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.

Prevalence, prognostic value, pathophysiology, and management of hyponatraemia in children and adolescents with COVID-19.

Hyponatraemia is frequently encountered in adults with coronavirus disease 2019 (COVID-19) and is associated with poor prognosis. This review aims to describe for the first time the prevalence, aetiology, prognostic value, pathophysiology, and management of hyponatraemia in children and adolescents with COVID-19, taking into account all relevant studies published in PubMed and Cochrane Library studies until 26th September 2021. Literature search did not detect any studies evaluating the prevalence and prognostic value of sodium disorders in paediatric patients with COVID-19. A broader literature review showed a high prevalence of hyponatraemia in children with bacterial pneumonia, while some studies have reported that hyponatraemia is relatively common in Multisystem Inflammatory Syndrome in Children (MIS-C). In adults with COVID-19, an inverse association between sodium and interleukin-6 levels has been found, indicating that hyponatraemia could be used as a surrogate marker for the risk of cytokine storm and may facilitate the identification of patients who could benefit from immunomodulatory agents. Studies are urgently needed to evaluate the frequency and prognostic impact of electrolyte abnormalities in children with COVID-19. In the meantime, clinicians are urged to consider hyponatraemia in children with COVID-19 as a potential red flag, investigate the cause and administer fluids and other therapies accordingly.

MANAGEMENT OF ENDOCRINE DISEASE: Dysnatraemia in COVID-19: prevalence, prognostic impact, pathophysiology, and management.

This review examines the prevalence, aetiology, pathophysiology, prognostic value, and investigation of dysnatraemia in hospitalised COVID-19 patients, taking into account all relevant studies published in PubMed and Cochrane Library studies until March 2021. Hyponatraemia is commonly observed in patients with bacterial pneumonia and is an independent predictor for excess mortality and morbidity. However, it remains unknown whether this association applies to coronavirus disease-2019 (COVID-19). Several studies reported a 20-35% prevalence for hyponatraemia and 2-5% for hypernatraemia in patients admitted with COVID-19. In addition, hyponatraemia on admission was a risk factor for progression to severe disease, being associated with an increased likelihood for the need for invasive mechanical ventilation, with an odds ratio (OR) of 1.83-3.30. Hyponatraemia seems to be an independent risk factor for mortality, with an OR of 1.40-1.50 compared to normonatraemia, while hypernatraemia is related to even worse outcomes than hyponatraemia. Furthermore, preliminary data show an inverse association between serum sodium and interleukin-6 levels, suggesting that hyponatraemia might be used as a surrogate marker for the risk of a cytokine storm and the need for treatment with interleukin antagonists. In conclusion, dysnatraemia is common and carries a poor prognosis in COVID-19 patients, indicating that it may play a future role in risk stratification and individualising therapy.

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.