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Cappellini MD, Cohen A, Porter J, et al., editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd edition. Nicosia (CY): Thalassaemia International Federation; 2014.
This publication is provided for historical reference only and the information may be out of date.
Endocrine abnormalities are among the most common complications of β-thalassaemia major (TM). Despite early establishment of appropriate chelation therapy, problems such as delayed growth and sexual maturation and impaired fertility may persist. Determining the prevalence of endocrine complications is difficult because of the considerable differences in the age of first exposure to chelation therapy, the degree and type of chelation, the haemoglobin level attained before blood transfusion, and the continuing improvement in survival in well-chelated patients. The growth rates and endocrine complications of a sample of 3,817 TM patients in 29 countries are reported in Figure 1 (De Sanctis 2004).
Growth and endocrine complications in thalassemia.Reproduced from Thalassaemia International Federation Study Group on Growth and Endocrine Complications in Thalassaemia (De Sanctis 2004).
Growth retardation occurs almost invariably in TM subjects. Significant size retardation is observed in stature, sitting height, weight, and biacromial (shoulder) and bicristal (iliac crest) breadths. After the age of 4 years, the longitudinal growth patterns display rates of growth consistently behind those of normal controls. The bone age is frequently delayed after the age of 6–7 years. Growth retardation becomes severe with the failure of the pubertal growth spurt. Key contributing factors to stunted growth in patients with thalassaemia include chronic anaemia, transfusional iron overload and chelation toxicity (De Sanctis 2013a). Other important contributing factors include nutritional deficiencies (protein-calorie malnutrition, vitamin D and A, zinc and carnitine deficiencies), growth hormone deficiency (GHD) /insufficiency (GHI), insulin-like growth factor-I (IGF-I) deficiency, chronic liver disease, hypogonadism, hypothyroidism and psychosocial stress.
The first step in the management of short stature or retarded growth is the regular (six-monthly intervals) and accurate measurement of standing and sitting height, pubertal staging (Table 1) and bone age, including examination of metaphyses. Interpretation of absolute height must take into account the height of the parents.
Pubertal assessment according to Tanner.
Initial endocrine studies that may be helpful include: thyroid function tests (FT4, TSH), assessment of the pituitary gonadal axis (testosterone, estradiol, LH, FSH) and pituitary growth axis (IGF-I), Insulin Growth Factor Binding Protein-3 (IGFBP-3) and Growth Hormone (GH) stimulation test when needed. Additional studies include: calcium homeostasis (calcium, phosphate, alkaline phosphatase, parathormone and 25-OH vitamin D levels), glucose tolerance tests and IgA transglutaminase antibodies to exclude coeliac disease. The secretion of GH is normal in the majority of patients with thalassaemia. Testing the hypothalamic-pituitary growth axis can be accomplished by directly measuring IGF-I level and performing a GH stimulation test (using clonidine, glucagon, or GHRH).
Radiological evaluation of the skeleton including assessment of bone maturation (bone age) and measuring bone mineral density during late childhood and early adolescence is recommended because of high prevalence of skeletal abnormalities and osteoporosis in TM patents. It is important to bear in mind that although the use of desferrioxamine has declined, it remains a cause of delayed growth (see Chapter 3 on Iron Overload and Chelation) as well as skeletal abnormalities.
Prevention and treatment of growth abnormalities in patients with TM should include (see Figure 2):
Practical approach to the treatment of growth retardation in thalassaemia. Reproduced with permission from (Soliman 2013).
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 2013a). 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 2013a). Hypogonadism in adolescents and adults with TM has prevalence of 38% in females and 43% in males (Figure 1).
The treatment of delayed or arrested puberty, and of hypogonadotrophic hypogonadism depends on factors such as age, severity of iron overload, damage to the hypothalamo-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 after 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.
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 hypogonadotrophic 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.
For pubertal arrest, the treatment consists of testosterone esters or topical testosterone gel, administered as for the treatment of delayed puberty and hypogonadotrophic 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.
This complication is mainly attributed to iron overload and is uncommon in optimally treated patients. Central hypothyroidism is uncommon (De Sanctis 2012a). 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 2012a).
Investigation of thyroid function should be performed annually, beginning at the age of 9 years (unless symptomatic hypothyroidism is observed) (Rindang 2011). Free T4 and TSH are the key investigations. Additional tests may include the following:
The following grades of hypothyroidism have been identified (De Sanctis 2012a):
The classical clinical signs of hypothyroidism in TM patients are not easy because most of the symptoms, especially in mild cases, are nonspecific and are frequently attributed to anaemia or associated diseases (Sabato 1983). Thalassaemic patients with overt hypothyroidism have been reported to exhibit stunted growth, delayed puberty, cardiac failure and pericardial effusion (De Sanctis 2013a). They are shorter with more delayed bone age than euthyroid TM patients.
