1 Pediatric and Adolescent Clinic, Quisisana Hospital, Ferrara, Italy, 2 Department of Pediatrics, Division of

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1 Selected Highlights of the VIII International Symposium of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A ) on Growth, Puberty and Endocrine Complications in Thalassaemia. Auditorium of the Sultan Qaboos University Hospital (SQUH) Muscat (Sultanate of Oman), 20th of December 2014 Vincenzo De Sanctis 1, MD, Ashraf T Soliman 2, MD, PhD, FRCP, Yasser Wali 3,7, MD Pead, FRCPCH (UK), Heba Elsedfy 4, MD, Shahina Daar 5, MD, Saif A.H. Al-Yaarubi 6, MD, FRCPC, Surikha Tony 3, MD, Mohamed Elshinawy 3,7, MD, Hanan Fawzy 3,7, MD, Taimoora Al-Subhi, MD 3, Abulhakim Al-Rawas 3, MD, FRCPC, Muhanna Al-Muslehi, MD, FRCPath 8, Mohamed El Kholy 4, MD 1 Pediatric and Adolescent Clinic, Quisisana Hospital, Ferrara, Italy, 2 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital Doha, Qatar, 3 Department of Child Health, Haematology/Oncology Unit, Sultan Qaboos University Hospital, Al-Khoud, Sultanate of Oman, 4 Department of Pediatrics, Ain Shams University, Cairo, Egypt, 5 Department of Hematology, Sultan Qaboos University Hospital, Al Khoud, Muscat, Sultanate of Oman, 6 Pediatric Endocrine Unit, Department of Child Health, Sultan Qaboos University Hospital, Al-Khoud, Sultanate of Oman, 7 Department of Pediatrics, Faculty of Medicine, Alexandria University, Egypt, 8 Hematology Department, Royal Hospital, Sultanate of Oman Corresponding author: Vincenzo De Sanctis, MD, Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy, Tel: , vdesanctis@libero.it 239 Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March 2015

2 Abstract T he VIII ICET-A International Symposium was held in Muscat (Sultanate of Oman) on the 20th of December, The symposium included four sessions on a wide range of topics covering growth disorders and endocrine complications in thalassaemia. Despite the fact that endocrine complications are very common in multi-transfused thalassaemia patients a recent survey conducted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) in 2014 in Acitrezza (Catania, Italy) showed that the major difficulties reported by hematologists or pediatricians experienced in thalassaemias or thalassaemia syndromes in following endocrine complications included: Lack of familiarity with medical treatment of endocrine complications, interpretation of endocrine tests, lack of collaboration and on-time consultation between thalassaemic centres supervised by haematologists and endocrinologists. Endocrinal monitoring of growth, pubertal development, reproductive ability and endocrine function in general are essential to achieve a good quality of life as well as controlling the pain which results from the defects of bone structure, all of which increase with the age of patients. Such comprehensive care is best provided by coordinated, multidisciplinary teams working in expert centres. The multidisciplinary team must include an en docrinologist, preferably someone experienced in the management of hormonal deficiencies caused early in life by transfusion-induced iron overload. Ref: Key words: Thalassemia, Growth, Endocrine complications, ICET-A symposium Presentation of the Symposium The VIII ICET-A International Symposium was held in Muscat (Sultanate of Oman) on the 20 th of December, 2014 at the Auditorium of Sultan Qaboos University Hospital (SQUH). The symposium, under the presidency of Prof Yasser Wali, Department of Child Health, Haematology/Oncology Unit, College of Medicine, Sultan Qaboos University Hospital, Sultanate of Oman, included four sessions on a wide range of topics on growth disorders and endocrine complications in thalassaemia. More than 60 participants (paediatricians, endocrinologists, haematologists) took part in this event. The symposium began with an open ceremony followed by an introduction by Prof Yasser Wali. The honorary lectures were presented by Professors Ashraf Soliman and Vincenzo de Sanctis on Growth and puberty in thalassemia and ICET-A an opportunity for improving thalassemia management. The chairs of the session were Prof Salam Alkindy and Dr Mahasen Saleh. The second session focused on adrenal function in thalassemia (Prof Mohamed El Kholy) and Osteoporosis: What s new in thalassemia (Prof Heba Elsedfy). The third session, chaired by Prof Moustafa Salama, included 3 honorary lecture presentations by Professors Yasser Wali ( New perspectives in initiating iron chelation therapy in thalassemia ), Vincenzo de Sanctis ( Diabetes in thalassemia ) and Shahina Daar ( Comprehensive care of thalassemia major in SQUH: A Difficult task ). The last session included the participants case presentations (Chairman: Dr Abdul Hakim Al Rawas) and the recommendations for management of endocrine complications in thalassemia (Prof Mohamed El Kholy). The closing remarks were done by Professors Yasser Wali and Ashraf Soliman. Introduction The haemoglobinopathies (thalassaemias and sickle-cell disease) are the most commonly inherited genetic disorders worldwide with some infants born annually with major haemoglobinopathies, and at least 190 million carriers. Haemoglobinopathies are common in Oman. Data from a community-based survey of the most common genetic blood disorders among Omani children has reported a prevalence rate of 2% for beta-thalassaemia trait, 0.07% for betathalassaemia major, 6% for sickle cell trait and 0.2% for sickle cell disease. Today many subjects with β-thalassaemia major (TM) successfully survive into adult life, due to remarkable improvement of medical care and better understanding of pathogenesis, clinical manifestations and prevention of endocrine complications. Nevertheless, despite improvement of treatment, the involvement of the endocrine system still burdens the life of these patients. In fact, several studies have reported that as many as 51% to 66% of patients may have pubertal failure, sexual dysfunction and infertility, due to hypogonadism. The causes of endocrine complications in the general population are multiple while in TM are classically considered to be mainly the result of iron deposition in the endocrine glands. Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March

