Effectiveness of Copeptin, MR-proADM and MR-proANP in Predicting Adverse Outcomes, Alone and in Combination with Traditional Severity Scores, a Secondary Analysis in COVID-19 Patients Requiring Intensive Care Admission.

Objective: To investigate whether copeptin, MR-proADM and MR-proANP, alone or integrated with the SOFA, MuLBSTA and SAPS II scores, are capable of early recognition of COVID-19 ICU patients at increased risk of adverse outcomes. Methods: For this predefined secondary analysis of a larger cohort previously described, all consecutive COVID-19 adult patients admitted between March and December 2020 to the ICU of a referral, university hospital in Northern Italy were screened, and clinical severity scores were calculated upon admission. A blood sample for copeptin, MR-proADM and MR-proANP was collected within 48 h (T1), on day 3 (T3) and 7 (T7). Outcomes considered were ICU and in-hospital mortality, bacterial superinfection, recourse to renal replacement therapy (RRT) or veno-venous extracorporeal membrane oxygenation, need for invasive mechanical ventilation (IMV) and pronation. Results: Sixty-eight patients were enrolled, and in-hospital mortality was 69.1%. ICU mortality was predicted by MR-proANP measured at T1 (HR 1.005, 95% CI 1.001-1.010, p = 0.049), although significance was lost if the analysis was adjusted for procalcitonin and steroid treatment (p = 0.056). Non-survivors showed higher MR-proADM levels than survivors at all time points, and an increase in the ratio between values at baseline and at T7 > 4.9% resulted in a more than four-fold greater risk of in-hospital mortality (HR 4.417, p < 0.001). Finally, when considering patients with any reduction in glomerular filtration, an early copeptin level > 23.4 pmol/L correlated with a more than five-fold higher risk of requiring RRT during hospitalization (HR 5.305, p = 0.044). Conclusion: Timely evaluation of MR-proADM, MR-proANP and copeptin, as well as changes in the former over time, might predict mortality and other adverse outcomes in ICU patients suffering from severe COVID-19.

Mild hyponatremia is not associated with degradation of trabecular bone microarchitecture despite bone mass loss.

CONTEXT: Hyponatremia is associated with increased risk of osteoporosis and fractures. The impact of hyponatremia on non-invasive indices of bone quality, however, is unknown. OBJECTIVE: To evaluate whether trabecular bone microarchitecture, assessed non-invasively by trabecular bone score (TBS), is altered in patients with hyponatremia. METHODS: We conducted a cross-sectional analysis of the population-based 2005-2008 cycles of the National Health and Nutrition Examination Survey (NHANES), in which TBS measurement was performed. The main outcome measures were TBS values and bone mineral density (BMD) T-scores at the lumbar spine, total hip and femoral neck. RESULTS: A total of 4204 subjects aged 50 years or older were included (4041 normonatremic, 163 hyponatremic - 90.8% with mild hyponatremia). Univariate analyses did not show any difference in TBS between patients with and without hyponatremia (1.308 ± 0.145 vs 1.311 ± 0.141, p = 0.806). Hyponatremic subjects had lower BMD T-score at total hip (-0.70 ± 1.46 vs -0.13 ± 1.32, p < 0.001) and femoral neck (-1.11 ± 1.26 vs -0.72 ± 1.14, p = 0.004), while no difference was observed at lumbar spine (-0.27 ± 1.63 vs -0.31 ± 1.51, p = 0.772). After adjustment for relevant confounders, hyponatremia was confirmed as an independent predictor of lower BMD T-score at the total hip (ß=-0.20, 95%CI:[-0.39, -0.02], p = 0.029), while the significance was lost at the femoral neck (p = 0.308). Again, no association between hyponatremia and lumbar spine BMD (p = 0.236) or TBS (p = 0.346) was observed. CONCLUSIONS: Hyponatremia, at least in mild forms, is not associated with a degradation of trabecular microarchitecture, assessed non-invasively by TBS. An independent association between hyponatremia and loss of bone mass is confirmed, particularly at the total hip.

