The management and outcome of hyponatraemia following transsphenoidal surgery: a retrospective observational study.

PURPOSE: Hyponatraemia is a common complication following transsphenoidal surgery. However, there is sparse data on its optimal management and impact on clinical outcomes. The aim of this study was to evaluate the management and outcome of hyponatraemia following transsphenoidal surgery. METHODS: A prospectively maintained database was searched over a 4-year period between January 2016 and December 2019, to identify all patients undergoing transsphenoidal surgery. A retrospective case-note review was performed to extract data on hyponatraemia management and outcome. RESULTS: Hyponatraemia occurred in 162 patients (162/670; 24.2%) with a median age of 56 years. Female gender and younger age were associated with hyponatraemia, with mean nadir sodium being 128.6 mmol/L on postoperative day 7. Hyponatraemic patients had longer hospital stay than normonatraemic group with nadir sodium being inversely associated with length of stay (p < 0.001). In patients with serum sodium ≤ 132 mmol/L, syndrome of inappropriate antidiuretic hormone secretion (SIADH) was the commonest cause (80/111; 72%). Among 76 patients treated with fluid restriction as a monotherapy, 25 patients (25/76; 32.9%) did not achieve a rise in sodium after 3 days of treatment. Readmission with hyponatraemia occurred in 11 cases (11/162; 6.8%) at a median interval of 9 days after operation. CONCLUSION: Hyponatraemia is a relatively common occurrence following transsphenoidal surgery, is associated with longer hospital stay and risk of readmission and the effectiveness of fluid restriction is limited. These findings highlight the need for further studies to better identify and treat high-risk patients, including the use of arginine vasopressin receptor antagonists.

Real-life experience of tolvaptan use in the treatment of severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone secretion.

OBJECTIVE: European guidelines do not recommend tolvaptan for treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH), principally owing to concerns about risk of overly rapid correction of hyponatraemia. This study evaluated the real-life effectiveness and safety of tolvaptan. DESIGN: Consecutive case series. PATIENTS: Inpatients treated with tolvaptan for SIADH in 2 UK hospitals over a 3-year period. MEASUREMENTS: The primary outcome measures were serum sodium (sNa) correction at 24 and 48 h after tolvaptan therapy. RESULTS: This case series included 61 patients aged 74·4 ± 15·3 years with (mean ± SD) sNa 119·9 ± 5·5 mmol/l. The mean sNa increase 24 h after tolvaptan initiation was 9 ± 3·9 mmol/l. Excessive correction of hyponatraemia was observed in 23% of patients with all these patients having baseline sNa <125 mmol/l, but no cases of osmotic demyelination syndrome were recorded. At the end of tolvaptan therapy, sNa increase was 13·5 ± 5·9 mmol/l with 96·7% of patients having sNa increase ≥5 mmol/l in 48 h. There was a negative significant correlation (P = 0·012) between baseline sNa and 24-h change; for every 1 mmol/l reduction in baseline value, sNa increased by an additional 0·23 mmol/l (95% CI 0·05-0·41). CONCLUSIONS: Tolvaptan is effective in correcting hyponatraemia. Without rigorous electrolyte monitoring, tolvaptan carries a significant risk of overly rapid sodium correction, especially in patients with starting sNa <125 mmol/l. Tolvaptan should be used with great caution under close electrolyte monitoring.

A case-control study of hyponatraemia as an independent risk factor for inpatient mortality.

OBJECTIVES: Hyponatraemia is strongly associated with increased inpatient mortality, but it is unknown whether hyponatraemia per se contributes to excess mortality. Our hypothesis was that if hyponatraemic patients had significantly greater mortality compared with controls despite no difference with regard to gender, age, comorbidities and type of primary pathology, this would incriminate hyponatraemia as an independent predictor of mortality. DESIGN: Single-centre, case-control study. PATIENTS: Cases (N = 139) were hospitalized patients with serum Na ≤ 128 mmol/l over 3 months. Controls were 254 age- and gender-matched patients residing in the same hospital ward with serum Na > 128 mmol/l. MEASUREMENTS: Data were collected about age, gender, comorbidities, drug history, serum creatinine, intensive care unit (ICU) admission and length of hospitalization. The main outcome measure was inpatient mortality. RESULTS: Hyponatraemic patients had an inpatient mortality rate of 17·3% and were more than three times more likely to die during their hospital stay compared with controls (OR 3·33, 95% CI 1·68-6·58, P < 0·01) despite no statistically significant difference with respect to age, gender, comorbidities, use of common drugs, serum creatinine, ICU admission rate and length of hospitalization. Comparison of cases with the normonatraemic subgroup of controls demonstrated that cases were almost 12 times more likely to die during admission than normonatraemic controls (OR 11·89, 95% CI 2·75-51·51, P < 0·01). CONCLUSIONS: This study showed that hyponatraemia is an independent predictor of mortality, and hyponatraemia per se is likely to contribute to excess mortality. Further studies are needed to examine whether correction of hyponatraemia can reduce mortality.