3 Iron overload may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with treatment. Other factors contributing to the variability of cellular iron overload are cell surface transferring receptors and the capacity of the cells to deploy defence mechanisms against inorganic iron. Liver disorders, chronic hypoxia and associated endocrine complications, such as diabetes may be additional factors. Toxicity starts when the iron load in a particular tissue exceeds the tissue or blood-binding capacity of iron, and free nontransferrin iron appears. The free iron is a catalyst of the production of oxygen species that damage cells and peroxidize membrane lipids, leading to cell destruction. The anterior pituitary gland is particularly sensitive to the free radicals produced by oxidative stresses and exposure to these radicals is injurious to the gland. Magnetic resonance imaging (MRI) shows that even a modest amount of iron deposition within the anterior pituitary can interfere with its function. Excess iron deposition in the anterior pituitary leads to degranulation of the adenohypophysis and decreased hormone storage with ensuing hypogonadism due to pituitary hyporesponsiveness to gonadotropin releasing hormone. Endocrinal monitoring of growth, pubertal development, reproductive ability and endocrine function in general are essential to achieve a good quality of life as well as controlling the pain which results from the defects of bone structure, all of which increase with the age of patients. Such comprehensive care is best provided by coordinated, multidisciplinary teams working in expert centres. The multidisciplinary team must include an en docrinologist, preferably someone experienced in the management of hormonal deficiencies caused early in life by transfusioninduced iron overload. ICET-A an Opportunity for Improving Thalassemia Management The practical objectives of ICET-A are to encourage and guide endocrinal follow up of multi-transfused patients in developing countries, to promote and support collaborative research in this field, to encourage and guide endocrinal follow up of multi-transfused patients, and to educate and train more endocrinologists and other paediatricians/physicians to prevent and improve management of the growth and endocrine complications in these patients. The team of doctors who have taken the initiative and have formed the initial core ICET A group include endocrinologists: Vincenzo de Sanctis (Italy), Ashraf Soliman (Qatar), Nicos Skordis (Cyprus), Mohamed El Kholy and Heba Elsedfy (Egypt), Giuseppe Raiola (Italy), Ploutarchos Tzoulis (UK), Saif A.H. Al Yaarubi and Irfan Ullah (Sultanate of Oman). In addition doctors experienced in thalassaemia care are supporting the group. These include: Christos Kattamis (Greece), Mohamed Yassin (Qatar), Mehran Karimi (Iran), Praveen Sobti (India), Bernadette Fiscina (USA), Duran Canatan and Yurdanur Kilinç (Turkey), Androulla Eleftheriou and Michael Angastiniotis (Cyprus), Rania Elalaily (Qatar), Hala Rimawi (Jordan), Ludmila Papusha, (Russia), Soad K Al Jaouni (Saudi Arabia), Shahina Daar and Yasser Wali (Sultanate of Oman), Maria Concetta Galati, Saveria Campisi and Salvatore Anastasi (Italy), Su Han Lum (Malaysia). Despite the fact that endocrine complications are very common in multi-transfused thalassaemia patients a recent survey conducted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) in 2014 in Acitrezza (Catania, Italy) showed that the major difficulties reported by hematologists or pediatricians experienced in thalassaemias or thalassaemia syndromes in following endocrine complications are: 1. Lack of familiarity with medical treatment of endocrine complications 2. Interpretation of endocrine tests 3. Lack of collaboration and on-time consultation between thalassaemia centres supervised by haematologists and endocrinologists Growth and Puberty in Thalassemia Growth retardation occurs almost invariably in TM. Significant deficit is observed in stature, sitting height, weight, biacromial (shoulder), and bicristal (iliac crest) breadths. After the age of 4 years the longitudinal growth patterns display rates consistently behind those of normal controls. The bone age is frequently delayed after the age of 6 7 years. Growth retardation becomes markedly severe with the failure of the pubertal growth spurt. With the introduction of high transfusion regimes and efficient iron chelation prepubertal linear growth has improved markedly. However, abnormal growth is still observed in a considerable number of patients (30-60%) during late childhood and adolescence. The childhood phase of growth is growth hormone (GH) dependent whereas the pubertal phase depends on both GH and sex steroids secretion. In addition, adequate nutrition plays an important role during all phases of growth. Iron deposition has been documented in the pituitary, thyroid, and adrenal glands and gonads as well as in the pancreas, liver and growth plate. Hemosiderosis-induced damage of these endocrine glands is implicated as one of the main causes for their growth failure. However, other factors could considerably contribute to the etiology of this growth 241 Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March 2015