Prolactin-secreting tumors, dopamine agonists and pregnancy: a longitudinal experience of a tertiary neuroendocrine center.

PURPOSE: Prolactin (PRL)-secreting tumours are associated with infertility and can be reverted by dopamine agonist (DA) therapy. The suspension of DA is recommended once pregnancy is established, as all DAs cross the placenta. The aim of the study was to evaluate the rate of maternal-foetal complications in women treated with cabergoline (CAB) or bromocriptine (BRM) for prolactinoma during gestation and the effect of pregnancy on prolactinoma progression. METHODS: This was a retrospective observational study involving 43 women affected by prolactinoma who became pregnant during therapy with CAB or BRM for a total of 58 pregnancies. For each patient, medical records were analysed by integrating the data with outpatient or telephone interview. RESULTS: At the time of conception, 18 women were in the BRM group, while 40 were in CAB group. No differences were found in obstetric or neonatal outcomes between the two groups. There was a significant difference (p = 0.046) in child complications reported in maternal interview found exclusively in the CAB group. No further confounding factors were detected. Disease remission rate after the first pregnancy was 42.9% and the main predictor was a lower PRL nadir before pregnancy (p = 0.023). No difference was detected between the two groups in terms of tumor remission. Breastfeeding did not modify the outcome. CONCLUSION: Foetal exposure to DAs during the first weeks of embryogenesis is not associated with a greater risk of complications. The transient and mild developmental disorders recorded resolved spontaneously and the prevalence was substantially overlapping with that observed in the general population.

Severe hypothyroidism as a trigger for Brugada-type ECG abnormalities: a case report and literature review.

Brugada syndrome (BrS) is an inherited disorder that can cause ventricular fibrillation and sudden cardiac death in individuals with otherwise structurally normal hearts. Several provoking factors are known to potentially unmask or exacerbate a typical Brugada ECG pattern in predisposed subjects. Hypothyroidism has been suggested as one of these triggers, but the exact mechanisms underlying this relationship remain poorly understood. Moreover, the severity of thyroid dysfunction beyond which a Brugada-type ECG alteration might be triggered is still unclear. We report the case of a 33-year-old male who displayed a Brugada type 1 ECG pattern and was diagnosed with severe hypothyroidism (TSH > 100 mU/L with undetectable levels of fT4 and fT3). Hormonal replacement therapy with levothyroxine was initiated at increasing doses; serial biochemical and ECG controls were performed, initially every 3 weeks up to 15 weeks and afterward every 3 months. The regression of typical Brugada ECG waveforms could be seen at an early stage, when the patient was still taking a low dose of levothyroxine (37.5 µg/day, i.e., one-fourth of his final requirements of 150 µg/day), and laboratory tests still showed a marked alteration of thyroid hormonal parameters. Hypothyroidism may act as a trigger for Brugada-type ECG abnormalities, but a very severe alteration of the hormonal parameters is necessary to prompt these alterations. In our case, the initiation of replacement therapy with levothyroxine rapidly reversed the ECG modifications, even at a low subtherapeutic dose.

Radiomic Analysis in Pituitary Tumors: Current Knowledge and Future Perspectives.

Radiomic analysis has emerged as a valuable tool for extracting quantitative features from medical imaging data, providing in-depth insights into various contexts and diseases. By employing methods derived from advanced computational techniques, radiomics quantifies textural information through the evaluation of the spatial distribution of signal intensities and inter-voxel relationships. In recent years, these techniques have gained considerable attention also in the field of pituitary tumors, with promising results. Indeed, the extraction of radiomic features from pituitary magnetic resonance imaging (MRI) images has been shown to provide useful information on various relevant aspects of these diseases. Some of the key topics that have been explored in the existing literature include the association of radiomic parameters with histopathological and clinical data and their correlation with tumor invasiveness and aggressive behavior. Their prognostic value has also been evaluated, assessing their role in the prediction of post-surgical recurrence, response to medical treatments, and long-term outcomes. This review provides a comprehensive overview of the current knowledge and application of radiomics in pituitary tumors. It also examines the current limitations and future directions of radiomic analysis, highlighting the major challenges that need to be addressed before a consistent integration of these techniques into routine clinical practice.

