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Objective Hyponatremia is the most common electrolyte disorder in hospitalized patients and occurs in about 30% of patients with pneumonia. Hyponatremia has been associated with a worse outcome in several pathologic conditions The main objective of this study was to determine whether serum sodium alterations may be independent predictors of the outcome of hospitalized COVID-19 patients. Design and methods In this observational study, data from 441 laboratory-confirmed COVID-19 patients admitted to a University Hospital were collected. After excluding 61 patients (no serum sodium at admission available, saline solution infusion before sodium assessment, transfer from another hospital), data from 380 patients were analyzed. Results 274 (72.1%) patients had normonatremia at admission, 87 (22.9%) patients had hyponatremia and 19 (5%) patients had hypernatremia. We found an inverse correlation between serum sodium and IL-6, whereas a direct correlation between serum sodium and PaO2/FiO2 ratio was observed. Patients with hyponatremia had a higher prevalence of non-invasive ventilation and ICU transfer than those with normonatremia or hypernatremia. Hyponatremia was an independent predictor of in-hospital mortality (2.7-fold increase vs normonatremia) and each mEq/L of serum sodium reduction was associated with a 14.4% increased risk of death. Conclusions These results suggest that serum sodium at admission may be considered as an early prognostic marker of disease severity in hospitalized COVID-19 patients.

Objective To perform a meta-analysis based on published studies that compared falls and bone fractures between patients with and without hyponatremia. Context There is evidence suggesting that hyponatremia is associated with an increased risk of falls and bone fractures. Design An extensive Medline, Embase and Cochrane search was performed to retrieve all studies published up to, 30 April 2017, using the following words: "hyponatremia" or "hyponatraemia" AND "falls" and "bone fractures." A meta-analysis was performed including all studies comparing falls and bone fractures in subjects with or without hyponatremia. Patients and results Of 216 retrieved articles, 15 studies satisfied inclusion criteria encompassing a total of 51 879 patients, of whom 2329 were hyponatremic. Across all studies, hyponatremia was associated with a significantly increased risk of falls (MH-OR = 2.14[1.71; 2.67]. This result was confirmed when only hospitalized patients were considered (MH-OR = 2.44 [1.97; 3.02]). A meta-regression analysis showed that the hyponatremia-related risk of falls was higher in those studies considering a lower serum [Na+ ] cut-off to define hyponatremia. Interestingly, the estimated risk of falls related to hyponatremia was already significantly higher when a serum [Na+ ] cut-off of 135 mmol/L was considered (MH-OR = 1.26[1.23;1.29]). The presence of hyponatremia was also associated with a higher risk of fractures, particularly hip fractures (MH-OR = 2.00[1.43;2.81]). Conclusions This study confirms that hyponatremia is associated with an increased risk of falls and bone fractures. The clinical, social and economic relevance of such association is strengthened by the increased incidence of hyponatremia in older people.

Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.

Chromaffin tumors are included among the causes of secondary hypertension because of the release of catecholamines. Nevertheless, the clinical, cardiovascular, and hypertensive picture of patients affected by pheochromocytomas/paragangliomas (PPGL) is extremely variable, due to the different quantitative and qualitative releasing activity of these tumors. A consistent percentage of these patients, about 20%, is normotensive and not affected by the characteristic symptomatic crises due to sudden release of catecholamines. The factors causing such wide clinical variability are many and probably not all known. It is well known that many of these tumors are genetically determined and that the genetic profile influences the biochemical characteristics and the biology of the tumors as well as the clinical presentation of the affected patients. The number of asymptomatic or poorly symptomatic patients is increased after the introduction of genetic screening and the early diagnosis in mutation carriers. In this paper we can review the genotype-phenotype correlation of PPGLs with a focus on the cardiovascular picture.