4 delay including: a. chronic anemic hypoxia secondary to low hemoglobin concentration (in-between transfusions) ; b. increased energy expenditure due to high erythropoietic turnover and cardiac work; c. nutritional deficiencies including calories, folic-acid, zinc, and vitamin A; d. disturbed calcium homeostasis and bone disease and e. impaired hepatic and pancreatic dysfunction and f. toxicity of chelation therapy (desferrioxamine). Many questions need to be addressed: # What is the prevalence of growth retardation and/or pubertal delay in BTM patients? # What is the effect of correction of their haemoglobin (Hb) on GH-IGF-I axis? # What is the effect of Intensive chelation therapy on growth? # Do children with thalassemia have abnormalities of GH/ insulin-like growth factor-i (IGF-I)/insulin-like growth factor binding protein 3 (IGFBP3) axis? # Does GH therapy increase linear growth in these patients? # Are these patients undernourished? What is the effect of increasing caloric intake on their growth? Does correction of nutritional deficiencies improve their growth? # What is the effect of bone marrow transplantation on their growth? I. Growth impairment both in stature and weight for height and/or BMI still occurs frequently in patients with TM and ranges between 32 and 62 % in different parts of the world (Height SDS (HtSDS) <-2) in thalassemia major. Delayed or failure of puberty occurs in 32% to 77% of patients and this is associated with attenuation or lack of pubertal growth spurt. Decreased weight for height, body mass index (BMI), muscle mass and subcutaneous fat thickness occurs frequently in a large number of these patients. II. Proper packed cell transfusion and chelation therapy when started early have positive effect on linear growth and normal adult height and pubertal development can be achieved in about 80% but not all patients. However, deferoxamine-induced growth retardation has been reported in some patients with TM and higher doses have toxic side effects on acoustic and visual pathways and therefore should not be used. The new oral chelators when used singly or in combination may attain better chelation with fewer side effects. Recently intensive and combined chelation has been shown to reverse many endocrine abnormalities in TM and hopefully may improve growth with early introduction and long term use. III. Many studies on GH secretion in thalassemic patients have shown reduced response to a variety of pharmacological stimuli (clonidine, glucagon, Insulin hypoglycemia, GHRH) (33% to 54%). Some of the short thalassemic children with normal GH response to provocation have low IGF-I and IGF-binding protein 3 (IGFBP3) levels due to disturbed pulsatile properties of GH (neuro-secretory dysfunction of GH secretion). The majority of patients (85% or more) have low IGF-I secretion secondary to either GH deficiency and/or hepatic dysfunction (siderosis and chronic hepatitis). The age-related levels in serum total IGF-I in children with TM is significantly decreased from early childhood to 18 years of age compared to normal subjects with lack or attenuation of pubertal rise of IGF-I level. In addition, defective IGF-I generation in response to exogenous GH injection has been reported in some but not all studies (partial resistance to GH). IV. These functional abnormalities of the GH/IGF-I/IGFBP3 axis are accompanied by structural abnormalities of the pituitary gland (pituitary siderosis and atrophy) and its stalk in patients with TM as well as with hepatic siderosis. Human GH therapy used for short (1-2 years) and long term (3-7 years) periods has been successful to improve linear growth in these patients. Long-term therapy with GH (>2-9 years) resulted in a final height gain of 2SD in males and 1.2 SD in females. These patients may need higher doses of GH compared to nonthalassemic GH deficient children because they may have a degree of GH resistance. V. Correction of anemia acutely increases secretion of IGF-I in children with TM. Hemoglobin concentration has been shown to correlate significantly with IGF-I concentration. However, correction of Hb does not increase GH secretion (in response to provocation) or IGF-I response to exogenous GH injection in thalassemic patients. VI. In both thalassemic boys and girls pubertal abnormalities are common and include: delayed onset of puberty, primary or secondary amenorrhea, hypo-gonadotropic hypogonadism (HH), and defective spermatogenesis and oogenesis. Investigations show low basal secretion of sex steroids, LH and FSH. LH and FSH response to stimulation by LHRH is defective or absent. The pulsatile properties of LH and FSH have been shown to be attenuated or absent. In some male patients with testicular siderosis, testosterone response to human chorionic gonadotropin is impaired. In children with TM, pubertal delay or failure has a deleterious effect on linear growth because of lack of sex-steroid stimulatory effect (direct effect on the growth plate, and indirect effect through stimulation of GH-IGF-I axis). On the other hand defective GH-IGF-I may delay the timely onset of puberty, slow the pace of pubertal maturation, attenuate phallic growth or reduces adult testicular size. In addition, low sex steroids and GH-IGF-I secretion have been associated with lower bone mineral density in adolescents and adults with TM. VII. Treatment of thalassemic patients with HH with increasing doses of estradiol in females and testosterone in males Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March

5 improves linear growth and the development of secondary sexual characteristics. The anabolic effects of testosterone are associated with increased pulsatile GH secretion, increased IGF-I synthesis in liver and bone cells, increased gut absorption and skeletal retention of calcium and magnesium and bone mass accretion. VIII. Many nutritional deficiencies have been described in children with TM including protein-energy deficiency (due to hyper-catabolism, increased metabolic work in bone marrow, cardiac and respiratory) and decreased appetite, zinc deficiency, vitamin D deficiency and carnitine deficiency. High caloric intake improves weight gain and IGF-I secretion in thalassemic children. In addition, zinc supplement for long time has been associated with better linear growth. Vitamin D deficiency is prevalent in many patients with TM and vitamin D therapy has been shown to increase IGF-I secretion and is vital for skeletal health. In addition, L-carnitine therapy has been shown to increase IGF-I secretion and improves growth in thalassemic