Are prolactin levels efficient in predicting a pituitary lesion in patients with hyperprolactinemia?

PURPOSE: Data regarding the presence of a prolactin (PRL) threshold above which a pituitary magnetic resonance imaging (MRI) is mandatory in patients with hyperprolactinemia (hyperPRL) are controversial and derived primarily from studies focused on female populations. Aim of our study was to evaluate in a cohort of patients of both sexes with confirmed hyperPRL, the possible correlation between PRL values and the presence of pituitary abnormalities. METHODS: We retrospectively analyzed data from patients who underwent serial PRL sampling at our Division between January 2015 and December 2022. Patients diagnosed with monomeric hyperPRL at serial sampling and with subsequent contrast-enhanced MRI results available for the pituitary region were included in the study. Exclusion criteria were prior pituitary disease, severe renal insufficiency, liver cirrhosis, uncompensated primary hypothyroidism and ongoing therapy with hyperprolactinemic drugs. Physiological causes of hyperPRL were also ruled out. RESULTS: Out of the 1253 patients who underwent serial PRL sampling, 139 patients (101 women and 38 men) met the inclusion criteria: 106 (76.3%) patients had some form of pituitary disease, with microlesions observed in 69.8%, macrolesions in 25.5% and other findings in 4.7% of subjects. PRL values showed a modest accuracy in predicting the presence of a pituitary abnormality and the best cut-offs identified were >25 µg/L (AUC 0.767, p = 0.003) and >44.2 µg/L (AUC 0.697, p < 0.001) in men and women, respectively; however, if only patients with PRL values > 500 µg/L were excluded from the analysis, as they were already supposed to harbor a macroprolactinoma, PRL levels were not able to predict the presence of a macrolesion neither in men nor women. CONCLUSION: Given the high prevalence of pituitary abnormalities in patients of both sexes with hyperPRL at serial sampling, performing a pituitary imaging in all cases of hyperPRL, even if mild, appears to be a cautious choice.

Severe hypothyroidism as a trigger for Brugada-type ECG abnormalities: a case report and literature review

SUMMARY Brugada syndrome (BrS) is an inherited disorder that can cause ventricular fibrillation and sudden cardiac death in individuals with otherwise structurally normal hearts. Several provoking factors are known to potentially unmask or exacerbate a typical Brugada ECG pattern in predisposed subjects. Hypothyroidism has been suggested as one of these triggers, but the exact mechanisms underlying this relationship remain poorly understood. Moreover, the severity of thyroid dysfunction beyond which a Brugada-type ECG alteration might be triggered is still unclear. We report the case of a 33-year-old male who displayed a Brugada type 1 ECG pattern and was diagnosed with severe hypothyroidism (TSH > 100 mU/L with undetectable levels of fT4 and fT3). Hormonal replacement therapy with levothyroxine was initiated at increasing doses; serial biochemical and ECG controls were performed, initially every 3 weeks up to 15 weeks and afterward every 3 months. The regression of typical Brugada ECG waveforms could be seen at an early stage, when the patient was still taking a low dose of levothyroxine (37.5 µg/day, i.e., one-fourth of his final requirements of 150 µg/day), and laboratory tests still showed a marked alteration of thyroid hormonal parameters. Hypothyroidism may act as a trigger for Brugada-type ECG abnormalities, but a very severe alteration of the hormonal parameters is necessary to prompt these alterations. In our case, the initiation of replacement therapy with levothyroxine rapidly reversed the ECG modifications, even at a low subtherapeutic dose.

