A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of ß- cell function and insulin sensitivity in patients with transfusion-dependent ß- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate ß-cell response, and the ability of ß-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent ß-thalassemia (ß-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for ß-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with ß-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

A Multicenter ICET-A Study on Age at Menarche and Menstrual Cycles in Patients with Transfusion-Dependent Thalassemia (TDT) who Started Early Chelation Therapy with Different Chelating Agents.

Introduction: To evaluate the effect of early chelation therapy (≤ 3 years) with a variety of chelating agents on age at menarche and menstrual characteristics in patients with transfusion-dependent thalassemia (TDT). Design: A retrospective multicenter study promoted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A). Setting: Eight of 13 International Thalassemia Centers (61.5%) in the ICET-A Network participated. Patients: Fifty-seven female TDT patients, aged 11 to 26 years, and with early iron chelation therapy, were eligible for the present study. They were enrolled from one center from Iran (33 patients), 3 centers from Bulgaria (9), 1 from Greece (8), one from Oman (4), 1 from Cyprus (2), and 1 from Italy (1). Seven patients were excluded, four still prepubertal (age 12-14 years) and 3 with primary amenorrhea. Therefore 50 patients were finally enrolled. Results: All fifty TDT patients developed spontaneous menarche at a mean age of 14.2 ± 2.24 years (range 9 - 20). A significant positive correlation was observed between age at menarche and serum ferritin levels (r: 0. 41, p=0.005). Regular menstrual cycles were reported from 32 (64%) patients, of whom 28 (83.3%) get menarche at age ≤ 14 years. Complications were more frequent in patients older than 14 years at menarche and in those with secondary amenorrhea. Conclusions: Age at menarche greater than 14 years was a forerunner of menstrual irregularities and associated complications in 36% of patients despite precocious chelation therapy. The poor adherence to treatment, to be demonstrated in future studies, could explain the finding.

Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (ß-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

BACKGROUND AND AIM: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic ß-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (ß-TM), also identified as transfusion-dependent thalassemia (TDT). STUDY DESIGN AND PATIENTS: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young ß-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal ß-TM females with AHH on HRT were followed for 8.26 ± 1.49 years. RESULTS: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 ß-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up. CONCLUSION: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.

Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and ß-cell secretion in eleven ß-thalassemia major patients with mild iron overload.

BACKGROUND: Iron chelation therapy (ICT) is the gold standard for treating patients with iron overload, though its long-term effects are still under evaluation. According to current recommendations regarding  transfusion-dependent  (TD)  ß-thalassemia major (ß-TM) patients, their serum ferritin (SF) levels should be maintained below 1,000 ng/mL and ICT should be discontinued when the levels are <500 ng/mL in two successive tests. Alternatively, the dose of chelator could be considerably reduced to maintain a balance between iron input and output of  frequent transfusions. STUDY DESIGN: Due to the paucity of information on long-term effects of ICT  in ß-TM with low SF levels on glucose homeostasis, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) promoted a retrospective and an ongoing prospective observational study with the primary aim to address the long-term effects of ICT on glucose tolerance and metabolism (ß-cell function and peripheral insulin sensitivity) in adult ß-TM patients with persistent SF level below 800 ng/mL. PATIENTS AND METHODS: 11 ß-TM patients (mean age: 35.5 ± 5.5 years; SF range: 345-777 ng/mL) with normal glucose tolerance test (OGTT) or abnormal glucose tolerance (AGT) for a median of 5.3(1.1-8.3) years. RESULTS: Abnormal glucose tolerance (AGT) was observed in 7 patients (63.6%) at first observation and ) persisted in 6 patients (54.5%) at last observation. None of them developed diabetes mellitus. AGT was reversed in two patients. One patient with NGT developed early glucose intolerance (1-h PG ≥155 and 2-h PG <140 mg/dL). Three out of  5 patients with isolated impaired glucose tolerance presented a variation of  ATG. Stabilization of low indices for ß-cell function and insulin sensitivity/resistance was observed. One patient developed hypogonadotrophic hypogonadism. Three out of 6 patients with SF below 500 ng/dL had hypercalciuria. CONCLUSION: Despite low SF level, the burden of endocrine complications remains a challenge in ß-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.

Thalassaemia-A global view.

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context.