children. IX. Bone marrow transplantation (BMT) has a positive effect on linear growth when accomplished during early childhood. Subjects who received BMT before 7 years had normal adult height in relation to their genetic target height. In one study, before BMT, 40% of thalassemic patients had HtSDS < -2 whereas 5 years after BMT only 15% had HtSDS < -2. The HtSDS increased by 0.6 SD (from -1.6 to 1) 5 years after BMT. A strict correlation has been found between age at time of transplant and final adult height. Children with TM who were <7 years had a less impaired growth rate than did patients who were >7 years. The greatest loss in height was observed with high ferritin and alanine transferase concentrations. Subjects who received BMT after 7 years of age, failed to achieve their full genetic potential. In conclusion, growth and pubertal disorders are still common in patients with TM. Proper application of blood transfusion and intensive chelation to decrease serum ferritin concentration between ng/ml, improving the nutritional status (protein-calorie, vitamin D, Zn, carnitine), correcting any GH and/or IGF-I deficiency by using GH therapy, inducing puberty at the proper time, implementing sex-steroid replacement for HH, prevention of hepatitis and employing bone marrow transplantation before 7 years of age can markedly improve growth and increase bone mineral mass in these children. What we Know about Fertility Potential in Male β-thal Patients? A Personal Experience Histologically, a reduced number of cells and moderate siderosis of the parenchymal cells of the anterior pituitary have been found. Testicular biopsies display various degrees of interstitial fibrosis and hyperpigmentation of undifferentiated seminiferous tubules and a decreased number of Leydig cells. Virtually very little is known about spermatogenesis in TM patients. A summary of the available findings include the followings: # A normal sperm count and motility in 45% of fully sexually mature TM subjects. # A possible detrimental effect of iron chelation therapy on spermatogenesis. Three out of four patients with serum ferritin levels lower than 500 ng/ml had poor sperm motility. # A higher degree of defective chromatin packaging in TM subjects with low sperm concentrations. # A low seminal plasma concentration of zinc, citric acid and prostate specific antigen. These data suggest an impaired prostatic secretion. # An increase of seminal lipo-peroxidation. # An increase of DNA sperm damage and a negative correlation with sperm motility. # These findings suggest that iron overload predispose sperm to oxidative injury could contribute to the impairment of sperm motility. # Blood transfusion is associated with significant acute enhancement of sperm parameters and increased concentrations of serum T, LH, FSH, and IGF-1. These "acute" effects on spermiogenesis are reached by an unknown mechanism and suggest a number of pathways that need further human and/or experimental studies. In addition, abnormal seminal parameters and low serum folic acid levels have been found in subjects with thalassaemia intermedia. In our experience, more and more adult thalassemic patients in their second and third decades of life develop late onset hypogonadism (LOH). It is possible to induce or restore spermatogenesis with exogenous gonadotropins in some of them. Assisted reproductive techniques may supplementary help these patients to overcome previously untreatable causes of male infertility. International guidelines are required to assist these patients because it is widely accepted that infertility and involuntary childlessness, and the decision to engage with assisted reproduction technology services as a patient, donor or surrogate can entail wide-ranging psychosocial issues. Adrenal Function in Thalassemia Major Secondary hemosiderosis due to excess iron has the potential to disrupt adrenal function by affecting the hypothalamicpituitary adrenal axis at hypothalamic or pituitary and/or adrenal level. Several studies reported a significant prevalence of biochemical adrenal insufficiency, ranging from 0-45%, in patients with thalassemia, due to different patient 243 Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March 2015

6 characteristics and different diagnostic tests used. Patients are usually asymptomatic. On the other hand, clinical adrenal insufficiency, i.e., adrenal crisis, is extremely rare. In a recent study at Ain Shams University, Children s Hospital, we studied 45 patients with thalassemia major of both sexes, 12 to 20 years of age (14.9± 2.2 years). They were receiving blood transfusions on a regular basis every 2-4 wk along with iron chelation therapy. Nineteen were in Tanner stage 1; 19 in Tanner 2 and 3 and 7 were in Tanner 4 and 5. All patients underwent the standard ACTH test in the morning. Blood samples for cortisol, dehydroepiandrosterone (DHEA) and androstenedione (Δ4) measurements were collected before and 60 min after IV of 250 μg ACTH. Using a minimum peak total cortisol level of 18 μg/ dl as normal, insufficiency was observed in 7 of 45 (15.5%) patients. Basal cortisol was normal in all patients with adrenal insufficiency except one patient whose basal cortisol was frankly low (2μg/dl). ACTH levels in patients with adrenal insufficiency ranged from pg/ ml i.e., secondary adrenal failure. All patients with adrenal insufficiency were asymptomatic and had no history of adrenal crisis. On the other hand, adrenal androgen levels decreased significantly with advancing Tanner stage. Pubic hair stage 4 and axillary hair stage 3 were only observed in 14.3% of patients in Tanner 4 and 5. This can also explain the poor development of pubic and axillary hair observed in thalassemic adolescents. The results seem to support additional direct damage of the adrenal gland while cortisol secretion is largely preserved in those with advanced puberty: there is dissociation between cortisol and adrenal androgen secretion. Diagnosis Manifestations of mild adrenal hypo function might be