Trabecular bone score as a marker of skeletal fragility across the spectrum of chronic kidney disease: a systematic review and meta-analysis.

CONTEXT: The impairment of bone microarchitecture is a key determinant of skeletal fragility in patients with chronic kidney disease (CKD). Trabecular bone score (TBS) has been developed as a reliable non-invasive index of bone quality. However, its utility in this setting is still debated. OBJECTIVE: The aim of this systematic review and meta-analysis was to summarize the available evidence about TBS as a marker of skeletal fragility across the spectrum of CKD. METHODS: PubMed/Medline, EMBASE and Cochrane Library databases were systematically searched until July 2023 for studies reporting data about TBS in patients with CKD. Effect sizes were pooled through a random-effect model. RESULTS: Compared to controls, lower TBS values were observed in CKD patients not on dialysis (-0.057, 95%CI:[-0.090, -0.024], p < 0.01), in dialysis patients (-0.106, 95%CI:[-0.141, -0.070], p < 0.01) and in kidney transplant recipients (KTRs) (-0.058, 95%CI:[-0.103, -0.012], p = 0.01). With respect to fracture risk, TBS was able to predict incident fractures in non-dialysis patients at unadjusted analyses (hazard ratio (HR) per standard deviation decrease: 1.45, 95%CI:[1.05,2.00], p = 0.02), though only a non-significant trend was maintained when fully adjusting the model for FRAX® (HR = 1.26, 95%CI:[0.88,1.80], p = 0.21). Dialysis patients with prevalent fractures had lower TBS values compared to unfractured ones (-0.070, 95% CI:[-0.111, -0.028], p < 0.01). Some studies supported a correlation between TBS and fracture risk in KTRs, but results could not be pooled due to the lack of sufficient data. CONCLUSIONS: CKD patients are characterized by an impairment of bone microarchitecture, as demonstrated by lower TBS values, across the whole spectrum of kidney disease. TBS can also be helpful in the discrimination of fracture risk, with lower values being correlated with a higher risk of prevalent and incident fractures.

Bone safety of dual-release hydrocortisone in patients with autoimmune primary adrenal insufficiency.

Background: Conventional glucocorticoids (C-GC) replacement regimens have a detrimental effect on skeletal health in patients with adrenal insufficiency (AI), ultimately leading to an increased fracture risk. The novel dual-release hydrocortisone (DR-HC) formulations are characterized by a more favourable safety profile on various clinical endpoints. Data comparing the impact of C-GC and DR-HC on bone, however, are scarce. Methods: Twenty-seven patients with autoimmune primary AI (PAI; 13 treated with C-GC and 14 treated with DR-HC) were evaluated to compare bone-related parameters between the two treatment groups. Results: No significant differences between the two treatments groups were observed with respect to bone turnover markers. Patients treated with C-GC showed a lower bone mineral density (BMD) at lumbar spine (LS; 0.791 ± 0.195 vs. 0.942 ± 0.124 g/cm2, p=0.025) and at femoral neck (FN; 0.633 ± 0.114 vs. 0.716 ± 0.088 g/cm2, p=0.045). Moreover, they were characterized by a lower trabecular bone score (TBS; 1.236 ± 0.035 vs. 1.383 ± 0.030, p=0.004) and by a higher mean number of vertebral fractures per patient (0.75 vs. 0 fractures, p=0.002). TBS was the best predictor of fracture risk, with a pseudo-R2 of 0.593; moreover, at mediation analysis, it was able to fully explain the observed detrimental effect of C-GC, compared to DR-HC, on fracture risk. Conclusions: These results suggest that DR-HC is associated with less bone-related complications compared to C-GC in patients with PAI. Moreover, TBS seems to play a pivotal role in the mediation of the relationship between glucocorticoid treatment regimens and fracture risk.

Prediction of Early and Long-Term Hospital Readmission in Patients with Severe Obesity: A Retrospective Cohort Study.