History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with ß thalassemia major.

Endocrinopathies are common complications of transfusional hemosiderosis among patients with ß thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI-R2 since 2008 and average 10-yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20 ms (P < 0.001 and P = 0.008, respectively) and increased age (P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 µg/L (P = 0.003) and >2000 µg/L (P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM.

Multicentre study of investigation and management of inpatient hyponatraemia in the UK.

PURPOSE: Hyponatraemia is associated with significant morbidity and mortality. The objectives of this study were to evaluate the investigation and management of hyponatraemia and to assess the use of different therapeutic modalities and their effectiveness in routine practice. STUDY DESIGN: This multicentre, retrospective, observational study was conducted at three acute NHS Trusts in March 2013. A retrospective chart review was performed on the first 100 inpatients with serum sodium (sNa) ≤128 mmol/L during hospitalisation. RESULTS: One hundred patients (47 male, 53 female) with a mean±SD age of 71.3±15.4 years and nadir sNa of 123.4±4.3 mmol/L were included. Only 23/100 (23%) had measurements of paired serum and urine osmolality and sodium, while 31% had an assessment of adrenal reserve. The aetiology of hyponatraemia was unrecorded in 58% of cases. The mean length of hospital stay was 17.5 days with an inpatient mortality rate of 16%. At hospital discharge, 53/84 (63.1%) patients had persistent hyponatraemia, including 20/84 (23.8%) with sNa <130 mmol/L. Overall 37/100 (37%) patients did not have any treatment for hyponatraemia. Among 76 therapeutic episodes, the most commonly used treatment modalities were isotonic saline in 38/76 cases (50%) and fluid restriction in 16/76 (21.1%). Fluid restriction failed to increase sNa by >1 mmol/L/day in 8/10 (80%) cases compared with 4/26 (15.4%) for isotonic saline. CONCLUSIONS: Underinvestigation and undertreatment of hyponatraemia is a common occurrence in UK clinical practice. Therefore, development of UK guidelines and introduction of electronic alerts for hyponatraemia should be considered to improve clinical practice.

Joint diabetes thalassaemia clinic: an effective new model of care.

Diabetes is a significant complication of ß-thalassemia major (ß-TM) and most patients receive fragmented diabetes care. In 2005, we developed a unique Joint Diabetes Thalassaemia Clinic, based at the Department of Diabetes, Whittington Health, London, UK, where patients were reviewed jointly by a multidisciplinary team, including Consultant Diabetologist and Hematologist. Study of the Joint Diabetes Thalassaemia Clinic (2005-2009) showed improvement in glycemic control with fructosamine reduction from 344 umol/L to 319 umol/L over a 1-year period as well as improvement in lipid profiles. The proportion of patients attending the Joint Clinic who achieved metabolic targets compared to the National Diabetes Audit for England was higher for glycemic control (73.0 Joint Diabetes Thalassaemia Clinic vs. 63.0% nationally), blood pressure control (58.0 Joint Diabetes Thalassaemia Clinic vs. 30.0% nationally) and cholesterol control (81.0 Joint Diabetes Thalassaemia Clinic vs. 78.0% nationally). Five patients (22.7%) had microvascular complications. A significant proportion of our patients had endocrinopathies (86.0% hypogonadism, 18.0% hypothyroidism, 23.0% hypoparathyroidism). The unique partnership of our Joint Diabetes Thalassaemia Clinic, allowed these very complex patients to be managed effectively.

Prevalence of low bone mass and vitamin D deficiency in ß-thalassemia major.