Glucose Homeostasis and Assessment of ß-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with ß-Thalassemia Major with Serum Ferritin below 1,000 ng/dL: Results from a Single ICET-A Centre.

Aims: The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indices of insulin sensitivity and resistance, during a 3-hour oral glucose tolerance test (OGTT), in ß-thalassemia major patients (ß-TM) with serum ferritin (SF) below 1,000 ng/mL. Patients and methods: The retrospective cohort study evaluated the medical records of 24 ß-TM patients from 2010 to 2022. At the year of study the mean age of patients was 31.0 ± 4.1 (20-37.11) years; 13 (54.1%) were females. The most commonly used iron chelator was deferoxamine (DFO: 75%), followed by deferiprone (DFP:12.5%) and deferasirox (DFX: 12.5%). Insulin sensitivity and resistance indices were derived from OGTT. A liver iron concentration (LIC) < 3 mg/g d.w. and a global heart T2* value > 20 ms were considered as conservative cut-off values for insignificant iron overload (IOL). Results: The mean SF levels in the whole study cohort population at the age of evaluation was 549.6 ± 232.3 ng/mL. Based on the SF levels, two groups were identified: Group A (N = 14) < 500 ng/mL and Group B (N=10) 500-1,000 ng/mL. Normal glucose tolerance (NGT) during OGTT was observed in 4 patients of Group A (28.5 %) and in 5 patients of Group B (50%) (P: 0.29). The remaining 15/24 patients (62.5%) had glucose dysregulation (GD). The mean age at starting iron chelation therapy (ICT) and the mean SF peak in Group A versus Group B were significantly higher in group A. The GD was associated with significantly attenuated IGI (first phase of insulin response) and impaired oral disposition index (oDI). Hypogonadotropic hypogonadism (HH) was the most common associated endocrine complication in both groups of patients. Conclusions: This study showed that efficient iron chelation monotherapy in patients with ß-TM and SF < 1,000 ng/ml did not entirely prevent glucose metabolism disorders, abnormalities of insulin secretion and sensitivity, and development of acquired hypogonadism.

Screening for glucose dysregulation in ß-thalassemia major (ß-TM): An update of current evidences and personal experience.

Glucose dysregulation (GD) in patients with ß-thalassemia major (ß-TM) usually develops gradually. Prediabetes consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), the latter detected by a standardized oral glucose tolerance test (OGTT). Diagnosis of prediabetes is essential for an early identification of high-risk individuals who will benefit from intensive iron chelation therapy and lifestyle modification. Therefore, patients with ß-TM should undergo annual screening for glucose abnormalities, according to international recommendations, starting from the age of 10 years. OGTT remains the preferred screening method as it is more sensitive for GD than fasting plasma glucose (FPG), although it is poorly reproducible. The use of HbA1c measurement has limited use as it is generally considered unreliable in patients with thalassemia. Continuous glucose monitoring system (CGMS) is an accurate method to detect the variability of glucose fluctuations and offers the opportunity for better assessment of glucose homeostasis in a selected group of ß-TM patients. Pancreatic Magnetic Resonance Imaging (MRI) associated with insulin secretion-sensitivity index-2 (ISSI-2) could be a complementary test, minimizing the necessity for OGTT and identifying high-risk patients before irreversible pancreatic damage occurs. The aims of this short report are to give practical guidance for an early identification of GD in ß-TM patients, to summarise our experience, and to offer an impetus for further research in the field.

A study of isolated hyperglycemia (blood glucose ≥155 mg/dL) at 1-hour of oral glucose tolerance test (OGTT) in patients with ß-transfusion dependent thalassemia (ß-TDT) followed for 12 years.