Adults with obesity have a higher risk of hospitalization and high hospitalization-related healthcare costs. However, a predictive model for the risk of readmission in patients with severe obesity is lacking. We conducted a retrospective cohort study enrolling all patients admitted for severe obesity (BMI ≥ 40 kg/m2) between 2009 and 2018 to the Istituto Auxologico Italiano in Piancavallo. For each patient, all subsequent hospitalizations were identified from the regional database by a deterministic record-linkage procedure. A total of 1136 patients were enrolled and followed up for a median of 5.7 years (IQR: 3.1-8.2). The predictive factors associated with hospital readmission were age (HR = 1.02, 95%CI: 1.01-1.03, p < 0.001), BMI (HR = 1.02, 95%CI: 1.01-1.03, p = 0.001), smoking habit (HR = 1.17, 95%CI: 0.99-1.38, p = 0.060), serum creatinine (HR = 1.22, 95%CI: 1.04-1.44, p = 0.016), diabetes (HR = 1.17, 95%CI: 1.00-1.36, p = 0.045), and number of admissions in the previous two years (HR = 1.15, 95%CI: 1.07-1.23, p < 0.001). BMI lost its predictive role when restricting the analysis to readmissions within 90 days. BMI and diabetes lost their predictive roles when further restricting the analysis to readmissions within 30 days. In conclusion, in this study, we identified predictive variables associated with early and long-term hospital readmission in patients with severe obesity. Whether addressing modifiable risk factors could improve the outcome remains to be established.

Predictive performance of aldosterone-to-renin ratio in the diagnosis of primary aldosteronism in patients with resistant hypertension.

Background: The systematic use of confirmatory tests in the diagnosis of primary aldosteronism (PA) increases costs, risks and complexity to the diagnostic work-up. In light of this, some authors proposed aldosterone-to-renin (ARR) cut-offs and/or integrated flow-charts to avoid this step. Patients with resistant hypertension (RH), however, are characterized by a dysregulated renin-angiotensin-aldosterone system, even in the absence of PA. Thus, it is unclear whether these strategies might be applied with the same diagnostic reliability in the setting of RH. Methods: We enrolled 129 consecutive patients diagnosed with RH and no other causes of secondary hypertension. All patients underwent full biochemical assessment for PA, encompassing both basal measurements and a saline infusion test. Results: 34/129 patients (26.4%) were diagnosed with PA. ARR alone provided a moderate-to-high accuracy in predicting the diagnosis of PA (AUC=0.908). Among normokalemic patients, the ARR value that maximized the diagnostic accuracy, as identified by the Youden index, was equal to 41.8 (ng/dL)/(ng/mL/h), and was characterized by a sensitivity and a specificity of 100% and 67%, respectively (AUC=0.882); an ARR > 179.6 (ng/dL)/(ng/mL/h) provided a 100% specificity for the diagnosis of PA, but was associated with a very low sensitivity of 20%. Among hypokalemic patients, the ARR value that maximized the diagnostic accuracy, as identified by the Youden index, was equal to 49.2 (ng/dL)/(ng/mL/h), and was characterized by a sensitivity and a specificity of 100% and 83%, respectively (AUC=0.941); an ARR > 104.0 (ng/dL)/(ng/mL/h) provided a 100% specificity for the diagnosis of PA, with a sensitivity of 64%. Conclusions: Among normokalemic patients, there was a wide overlap in ARR values between those with PA and those with essential RH; the possibility to skip a confirmatory test should thus be considered with caution in this setting. A better discriminating ability could be seen in the presence of hypokalemia; in this case, ARR alone may be sufficient to skip confirmatory tests in a suitable percentage of patients.

Copeptin adaptive response to SGLT2 inhibitors in patients with type 2 diabetes mellitus: The GliRACo study.