Treatment depends upon the severity of organ failure. Good compliance with chelation therapy may prevent or improve hypothyroidism (sub-clinical hypothyroidism - basal TSH 5 to 10 mUI/ml).
Subclinical hypothyroidism requires regular medical follow-up and intensive iron chelation therapy. Patients with overt hypothyroidism should be given L-thyroxine (De Sanctis 2013a). A notable caution in thalassaemics with subclinical hypothyroidism and cardiomyopathy: treatment with amiodarone may result in the rapid progression to severe hypothyroidism, which in turn causes deterioration of cardiac function (Alexandrides 2000).
IGT and DM are relatively common complications in patients who have been inadequately iron chelated, although these abnormalities have been also 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 2013b, De Sanctis 2004, Iancu 1990).
The prevalence of IGT and insulin-dependent diabetes mellitus (IDDM) in adolescents and young adults with TM treated mainly with desferrioxamine varies in different series from 0 to 17 % (Skordis 2013). DM 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 both puberty and thalassaemia associated risk factors on insulin action may partly explain the increase of insulin resistance in adolescent thalassaemics (Skordis, 2013).
The initial insult appears to be due to 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 2013).
Pancreatic β-cell function in thalassaemia is characterised by the following sequence (Figure 3):
Pathogenesis of abnormal glucose homeostasis in thalassaemia. Reproduced with permission from (De Sanctis V. TIF Congress, Dubai – 2006).
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 DM, at least in adulthood (De Sanctis 2013a). 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 2013).
The diagnostic criteria for glucose tolerance (Figure 4) are as follows:
The diagnostic criteria for the glucose tolerance.
Pancreatic iron is the strongest predictor of β cell toxicity, which can be evaluated by the MRI of the pancreas (Noetzli 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, they may identify high-risk patients before irreversible pancreatic damage occurs. Nevertheless oral glucose tolerance testing still remains the gold standard test for glucose homeostasis. Screening for hepatitis infections and use of regular chelation therapy are important measures in preventing the development of diabetes.
Management of impaired glucose tolerance and diabetes (De Sanctis 2013a, De Sanctis 2013b, Skordis 2013) is based on:
Therapeutic approach to abnormal glucose tolerance and diabetes in thalassaemia Reproduced with permission from (De Sanctis V. TIF Congress, Dubai – 2006).
Monitoring glycaemic control in thalassaemic patients with DM is not different from that in the general diabetic population (De Sanctis 2013a, De Sanctis 2013b):
HPT has been considered as a typical complication of the second decade of life in transfusion dependent patients with thalassemia major. The incidence of HPT varies from centre to centre (from 1.2% to 19 %) and HPT seems to affect men more frequently (male/female ratio = 1.35) (Vogiatzi 2009, Sleem 2007, De Sanctis 2004). Recently, abnormal cerebral computed tomography findings have been reported in a high percentage of patients with thalassemia and HPT (Karimi 2009, Soliman 2008). An electrocardiogram (ECG) can detect an abnormality in the electrical activity of the heart.
The majority of patients show a mild form of the disease accompanied by paraesthesia. More severe cases may demonstrate tetany, seizures or cardiac failure (Skordis 2013).
Investigations should begin from the age of 16 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 2013).
Treatment of HPT aims to prevent acute and chronic complications of hypocalcemia. 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 calcifications (De Sanctis 2013a). Treatment includes:
No special diet is required, but some doctors recommend consulting a dietician, who is likely to advise a diet that is:
Several studies reported a significant prevalence of “biochemical” adrenal insufficiency in patients with thalassemia ranging from 0-45%. “Clinical” adrenal insufficiency, i.e. adrenal crisis, on the other hand, is extremely rare (El Kholy 2013).
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.
Cortisol levels both basal and 30-60 minutes after ACTH or insulin stimulation, are used for assessment of adrenal function. It is advised to test adrenal function every 1–2 years, especially in GHD patients during rhGH therapy (El Kholy, 2013), because patients with GH deficiency may have additional anterior pituitary hormone deficits, and are at risk of developing complete or partial corticotropin (ACTH) deficiency.
Subclinical impairment of adrenocortical function in patients with TM is not uncommon; however, it is of little or no clinical impact under basal conditions but may have a potential relevance during stressful events. Accordingly, glucocorticoid treatment coverage might be advised only for stressful conditions (El Kholy 2013). Clinical adrenal insufficiency and adrenal crisis are very rare.
Endocrine complications, growth and pubertal delay are common manifestations of iron overloading in TM and carry significant morbidity. As such, patients with TM need regular monitoring for signs and symptoms of endocrine complications. Prevention remains the first priority, and there are limited data to support a role for chelation therapy in this. Once endocrine complications have developed, management should focus on halting the progression of such complications and treating associated symptoms.
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