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.

Atrial Fibrillation and Aortic Ectasia as Complications of Primary Aldosteronism: Focus on Pathophysiological Aspects.

Primary aldosteronism (PA) is the most common cause of secondary hypertension. A growing body of evidence has suggested that, beyond its well-known effects on blood pressure and electrolyte balance, aldosterone excess can exert pro-inflammatory, pro-oxidant and pro-fibrotic effects on the kidney, blood vessels and heart, leading to potentially harmful pathophysiological consequences. In clinical studies, PA has been associated with an increased risk of cardiovascular, cerebrovascular, renal and metabolic complication compared to essential hypertension, including atrial fibrillation (AF) and aortic ectasia. An increased prevalence of AF in patients with PA has been demonstrated in several clinical studies. Aldosterone excess seems to be involved in the pathogenesis of AF by inducing cardiac structural and electrical remodeling that in turn predisposes to arrhythmogenicity. The association between PA and aortic ectasia is less established, but several studies have demonstrated an effect of aldosterone on aortic stiffness, vascular smooth muscle cells and media composition that, in turn, might lead to an increased risk of aortic dilation and dissection. In this review, we focus on the current evidence regarding the potential role of aldosterone excess in the pathogenesis of AF and aortic ectasia.

Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight.

Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are "high-risk phenotypes", associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of "non-classical" effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients.

The Cut-off Limits of Growth Hormone Response to the Insulin Tolerance Test Related to Body Mass Index for the Diagnosis of Adult Growth Hormone Deficiency.

INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) in adults is based on a reduced GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone (GHRH) + arginine (ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. To date, there are no ITT cut-offs related to body mass index (BMI). OBJECTIVE: We aimed to evaluate the diagnostic cut-offs of GH response to the ITT in the function of BMI. METHODS: The GH response to the ITT was studied in 106 patients with a history of hypothalamic-pituitary disease, a mean age of 48.2 ± 12.4 years, and a mean BMI of 26.8 ± 6.1 kg/m2). Patients were divided into lean, overweight, and obese groups according to their BMI. The lack of GH response to GHRH + ARG test was considered the gold standard for the diagnosis of GHD. The best GH cut-off in the ITT, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using receiver-operating characteristics curve (ROC) analysis. RESULTS: The best GH cut-off in the ITT was 3.5 µg/L in lean subjects (SE 82.1%; SP 85.7%), 1.3 µg/L in overweight subjects (SE 74.1%; SP 85.7%), and 2.2 µg/L in obese subjects (SE 90.0%; SP 50.0%). The diagnostic accuracy was 97.2, 76.5, and 76.7%, respectively. CONCLUSIONS: Our data show that the ITT represents a reliable diagnostic tool for the diagnosis of adult GHD in lean subjects if an appropriate cut-off limit is assumed. Overweight and obesity strongly reduce the GH response to the ITT, GH BMI-related cut-off limits, and the diagnostic reliability of the test.

Morning Serum Cortisol Level Predicts Central Adrenal Insufficiency Diagnosed by Insulin Tolerance Test.

INTRODUCTION: According to guidelines, a morning serum cortisol level <83 nmol/L is diagnostic for central adrenal insufficiency (CAI), a value >414 nmol/L excludes CAI, while values between 83 and 414 nmol/L require stimulation tests. However, there are no currently reliable data on morning serum cortisol for prediction of cortisol response to insulin tolerance test (ITT). OBJECTIVE: Using the receiver-operating characteristic curve analysis, the purpose of this study was to detect the morning serum cortisol cutoff with a specificity (SP) or a sensitivity (SE) above 95% that identify those patients who should not be tested with ITT. METHODS: We included 141 adult patients (83 males) aged 42.7 ± 12.3 (mean ± standard deviation) years old. Based on the serum cortisol response to ITT, patients have been divided into 2 groups: subjects with CAI (peak serum cortisol <500 nmol/L; 65 patients) and subjects with preserved adrenocortical function (peak cortisol >500 nmol/L; 76 patients). RESULTS: The best morning cortisol cutoff, in terms of SE (87.7%) and SP (46.1%), was ≤323.3 nmol/L. The cutoff of morning serum cortisol concentration that best predicted a deficient response to ITT was ≤126.4 nmol/L (SE 13.8%, SP 98.7%). The cutoff of morning serum cortisol concentration that best predicted a normal response to ITT was >444.7 nmol/L (SE 96.9%, SP 14.5%). CONCLUSIONS: This is the first study that identifies a morning serum cortisol cutoff that best predict the response to ITT in order to simplify the diagnostic process in patients with suspected CAI. A new diagnostic flow-chart for CAI is proposed.