Introduction: In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount. Aim: To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients. Methods: The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90. Results: Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability (7.5 pmol/L at T0, 9.8 pmol/L at T30, 9.5 pmol/L at T90; p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition (p < 0.001), while copeptin did not. Conclusion: In patients with T2DM, SGLT2i promote the release of AVP, thus compensating for persistent osmotic diuresis. This mainly occurs because of a proportional dehydration process between intra and extracellular fluid (i.e., intracellular dehydration rather than extracellular dehydration). The extent of fluid reduction, but not the copeptin response, is affected by the patient's baseline volume conditions. Clinical trial registration: Clinicaltrials.gov, identifier NCT03917758.

Psychiatric disorders and anger in patients with controlled acromegaly.

BACKGROUND: Acromegaly (ACRO) is a chronic rare disease caused by a pathological increase in growth hormone (GH) secretion. In ACRO an increased prevalence of psychiatric disorders has been demonstrated, in particular depressive disorders, associated to a significant deterioration of the quality of life, independently from disease control. In addition, anger feelings, often detected in subjects affected by chronic disease, have not yet been investigated, in pituitary patients. Aim of the study was to evaluate in ACRO patients with a controlled disease, compared to patients suffering for non-functioning pituitary adenoma (NFPA) 1) prevalence of depressive and anxiety disorders, and 2) expression and control of anger feelings. The second purpose was to evaluate the correlation between psychiatric disorders, anger feelings and the "activity of disease," that is active ACRO that needs medical treatment versus cured ACRO. METHODS: This is a cross-sectional, observational study, which included 53 patients enrolled at the Neuroendocrinology Outpatient Clinic of "Città della Salute e della Scienza di Torino". Of the 53 enrolled patients (24 male and 29 female), 34 had ACRO, while 19 had NFPA, as control group. All subjects went through the following self-administered, validated psychological tools: SF-36 (Short-Form 36 Item); STAXI - 2; BDI-II (Beck Depression Inventory -II); STAI (State-Trait Anxiety Inventory). Only in ACRO group, patients completed PASQ (Patient-Assessed Acromegaly Symptom Questionnaire) and ACROQoL (Acromegaly Quality of Life Questionnaire) questionnaires. In addition 45 patients underwent the International Neuropsychiatric Short Interview to assess the presence of a psychiatric disorder. For each patient, anthropometric, clinical and biochemical information was collected. RESULTS: A higher frequency of psychiatric anxiety and mood disorders (not reported in the medical history) was observed in patients with controlled ACRO. In the SF-36 questionnaire, a lower score was found in the "emotional well-being" items in ACRO compared to NFPA, particularly in those with cured ACRO. Cured acromegalic patients had a worse score in "emotional well-being," "energy/fatigue" and "general health" items. Finally, subjects in ACRO group obtained a lower score in the ability to control anger and a higher score in the physical expression of it, demonstrating a tendency to more aggressive behaviors. CONCLUSIONS: This study showed that psychiatric illness is often hidden in patient suffering from ACRO, despite normal IGF-I levels. Recovery from the disease do not necessarily improve QoL scores, in fact in cured patients the quality of life can be even worse.

Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma.

Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.

Isolated anterior pituitary dysfunction in adulthood.