The aim of the present study was to evaluate the role of hypothyroidism as a cause of hyponatremia in a clinical model of iatrogenic acute hypothyroidism due to thyroid hormone withdrawal prior to ablative radioactive iodine (RAI) therapy after total thyroidectomy. The study group consisted of 101 differentiated thyroid cancer (DTC) patients (77 women and 24 men). Plasma concentration of thyroid-stimulating hormone ([TSH]) and sodium ([Na+]) was evaluated before total thyroidectomy (pre[TSH] and pre[Na+]) and on the day of RAI therapy (post[TSH] and post[Na+]). The frequency of hypothyroidism-associated hyponatremia was 4 % (4/101). Pre[Na+] was significantly higher than post[Na+] (140.7 ± 1.6 vs 138.7 ± 2.3 mEq/L, p = 0.012). Moreover, a linear correlation was identified between pre[Na+] and post[Na+]. Iatrogenic acute hypothyroidism-related hyponatremia is uncommon. However, because of the significant reduction of [Na+] in the transition from euthyroidism to iatrogenic hypothyroidism, the value of pre[Na+] should be viewed as a parameter to be considered. Since it acts as an independent risk factor for the development of hyponatremia, patients with a pre[Na+] close to the lower limit of normal range may deserve a closer monitoring of [Na+].

L’ipertensione e un fattore di rischio cardiovascolare spesso associato ad altri fattori di rischio quali obesita e diabete. La sua prevalenza aumenta con l’eta. L’esercizio fisico, sia di tipo aerobico che contro resistenza, e capace di prevenire l’insorgenza dell’ipertensione e di migliorare i valori pressori nei pazienti ipertesi. I meccanismi con cui l’esercizio migliora i valori pressori sono molteplici e ancora non del tutto noti. L‘esercizio svolge un ruolo importante sia a livello del metabolismo glicidico e lipidico che a livello dell’apparato cardiovascolare. La prescrizione dell’esercizio fisico ai pazienti ipertesi e un aspetto terapeutico importante e deve tener conto di molti elementi clinici come l’eta, le condizioni generali del paziente, la presenza di comorbidita o di danni d’organo e l’eventuale terapia antiipertensiva gia in atto.

Primary aldosteronism (PA) causes cardiovascular damage in excess to the blood pressure elevation, but there are no prospective studies proving a worse long-term prognosis in adrenalectomized and medically treated patients. We have, therefore, assessed the outcome of PA patients according to treatment mode in the PAPY study (Primary Aldosteronism Prevalence in Hypertension) patients, 88.8% of whom were optimally treated patients with primary (essential) hypertension (PH), and the rest had PA and were assigned to medical therapy (6.4%) or adrenalectomy (4.8%). Total mortality was the primary end point; secondary end points were cardiovascular death, major adverse cardiovascular events, including atrial fibrillation, and total cardiovascular events. Kaplan–Meier and Cox analysis were used to compare survival between PA and its subtypes and PH patients. After a median of 11.8 years, complete follow-up data were obtained in 89% of the 1125 patients in the original cohort. Only a trend ( P =0.07) toward a worse death-free survival in PA than in PH patients was observed. However, at both univariate (90.0% versus 97.8%; P =0.002) and multivariate analyses (hazard ratio, 1.82; 95% confidence interval, 1.08–3.08; P =0.025), medically treated PA patients showed a lower atrial fibrillation–free survival than PH patients. By showing that during a long-term follow-up adrenalectomized aldosterone-producing adenoma patients have a similar long-term outcome of optimally treated PH patients, whereas, at variance, medically treated PA patients remain at a higher risk of atrial fibrillation, this large prospective study emphasizes the importance of an early identification of PA patients who need adrenalectomy as a key measure to prevent incident atrial fibrillation.

The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.

Background Current guidelines recommend use of the aldosterone‐renin ratio ( ARR ) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false‐positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. Methods and Results We interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone‐producing adenoma as reference index. We also assessed whether the post‐captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false‐positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post‐captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between‐area under the curve difference, 0.005; 95% CI , −0.031 to 0.040; P =0.7 for comparison, and 0.05; 95% CI , −0.061 to 0.064; P =0.051 for comparison, respectively). Conclusions These results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure.

About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism.We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation.We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry.Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism.Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.