A Simplified Ultrasonographic Score for the Prediction of Cytologically Suspicious Thyroid Nodules.

PURPOSE: The major aim of ultrasound (US)-based risk stratification systems is to reduce unnecessary thyroid biopsies without losing the ability to recognize nodules with clinically significant malignancy. Each of the classic suspicious features of a thyroid nodule detected on US scan (hypoechoic pattern, microcalcifications, irregular margin, taller than wide shape, irregular vascularization) is significantly independently associated with the probability of malignancy, but none of them has good diagnostic accuracy. Thus, we evaluated the predictive value of a binary score simply based on the combination of these US features, regardless of the specific predictive value of each US feature, against the outcome of suspected malignancy at cytological diagnosis (TIR3 to TIR5 categories by SIAPEC-IAP [TIR+]). MATERIALS AND METHODS: 1009 thyroid nodules from 1081 patients were considered. The US features of suspicion of all nodules were categorized in 5 binary scores (U1 to U5), each including from 1 to 5 of those features. RESULTS: U2 (at least 2 US suspicious features) was the most balanced predictor of TIR+ (PPV 0.48, NPV 0.93, LR+ 3.05 and LR- 0.24). Weighting the predictivity of the single features did not improve the estimate. Using U2 as the criterion to send nodules to FNAC would have reduced the number of biopsies by 60 % (604 patients) and the false negatives would have only accounted for 41 cases out of 237 TIR+ (17 %) with 39 cases of TIR3 and 2 cases of TIR4, including only 6 malignant nodules on histological examination. U2 performed much better than the ATA recommendations for detecting those nodules, resulting in TIR+ at cytology. CONCLUSION: This simple and reproducible sonographic score based on 2 US features of suspicion of malignancy has quite a good performance with respect to identifying thyroid lesions categorized by cytology as medium-high risk of malignancy and could allow us to reduce cytology costs for low-risk nodules.

Primary Pituitary Lymphoma As Rare Cause Of A Pituitary Mass And Hypopituitarism In Adulthood.

OBJECTIVE: Differential diagnosis of nonadenomatous sellar masses causing hypopituitarism is still a challenge. Among these masses, growing evidence has demonstrated that primary pituitary lymphoma is a specific and emerging entity. The aim of our study was to describe our experience with a case of primary pituitary lymphoma and to perform a review of the available literature. METHODS: We searched relevant databases up to March 2020, identifying 36 suitable articles basing on inclusion criteria (primary pituitary lymphoma in adult immunocompetent subjects). Overall, 43 cases were included in the review, adding a new case diagnosed and treated in our hospital. Epidemiologic data, clinical presentation, hormonal status, radiologic findings, pathology, treatment, and outcome were extracted. RESULTS: Mean age at diagnosis was 58.9 years, without gender difference. Symptoms related to mass were common (52.3%), in particular cranial nerve palsy (70.5%), headache (56.8%), and alteration in visual field (40.9%). Impaired hormonal status was detected in 89.7% of patients; of them, 58.9% presented with anterior pituitary failure (partial or total), while 25.6% presented with panhypopituitarism. Overall, diabetes insipidus was present in 30.8% and hyperprolactinemia in 41.0% of patients. The majority of patients presented a radiologically invasive mass in the suprasellar region and cavernous sinus (65.9% and 40.9%, respectively) and histologic diagnosis of diffuse B-cell lymphoma (54.5%). CONCLUSION: The differential diagnosis of sellar and parasellar masses causing hypopituitarism should include primary pituitary lymphoma, even in absence of systemic symptoms or posterior pituitary dysfunction. The disease has a heterogeneous pattern, so a collaboration between endocrinologists, neuroradiologists, neurosurgeons, and hematologists is desirable.

Hyperthyroidism in patients with ischaemic heart disease after iodine load induced by coronary angiography: Long-term follow-up and influence of baseline thyroid functional status.