Low bone mass, a major cause of morbidity in patients with ß-thalassemia major (ß-TM), is multifactorial. There is lack of data about the current prevalence of low bone mass in patients with ß-TM. The aims of this study are to examine the current prevalence of low bone mass in ß-TM patients and the association between demographic characteristics, markers of iron overload, endocrinopathies, glycemic status and bone mineral density (BMD) as well as to study the 25-OH-vitamin D status of the patients and its relationship with BMD. Our institution serves the largest cohort of ß-TM patients in the UK. From 99 patients (49 males, 50 females) with a mean ± standard deviation (SD) age of 36 ± 9 years, 55.5% had low BMD for their age as defined by Z-score BMD <-2.0 either at the lumbar spine (43.9%) or at the hip (25.5%). The only statistically significant association on the multivariate analysis was between hypogonadism and low BMD at the lumbar spine. In our study, 29.9% of patients had vitamin D deficiency, 65.7% had vitamin D insufficiency and 12.4% had optimal levels. No association between vitamin D status and low bone mass was found. Our study demonstrated a much lower prevalence of low bone mass in adults with ß-TM compared to previous studies. Further studies are needed to examine whether this suggests a widespread improvement across patients with ß-TM possibly due to advances in therapeutics. Most patients had suboptimal 25-OH-vitamin D levels, but no association between vitamin D status and bone mass was demonstrated.

A Real-World Study of the Effectiveness and Safety of Semaglutide for Weight Loss.

Introduction Recent randomized controlled trials (RCTs) have shown the great efficacy of semaglutide in achieving significant weight loss in overweight and obese adults. However, real-world data about its effectiveness are still limited. This study evaluated the effectiveness and adverse events of semaglutide for weight management in a real-life setting, excluding patients with diabetes mellitus (DM). Methods This is a retrospective chart review of 40 overweight or obese individuals with a median age of 47 years, weight of 111.7 kg, and body mass index (BMI) of 39.7 kg/m2 who were prescribed semaglutide for weight management. Results After three months of semaglutide administration, the median weight reduction was 7.4 kg (6.6% of the baseline weight), with 28 (70%) and eight patients (20%) achieving greater than 5% (5.6 kg) and 10% (11.2 kg) weight loss, respectively. Among 25 patients with six-month data, 22 (88%), 17 (68%), and eight (32%) patients exceeded 5% (5.6 kg), 10% (11.2 kg), and 15% (16.8 kg) weight loss, respectively. The maintenance semaglutide dose was 1 mg in 16 cases and 2 mg in nine cases, leading to a similar weight loss of 13.6% (14.9 kg) and 12.8% (14 kg), respectively. Relatively low response rates were observed in males, with seven responders out of 12 (58.4%) compared to 24 out of 28 (85.8%) in females (P value = 0.057), and in five out of nine (55.6%) among those with a history of psychiatric disease. The rate of adverse events was 26 out of 40 patients (65%), mostly mild to moderate and of short duration, leading to discontinuation in only a single case (2.5%). Conclusion This retrospective study demonstrated the significant effectiveness of semaglutide for weight loss, even at lower than approved maintenance doses, combined with a good safety profile. Therefore, semaglutide may dramatically change the landscape of obesity treatment.

Can we Predict Incipient Diabetes Mellitus in Patients with Transfusion Dependent ß-Thalassemia (ß-TDT) Referred with a History of Prediabetes?

Background: Prediabetes and diabetes mellitus (DM) are complications in adult patients with transfusion-dependent ß-thalassemia (ß-TDT), with their incidence increasing with age. Objective: This retrospective observational study describes the glycemic trajectories and evaluates predictive indices of ß-cell function and insulin sensitivity/resistance in ß-TDT patients with prediabetes, both in a steady state and during 3-h oral glucose tolerance test (OGTT), in order to identify patients at high risk for incipient diabetes. Setting: The study was mainly conducted at the Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara (Italy), in collaboration with thalassemia referring centers across Italy. Patients: The study included 11 ß-TDT (aged 15.11-31.10 years) with prediabetes. Methods: The ADA criteria for the diagnosis of glucose dysregulation were adopted. Investigations included evaluating plasma glucose levels and insulin secretion, analyzing glycemic trajectories and indices of ß-cell function, and insulin sensitivity/resistance assessed in steady state and during OGTT. Results: The duration of progression from prediabetes to DM, expressed in years, showed a positive direct correlation with corrected insulin response (CIR-30 = r: 0.7606, P: 0.0065), insulinogenic index (IGI 0-120 = r: 0.6121, P:0.045), oral disposition index (oDI = r: 0.7119, P:0.013), insulin growth factor-1 (IGF-1= r: 0.6246, P: 0.039) and an inverse linear correlation with serum ferritin (SF = r: -0.7197, P: 0.012). The number of patients with 1-hour post-load PG value ≥ 155 mg/dL ( ≥ 8.6 mmol/L) was at -4 years: 4/9 (44.4%); -3 years: 8/9 (88.8%); - 2 years: 7/10 (70 %) and at -1 year: 11/11 (100%) (PG range:162-217 mg/dL). Conclusions: A progressive increase in 1-hour PG in response to OGTT is associated with progressive ß-cell failure, peripheral resistance to insulin action, and reduced oDI and may be considered a relevant marker for incipient DM in ß-TDT patients with prediabetes.