OBJECTIVE: Subjects with normal glucose tolerance (NGT) but 1-hour post-load plasma glucose (1-h OGTT) ≥ 155 mg/dl (8.6 mmol/L; H-NGT) have an increased risk for developing Type 2 diabetes mellitus (T2DM), determining a new risk factor category with deeper metabolic impairment. The aim of this study was to evaluate the H-NGT as a diagnostic predictor of future dysglycemia in ß-transfusion dependent thalassemia (ß-TDT). Indices of insulin secretion and insulin sensitivity derived at baseline from OGTTs, were also reviewed. STUDY DESIGN AND METHODS: OGTT and indices of insulin secretion and insulin sensitivity, derived at baseline during OGTT, in 17 ß-TDT with H-NGT and 29 ß-TDT with normal OGTT (NGT) and without H-NGT followed for 12 years were studied. RESULTS: H-NGT was associated with decreased insulin sensitivity and progressive deterioration of glucose tolerance. At baseline, serum ferritin and serum alanine aminotransferase (ALT) levels were higher in patients with H-NGT compared to patients with NGT. A strong correlation was observed between ALT and 1-hour plasma glucose value during OGTT in the total group of 36 patients . Compliance to iron chelation therapy was poor in ß-TDT patients with H-NGT. An inverse correlation was found between 1-hour plasma glucose value during OGTT and insulin secretion-sensitivity index-2 (ISSI-2) (r: -0.3298; p: 0.025), between ISSI-2 and ALT (r: -0.3262; p: 0.027), and between 1-hour plasma glucose value and ISSI-2 (r: -0.537; p: 0.005) in the whole group of ß-TDT patients enrolled in our study. CONCLUSIONS: This retrospective study displayed that finding an isolated high 1-hour post-load glucose level (≥155 mg/dL; H-NGT) during the OGTT may serve as a simple biomarker to detect high-risk patients, with chronic liver disease and/or iron overload, who need periodic glycemic surveillance. Measuring the ISSI 2 represented another valuable predictive marker in the assessment of glycemia in these patients.

The Pancreatic changes affecting glucose homeostasis in transfusion dependent ß- thalassemia (TDT): a short review.

BACKGROUND: The natural history of the glycometabolic state in transfusion-dependent ß-thalassemia (TDT) patients is characterized by a deterioration of glucose tolerance over time. AIMS: This review depicts our current knowledges on the complex and multifacet pathophysiologic mechanisms implicated in the development of alteration of glucose homeostasis in patients with TDT. SEARCH STRATEGY: A systematic search was done on December 2020 including Web of Science (ISI), Scopus,  PubMed, Embase, and Scholar for papers published in the last 20 years. Moreover, we checked the reference lists of the relevant articles and previously performed reviews for additional pertinent studies. The personal experience on the care of patients with thalassemias is also reported. CONCLUSION: A regular packed red blood cells (PRBCs) transfusion program, optimization of chelation therapy, and prevention and treatment of liver infections are critical to achieve adequate glucometabolic control in TDT patients. Many exciting opportunities remain for further research and therapeutic development.

Abnormal diastolic function and Global longitudinal strain in patients with Thalassemia Major on long term chelation therapy.

Cardiac complications are the major cause of mortality in patients with Thalassemia major (TM). Cardiac T2* MRI is currently the gold standard for assessing myocardial iron concentration. The aim of our study was to assess whether any echocardiographic parameter would correlate with these findings in patients well established on chelation therapy. This was a prospective study on patients with TM who are regularly followed in our clinic. Patients had a cardiac MRI and echocardiogram within 2 months of each other. Echo parameters included global longitudinal strain and diastolic function. We also compared these findings with those from a cohort of thalassemia intermedia (TI) and normal controls. A total of 84 patients (mean age 26.3 ± 6.1 years, 42.8% male) with TM were enrolled. All had normal left ventricular ejection fraction and only 8 patients had MRI T2* < 10. As compared to 17 patients with TI and 53 controls, these patients had significantly higher E/E' and lower pulmonary vein s/dd ratio suggesting early diastolic dysfunction. 28 patients fulfilled criteria for diastolic dysfunction even in the presence of normal MRI T2*. Global longitudinal strain (GLS) was significantly lower in the TM group as compared to the TI and controls. We found no correlation between any of the echo findings and the MRI T2*in TM patients. In patients with thalassemia and MRI T2* > 20 ms features of diastolic dysfunction persist even in the presence of normal LV function and normal GLS. This suggests that diastolic function remains abnormal even when myocardial iron concentrations are normal and follow up therefore is essential.

A complication risk score to evaluate clinical severity of thalassaemia syndromes.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment.

Cardiac T2* MR in patients with thalassemia major: a 10-year long-term follow-up.