masked by symptoms commonly complained of by patients with TM, such as asthenia, muscle weakness, arthralgias and weight loss. Accordingly, measurement of both basal serum cortisol level and cortisol response to stimulation by adrenocorticotropic hormone (ACTH) or insulin stimulation (ITT) are advised for the assessment of adrenal function. Even though ITT has been considered the gold standard to disclose an impaired adrenal function, the ACTH stimulation test has been used for many years as an acceptable alternative with the advantage of lacking relevant adverse effects. While the low dose ACTH (1μg) may result in a higher falsepositive rate; the standard dose (250 μg) provides a supraphysiological stimulus that may mask partial adrenocortical insufficiency. In a survey done by the British Society of Paediatric Endocrinology and Diabetes in the UK and Ireland, 69% of centres use both tests. Lastly, it was found that in most clinical situations, the 30-minute cortisol value during a standard-dose has a diagnostic accuracy close to that of a lowdose test. It is advised to test adrenal function every 1 2 years, especially in growth hormone deficient patients during rhgh therapy. Screening of basal cortisol is usually done at 10 years of age or earlier if clinically indicated. ACTH stimulation is performed if basal cortisol is low or the patient is undergoing stressful events. Management Subclinical impairment of adrenocortical function in patients with TM is of little or no clinical impact under basal conditions but may have a potential relevance during stressful events. Consequently, glucocorticoid treatment coverage might be advised only for stressful conditions in those patients with subnormal cortisol response to ACTH stimulation. Osteoporosis in Thalassemia Major In well treated TM patients, the reported frequency of osteoporosis is approximately 40 50%. Fracture prevalence in iron-overloaded patients with TM ranged between 38% and 41% in two large studies in the US where self-reporting methodology was used. Unlike healthy individuals in whom fractures are common in adolescence with increased recreational activity, patients with TM experience fractures in adulthood, that are mainly attributed to vitamin D deficiency and low BMD. In thalassemia, progressive aging of the bone starts even in childhood by the gradual development of an imbalance between augmented osteoclastic resorption and insufficient osteoblastic bone formation, resulting in diminished BMD more evident in the lumbar spine. Alterations in the RANK/RANKL/OPG system in favour of osteoclasts occur in thalassaemia due to complicated mechanisms involving chronic anemia, iron toxicity, and endocrine complications. The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone. In the absence of vertebral compression fractures, the diagnosis of osteoporosis is indicated by the presence of both a clinically significant fracture history and bone mineral density (BMD) Z-score -2.0 i.e. adjusted for age, gender and body size, as appropriate. A clinically significant fracture history is one or more of the following: Two or more long bone fractures by age 10 yr. Three or more long bone fractures at any age up to 19 yr. The best established diagnostic techniques to assess osteoporosis focus on BMD (i.e., DXA and QCT). Conventional radiographs are not suited for determining bone mass but Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March

7 are essential for assessing osteoporotic fractures, which are particularly important in the spine. Using DXA, BMD is determined at the spine (AP or lateral), at the proximal femur and total body less head (TBLH). The hip (including total hip and proximal femur) is not a reliable site for measurement in growing children due to significant variability in skeletal development and lack of reproducible regions of interest. However, data from the Bone Mineral Density in Childhood Study (BMDCS) suggest that age-related precision of the total hip and femoral neck is comparable to both that of the spine and TBLH. Currently, normative data for total hip are available for children and adolescents but are more limited than for the spine and WB. Moreover, DXA systems are capable of acquiring the whole spine in a single projection in both the posterioranterior and lateral projections; whereas with conventional radiographs, the thoracic and lumbar spine requires 2 separate exposures/films. Vertebral Fracture Assessment (VFA) scan is approximately times lower than the radiation dose from lumbar and thoracic spine radiography. The minimum time interval for repeating a bone density measurement to monitor treatment with a bone-active agent or disease processes is 6 months. To be considered significant, the percent change in BMD must exceed the precision (or reproducibility) of the study itself i.e., the precision of the scanner and the operator. A typical precision range is a 1% to 3% change in bone density for measurements of the spine and a 3% to 5% change in bone density for measurements of the hip. In children with linear growth or maturational delay, spine and TBLH BMC and areal BMD results should be adjusted for height Z-score. Successive BMD studies should be done using the same machine, scanning mode, software, and analysis when appropriate. In conclusion, in patients with thalassemia major, spine and total body less head (TBLH) BMC and areal BMD should be measured at fracture presentation or at age 10 years, whichever is earlier. An Approach to Healthy Bones in Thalassemia Includes: Correction of Risk Factors: # Ineffective erythropoiesis and bone marrow expansion # Endocrine complications # Estrogen and testosterone deficiency # IGF-I deficiency # Iron overload and iron chelation therapy (deferoxamine) # Vitamin deficiencies # Decreased physical activity Applying Lifestyle Changes # Encourage physical activity: Weight bearing exercise, including activities that involve walking, running, and jumping, is best # Adequate calcium intake ( mg/day) # Adequate vitamin D intake (1000 IU/day) # In addition, all patients should be educated about the importance of avoiding unhealthy habits like cigarette smoking and drinking alcohol in excess Pharmacological Intervention Osteoporosis therapy should prevent both vertebral (mostly trabecular bone) and nonvertebral (mostly cortical) fractures. This could be achieved by inhibiting bone resorption and/or by stimulating bone formation. Antiresorptive agents are the ones commonly used. Both bisphosphonates and denosumab have been tested in thalassemia with good results. Impaired Glucose Tolerance (IGT) and Diabetes Mellitus (DM) 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 anemia, 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 The prevalence of IGT and IDDM in adolescents and young adults with TM mainly treated with desferrioxamine varies in different series from 0 to 17%. 