Hypopituitarism is defined as a complete or partial deficiency in one or more pituitary hormones. Anterior hypopituitarism includes secondary adrenal insufficiency, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency and prolactin deficiency. Patients with hypopituitarism suffer from an increased disability and sick days, resulting in lower health status, higher cost of care and an increased mortality. In particular during adulthood, isolated pituitary deficits are not an uncommon finding; their clinical picture is represented by vague symptoms and unclear signs, which can be difficult to properly diagnose. This often becomes a challenge for the physician. Aim of this narrative review is to analyse, for each anterior pituitary deficit, the main related etiologies, the characteristic signs and symptoms, how to properly diagnose them (suggesting an easy and reproducible step-based approach), and eventually the treatment. In adulthood, the vast majority of isolated pituitary deficits are due to pituitary tumours, head trauma, pituitary surgery and brain radiotherapy. Immune-related dysfunctions represent a growing cause of isolated pituitary deficiencies, above all secondary to use of oncological drugs such as immune checkpoint inhibitors. The diagnosis of isolated pituitary deficiencies should be based on baseline hormonal assessments and/or dynamic tests. Establishing a proper diagnosis can be quite challenging: in fact, even if the diagnostic methods are becoming increasingly refined, a considerable proportion of isolated pituitary deficits still remains without a certain cause. While isolated ACTH and TSH deficiencies always require a prompt replacement treatment, gonadal replacement therapy requires a benefit-risk evaluation based on the presence of comorbidities, age and gender of the patient; finally, the need of growth hormone replacement therapies is still a matter of debate. On the other side, prolactin replacement therapy is still not available. In conclusion, our purpose is to offer a broad evaluation from causes to therapies of isolated anterior pituitary deficits in adulthood. This review will also include the evaluation of uncommon symptoms and main etiologies, the elements of suspicion of a genetic cause and protocols for diagnosis, follow-up and treatment.

Adrenocortical, somatotropic, and antidiuretic response to nasal glucagon in healthy subjects.

OBJECTIVE: The glucagon stimulation test involves the peptide intramuscular or subcutaneous administration for the diagnosis of hypopituitarism. To date, no data are available regarding its intranasal formulation. Our study intended to investigate the role of intranasal glucagon as a potential stimulus test for the evaluation of the corticotropic, somatotropic, and antidiuretic axes. DESIGN: Non-randomized, single-blinded, cross-over study including 10 healthy subjects (50% women). METHODS: All participants underwent 2 days of testing, and intranasal glucagon or placebo was administered. At baseline, every 15' up to +90', and then every 30' up to +180', a blood sample was taken for adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), copeptin, glucose, insulin, sodium, potassium, and plasma osmolarity. At baseline and at the end of the test, urinary osmolarity was evaluated as well. RESULTS: After administration of both glucagon and placebo, ACTH and cortisol values decreased progressively (P < 0.001), but in the drug group, the reduction in cortisol was less accentuated up to +90' (P < 0.05). Growth hormone values decreased after placebo administration (P < 0.001); on the other hand, after glucagon, an increasing, yet non-significant trend was observed (P = 0.096) with the difference between the two groups evident starting from +120' onwards (P < 0.005). The placebo administration led to a reduction of copeptin, while its stability was observed after glucagon administration. Six subjects developed hypokalemia (ie, potassium <3.5 mmol/L) post-glucagon, with the nadir at 45' (3.6 [3.2-3.8] mmol/L) significantly correlated with the immediate post-glycemic rise insulin peak (Spearman's rho -0.719; P = 0.019). No significant differences were observed compared to the other analytes tested. CONCLUSIONS: Intranasal glucagon administration is not an effective stimulus for hypophyseal secretion. Hypokalemia secondary to hyperinsulinemic rebound appears to be a frequent complication of its acute administration.

Trabecular Bone Score as an Index of Bone Fragility in Patients with Acromegaly: A Systematic Review and Meta-Analysis.

BACKGROUND: Acromegaly is characterized by impaired bone quality and increased fracture risk. However, due to the pathophysiology of acromegalic osteopathy, bone mineral density (BMD) does not represent a reliable predictor for fragility fractures in this setting. Trabecular bone score (TBS) has been recently evaluated as an alternative index of skeletal fragility in acromegalic patients. However, no conclusive data are still available in this regard. METHODS: PubMed/Medline, EMBASE, Cochrane Library, Ovid, and CINAHL databases were systematically searched until June 2022 for studies reporting data either about the comparison of TBS values between acromegalic patients and non-acromegalic controls or about the relationship - within acromegalic patients - between TBS values and fracture risk. Effect sizes were pooled through a random-effect model. RESULTS: Eight studies were eligible for inclusion in the meta-analysis, encompassing 336 acromegalic patients and 490 non-acromegalic controls. Overall, TBS was significantly lower in acromegalic patients compared to controls (-0.089, 95% CI: [-0.111, -0.067], p < 0.01), irrespective of acromegaly disease activity and gonadal status. With respect to fracture risk, TBS was significantly lower in acromegalic patients with vertebral fractures than in those without (-0.099, 95% CI: [-0.166, -0.032], p < 0.01). CONCLUSION: In this meta-analysis, we specifically assessed the role of TBS as an index of bone quality and fracture risk in patients with acromegaly. Our results support the notion that TBS could be of value in the assessment and management of skeletal fragility in acromegalic patients, especially in light of the poor information provided in this setting by BMD.