The consequence of regular blood transfusion in patients with thalassemia major (TM) is iron overload. Herein, we report the long-term impact of chelation on liver iron concentration (LIC) and cardiac T2* MR in patients with TM. This is a retrospective cohort study over 10 years of adolescents and adults with TM aged at least 10 years who had their first cardiac T2* MR between September 2006 and February 2007. One-year chelation therapy was considered the unit of analysis. A total of 99 patients were included in this study with a median age of 18 years. The median cardiac T2* MR and LIC at baseline were 19 ms and 11.6 mg/g dw, respectively. During follow-up, 18 patients died and six underwent successful bone marrow transplantation. Factors associated with decreased survival were older age (HR 1.12, p = 0.014) and high risk cardiac T2* (HR 8.04, p = 0.004). The median cardiac T2* and LIC significantly improved over the 10-year follow-up period (p = 0.000011 and 0.00072, respectively). In conclusion, this long-term "real-life" study confirms that low cardiac T2* adversely impacts the overall survival in patients with TM. Higher baseline LIC predicts a larger reduction in LIC, and lower baseline cardiac T2* predicts a larger improvement in T2*.

Prevalence, attitude and practice of self-medication among adolescents and the paradigm of dysmenorrhea self-care management in different countries.

Self-medication (SM) is an important worldwide public health issue affecting children and adolescents. The pattern of SM varies in different communities, affected by factors such as age, sex, income, expense, self-care orientation, educational level and medical knowledge. It is a fairly common practice: for minor health problems, it often provides cheap, rapid, and convenient solutions, outside of the health care system of many countries. Painkillers, antipyretics, cough medicines, cold preparations, dermatological products, nutritional supplements and antibiotics are the drugs most frequently used. Potential risks include incorrect self-diagnosis, improper dosage, inappropriate choice of therapy, masking of severe disease and drug interactions. Lack of awareness of warnings and precautions, storage conditions, the recommended shelf-life and adverse reactions increase the risk of side effects. Little is known about the SM of dysmenorrhea by adolescent girls. Attitudes towards treatment are influenced by cultural, ethnic, and religious factors. Some girls discuss dysmenorrhea with family and friends, and the majority may not seek medical advice. As dysmenorrhea is a common problem for adolescents, it is essential that these girls be aware of the normal and abnormal symptoms of menstruation. In the light of these findings, the roles of family, school, health professionals and health authorities are of utmost importance for the implementation of measures to approach this health problem in a more efficient way.

Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries.

BACKGROUND: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. AIMS OF THE STUDY: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. RESULTS: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with ß- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other "general medical and non-medical conditions". CONCLUSIONS: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care.

Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment.

Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are frequent and well recognized disturbances among male patients with transfusion dependent (TD) thalassaemia major (ß-thal). These problems are attributed mainly to the damage caused by chronic anaemia and the deposition of excess iron in the pituitary gland and testicles. This is a short review of male pubertal disorders in patients with ß-thal written by pediatric endocrinologists and haematologists with an interest and active involvement, in the diagnosis and management of these complications in this group of patients. A vigilant clinical evaluation of growth and puberty, as well as an appropriate hormonal evaluation in poly-transfused (TD ß-thal) patients is strongly recommended for early detection and treatment of endocrine dysfunction. Of crucial importance also, is the implementation of an efficient chelation regime from early life, to prevent severe iron load and permanent damage to the endocrine glands, particularly those responsible for gonadal function.

An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Major and Intermedia: A preliminary report.

Hypoparathyroidism (HPT) is a rare disease with leading symptoms of hypocalcemia, associated with high serum phosphorus levels and absent or inappropriately low levels of parathyroid hormone (PTH). In patients with thalassemias it is mainly attributed to transfusional iron overload, and suboptimal iron chelation therapy. The main objectives of this survey were to provide data on the prevalence, demographic and clinical features of HPT in thalassemia major (TM) and intermedia (TI) patients living in different countries, and to assess its impact in clinical medical practice. A questionnaire was sent to all Thalassemia Centres participating to the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) Network.Seventeen centers, treating a total of 3023 TM and 739 TI patients, participated to the study. HPT was reported in 206 (6.8%) TM patients and 33 (4.4%) TI patients. In general, ages ranged from 10.5 to 57 years for the TM group and from 20 to 54 years for the TI group. Of the 206 TM patients and 33 TI patients with HPT, 117 (48.9%) had a serum ferritin level >2.500 ng/ml (54.3% TM and 15.1% TI patients) at the last observation. Hypocalcemia varied in its clinical presentation from an asymptomatic biochemical abnormality to a life-threatening condition, requiring hospitalization. Calcium and vitamin D metabolites are currently the cornerstone of therapy in HPT. In TM patients, HPT was preceded or followed by other endocrine and non-endocrine complications. Growth retardation and hypogonadism were the most common complications (53.3% and 67.4%, respectively). Although endocrine complications were more common in patients with TM, non-transfused or infrequently transfused patients with TI suffered a similar spectrum of complications but at a lower rate than their regularly transfused counterparts.In conclusion, although a large international registry would help to better define the prevalence, comorbidities and best treatment of HPT, through the result of this survey we hope to give a clearer understanding of the burden of this disease and its unmet needs. HPT requires lifelong therapy with vitamin D or metabolites and is often associated with complications and comorbidities.Therefore, it is important for endocrinologists and other physicians, who care for these patients, to be aware of recent advances of this disorder.