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 parallel to puberty. The combined adverse effects of both puberty and thalassaemia on insulin secretion and action may partly explain the increase of glycaemic abnormalities in adolescent thalassaemics. 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. 245 Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March 2015

8 Pancreatic β-cell function in thalassaemia is characterised by the following sequence: 1. Insulin-resistance with hyperinsulinemia and normal glucose tolerance. 2. Insulin-resistance with impaired glucose tolerance (IGT) and progressive impairment of β-cell function with reduction of insulin secretion, and finally 3. Insulin dependent DM. β-cell function remains normal until the later stages of disease, but insulin sensitivity correlates inversely with iron overload and age. Fasting pro-insulin and pro-insulin to insulin ratio is significantly increased and correlate positively with hepatic iron but C-peptide levels are variable indicating variable β-cell function. Additional suggested factors are: genotype IVS II nt 745, zinc deficiency, small pancreas volume and presence of fat content detected with the MRI of pancreas and disturbed microcirculation in the pancreas. Moreover selective oxidative damage to pancreatic β-cells may also occur as a result of autoimmunity. The proposed risk factors for the development of glucose intolerance in TM patients were elevated ferritin levels, hepatitis C infection, age, family history of diabetes, and splenectomy. Early recognition of glucose abnormalities is essential. OGTT should be done in every patient with thalassaemia after the age of ten or earlier if needed. Pancreatic iron is the strongest predictor of β cell toxicity, which can be evaluated by MRI of the pancreas, although not standardized yet to be used in routine clinical practice. MRI and fasting glucose/insulin are complementary screening tools and if proven, may identify high-risk patients before irreversible pancreatic damage occurs. Nevertheless oral glucose tolerance testing still remains the standard test for glucose homeostasis; CGM has been proved to be superior to OGTT for the diagnosis of glycemic abnormalities in adolescents with thalassemia. Screening for hepatitis infections and use of regular chelation therapy are important measures in preventing the development of diabetes. Management Management of impaired glucose tolerance and diabetes is based on: 1. Strict diabetic diet 2. Regular physical activity 3. Intensive chelation therapy: enhanced iron chelation therapy with desferrioxamine and deferiprone is effective to normalise β-cell function and may improve insulin secretion and glucose tolerance particularly in patients in early stages of glucose intolerance 4. Oral hypoglycemic drugs: introducing oral hypoglycemic drugs in the early stage of DM before dependence on insulin may be beneficial, although limited data on the effect of oral antidiabetic drugs have been reported. 5. Insulin: symptomatic patients or patients with persistently elevated blood glucose despite other measures need more definitive treatment with insulin therapy. A joint thalassaemia and diabetes clinic was established at the Department of Diabetes, Whittington Health in London in Patients were reviewed by a multidisciplinary team including a consultant diabetologist and haematologist. Twentytwo TM patients were followed who were on medications relating to diabetes and management of complications; 16 patients (73%) were on insulin; 6 patients (27%) were on oral antidiabetic drugs (metformin, glimepiride) and 3 patients (14%) were on diet control alone. Five patients (23%) were on antihypertensive medication ]angiotensin-converting enzyme )ACE( inhibitors or angiotensin-ii receptor antagonists[; 5 patients (23%) were on lipid lowering agents (statins or fibrates) and 7 patients (32%) were on antiplatelet or anticoagulant therapy (aspirin or warfarin). A four-year study showed improvement in glycaemic control with fructosamine reduction and improved lipids. When patients attending the clinic were compared to a national diabetes audit, the number achieving goals for glycaemic, blood pressure and cholesterol control were significantly higher. However, 22.7% of the patients had microvascular complications. A significant proportion of patients also had other endocrinopathies (86.0% hypogonadism, 18.0% hypothyroidism, 23.0% hypoparathyroidism) In our experience the incidence of microvascular complications is low and no macrovascular complications (cardio-, cerebroor peripheral-vascular disease) have been documented. However, the prevalence of associated endocrine and non endocrine complications is high. Monitoring glycaemic control in thalassaemic patients with DM is not different from that in the general diabetic population on: 1. Daily home capillary glucose monitoring 2. Urine ketones if blood sugar is above 250 mg/dl 3. Fructosamine estimation every month. HbA1c is not a reliable indicator of glycaemic control because of reduced red cell lifespan, ineffective haemopoiesis and frequent blood transfusions, all of which may potentially affect the validity of the HbA1c result 4. Assessment of renal function 5. Urinary microalbumin and protein 6. Evaluation of retinopathy Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March