Hyponatremia, defined as serum sodium concentration

SUMMARY Metastatic pheochromocytomas (PHEOs) and paragangliomas (sPGLs) are rare neural crest-derived tumors with a poor prognosis. About 50% of them are due to germ-line mutations of the SDHB gene. At present, there is no cure for these tumors. Their therapy is palliative and represented by different options among which antiangiogenic drugs, like sunitinib, have been hypothesized to be effective especially in malignant SDHB mutated tumors. We report the effects of sunitinib therapy in a SDHB mutation carrier affected by a malignant sPGL. During 101 weeks of therapy at different doses, sunitinib was able to cause a partial response and then a stable disease for a total of 78 weeks. This favorable response is the longest, out of the 35 so far reported in the literature, registered in a patient treated exclusively with sunitinib but, similarly to the other responses, the effect was limited in time. From our analysis of the scanty data present in the literature, the effect of sunitinib does not seem to be different among wild-type patients and those carrying a cluster 1 germ-line mutation. Sunitinib seems able to slow the disease progression in some patients with malignant PHEO/PGL and therefore may represent a therapeutic option, although randomized controlled studies are needed to assess its efficacy definitively in the treatment of these aggressive tumors.

Una riduzione dei livelli plasmatici di sodio si riscontra nel 15–30% dei pazienti ricoverati in ospedale. Molteplici possono essere le cause che determinano iponatremia e in uno stesso paziente, soprattutto nell’anziano, possono coesistere piu patologie capaci di determinare questa alterazione elettrolitica. L’iponatremia deve essere vista come un segno clinico meritevole di grande attenzione anche nelle forme piu modeste e apparentemente asintomatiche. Anche lievi riduzioni dei livelli plasmatici di sodio possono determinare, qualora perdurino nel tempo, importanti ripercussioni cliniche, come ad esempio alterazioni dell’equilibrio con maggiore facilita di cadute a terra ed anche riduzione della densita ossea, come e stato recentemente dimostrato. Ne consegue che e fondamentale effettuare un percorso diagnostico rigoroso in modo da definire con precisione l eziopatogenesi dell iponatremia e quindi potere iniziare un corretto ed efficace trattamento. Questo articolo trattera le diverse situazioni in cui si puo verificare iponatremia, le manifestazioni cliniche ad essa correlate, le modalita da utilizzare per formulare una corretta diagnosi e decidere la strategia terapeutica appropriata. A questo riguardo, una sezione sara dedicata alla promettente novita farmacologica rappresentata dagli antagonisti recettoriali della vasopressina, i vaptani.

Background: Subarachnoid hemorrhage (SAH) is a potential cause of hypopituitarism. Most of the studies regarding the relationship between SAH and anterior pituitary function were retrospective and hormonal assessment was performed several months after SAH. Aim: To prospectively evaluate the prevalence of anterior pituitary hormone deficiencies in the acute phase after spontaneous SAH and their possible correlation with clinical and radiological parameters. Methods: Pituitary function was tested in 60 patients within 72 h after spontaneous SAH. Results: 56.9% of the patients showed at least one anterior pituitary hormone deficiency: gonadotropin and GH secretion failure represented the most prevalent hormonal deficiencies (33.3 and 22.0%, respectively), whereas ACTH and TSH deficiency was less frequent (7.1 and 1.8%, respectively). With the exception of secondary hypogonadism, the prevalence of other pituitary hormone deficiencies is in agreement with previous studies, which evaluated pituitary function on long-term follow up after SAH. No correlation was found between hypopituitarism and clinical status, as assessed with Hunt-Hess and Glascow Coma Scales. Moreover, no correlation was found between hypopituitarism and bleeding severity evaluated with Fisher’s scale. Conclusions: We demonstrated a high prevalence of anterior pituitary hormone deficiencies acutely after SAH. Although part of GH and gonadotropin deficiencies might be a consequence of functional alteration due to SAH itself, the finding of low cortisol levels in this stressful condition strongly suggests the presence of true hypocortisolism. Therefore, an evaluation of pituitary function shortly after SAH might be useful to identify a subset of patients who deserve a more accurate follow-up.