Immunotherapy for endocrine tumours: a clinician's perspective.

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

Association of hyponatremia with bone mineral density and fractures: a narrative review.

Recent studies suggest a possible association of hyponatremia with osteoporosis, falls and bone fractures. The objectives of this narrative review were to further explore this association and the related pathophysiological mechanisms and to suggest a practical approach to patients with osteoporosis or chronic hyponatremia in clinical practice. We conducted an extensive PubMed search until October 2022 with the combination of the following keywords: 'hyponatremia' or 'sodium' or 'SIADH' and 'fractures' or 'bone' or 'osteoporosis', as MeSH Terms. Review of numerous observational studies confirms a significant independent association of, even mild, hyponatremia with two- to three-fold increase in the occurrence of bone fractures. Hyponatremia is a risk factor for osteoporosis with a predilection to affect the hip, while the magnitude of association depends on the severity and chronicity of hyponatremia. Chronic hyponatremia also increases the risk for falls by inducing gait instability and neurocognitive deficits. Besides the detrimental impact of hyponatremia on bone mineral density and risk of falls, it also induces changes in bone quality. Emerging evidence suggests that acute hyponatremia shifts bone turnover dynamics towards less bone formation, while hyponatremia correction increases bone formation. The key unanswered question whether treatment of hyponatremia could improve osteoporosis and lower fracture risk highlights the need for prospective studies, evaluating the impact of sodium normalization on bone metabolism and occurrence of fractures. Recommendations for clinical approach should include measurement of serum sodium in all individuals with fracture or osteoporosis. Also, hyponatremia, as an independent risk factor for fracture, should be taken into consideration when estimating the likelihood for future fragility fracture and in clinical decision-making about pharmacological therapy of osteoporosis. Until it is proven that normalization of sodium can lower fracture occurrence, correcting hyponatremia cannot be universally recommended on this basis, but should be decided on a case-by-case basis.

New Onset or Deterioration of Thyroid Eye Disease After mRNA SARS-CoV-2 Vaccines: Report of 2 Cases and Literature Review.

CONTEXT: Occurrence of Graves' disease (GD) has been reported following SARS-CoV-2 vaccine administration, but little is known about thyroid eye disease (TED) after SARS-CoV-2 vaccination. OBJECTIVE: We describe 2 cases of TED activation following mRNA SARS-CoV-2 vaccination and review additional cases reported in the literature. METHODS: We report 2 cases of TED activation following SARS-CoV-2 vaccination: 1 case of TED worsening in a patient with GD, and 1 of de novo active TED progressing to dysthyroid optic neuropathy in a patient with a history of Hashimoto hypothyroidism. Our literature search revealed 8 additional reported TED cases associated with SARS-CoV-2 vaccination until June 2022. We review the characteristics, duration, and management of TED following SARS-CoV-2 vaccination in these cases. RESULTS: Of all 10 reported TED cases following SARS-CoV-2 vaccination, 4 developed new-onset TED and 6 previously stable TED cases experienced significant deterioration. Six patients had known GD and 2 patients had Hashimoto thyroiditis. Two cases progressed to dysthyroid optic neuropathy, 6 had moderate/severe active disease, and 2 had mild disease that did not require treatment. Seven TED cases received teprotumumab and had a favorable response, 2 of whom had prior limited response to initial prednisone or methylprednisolone and tocilizumab therapy. CONCLUSION: New diagnosis or deterioration of TED after mRNA SARS-CoV-2 vaccination can occur, with most cases described in patients with underlying autoimmune thyroid disease. Our report raises awareness to this potential complication to promote early recognition and prompt management of TED associated with mRNA SARS-CoV-2 vaccines. Further studies are needed to explore the mechanism, risk factors, prevention, and treatment of TED following mRNA SARS-CoV-2 vaccination.

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.

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.

Unilateral breast enlargement in males during adolescence (10-19 years): Review of current literature and personal experience.