9 The impact of diabetes in thalassaemia must be considered in many situations. In pregnancy, diabetes in the mother can lead to a four-fold increased risk of foetal anomaly and threefold increase in perinatal mortality. In patients with cardiac complications, diabetes can adversely affect cardiac function and should be monitored. The physiological stress associated with surgery can lead to significant deterioration in glycaemic control, which itself can lead to increased morbidity and mortality from surgery. New Perspectives in Initiating Iron Chelation Therapy in Thalassemia The current TIF guidelines recommend the start of iron chelation therapy at the age of 3 years or if serum ferritin exceeds 1000ng/ml. In SQUH, and in this part of the world, a severe form of B thalassaemia major that needs a transfusion as early as 3 months of age prevails. We found that most of the patients who were started on iron chelation therapy based on these guidelines, had high serum ferritin concentrations that required a significantly long time to create a negative iron balance and remove excess deposited iron from liver and heart. The main concern of starting iron chelation therapy at an earlier age was the availability of a sole iron chelator (deferrioxamine) which if started prematurely might cause serious adverse events affecting bone growth, hearing and vision, especially with lower serum ferritin levels. With the accessibility of the newer oral iron chelators (deferiprone and deferasirox), we decided to start chelation therapy at a younger age (as early as 18 months) and with a lower serum ferritin cut off (500 ng/ml). Currently we have 63 patients at the Paediatric Thalassemia Day Care Centre SQUH, Oman, (age range 8 months - 10 years). They have been started on Iron chelation therapy (Deferasirox and Deferiprone) at a mean age of 18 months (range months) with a mean serum ferritin of 625ng/ml (range ng/ml). These patients did much better than the older age group and maintained a much lower serum ferritin with a significant less dose of the iron chelators. We are in the process of finalizing the data and writing the manuscript. Comprehensive Care of Thalassemia Major in SQUH: A Difficult Task The Sultanate of Oman is situated in the South-East corner of the Arabian Peninsula. The prevalence of haemoglobinopathies is similar to other countries in the region, with prevalence of HbS at 5.7% and beta thalassaemia at 2.7%. The thalassaemia unit at Sultan Qaboos University Hospital (SQUH) was started shortly after the opening of the hospital in 1990; by 1993, 93 patients with thalassaemia major (TM) aged 2-20yrs were being managed in the day care unit. This encompassed >95% of all TM patients being treated in Oman at the time. The age range was 1-20 years (mean 8.3 years) and S Ferritin ranged from 564ng/ml-9036ng/ml (mean 3750, median 4445). The data showed that almost all TM patients were dying before the 3rd decade of life. We also found that very few patients were being regularly chelated. Since 1991, all TM patients get adequate transfusion and all are on regular iron chelation therapy. Bone marrow transplantation was started at SQUH in 1995 and MRI T2* has been available in our institution since Endocrine Complications in 139 TM patients born before 2002 Hypogonadism (both primary and secondary) was identified in 57% of patients, diabetes (both insulin dependent and non- insulin dependent) in 24.5%; hypothyroidism in 8.6% and hypoparathyroidism in 7.9%. The prevalence of hypogonadism is similar to that found in other populations. However, diabetes is much more prevalent in our TM population, possibly due to the known genetic predisposition in the Middle Eastern population. We compared two cohorts of TM patients: those born before 1985 (who had very poor or no chelation until 1991), and those born after 1985 (who had access to good chelation from a young age). There is a significant difference in the prevalence of hypogonadism: 80% of older patients compared to 40% in younger patients. Similar findings are present regarding prevalence of diabetes (45% compared to 10%). There is no significant difference between the two cohorts regarding prevalence of hypothyroidism and hypoparathyroidism which are relatively uncommon complications. The difference in prevalence of diabetes may also be due to the much higher prevalence of HCV infection in the older age group. The association between HCV infection and diabetes has been described in the literature. Since patients (194 TM and 41 thalassaemia intermedia) have been regularly followed in day care at SQUH. Among the 194 TM patients, 43 have undergone bone marrow transplantation and there have been 45 deaths, 22 due to cardiac iron load, 10 due to infection, and 13 due to other causes such as HIV (in the early years), HCV related causes, etc. We have seen a marked improvement in total body iron load with the majority of patients now < 2000ng/ml (21 < 500ng/ml). In addition, there has been an improvement in endocrinopathies in patients who have a low S ferritin for a prolonged period of time, including reversal of hypogonadism in 4 patients, and normalisation of deranged glucose tolerance OGTT in 6 patients. We have also seen an improvement in cardiac and liver iron load based on T2* MRI in the cohort as a whole, but we still have patients who are heavily iron loaded. Survival has improved with many patients now in the 3 rd decade of life and some entering the 4 th decade. However the current number of patients with thalassaemia major followed at the University 247 Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March 2015