OBJECTIVE: To study the effect of a iodine load on thyroid function of patients with ischaemic heart disease (IHD) and the long-term influence of unknown subclinical hyperthyroidism. CONTEXT: Subclinical hyperthyroidism is considered an independent risk factors for cardiovascular morbidity of patients with IHD. They routinely undergo coronary angiography with iodine contrast media (ICM) which may induce or even worsen hyperthyroidism. DESIGN: A cross-sectional study followed by a longitudinal study on patients with subclinical hyperthyroidism. PATIENTS: 810 consecutive IHD outpatients without known thyroid diseases or treatment with drugs influencing thyroid activity undergoing elective coronary angiography. MEASUREMENTS: We evaluated thyroid function either before and 1 month after ICM; patients with thyrotoxicosis at baseline or after ICM were then followed up for 1 year. RESULTS: 58 patients had hyperthyroidism at baseline (HB, 7.2%), independently associated to FT4 levels, thyroid nodules and family history of thyroid diseases. After ICM, the prevalence of hyperthyroidism was 81 (10%). Hyperthyroidism after ICM was positively predicted by baseline fT4 levels, thyroid nodules, age over 60, male gender, family history of thyroid diseases. Three months after ICM, 34 patients (4.2%) still showed hyperthyroidism (22 from HB, 13 treated with methimazole). One year after ICM, hyperthyroidism was still present in 20 patients (2.5%, all from HB, 13 treated). CONCLUSIONS: The prevalence of spontaneous subclinical hyperthyroidism in IHD is surprisingly elevated and is further increased by iodine load, particularly in patients with thyroid nodules and familial history of thyroid diseases, persisting in a not negligible number of them even after one year.

Enhanced oxidative stress and platelet activation in patients with Cushing's syndrome.

OBJECTIVE: Cushing Syndrome (CS) is implicated by increased cardiovascular risk (CVR) leading to increased morbidity and mortality. Oxidative stress (OS) and platelet activation (PA) are associated with increased CVR. However, scarce data of OS in CS exist. Our objective was to determine the oxidant-antioxidant balance in CS. DESIGN: Fourteen patients with CS at diagnosis and fourteen healthy subjects (NS) were evaluated OS by measuring plasma 15-F2t -Isoprostane (15-F2t -IsoP), PA by thromboxaneB2 levels (TXB2 ), and antioxidant reserve measuring total antioxidant capacity (TAC) and serum vitamin E. RESULTS: 15-F2t -IsoP and TXB2 levels were significantly higher (P < 0·01) in CS, while vitamin E levels were higher in NS (P < 0·03). 15-F2t -IsoP levels were significantly higher (P < 0·01) in complicated vs not-complicated CS and NS and significantly higher (P < 0·03) in CS not-complicated vs NS. TXB2 levels were significantly reduced (P < 0·03) in NS vs complicated and not-complicated CS. A negative correlation between Vitamin E and UFC was observed in CS (P < 0·05 r = -0·497). TXB2 correlated with glucose, HbA1c and T-score (P < 0·05 r = 0·512, P < 0·03 r = 0·527 and P < 0·01 r = 0·783, respectively) and HDL (P < 0·01 r = -0·651). 15-F2t -IsoP correlated with triglicerides, HbA1c and diastolic pressure (P < 0·01 r = 0·650, P < 0·03 r = 0·571 and P < 0·05 r = 0·498, respectively) and HDL (P < 0·03 r = -0·594). CONCLUSIONS: This study emphasizes the major role of OS in CS. As our findings demonstrated that enhanced OS and PA take place in this rare metabolic disorder which is associated with increased CVR, it could be suggested that these biochemical alterations can further contribute in the pathogenesis of atherosclerosis, increased CVR and mortality in CS.

Cushing's syndrome is associated with sleep alterations detected by wrist actigraphy.

