerance test (OGTT) should be done in every patient with thalassaemia after the age of ten or earlier if needed (Skordis, 2012).

Diagnosis

The diagnostic criteria for glucose intolerance (Figure 9) are as follows:

Figure 9

Optimal testing strategy for evaluating patients with potential hypothalamic-pituitary –adrenal insufficiency (HPAI). [ACTH, adrenocorticotropic hormone; ITT, insulin tolerance test].

• Fasting glucose >126 mg/dl is diagnostic of diabetes mellitus.
• OGTT serum glucose at 2 hours >200 mg/dl is diagnostic of diabetes mellitus.
• OGTT serum glucose at 2 hours >140 <200 mg/dl indicates glucose intolerance (Figure 6).

Figure 6

The diagnostic criteria for the glucose tolerance. FPG: fasting plasma glucose; OGTT, oral glucose tolerance test; PG, plasma glucose.

Pancreatic iron is the strongest predictor of β-cell toxicity and can be evaluated by MRI of the pancreas (Noetzli et al., 2009), although this technique is yet to be standardised for use in routine clinical practice. MRI and fasting glucose/insulin are complementary screening tools and if proven valid, they may identify high-risk patients before irreversible pancreatic damage occurs. Nevertheless, oral glucose tolerance testing remains the gold standard test for assessing glucose homeostasis. Screening for viral hepatitis and regular chelation therapy are important measures in preventing the development of diabetes.

Management

Management of impaired glucose tolerance and diabetes (De Sanctis et al., 2016c; Skordis, 2012) is based on:

• Intensive iron-chelation therapy and prevention and treatment of chronic hepatitis C infection are now the most important issues in managing impairment of glucose homeostasis in patients with transfusion-dependent β-thalassaemia. Intensive chelation therapy is effective to normalise β-cell function and may improve insulin secretion and glucose tolerance and reduce liver iron deposition (Berdoukas et al., 2012).
• Management of IDDM should be individualised
• Healthy diet suitable for IDDM (as assessed and advised by expert dietician)
• Regular physical activity
• There is very limited published data on the efficacy and safety of oral antidiabetic agents in patients with TM. The only drugs used in small studies in this context with good effect were metformin, glibenclamide, sitagliptin and acarbose.
• When overt IDDM develops, patients require daily subcutaneous injections of insulin to normalise blood sugar levels.
• Diabetic patients with TM should be seen regularly by a specialised multidisciplinary team with expertise in both diabetes and TM. There should be ongoing diabetes self-management education. The team should include an endocrinologist and dietician with experience in TM.
• TM women with pre-existing diabetes should have pre-pregnancy counselling and planning to aim for optimal glycaemic control before and throughout pregnancy to minimise adverse pregnancy outcomes.

Monitoring glycaemic control in thalassaemia patients is the same as with non-thalassaemic patients with IDDM (De Sanctis et al., 2016c):

• Self-glucose monitoring (SGM) at home using glucometers.
• Urine ketones if blood sugar >250 mg/dl.
• Fructosamine determination is useful for monitoring diabetes in these patients (De Sanctis et al., 2016c).
• Periodic assessment of renal function.
• A microalbumin test is used to detect early signs of kidney damage in people who are at risk of developing kidney disease (once a year). If albumin in the urine (micro-albuminuria) is detected, it should be confirmed by retesting twice within a 3-6 month period.
• Evaluation of retinopathy.

Hypoparathyroidism (hypoPT)

HypoPT has been considered as a typical complication of the second decade of life in transfusion-dependent patients with thalassaemia major (Figure 7). The incidence of hypoPT varies from centre to centre (from 1.2% to 19%) and hypoPT seems to affect men more frequently (male/female ratio = 1.35) (De Sanctis et al., 2018; Sleem, Al-Zakwani & Almuslahi, 2007; Vogiatzi et al., 2009). Recently, abnormal cerebral computed tomography findings have been reported in a high percentage of patients with thalassaemia and hypoPT (Karimi et al., 2009; Soliman et al., 2008). An ECG can detect an abnormality in the electrical activity of the heart.

Figure 7

Age at presentation of hypoparathyroidism and number of thalassaemia major patients (De Sanctis V, personal experience).

