Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Longitudinal changes of endocrine and bone disease in adults with ß-thalassemia major receiving different iron chelators over 5 years.

In this study, we compared the long-term effects of different iron chelation regimens (deferoxamine, deferiprone, deferoxamine + deferiprone, and deferasirox) in preventing or reversing endocrinopathy (diabetes mellitus, hypothyroidism, or hypogonadism) and bone disease (measured through DEXA) in 165 adults with ß-thalassemia major (TM) (mean age 39.9 ± 8.3 years, 43 % males). After five consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy compared to other chelators which either had no change (deferiprone and deferoxamine) or had an increase (deferoxamine + deferiprone), p = 0.015. This was attributed to a lower proportion of patients on deferasirox developing new-onset endocrinopathy and higher proportion showing reversal of disease, compared to other chelators. A serum ferritin level of >1300 ng/mL predicted the development of new endocrinopathy (p = 0.025) while a level of <200 ng/mL predicted reversal of existing endocrinopathy (p = 0.147). A significant increase in mean BMD T-score (p < 0.001) and a considerable decrease in osteoporosis prevalence were observed in patients receiving deferasirox but not other chelators. Iron chelation therapy with deferasirox has a role in the prevention of endocrinopathy and reversal of existing disease.

Characteristics and outcomes of Italian patients from the observational, multicentre, hypopituitary control and complications study (HypoCCS) according to tertiles of growth hormone peak concentration following stimulation testing at study entry.

OBJECTIVE: To determine whether characteristics and outcomes of Italian patients in the observational global Hypopituitary Control and Complication Study (HypoCCS) differed according to the degree of GH deficiency (GHD). DESIGN: Patients were grouped by tertiles of stimulated GH peak concentration at baseline (Group A lowest tertile, n = 342; Group B middle tertile, n = 345; Group C highest tertile, n = 338). RESULTS: Baseline demographics, lipid levels, body mass index categories and mean Framingham cardiovascular risk indexes were similar in the three groups and remained substantially unchanged over time, with no subsequent significant between-group differences (except mean levels of triglycerides increased in the highest tertile group). GHD was adult-onset for >75% of patients in all groups. The percentage of patients with multiple pituitary deficiencies was higher in Group A than in the other groups; isolated GHD was reported with highest frequency in Group C. Patients in Group A received the lowest mean starting dose of GH. Hyperlipidaemia at baseline was reported in 35·1%, 31·1% and 24·7% of patients in groups A, B and C, respectively (P = 0·029). Mean duration of GH treatment was 7·21, 5·45 and 4·96 years, respectively. The proportion of patients with adverse events did not differ significantly between groups, with a low prevalence over time of diabetes and cancer. CONCLUSIONS: In Italian patients from HypoCCS, the level of GH deficit did not influence changes over time in metabolic parameters or adverse event profile, despite differences in GHD severity at baseline and in the starting GH dose.

Long-term pasireotide-LAR treatment in the personalized therapy of patients with complex acromegaly: a collection of clinical experiences.

Pasireotide-LAR is recommended as a second-line treatment for patients with acromegaly. Although the effects of pasireotide-LAR have been well characterized in clinical studies, real-practice evidence is scant, especially in the long term and within the individualization of therapy in patients with comorbidities. To provide additional insight on the individualized approach to acromegaly management, six clinical cases of complex acromegaly treated with pasireotide-LAR for more than 5 years were reported. Pasireotide-LAR allowed the normalization of insulin-like growth factor 1 (IGF1) values in all patients and reduced tumour residue volume where present. A good safety profile and long-term tolerability were also reported.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells.

Thiazolidinediones, specific peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-γ-inhibitor, showed that rosiglitazone acts through both PPAR-γ-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-γ. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPKα and beclin-1. The autophagy seems to be independent of PPAR-γ activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

Cortisol Deficiency in Lenvatinib Treatment of Thyroid Cancer: An Underestimated Common Adverse Event.