10 hospital (196) with age range 6 months 41years (mean 16 years, median 14 years) shows that the continued high number of new births of patients with haemoglobinopathies in Oman remains a major problem. Disclosure The authors declare that they have no competing interests. References 1. Rajab AG, Patton MA, Modell B. Study of hemoglobinopathies in Oman through a national register. Saudi Med J 2000;21: Al-Riyami A, Ebrahim GJ. Genetic Blood Disorders Survey in the Sultanate of Oman. J Trop Pediatr 2003;49(Suppl 1):i1-i20 3. De Sanctis V, Eleftheriou A, Malaventura C. Thalassaemia International Federation Study Group on Growth and Endocrine Complications in Thalassaemia. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF). Pediatr Endocrinol Rev 2004;2(Suppl 2): De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, Karimi M, Yassin MA, El Awwa A, Stoeva I, Raiola G, Galati MC, Bedair EM, Fiscina B, El Kholy M. Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab 2013;17: Soliman A, De Sanctis V, Elsedfy H, Yassin M, Skordis N, Karimi M, Sobti P, Raiola G, El Kholy M. Growth hormone deficiency in adults with thalassemia: an overview and the I-CET recommendations. Georgian Med News 2013;333: Soliman A, De Sanctis V, Yassin M, Abdelrahman MO. Growth hormone - insulin-like growth factor-i axis and bone mineral density in adults with thalassemia major. Indian J Endocrinol Metab : De Sanctis V, Soliman AT, Candini G, Yassin M, Raiola G, Galati MC, Elalaily R, Elsedfy H, Skordis N, Garofalo P, Anastasi S, Campisi S, Karimi M, Kattamis C, Canatan D, Kilinc Y, Sobti P, Fiscina B, El Kholy M. Insulin-like Growth Factor-1 (IGF-1): Demographic, Clinical and Laboratory Data in 120 Consecutive Adult Patients with Thalassaemia Major. Mediterr J Hematol Infect Dis 2014 Nov 1;6(1):e doi: /MJHID Soliman A, De Sanctis V, Yassin M, Abdelrahman MO. Growth hormone - insulin-like growth factor-i axis and bone mineral density in adults with thalassemia major. Indian J Endocrinol Metab 2014;18: El Kholy M. Adrenal disorders. In: The Ludhiana Booklet. Growth and endocrine complications in thalassaemia. EndoThal 2013;(Suppl.1): Elsedfy HH, El Kholy M, Tarif R, Hamed A, Elalfy M. Adrenal function in thalassemia major adolescents. Pediatr Endocrinol Rev 2011;8(Suppl 2): Soliman AT, Yassin M, Majuid NM, Sabt A, Abdulrahman MO, De Sanctis V. Cortisol response to low dose versus standard dose (back-to-back) adrenocorticotrophic stimulation tests in children and young adults with thalassemia major. Indian J Endocrinol Metab 2013;17: Poomthavorn P, Isaradisaikul B, Chuansumrit A, Khlairit P, Sriphrapradang A, Mahachoklertwattana P. High prevalence of "biochemical" adrenal insufficiency in thalassemics: is it a matter of different testings or decreased cortisol binding globulin? J Clin Endocrinol Metab 2010;95: Huang KE, Mittelman SD, Coates TD, Geffner ME, Wood JC. A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing. J Pediatr Hematol Oncol 2015;37: De Sanctis V, Soliman AT, Elsedfy H, Yassin M, Canatan D, Kilinc Y, Sobti P, Skordis N, Karimi M, Raiola G, Galati MC, Bedair E, Fiscina B, El Kholy M. I-CET (International Network on Growth Disorders and Endocrine Complications in Thalassemia). Osteoporosis in thalassemia major: an update and the I-CET 2013 recommendations for surveillance and treatment. Pediatr Endocrinol Rev 2013;11: Yassin MA, Soliman AT, De Sanctis V, Abdelrahman MO, Aziz Bedair EM, AbdelGawad M. Effects of the anti-receptor activator of nuclear factor kappa B ligand denusomab on beta thalassemia major-induced osteoporosis. Indian J Endocrinol Metab 2014;18: Vogiatzi MG, Macklin EA, Trachtenberg FL, Fung EB, Cheung AM, Vichinsky E, Olivieri N, Kirby M, Kwiatkowski JL, Cunningham M, Holm IA, Fleisher M, Grady RW, Peterson CM, Giardina PJ. Thalassemia Clinical Research Network. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America.Br J Haematol 2009;146: Soliman AT, Yasin M, El-Awwa A, De Sanctis V. Detection of glycemic abnormalities in adolescents with beta thalassemia using continuous glucose monitoring and oral glucose tolerance in adolescents and young adults with β-thalassemia major: Pilot study. Indian J Endocrinol Metab 2013;17: De Sanctis V, Soliman A, Yassin M.Iron overload and glucose metabolism in subjects with β-thalassaemia major: An overview. Curr Diabetes Rev 2013;9: Barnard M, Tzoulis P. Diabetes and thalassaemia. Thal Reports doi. org/ /thal.2013.s1.e Tzoulis P, Shah F, Jones R, Prescott E, Barnard E. Joint diabetes thalassaemia clinic: An effective new model of care. Hemoglobin 2014;38: Farmaki K, Angelopoulos N, Anagnostopoulos G, Gotsis E, Rombopoulos G, Tolis G. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major. Br J Haematol 2006;134: Berdoukas V, Farmaki K, Wood JC, Coates T. Iron chelation in thalassemia: time to reconsider our comfort zones. Expert Rev Hematol 2011;4: Noetzli LJ, Papudesi J, Coates TD, Wood JC. Pancreatic iron loading predicts cardiac iron loading in thalassemia major. Blood 2009;114: El Kholy M, Elsedfy H, Soliman A, Anastasi S, Raiola G, De Sanctis V. Towards an optimization of the management of endocrine complications of thalassemia. J Pediatr Endocrinol Metab 2014;27: Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V. Guidelines for the Management of Transfusion Dependent Thalassaemia, Thasassemia International Federation 3rd Edition, Zachariah M, Tony S, Bashir W, Al Rawas A, Wali Y, Pathare A. Comparative Assessment of Deferiprone and Deferasirox in Thalassemia Major Patients in the First Two Decades-Single Centre Experience. Pediatr Hematol Oncol 2013;30: Al-Lamki Z, Wali YA, Wasifuddin MS, Zacharia M, Shakeel A, Rafique B. Natural History of Sickle hemoglobinopathy in Omani Children. Int J Pediatr Hematol Oncol 2000;7: Alkindi S, Al Zadjali S, Al Madhani A, Daar S, Al Haddabi H, Al Abri Q, Gravell D, Berbar T, Pravin S, Pathare A, Krishnamoorthy R. Forecasting hemoglobinopathy burden through neonatal screening in Omani neonates. Hemoglobin 2010;34: Al-Riyami AA, Suleiman AJ, Afifi M, Al-Lamki ZM, Daar S. A community-based study of common hereditary blood disorders in Oman. East Mediterr Health J 2001;7: Pediatric Endocrinology Reviews (PER) n Volume 12 n No 3 n March