Idiopathic unilateral breast enlargement (UBE) in males is a, commonly overlooked, diagnosis of exclusion that requires careful history, meticulous physical examination, and pertinent laboratory studies to exclude the possible pathologic causes. The aims of the present update are to review the current literature on UBE in subjects during adolescent age (10-19 years) in 18 cases, and to report the personal experience in 13 adolescents referred to our unit during the last four decades. In total, our survey and personal experience include 31 UBE cases, 10 of whom (32.2 %) being idiopathic or familial gynecomastia (GM). In 3/31 (9.6%) UBE was due to breast sarcoma/ carcinoma; one patient (11-years old) had a 5-year history of painless lump in the right breast, which increased gradually in size followed by bloody nipple discharge. In the personal cases of 13 adolescents, a moderate to marked UBE was secondary to: treatment with androgens (2 ß-thalassemic patients with hypogonadism), high estrogen/androgen ratio in 2 Klinefelter syndrome patients, peripheral aromatization of androgens in 1 patient with non-classical 21-hydroxylase deficiency (NC-21-OH-D). One patient had subareolar hematoma due to injury. In 2 patients (15,3%) marked UBE was due to cystic lymphangioma (histologically proved). Furthermore, 5 patients were characterized as idiopathic UBE In clinical practice, the persistence of UBE for long period before diagnosis necessitates attention and further evaluation. Underlying causes should be treated, when possible, while surgery can be offered to patients with persistent or atypical signs and/or symptoms of UBE. For the optimal management of this condition, better collaboration between primary care physician and specialists is mandatory.

Recent advancements in glucose dysregulation and pharmacological management of osteoporosis in transfusion-dependent thalassemia (TDT): an update of ICET-A (International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine).

PURPOSE OF REVIEW: The aim of this short review is to provide an update on glucose homeostasis, insulin secretion and pharmacological management of osteoporosis in transfusion-dependent thalassemia (TDT). RECENT FINDINGS: A retrospective study, documenting the changes in glucose-insulin homeostasis from early childhood to young adulthood, has advanced our understanding of the evolution of glucose regulation in patients with TDT. Magnetic Resonance Imaging (T2* MRI) is considered to be a reliable tool to measure pancreatic iron overload. Continuous glucose monitoring systems (CGMS) can be used in early diagnosis of glucose dysregulation and in disease management in patients with already diagnosed diabetes. Oral glucose-lowering agents (GLAs) are effective and safe for the treatment of diabetes mellitus (DM) in patients with TDT, achieving adequate glycemic control for a substantial period of time. Current modalities for the management of osteoporosis in adults with TDT include inhibitors of bone remodeling such as bisphosphonates and denosumab as well as stimulators of bone formation (e.g., teriparatide), Considering the unique characteristics of osteoporosis associated with TDT, early diagnosis, treatment initiation and treatment duration are critical issues in the management this special population. CONCLUSIONS: Advances in the care of TDT patients  have led to improved survival and quality of life. Nevertheless, many chronic endocrine complications still remain. Their routine screening and a high index of suspicion are imperative in order to provide timely diagnosis and  treatment.

Assessment of glucose homeostasis in young adult female ß-thalassemia major patients (ß-TM) with acquired hypogonadotropic hypogonadism (AHH) never treated with sex steroids compared to eugonadal ß-TM patients with spontaneous menstrual cycles.

BACKGROUND: Acquired ypogonadotropic hypogonadism (AHH) is the most prevalent endocrine complication in thalassemia major (TM). STUDY DESIGN: Considering the detrimental effect of estrogen deficiency on glucose metabolism, the ICET-A Network promoted a retrospective study on the long-term effects of estrogen deficiency on glucose homeostasis in female ß-TM patients with HH without hormonal replacement therapy (HRT). PATIENTS AND METHODS: Seventeen ß-TM patients with AHH (4 had arrested puberty; Tanners' breast stage 2-3), never treated with sex steroids, and 11 eugonadal ß-TM patients with spontaneous menstrual cycles at the time of referral were studied. A standard 3-h OGTT was performed in the morning, after an overnight fast. Six-point plasma glucose and insulin level determinations, indices of insulin secretion and sensitivity, early-phase insulin insulinogenic index (IGI), HOMA-IR and ß-cell function (HOMA-ß), oral disposition index (oDI), glucose and insulin areas under the OGTT curves were evaluated. RESULTS: Abnormal glucose tolerance (AGT) or diabetes was observed in 15 (88.2%) of 17 patients with AHH and 6 (54.5%) of 11 patients with eumenorrhea. The difference between the two groups was statistically significant (P: 0.048). However, the group of eugonadal patients was younger compared to AHH patients (26.5 ± 4.8 years vs. 32.6 ± 6.2 years ; P: 0.010). Advanced age,  severity of iron overload, splenectomy, increased ALT levels and reduced IGF-1 levels were the main clinical and laboratory risk factors for glucose dysregulation observed in ß-TM with AHH compared to eugonadal ß-TM patients with spontaneous menstrual cycles. CONCLUSION: These data further support the indication for an annual assessment of OGTT in patients with ß-TM. We believe that a registry of subjects with hypogonadism is necessary for a better understanding of the long-term consequences of this condition and  refining treatment options.

