Absence of teratogenicity of deferasirox treatment during pregnancy in a thalassaemic patient.

A 34 year-old female thalassaemia major patient regularly followed in our Thalassaemia Centre was diagnosed at 16 years of age with primary amenorrhea. The endocrine investigations were compatible with hypogonadotropic hypogonadism. Puberty was induced with oral oestrogens and progesterone, followed by transdermal hormone replacement therapy. She had initiated regular blood transfusions at 8 months of age and iron chelation therapy with desferioxamine at the age of 2 years, and in 2006 she was switched to treatment with the oral iron chelator deferasirox (DFX). In November 2009, the patient reported a temporary interruption of transdermal hormone replacement therapy during the previous July and August, and complained of the absence of menstrual flow since then. We suspected a pregnancy that was confirmed by pelvic ultrasound (presence of a fetus of 20 weeks' gestational age) and positive plasma b-hCG levels (14000 mIU/ ml). DFX was immediately discontinued and the patient was managed jointly with an obstetrician expert in haemoglobin disorders. In March 2010 she delivered via caesarean section, at 38 weeks of gestation, a male neonate with a weight of 3.300 Kg with no complications or malformations. The main messages from this patient are that: (i) the hypogonadotropic hypogonadism, secondary to iron overload, may be reversible, (ii) transdermal hormone replacement therapy and regular iron chelation therapy may have had a synergistic action on the activation of hypothalamic-pituitary-gonadal axis, (iii) the deferasirox treatment during pregnancy may be harmless for the fetus at the usually recommended therapeutic doses, (iv) periodic patient education is needed in order to fully explain the aim and the effects of sex steroid hormone replacement therapy given transdermally. The Authors discuss the current knowledge on iron chelation therapy during pregnancy.

An ICET-A survey on occult and emerging endocrine complications in patients with ß-thalassemia major: Conclusions and recommendations.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the  reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of  physicians' current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended.

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.

The ICET-A Survey on Current Criteria Used by Clinicians for the Assessment of Central Adrenal Insufficiency in Thalassemia: Analysis of Results and Recommendations.

BACKGROUND: In March 2015, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) implemented a two-step survey on central adrenal insufficiency (CAI) assessment in TM patients and after analysis of the collected data, recommendations for the assessment of hypothalamic-pituitary- adrenal (HPA) axis in clinical practice were defined. METHODS: To ascertain the current practice for assessment of CAI in thalassemia, the Coordinator of ICET-A sent two questionnaires by email: i) The first to evaluate the current interpretation of basal serum cortisol level (first step) and ii) The second to assess the current usage of ACTH test and the variability in practice" (second step). Based on the surveys the core ICET-A group prepared the recommendations for the assessment of suspected CAI in thalassemia (third step). RESULTS: A total of 19 thalassemologists/endocrinologists have participated in the first survey and 35 specialists participated in the second step questionnaire. The study demonstrated a considerable variability in almost all aspects of relevant current criteria used for the diagnosis of CAI. An ROC analysis using peak value > 20 µg/dl (> 550 nmol/L), after ACTH stimulation test, was performed with the aim of identifying the optimal basal serum cortisol cut-off. The optimal threshold that maximizes sensitivity plus specificity for morning basal cortisol against peak post-ACTH value >20 µg/dl (>550 nmol/L) was 10 µg/dl (275 nmol/L). Furthermore, the values associated with the highest negative predictive value (NPV) and highest, positive predictive value (PPV) were 4.20 (115 nmol/L) and 18.45 µg/dl (510 nmol/L), respectively. Surprisingly, 20 specialists in thalassemia working in blood bank, thalassemia centres (day hospital), internal medicine, hematology and onco-hematology had poor knowledge and experience in testing for CAI and stopped filling the questionnaire after the second question. In contrast, 9 endocrinologists (8 pediatricians) and 6 hematologists working in collaboration with endocrinologists completed the questionnaire. CONCLUSIONS: While waiting for more extensive adequately powered and targeted studies, physicians should adopt an acceptable policy for accurate assessment of HPA in TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are also recommended. The ICET-A recommendations are reported in order to facilitate for interested physicians the approach to a successful assessment of adrenal function in thalassemia.

Towards an optimization of the management of endocrine complications of thalassemia.

Children with thalassemia are living longer due to better care. Physicians dealing with this group of patients now have to contend with new challenges resulting from iron overload. Endocrine complications represent the most common morbidities encountered. To provide a better quality of life, these complications have to be addressed in a consistent way. For this purpose, we have compiled a set of recommendations to help physicians provide the best care possible to these patients.

Insulin-like Growth Factor-1 (IGF-1): Demographic, Clinical and Laboratory Data in 120 Consecutive Adult Patients with Thalassaemia Major.

INTRODUCTION: IGF-1 deficiency in TM patients in children and adolescents has been attributed to chronic anemia and hypoxia, chronic liver disease, iron overload and other associated endocrinopathies, e.g. growth hormone deficiency (GHD). Few data are available in the literature regarding adult TM patients and growth disorders. The aim of this study was to measure IGF-1 values and other clinical data in a large number of adult patients with TM to evaluate the possible relationships between them. PATIENTS AND METHODS: A cohort of 120 adult patients with TM was studied for plasma levels of IGF-1. Plasma total IGF-1 was determined by chemiluminescent immunometric assay (CLIA) method. In eleven patients (3 females) the GH response during glucagon stimulation test (GST) was also evaluated. RESULTS: Fifty percent of patients (33 males and 27 females) had IGF-1 levels <- 2 SDs below normative values for healthy subjects matched for age and sex. In these patients endocrine complications and elevations of aminotransferases (ALT) were more common compared to TM patients with IGF1 > -2SDs. In multivariate regression analyses, height, weight, BMI, serum ferritin, ALT, HCV serology and left ventricular ejection fraction (LVEF) were not significantly related to IGF-1, but a significant correlation was found in females between HCV-RNA positivity and IGF-1, ALT and serum ferritin. AGHD was diagnosed in 6 (4 males) out of 11 patients (54.5%) who had glucagon stimulation tests and in 5 out of 8 (62.5%) with IGF-1 <-2SD. The mean age of patients with GHD was 39.3 years (range: 25-49 years, median: 39 years) versus 35.8 years (range: 27-45 years, median: 37.5 years) in non-GHD patients. A positive correlation between GH peak after GST and IGF-1 level was found (r: 0.6409; p: < 0.05). CONCLUSIONS: In 50% of TM patients the IGF-1 levels were 2SDs below average values for healthy individuals. IGF-1 deficiency was more common in TM patients with associated endocrine complications, and a significant correlation was found in HCV-RNA positive females among IGF-1, ALT, and serum ferritin. Further data in a larger group of patients are needed to confirm whether IGF-1 level <-2 SDs may be a potential criterion for additional studies in TM patients. This datum could avoid performing GH stimulation tests in the majority of them.