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Objective: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations. Study design and method: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network. Results: Eight thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%). In 68 (61.2) patients GLAs was prescribed as monotherapy, while the remaining 49 (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12-120 months), required insulin therapy for better metabolic control. Conclusion: This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time. (www.actabiomedica.it). © 2022, Mattioli 1885. All rights reserved.

Objective: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations. Study design and method: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network. Results: Eight thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%). In 68 (61.2) patients GLAs was prescribed as monotherapy, while the remaining 49 (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12-120 months), required insulin therapy for better metabolic control. Conclusion: This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time. (www.actabiomedica.it). © 2022, Mattioli 1885. All rights reserved.

Objective: To study the endocrine pancreas' function in transfusion-dependent β-thalassemia (β-TDT) patients with a normal glucose tolerance test (NGT) and hypoinsulinemia. In addition, the prospective long-term follow-up using an annual oral glucose tolerance test (OGTT) to detect any abnormality of glucose metabolism. Patients and methods: Seven β-TDT patients (mean age 22.4 ± 4.2 years) with NGT and inadequate insulin response (hypoinsulinemia) to OGTT were referred for a second opinion to an Italian Centre. Results: The first-phase insulin response (FPIR), expressed as the sum of 1 and 3 minutes insulin, to intravenous glucose tolerance test (IVGTT), was between the 1st and 3rd percentile in two patients and between the 3rd and 10th percentile in five. The results were not associated with β-cell autoimmunity. After 43 ± 26 months (range 11 - 80 months) of follow-up, two patients developed impaired glucose tolerance (IGT), three both IGT and impaired fasting glucose (IFG) and two overt diabetes mellitus (DM). Interestingly, the patients who developed DM had, at baseline, the lowest value of the insulinogenic index (IGI: 0.08 and 0.25), defined as the ratio of the increment of plasma insulin to plasma glucose during the first 30 minutes after OGTT. Moreover, a significant correlation was found between the IGI at baseline and at follow-up in the patients who developed IGT with or without IFG (R= 0.927; P: 0.023). A significant reduction of Matsuda insulin sensitivity index (ISIM) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) was documented in the study cohort at the diagnosis of IFG, IGT, and DM. There was a significant inverse correlation between ISSI-2 and area under the curve plasma glucose (AUC-PG). Conclusions: These data demonstrated, for the first time, progressive deterioration in glucose homeostasis in β-TDT subjects with NGT and hypoinsulinemia and that the ISSI-2 index may be a valuable parameter to identify patients at high risk for developing glucose dysregulation. © 2021 Universita Cattolica del Sacro Cuore. All rights reserved.

Background: Patients with transfusion dependent β-thalassemia (TDT) are at high risk for developing, over the time, a form of diabetes distinct from type 1 and type 2 diabetes, but with similarities to both. Aims of study: The aim of this study is to describe the clinical and laboratory data, and the insulin secretion and sensitivity, in TDT patients recently diagnosed with diabetes mellitus (DM). Materials and Methods: The medical records of 25 TDT patients with DM, diagnosed by standardized oral glucose tolerance test (OGTT) and insulin secretion, were analysed; data were compared to TDT patients without diabetes and to a group of healthy subjects. Natural history of glucometabolic status before the diagnosis of DM was also reviewed. Results: On average, the TDT patients with DM were younger compared to TDT patients without diabetes. The mean age at diagnosis of DM in female and male TDT patients was 24.0 ± 7.1 years and 31.9 ± 5.6 years, respectively (P: 0.007). Serum alanine aminotransferase values, basal insulin levels and prevalence of hypogonadism were consistently higher in TDT patients with DM compared to those without diabetes. Decreased insulin secretion and increased insulin resistance was observed in patients with DM. Conclusion: The natural history of glucometabolic status in TDT patients is characterized by a deterioration of glucose tolerance over time. Iron overload and liver dysfuction are the main factors responsible for glucose disturbances (GD) in TDT patients. The therapeutic approach must be individualized and followed by a multidisciplinary team. (www.actabiomedica.it). © Mattioli 1885.

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 β-transfusion dependent thalassemia (β-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 β-TDT with H-NGT and 29 β-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 β-TDT patients with H-NGT. An inverse correlation was found between 1-hour plasma glucose value during OGTT and insulin secretion-sen-sitivity 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 β-TDT patients enrolled in our study. Conclusions: It is of paramount importance to screen early β-TDT patients at increased risk for glucose dysregulation. 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. © Mattioli 1885.

Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P = 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P = 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

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. (www.actabiomedica.it). © Mattioli 1885.

PubMedID: 30657116 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. (www.actabiomedica.it). © Mattioli 1885.

Five days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0–5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy. © 2018 The authors.

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. (www.actabiomedica.it). © Mattioli 1885.

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. © 2016.