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.

A retrospective study of glucose homeostasis, insulin secretion, sensitivity/resistance in non- transfusion-dependent ß-thalassemia patients (NTD- ß Thal): reduced ß-cell secretion rather than insulin resistance seems to be the dominant defect for glucose dysregulation (GD).

AIMS: Non-transfusion - dependent ß-thalassemias (NTD-ßThal) can cause iron overload and serious iron-related organ complications as endocrine dysfunction, including glucose dysregulation (GD). PATIENTS AND METHODS: We retrieved data of all NTD- ß Thal patients referred consecutively to a single Outpatient Italian Clinic from October 2010 to April 2023. All patients underwent a standard 3-h oral glucose tolerance test (OGTT) for analysis of glucose homeostasis, insulin secretion and sensitivity/resistance (IR), using conventional surrogate indices derived from the OGTT. The collected data in NTD- ß Thal patients were compared to 20 healthy subjects. RESULTS: Seventeen of 26 (65.3 %) NTD- ß Thal patients (aged: 7.8 -35.1 years) had normal glucose tolerance, 1/26 (3.8 %) had impaired fasting glucose (IFG), 5/26 (19.2 %) impaired glucose tolerance (IGT), 1/26 (3.8%) IFG plus IGT and 2/26 (7.6%) plasma glucose (PG) level ≥155 mg/dL 1-h after glucose load. GD was observed exclusively in young adult patients; none of them had diabetes mellitus (DM). These findings were associated with a low insulinogenic index (IGI) and oral disposition index. HOMA-IR and QUICKI were not significantly different compared to controls. Interestingly, in young adult patients, ISI-Matsuda index was statistically higher compared to the control group, suggesting an increased insulin sensitivity. CONCLUSIONS: This study reported a high prevalence of GD in young adults with NTD- ß Thal. The documented reduction of IGI rather than the presence of IR, indicates reduced insulin secretory capacity as the pathophysiological basis of dysglycemia that may represent a novel investigational path for future studies on the mechanism(s) responsible for GD in NTD- ß Thal patients.

The effects of excess weight on glucose homeostasis in young adult females with ß-thalassemia major (ß-TM): a preliminary retrospective study.

BACKGROUND: With the rising prevalence of obesity worldwide, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent type 2 diabetes (T2D) development. STUDY DESIGN: The present retrospective observational study aimed to evaluate the relationship between BMI and glucose metabolism, insulin secretion and sensitivity indices, derived from glucose tolerance test (OGTT), in ß -TM female patients who were overweight (BMI 25-29.9 kg/m2) and follow its outcome over time. SUBJECTS AND METHODS: Eleven overweight and 11 females with ideal weight and ß -TM, matched for age, were recruited. OGTT was undertaken and different indices for ß-cell function, insulin sensitivity and insulin secretion were calculated. RESULTS: At first evaluation, 7 of 11 overweight ß -TM patients (63.6%) and 3 of 11 normal weight ß-TM patients (27.2%) had glucose dysregulation (GD) during OGTT. Overweight patients with ß-TM had increased HOMA-IR and QUICKI indices associated with decreased Matsuda WBISI index. The mean ± SD duration of follow-up was 4.5 ± 1.2 years. At last observation, 2/11 overweight patients had developed T2D (18.1%). In patients with normal weight, GD increased from 3/11 (27.2%) to 5/11 (45.4%), but none developed T2DM. The difference between SF at first and last observation (1,220 ± 702 vs.1,091 ± 454 ng/mL; P: 0.61) was not significant. CONCLUSION: Overweight seems to be an additional risk factor for the development of GD in ß-TM patients. This is particularly important in clinical practice, due to the lack of appropriate guidelines dedicated to this group of patients.