Background: Lenvatinib treatment has shown a significant improvement in progression-free survival in patients with metastatic, progressive, radioiodine-refractory differentiated thyroid cancer, although its use is associated with considerable toxicity. Fatigue is one of the most frequent adverse events (AEs). It has been reported that adrenal insufficiency (AI) may be involved in lenvatinib-related fatigue. In our study, we assessed the pituitary/adrenal axis before and during treatment, and the possible involvement of AI in lenvatinib-related fatigue. This was done to clarify the incidence, development, and time course of AI during lenvatinib treatment. Methods: We studied 13 patients who were selected for lenvatinib therapy. Adrenal function was evaluated by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and through the ACTH (250 µg) stimulation test. Results: During treatment, seven patients (54%) developed AI. High levels of ACTH were observed in accordance with the diagnosis of primary AI (PAI). By evaluating the first ACTH test, before starting lenvatinib treatment, we found that patients with <646.6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. Fatigue was observed in 11 patients (84.6%) during lenvatinib treatment. Cortisone acetate treatment induced an improvement in fatigue in six of seven patients (85.7%) in the PAI group, without the need to change the lenvatinib dosage. Conclusions: PAI may be considered one of the most common AEs associated with lenvatinib. Our data strongly suggest that PAI could be involved in lenvatinib-associated fatigue, particularly in patients with extreme fatigue. In this context, early diagnosis of PAI is essential, especially since glucocorticoid replacement therapy can induce a significant improvement in fatigue, without the need to reduce the dosage of lenvatinib. However, further studies are required to confirm these preliminary findings.

Machine Learning-Based Texture Analysis in the Characterization of Cortisol Secreting vs. Non-Secreting Adrenocortical Incidentalomas in CT Scan.

New radioimaging techniques, exploiting the quantitative variables of imaging, permit to identify an hypothetical pathological tissue. We have applied this potential in a series of 72 adrenal incidentalomas (AIs) followed at our center, subdivided in functioning and non-functioning using laboratory findings. Each AI was studied in the preliminary non-contrast phase with a specific software (Mazda), surrounding a region of interest within each lesion. A total of 314 features were extrapolated. Mean and standard deviations of features were obtained and the difference in means between the two groups was statistically analyzed. Receiver Operating Characteristic (ROC) curves were used to identify an optimal cutoff for each variable and a prediction model was constructed via multivariate logistic regression with backward and stepwise selection. A 11-variable prediction model was constructed, and a ROC curve was used to differentiate patients with high probability of functioning AI. Using a threshold value of >-275.147, we obtained a sensitivity of 93.75% and a specificity of 100% in diagnosing functioning AI. On the basis of these results, computed tomography (CT) texture analysis appears a promising tool in the diagnostic definition of AIs.

Good Clinical Practice of the Italian Society of Thalassemia and Haemoglobinopathies (SITE) for the Management of Endocrine Complications in Patients with Haemoglobinopathies.

BACKGROUND: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. METHODS: The Management Committee of SITE selected and gathered a multidisciplinary and multi-professional team, including experts in haemoglobinopathies and experts in endocrinopathies, who have been flanked by experts with methodological and organizational expertise, in order to formulate recommendations based on the available scientific evidence integrated by personal clinical experience. The project followed the systematic approach for the production of clinical practice guidelines according to the methodology suggested by the National Center for Clinical Excellence, Quality and Safety of Care (CNEC). RESULTS: Out of 14 topics, 100 clinical questions were addressed, and 206 recommendations were elaborated on. The strength of recommendations, panel agreement, a short general description of the topic, and the interpretation of evidence were reported. CONCLUSIONS: Good Practice Recommendations are the final outcome of translational research and allow one to transfer to the daily clinical practice of endocrine complications in haemoglobinopathies.

Partial response to first generation SSA guides the choice and predict the outcome of second line therapy in acromegaly.

INTRODUCTION: Treatment of acromegaly resistant to first generation somatostatin analogues (first gen-SSA) is often difficult. We aimed to investigate the role of partial response and resistance to first gen-SSA in the choice of second line treatments and their outcomes. PATIENTS AND METHODS: A retrospective and multicenter study was conducted on 100 SSA-resistant acromegaly patients and treated with Pasireotide Lar (Pasi-Lar), Peg-V in monotherapy (m-Peg-V) or in combination with first gen-SSA (c-Peg-V). RESULTS: Thirty-three patients (33%) were treated with m-Peg-V, 36 (36%) with c-Peg-V and 31 with Pasi-Lar (31%). According to logistic regression, m-Peg-V was chosen in older patients (p = 0.01) and with not-invasive adenomas (p = 0.009), c-Peg-V therapy in younger patients (p = 0.001), with invasive adenomas (p = 0.02), Pasi-Lar was in invasive adenomas (p = 0.01) and in patients partially responsive to first-gen SSA (p = 0.01). At the last follow-up, 68 patients (68%) reached the acromegaly control: 22 with m-Peg-V (32.4%), 23 with c-Peg-V (33.8%) and 23 with Pasi-Lar (33.8%). Patients non-responsive to c-Peg-V had higher IGF-I levels (median 3.2 x ULN, IQR: 1.6, p < 0.001) and required higher Peg-V dosage (median 30 mg/daily IQR: 10, p = 0.002) as compared to responsive patients (median IGF-I x ULN: 2.1 IQR: 1.4; median Peg-V dosage 20 mg/daily IQR: 10). All patients responsive to Pasi-Lar were partially responsive to first gen-SSAs (p = 0.02). CONCLUSION: Our data showed that c-Peg-V and Pasi-Lar are chosen for the treatment of invasive tumors. The partial response to first gen-SSA seems to be the main determinant for the choice of Pasi-Lar and positively predicts the treatment outcome.