Long-term efficacy of empagliflozin as an add-on treatment for chronic SIAD: a case report and literature review.

BACKGROUND: SLGT-2 inhibitors have recently been investigated as a promising therapy for syndrome of inappropriate antidiuresis (SIAD). However, to our knowledge, no report has been published about their use for this indication in the long term. CASE PRESENTATION: We report the case of a 68-year-old male with type 2 diabetes and chronic SIAD, in whom serum sodium levels were not adequately controlled by urea monotherapy. Other treatment options were not viable due to inefficacy or adverse effects. The initiation of empagliflozin, in addition to urea, led to the full normalization of serum sodium. Reduction and subsequent discontinuation of urea were attempted upon patient request, but this resulted in a relapse of hyponatremia. Nevertheless, stable normonatremia was again achieved and maintained for more than 6 months after re-establishing a combination therapy with empagliflozin and urea. CONCLUSIONS: SGLT2 inhibitors might represent an effective treatment for SIAD, even in the long term. Specific clinical trials are needed to confirm this result.

Mortality and parenteral nutrition weaning in patients with chronic intestinal failure on home parenteral nutrition: A 30-year retrospective cohort study.

BACKGROUND: Home parenteral nutrition (HPN) is the standard treatment for patients with chronic intestinal failure (CIF). Mortality and weaning rates of these patients differ widely among cohorts; however, these outcomes were often considered independent-rather than competing-events, leading to an upward bias of the retrieved estimates. OBJECTIVES: The aim of this retrospective cohort study was to evaluate, evaluating through a competing risk analysis, the rates and predictors of mortality and weaning in CIF patients from an Italian referral center. METHODS: All adult patients with CIF receiving > 3 mo HPN from 1985 until 2016 were enrolled. Clinical information was collected from the database of the Intestinal Failure Unit of Torino, Italy. Patients were stratified according to the presence or not of short bowel syndrome (SBS). RESULTS: The cumulative incidences of death and weaning were 27.3% and 32.3% and 39.0% and 33.7% at 5 and 10 y from HPN initiation, respectively. At multivariable competing risk analyses, mortality was predicted by age (sub-distribution hazard ratio [SHR] = 1.65 per 10-y increase; 95% CI, 1.35-2.01), type 3 SBS (SHR = 0.38; 0.15-0.94), small bowel length ≥ 100 cm (SHR = 0.42; 0.22-0.83), and reconstructive surgery (SHR = 0.11; 0.02-0.64) in SBS patients, and by age (SHR = 1.38 per 10-y increase; 1.16-1.64) and presence of stoma (SHR = 0.30; 0.12-0.78) in non-SBS patients. In the same model, weaning was predicted by type 3 SBS (SHR = 6.86; 3.10-15.16), small bowel length ≥ 100 cm (SHR = 3.54; 1.99-6.30), and reconstructive surgery (SHR = 2.86; 1.44-5.71) in SBS patients, and by age (SHR = 0.79 per 10-y increase; 0.66-0.94) and presence of stoma (SHR = 2.64; 1.38-5.07) in non-SBS patients. CONCLUSIONS: Surgical procedures strongly affected mortality and weaning risk in CIF patients.