Review and Recommendations on Management of Adult Female Thalassemia Patients with Hypogonadism based on Literature Review and Experience of ICET-A Network Specialists.

BACKGROUND: Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists. The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed. METHODS: In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network. RESULTS: The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients' compliance to treatment was reported as good in 81.2 % of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating centers. CONCLUSIONS: Doctors taking care of TM patients should have sound knowledge of the pathophysiology of hypogonadism in adult females with TM. They should know the potential effects of HRT including advantages and disadvantages of estrogen and progestins. Moreover, they should keep in consideration the emotional needs of these patients dreaming of attaining a full pubertal development.

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 (SQU) Muscat (Sultanate of Oman), 20th of December 2014.

The VIII ICET-A International Symposium was held in Muscat (Sultanate of Oman) on the 20th of December, 2014. 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. Endocrine 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 endocrinologist, preferably someone experienced in the management of hormonal deficiencies caused early in life by transfusion-induced iron overload.

Pregnancy Outcomes in Women with Homozygous Beta Thalassaemia: A single-centre experience from Oman.

OBJECTIVES: Pregnancy in women with homozygous beta thalassaemia (HBT) carries a high risk to both the mother and fetus. The aim of this study was to investigate pregnancy outcomes among this group at a single tertiary centre. METHODS: This retrospective descriptive study was conducted between January 2006 and December 2012 on all women with HBT who received prenatal care and subsequently delivered at Sultan Qaboos University Hospital, Muscat, Oman. Women who delivered elsewhere and women with the beta thalassaemia trait were excluded. RESULTS: Ten women with HBT were studied with a total of 15 pregnancies and 14 live births. The mean maternal age ± standard deviation (SD) was 27.9 ± 3.7 years, with a range of 24-35 years. There were 14 spontaneous pregnancies and one pregnancy following hormone treatment. Eight women had been on chelation therapy before pregnancy, one of whom needed chelation during late pregnancy. Of the pregnancies, 93% had a successful outcome with a mean ± SD gestational age at delivery of 38.6 ± 0.9 weeks, with a range of 37-40 weeks. Eight babies (57%) were delivered by Caesarean section. The mean ± SD birth weight was 2.6 ± 0.2 kg, with a range of 1.9-3.0 kg. Three babies (21%) were born with low birth weights. CONCLUSION: Pregnancy is safe and usually has a favourable outcome in patients with HBT, provided that a multidisciplinary team is available. This is the first study of Omani patients with HBT whose pregnancies have resulted in a successful outcome.

Correlation of iron overload and glomerular filtration rate estimated by cystatin C in patients with ß-thalassemia major.

Historically, renal involvement has not been a commonly recognized complication in patients with ß-thalassemia major (ß-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with ß-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3 ± 9 years (range 2.5-38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient -0.25). In the univariable analyses, serum ferritin (p = 0.004), diabetes status (p < 0.001) and chelation therapy (p < 0.001) were statistically significant. In the multivariable model, age (p = 0.033), chelation with DFX (p = 0.05) and diabetes status (p < 0.001) were statistically significant. We found a very weak inverse linear correlation between serum ferritin and Cyst C eGFR. However, when concomitant use of chelation therapy was considered, serum ferritin did not associate with glomerular function. Prospective and larger studies are needed to confirm these findings.