Summary Context The von Hippel-Lindau (VHL) syndrome is an inherited multitumour disorder characterized by clinical heterogeneity and high penetrance. Pheochromocytoma (Pheo) is present in 10%–15% of cases and can be isolated or associated with other lesions such as haemangioblastomas, kidney cysts or cancer and pancreatic lesions. In VHL patients, Pheos generally secrete norepinephrine and are located in the adrenals. Extra-adrenal Pheos (paragangliomas, PGLs) are rare. Objective While performing genetic testing in patients affected by apparently sporadic Pheos or PGLs, we found two novel different VHL germline mutations in two females who presented with two distinct very uncommon clinical pictures. One patient was studied for the presence of an adrenal incidentaloma and the other for the presence of a neck tumour. Methods and results Patients coding regions and exon–intron boundaries of RET (exons 10, 11, 13–15), VHL, SDHD, SDHB and SDHC genes were amplified and sequenced. We identified two novel VHL point mutations: a L198V missense mutation in a 32-year-old female affected by a right adrenal compound and mixed tumour constituted by an epinephrine secreting Pheo, a ganglioneuroma and an adrenocortical adenoma, and a T152I missense mutation in a 24-year-old female affected by a left carotid body tumour. No other lesions were found in the patients or in the VHL mutation positive relatives. Conclusions These cases enlarge the list of VHL mutations and add new insights in the clinical variability of VHL disease, thus confirming the importance of genetic testing in patients affected by apparently sporadic Pheos or PGLs.

The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively. Although the pathogenesis of pheochromocytoma/paraganglioma formation is still largely unknown, studies of the familial forms have started to uncover some pathways that favor tumor formation, such as activation of tyrosine-kinase, induction of hypoxia-inducible factors, activation of the oncogene Ras or reduced apoptosis. These studies have also demonstrated that various gene mutations can differently affect the biological characteristics of pheochromocytoma: for example, while the tumors are mostly adrenergic (epinephrine secreting) and episodically secreting in MEN 2, they are mostly noradrenergic (norepinephrine secreting) and continuously secreting in VHL. Biological variability can also be observed in the PGL syndromes where tumors develop in the head and neck and are parasympathetic in origin and non-secreting, or in the thorax and the abdomen, where they are sympathetic in origin and catecholamine secreting. Genetic testing in patients with pheochromocytomas or paragangliomas is, at present, strongly recommended and is mandatory in young patients or in cases of multiple or recurrent tumors. The clinical picture and the biological characteristics of the tumor may suggest the priority of the genes to be tested first.

Background A 43-year-old woman was referred to the Psychiatric Unit of the University of Florence Hospital, 1 year after the development of a clinical picture characterized by nausea, hyporexia, muscle weakness, insomnia, weight loss, amenorrhea and severe depression. These clinical manifestations had started 2 months after delivery of her first child. Initial laboratory investigations revealed hypoglycemia and hyponatremia. The patient was, therefore, transferred to the Endocrine Unit of the same hospital for further evaluation of the case. Investigations Physical examination to evaluate extracellular volume status, standard laboratory investigations, and evaluation of plasma and urinary osmolality and urinary sodium excretion. Basal and dynamic evaluation of anterior pituitary function and a pituitary MRI were also performed. Diagnosis Hyponatremia caused by central hypocortisolism (isolated adrenocorticotropic hormone deficit). Management Glucocorticoid therapy (25 mg cortisone acetate tablets, 1.5 tablets per day).

Objectives We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. Background The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. Methods Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+and K+in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) ≥50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). Results A total of 1,180 patients (age 46 ± 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. Conclusions In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.