BACKGROUND: The association between the hypothalamic-pituitary-adrenal (HPA) axis and sleep is well described. It is also known that HPA axis disturbances have an effect on sleep. In fact, patients affected by Cushing's syndrome (CS) often complain about poor sleep quality. Our aim was to evaluate objective sleep quality and duration in patients with Cushing's syndrome in active phase, using wrist actigraphy. PATIENTS AND METHODS: In 12 patients with active CS without ongoing specific therapy (11 F, 1 M; age 40.0 ± 10.9 years; BMI 28.4 ± 6.7 kg/m(2)) and 12 healthy control subjects (HS) (11 F, 1 M; age 44.0 ± 11.0 years; BMI 23.9 ± 4.2 kg/m(2)) an actigraphic evaluation was performed on 3 consecutive days under free living conditions. Objective measurement of sleep duration and quality was estimated by an actiwatch, which is a wristwatch-like device used to detect motor activity. RESULTS: In CS patients, wrist actigraphy showed higher fragmented sleep (fragmentation index CS 16.2 ± 4.2, HS 13.0 ± 3.6; p = 0.034) and increased nocturnal motor activity (total activity score CS 8318 ± 4308, HS 4971 ± 2372; p = 0.020; mean activity score CS 8.7 ± 4.2, HS 5.4 ± 2.2; p = 0.030; mean score in active time CS 104.8 ± 39.2, HS 74.8 ± 23.1; p = 0.030). On the contrary, actual sleep time resulted similar in CS and HS. No correlation was found between sleep alterations and urinary free cortisol in patients. CONCLUSIONS: The impaired actigraphic parameters described in our study suggest that hypercortisolism is associated with sleep alterations, which could contribute to the worsening of life quality and metabolic comorbidities associated with CS. These results have to be confirmed in a larger cohort of patients, using more accurate instruments for sleep assessment.

Urinary cortisol and psychopathology in obese binge eating subjects.

BACKGROUND: Investigations on the relationship between obesity, binge eating and the function of hypothalamic-pituitary-adrenal (HPA) axis have led to inconsistent results. General psychopathology affects HPA axis function. The present study aims to examine correlations between binge eating, general psychopathology and HPA axis function in obese binge eaters. METHODS: Twenty-four hour urinary free cortisol (UFC/24 h) was measured in 71 obese binge eating women. The patients were administered psychometric tests investigating binge eating, psychopathology and clinical variables. The relationship between binge eating, psychopathology and urinary cortisol was investigated, controlling for age and BMI. RESULTS: We found an inverse correlation between UFC/24 h and binge eating, depression, obsessive-compusive symptoms, somatization and sensitivity. In a regression model a significant inverse correlation between urinary cortisol and psychopathology was confirmed. CONCLUSIONS: Urinary cortisol levels in obese patients with binge eating disorder show an inverse correlation with several dimensions of psychopathology which are considered to be typical of a cluster of psychiatric disorders characterized by low HPA axis function, and are very common in obese binge eating patients. If these results are confirmed, UFC/24 h might be considered a biomarker of psychopathology in obese binge eaters.

Pituitary Hyperplasia Due to Longstanding Primary Hypothyroidism: A Case Report and Comprehensive Review of the Literature.

Hypothyroidism is a frequently diagnosed endocrine disorder. Common signs and symptoms include fatigue, cold intolerance, hoarseness, dry skin, constipation, a slow relaxation phase of deep tendon reflexes, and bradycardia. However, some patients may exhibit atypical signs and symptoms, which can result in diagnostic confusion. Pituitary hyperplasia resulting from longstanding primary hypothyroidism was first described by Niepce in 1851. It is usually asymptomatic, but sometimes, in addition to symptoms of overt hypothyroidism, patients may complain of headaches, hypopituitarism, visual field impairment, and hyperprolactinemia. Furthermore, on imaging, pituitary hyperplasia can be mistaken for a pituitary adenoma. Distinguishing between the two is crucial, as their management differs; the former often responds to thyroid hormone replacement therapy, while the latter might need treatment with surgery and/or radiotherapy. Here we describe a patient who developed pituitary hyperplasia in the setting of longstanding uncompensated primary hypothyroidism due to a lack of compliance with levothyroxine replacement therapy. We also review the clinical, laboratory, and radiologic findings of the case reports available in the literature up to now in order to improve the knowledge and the care of the disease.

Adjustable-tip needles versus fixed-tip needles in radiofrequency ablation of symptomatic benign thyroid nodules: a single-center Italian experience.

PURPOSE: In this retrospective, observational study we aim to compare the outcomes of the RFA treatment of benign thyroid nodules, carried out respectively with the standard fixed-needle approach (FTN) and the adjustable-tip needle technique (ATN), considered a more tailored, quicker and easier technical approach. METHODS: We enrolled 36 patients who underwent RFA treatment of symptomatic, benign, thyroid nodule, 18 with the ATN and 18 with the FTN approach, respectively. Data about absolute volume reduction, volume reduction rate (VRR) and success rate (defined as VRR ≥ 50%), after 1, 3 and 6 months of follow-up were compared. RESULTS: Our study suggested no substantial difference between the approaches, up to 6 months of follow-up, both in terms of absolute reduction (p = 0.27) and VRR (p = 0.14). These results were confirmed when the success rates, both in terms of 50%-reduction (p = 0.12) and absolute reduction (p = 0.42), was considered. Only at the 6-month evaluation, the FTN procedure showed a better success rate, yet without statistical significance (88.9% vs. 61.1%, p = 0.12). No difference emerged both in terms of patients' satisfaction and safety. CONCLUSION: Our small experience suggested no substantial difference between ATN and FTN, in terms of outcomes. On the other hand, ATN was considered to be more straightforward and could consequently allow for a shorter operator learning curve.