Signs and symptoms

Most patients show a mild form of the disease accompanied by paraesthesia and prolonged QTC interval (Figure 8). More severe cases may demonstrate tetany, seizures or cardiac failure (Skordis, 2012).

Figure 8

Prolonged QTC interval in a male thalassaemic patient with hypoparathyroidism.

Investigations

Investigations should begin from the age of 16 years and should include serum calcium, serum phosphate and phosphate balance. In cases with low serum calcium and high phosphate levels, parathyroid hormone should also be measured (Skordis, 2012).

Management

Treatment of hypoPT aims to prevent acute and chronic complications of hypocalcaemia. The primary goals of management include: control of symptoms, maintaining serum calcium in the low to normal range, maintaining serum phosphorus within normal limits, maintaining 24-hour urine calcium under 7.5 mmol/day (300 mg/day) and maintaining a calcium-phosphate product under 55 mg/dl (4.4 mmol/l) to guard against the development of nephrolithiasis, nephrocalcinosis and soft-tissue calcification (Skordis, 2012).

Treatment includes:

• Oral administration of vitamin D or one of its analogues. Some patients require high doses of vitamin D to normalise their serum calcium levels. This should be carefully monitored, as hypercalcaemia is a common complication of this treatment (De Sanctis et al., 2018, 2013).
• Calcitriol, 0.25-1.0 μg, twice daily, is usually sufficient to normalise plasma calcium and phosphate levels. At the start of the treatment, weekly blood tests are required. These are followed by quarterly plasma and 24-hour urinary calcium and phosphate measurements.
• In patients with persistently high serum phosphate levels, a phosphate binder (except aluminium) may be considered.
• Tetany and cardiac failure due to severe hypocalcaemia require intravenous administration of calcium, under careful cardiac monitoring, followed by oral vitamin D.
• In some studies, synthetic human parathormone 1-34 (PTH), once or twice daily, has been shown to effectively treat children with hypoPT. However, this therapy is not yet approved for the treatment of hypoPT and no data are available in the literature in subjects with thalassaemia.
• In some patients with hypoPT treated with calcium and vitamin D, the development of hypercalciuria is a potential unwanted effect, due to the anticalciuric effect of PTH. In these cases, restriction of sodium intake, use of thiazide diuretics or reduction in the doses of calcium or 1 alpha-hydroxylated vitamin D may be required. Such measures may also be employed at the beginning of treatment to prevent hypercalciuria (De Sanctis et al., 2018, 2013).

Dietary steps

No special diet is required, but some doctors recommend consulting a dietician, who is likely to advise a diet that is:

• Rich in calcium. This includes dairy products, green leafy vegetables, broccoli, kale, fortified orange juice and breakfast cereals.
• Low in phosphorus-rich items. This means avoiding carbonated soft drinks, which contain phosphorus in the form of phosphoric acid. Eggs and meats also tend to be high in phosphorus.

Adrenal Insufficiency

Several studies reported a significant prevalence of ‘biochemical’ adrenal insufficiency in patients with thalassaemia ranging from 0 to 45%. ‘Clinical’ adrenal insufficiency, i.e. adrenal crisis, on the other hand, is extremely rare (El Kholy, 2012; Soliman et al., 2013b).

Diagnosis

Manifestations of mild adrenal hypofunction might be masked by symptoms that are commonly complained of by thalassaemic patients, such as asthenia, muscle weakness, arthralgias and weight loss.

Laboratory tests

Cortisol levels both basal and 30-60 minutes after adrenocorticotropic hormone (ACTH) or insulin stimulation, are used for the assessment of adrenal function (Figure 9).

It is advised that adrenal function be tested every 1–2 years, especially in growth hormone (GH) deficient patients during recombinant human growth hormone (rhGH) therapy (El Kholy, 2012; Soliman et al., 2013b), because patients with GH deficiency may have additional anterior pituitary hormone deficits and are at risk of developing complete or partial corticotropin (ACTH) deficiency.

Treatment

Subclinical impairment of adrenocortical function in patients with TM is not uncommon; however, it has little or no clinical impact under basal conditions although it may have a potential relevance during stressful events. Accordingly, glucocorticoid treatment coverage might be advised only for stressful conditions (El Kholy, 2012; Soliman et al., 2013b). Clinical adrenal insufficiency and adrenal crisis are rare.

Box

Summary.

References

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