[The Management of Endocrine Complications in Patients with Haemoglobinopathies: Good Clinical Practice of the Italian Society of Thalassemia and Haemoglobinopathies (SITE).] / Le principali complicanze endocrinologiche nelle emoglobinopatie: buone pratiche cliniche della Società Italiana Talassemie ed Emoglobinopatie (SITE).

BACKGROUND: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. METHODS: The Management Committee of SITE selected and gathered a multidisciplinary and multiprofessional team including experts in haemoglobinopathies and experts in endocrinopathies, who have been flanked by experts with methodological and organizational expertise, in order to formulate recommendations based on the available scientific evidence integrated by clinical experience. The project followed the systematic approach for the production of clinical practice guidelines according to the methodology suggested by the National Center for Clinical Excellence, Quality and Safety of Care (CNEC). RESULTS: Out of 14 topics 100 clinical questions were addressed and 206 recommendations were elaborated. Strength of recommendations, panel agreement, general description of the topic, and interpretation of evidence were reported. CONCLUSIONS: Good Practice Recommendations are the final outcome of translational research and allow to transfer the latest research knowledge to the daily clinical practice of endocrine complications in haemoglobinopathies.

Italian Association of Clinical Endocrinologists (AME) and International Chapter of Clinical Endocrinology (ICCE). Position statement for clinical practice: prolactin-secreting tumors.

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

Malignancies in ß-thalassemia patients: first description of two cases of thyroid cancer and review of the literature.

ß-Thalassemias are a group of hereditary blood disorders characterized by abnormalities in the synthesis of the ß hemoglobin (Hb) chains. This disease causes excessive storage of iron in all organs and endocrine glands. Treatment of ß-thalassemia major (ß-TM) consists of regular blood transfusions, iron chelation and management of secondary complications of iron overload. Endocrine abnormalities are frequently observed. In the last 25 years, the clinical picture of the disease has changed progressively thanks to improvement of treatments. Today, the majority of thalassemic patients reach adult age. The better prognosis and the longer lifespan of affected patients could be responsible for the susceptibility to other concomitant diseases which can manifest during their life. In this context, the possibility and recent literature reports about some cases of malignancy in thalassemic patients open new scenarios for oncoming years. We describe first reports of endocrine malignancies in thalassemic patients.

The Quality of Life of Thalassemic Patients: The Role of Endocrine Defect Compensation.

BACKGROUND: The improvement of beta thalassaemia treatments has led to an increase in life expectancy. This implies the emergence of new comorbidities. Amongst others, endocrine glands are extremely sensitive to iron overload. OBJECTIVE: We aimed to understand the impact of the endocrine conditions on the patient's quality of life (QOL). RESULTS: Hypogonadism may present with lack or delay of pubertal development, sexual dysfunctions and impaired fertility, which impact QOL in both sexes. Early recognition and treatment, as well as choosing the most appropriate therapy, according to patient's needs (fertility, pubertal development, psychological concerns, comorbidities), are advisable. Osteoporosis affects QOL irrespective of symptoms. Growth hormone deficiency may occur both in childhood and in adulthood, and it affects different aspects of QOL. In adults, it could be difficult to examine if the symptoms are due to GHD, and a trial of GH replacement could be useful to identify benefits and needs. Glucose metabolism impairment is common in thalassaemic patients and early recognition is mandatory because long-term complications can have a detrimental impact on QOL (as blindness or dialysis). Although the incidence of adrenal insufficiency seems to be rare in thalassaemic patients, when it occurs, it has a severe impact on QOL. CONCLUSION: Limited data is available on QOL in thalassaemic patients, and is even less related to endocrinopathies. We can speculate that endocrinopathies have an impact on everyday life. More studies are needed to allow our patients to achieve not just a longer life but also a better quality of life.

Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Acromegaly - Part 1: Diagnostic and Clinical Issues.

Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and strict criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas.

Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Acromegaly - Part 2: Therapeutic Issues.

Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas. The therapeutic management of acromegaly always requires a personalized strategy. Normal age-matched IGF-I values are the treatment goal. Transsphenoidal surgery by an expert neurosurgeon is the primary treatment modality for most patients, especially if there are neurological complications. In patients with poor clinical conditions or who refuse surgery, primary medical treatment should be offered, firstly with somatostatin analogs (SSAs). In patients who do not reach hormonal targets with first-generation depot SSAs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with SSA) should be offered. Irradiation could be proposed to patients with surgical remnants who would like to be free from long-term medical therapies or those with persistent disease activity or tumor growth despite surgery or medical therapy. Since the therapeutic tools available enable therapeutic targets to be achieved in most cases, the challenge is to focus more on the quality of life.

A rare case of follicular thyroid carcinoma in a patient with thyrotropin-secreting pituitary adenoma.

OBJECTIVE: To report a rare case of a thyrotropin (TSH)-secreting pituitary adenoma associated with thyroid carcinoma. METHODS: We report the clinical history, imaging studies, and laboratory and pathologic data in a male patient affected by TSH-secreting pituitary adenoma and goiter; histologic evaluation revealed thyroid carcinoma. RESULTS: A 50-year-old man complained of years of palpitations, hypertensive crisis, and excessive nervousness that tended to progressively worsen. The basal and dynamic hematologic evaluation showed the presence of high free thyroid hormone levels with inappropriate levels of TSH. The thyroid morphologic study using Doppler ultrasonography showed a gland of increased volume with multiple nodular lesions bilaterally. The nuclear magnetic resonance of the pituitary gland described a microadenoma. A total thyroidectomy was performed followed by neurosurgical treatment of the pituitary lesion. The definitive thyroid histologic examination showed the presence of minimally invasive follicular carcinoma of 17 mm diameter. The patient firmly refused surgical removal of the pituitary adenoma. He was started on replacement therapy with thyroxine. Twelve months later, the hematologic examinations showed normal thyroid hormone levels and a TSH of 6.97 uIU/mL. The pituitary nuclear magnetic resonance showed a stable lesion without difference in size. CONCLUSION: The clinical association between thyroid carcinoma and TSH-producing adenoma is rare, with the removal of the pituitary lesion being mandatory. Pituitary surgery, in this case, is impossible, showing that TSH-producing microadenoma could seldom have an indolent behavior.

Management of the aging beta-thalassemia transfusion-dependent population - The Italian experience.

Thalassemia is among the most common monogenic diseases worldwide. Stem cell transplantation can be curative but is reserved for young patients, as probably gene therapy will be in the future. Adult thalassemia patients are treated with transfusion therapy and iron chelation, and improvements in the safety of transfusion protocols, use of iron chelation, monitoring of iron overload, and management of comorbidities have substantially prolonged survival, increasing the proportion of adult patients in the thalassemic population. However, older patients are more likely to develop multiple disease-related morbidities, including osteoporosis, endocrine disorders, liver disease, renal dysfunction, and cancer. Thus, the main objective of this article is to describe new challenges posed by the increasing life expectancy of patients with thalassemia, focusing on data from Italy where there is a well-documented history of thalassemia management. It is hoped that the mortality and morbidity benefits already seen in patients with thalassemia will continue to improve with ongoing advances in the quality of treatment.

New Insights and Methods in the Approach to Thalassemia Major: The Lesson From the Case of Adrenal Insufficiency.

Background: Thalassemia Major (TM) is a complex pathology that needs a highly skilled approach. Endocrine comorbidities are nowadays the most important complications, including hypogonadism, hypothyroidism, diabetes mellitus, and bone diseases. Recent works stated that there could be a relevant prevalence of adrenal insufficiency (AI) present in TM, and this fact may become crucial, especially in case of major stressful events. Aim: Test the reliability of the standard test to diagnose AI in a group of TM and correlate it with clinical, hematological, and radiological data. Methods: We evaluated endocrine damages and the efficacy of iron chelation therapy in 102 patients affected by TM. AI was assessed by tetracosactide (Synacthen) 1 mcg iv (low-dose test, LDT) stimulation test. Patients with a subnormal response (peak cortisol < 500 nmol/L) were followed up to 5 years to check the symptoms and signs of AI. Results: We found AI in 13.7% of the population studied. We did not find any correlation between AI and all data evaluated. Only female gender seems to be a protective factor. A follow up of the patients affected by AI showed no signs of adrenal crisis, in spite of no replacement therapy. Conclusions: Our study shows a relevant prevalence of AI in TM, especially in males. The absence of an adrenal crisis, in spite of no replacement therapy, during the long-term follow up, seems to underline that current methods to evaluate AI, in TM, should consider a different and specific diagnostic test or different cut off for diagnosis.