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.

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.

Adipose Tissue Dysfunction in Obesity: Role of Mineralocorticoid Receptor.

The mineralocorticoid receptor (MR) acts as an essential regulator of blood pressure, volume status, and electrolyte balance. However, in recent decades, a growing body of evidence has suggested that MR may also have a role in mediating pro-inflammatory, pro-oxidative, and pro-fibrotic changes in several target organs, including the adipose tissue. The finding that MR is overexpressed in the adipose tissue of patients with obesity has led to the hypothesis that this receptor can contribute to adipokine dysregulation and low-grade chronic inflammation, alterations that are linked to the development of obesity-related metabolic and cardiovascular complications. Moreover, several studies in animal models have investigated the role of MR antagonists (MRAs) in preventing the metabolic alterations observed in obesity. In the present review we will focus on the potential mechanisms by which MR activation can contribute to adipose tissue dysfunction in obesity and on the possible beneficial effects of MRAs in this setting.

Clinical and Pathological Tools for Predicting Recurrence and/or Metastasis in Patients with Pheochromocytoma and Paraganglioma.

Pheochromocytomas and paragangliomas are endocrine tumors belonging to the family of neural crest cell-derived neoplasms. They have an extremely variable clinical course, characterized by a non-negligible percentage of relapse and/or metastasis after radical surgery. To date, there are no reliable methods to predict the metastatic potential of these neoplasms, despite several clinical, molecular, and histopathological factors that have been extensively studied in the literature as predictors of the recurrence and/or metastasis in these neoplasms with different performances and results. In this review, we aimed to discuss and analyze the most important clinical and histopathological tools for predicting recurrence risk in patients affected by pheochromocytomas or paragangliomas. Thus, we compared the main available predictive models, exploring their applications in stratifying patients' risks. In conclusion, we underlined the importance of simple and validated tools to better define disease aggressiveness and establish tailored patients' treatments and follow-ups.

The Accuracy of Simple and Adjusted Aldosterone Indices for Assessing Selectivity and Lateralization of Adrenal Vein Sampling in the Diagnosis of Primary Aldosteronism Subtypes.

OBJECTIVE: This study aimed to evaluate the reliability of simple and corrected aldosterone indices for assessing the selectivity and lateralization of adrenal vein sampling (AVS) in patients with primary aldosteronism. METHODS: Data of all consecutive patients with primary aldosteronism who underwent AVS for subtype diagnosis, followed at two Italian referral centers, were analyzed retrospectively. RESULTS: AVS achieved bilateral selectivity in 112/144 patients. Unilateral disease was diagnosed in 60 cases (53.6%) and idiopathic hyperaldosteronism in 52 individuals (46.4%). The aldosterone index (aldosterone ratio between an adrenal vein and the inferior vena cava) showed a high accuracy in predicting selectivity, compared to a cortisol selectivity index of 1.1, and a moderate accuracy, compared to cortisol cut-offs of 2 and 3. The simple aldosterone index showed a moderate accuracy in predicting ipsi/contralateral aldosterone hypersecretion, while lesion side- and hypokalemia-corrected aldosterone index revealed a significant improvement in predicting ipsi/contralateral disease. Moreover, the comparative aldosterone index (aldosterone ratio in the dominant vs the non-dominant adrenal vein) revealed a high accuracy in predicting unilateral primary aldosteronism. For an immediate clinical application of our results, the adjusted cut-offs were calculated, according to the Youden's criterion and to a pre-established specificity of 90%, for all possible combinations of lesion side at imaging and presence/absence of hypokalemia. CONCLUSIONS: This study demonstrated the diagnostic accuracy of simple and clinical-/imaging-corrected aldosterone indices for adrenal vein sampling in subtype diagnosis of primary aldosteronism and suggests the potential application of these tools to select patients for adrenalectomy when standard indices cannot be performed.