La gravidanza in corso di malattia di Addison non e frequente; tuttavia, ove si verifichi, e un evento stressante che puo precipitare una condizione di iposurrenalismo frustro. In questo caso la diagnosi e molto difficile perche il morbo di Addison si manifesta con segni e sintomi che in forma piu attenuata sono normalmente presenti in gravidanza (ipotensione, nausea, talora vomito, iperpigmentazione). La mancata diagnosi e il mancato trattamento sostitutivo nella madre comportano seri rischi sia per il feto che per la gestante. Nel corso della gravidanza si registra una maggior attivita dell’asse ACTH-cortisolo materno con aumento del cortisolo plasmatico sia totale sia libero, ma senza segni di ipercortisolismo per la competizione a livello recettoriale esercitata dalle alte concentrazioni di progesterone. Anche l’asse renina-angiotensina-aldosterone risulta attivato probabilmente in risposta all’azione natriuretica del progesterone. La diagnosi, oltre che sulla clinica, si basa sui reperti di laboratorio, che pero devono essere interpretati tenendo conto del fisiologico aumento dei valori di ACTH, cortisolo, attivita reninica e aldosterone in corso di gravidanza. Nonostante questi aumenti, le pazienti conmorbo di Addison non necessitano generalmente di modificare la posologia della terapia sostitutiva. E solo consigliabile l’aumento del mineralcorticoide nel 3° trimestre. Sconsigliabile e invece l’uso di desametasone e betametasone che non sono degradati dall’ 11 β-idrossi-steroidodeidrogenasi tipo 2 placentare e possono inibire l’asse ipofisi-surrene fetale. La posologia della terapia sostitutiva va aumentata nel caso di eventi intercorrenti stressanti e va effettuata per via parenterale nel caso di iperemesi gravidica. Al momento del parto e suggerita la somministrazione per via parenterale di una dose aggiuntiva di idrocortisone, tanto maggiore quanta piu lungo e impegnativo il travaglio o in caso di parto cesareo.

The diagnosis of Cushing's syndrome (CS) may sometimes be cumbersome. In particular, in ACTH-dependent CS it may be difficult to distinguish between the presence of an ACTH-secreting pituitary adenoma and ectopic ACTH and/or CRH secretion. In such instances, the etiology of CS may remain unknown despite extensive diagnostic workout, and the best therapeutic option for each patient has to be determined. We report here the case of a 54-yr-old man affected by ACTH-dependent CS in association with a left adrenal adenoma and medullary thyroid carcinoma (MTC). He presented with clinical features and laboratory indexes of hypercortisolism associated with elevated levels of calcitonin. Ectopic CS due to MTC was reported previously. In our case hypercortisolism persisted after surgical treatment of MTC. Thorough diagnostic assessment was performed, in order to define the aetiology of CS. He was subjected to basal and dynamic hormonal evaluation, including bilateral inferior petrosal sinus sampling. Extensive imaging evaluation was also performed. Overall, the laboratory data together with the results of radiological procedures suggested that CS might be due to inappropriate CRH secretion. However, the source of CRH secretion in this patient remained unknown. It was then decided to remove the left adenomatous adrenal gland. Cortisol level fell and has remained within the normal range nine months after surgery. This case well depicts the complexity of the diagnostic workout, which is needed sometimes to correctly diagnose and treat CS, and suggests that monolateral adrenalectomy may represent, at least temporarily, a reasonable therapeutic option in occult ACTH-dependent hypercortisolism.

Gli inibitori del sistema renina-angiotensina comprendono un vasto gruppo di farmaci che esercitano la loro azione come inibitori dell’Angiotensin Converting Enzyme (ACE-inibitori), come antagonisti del recettore AT1 dell’angiotensina II o come inibitori della renina. Questi farmaci sono ampiamente utilizzati per la terapia dell’ipertensione arteriosa, ma costituiscono anche l’unica arma, apparentemente totipotente, per arrestare quella serie di eventi patologici che conduce alla sclerosi renale. I benefici effetti degli inibitori del sistema renina-angiotensina si manifestano indipendentemente dall’eziologia della sclerosi renale: scompenso metabolico del diabete mellito, ipertensione arteriosa, effetti tossici della ciclosporina nei reni trapiantati. A seconda del punto d’azione questi farmaci dimostrano una potenza inibitoria diversa sul sistema reninaangiotensina. Appare quindi utile riassumere le conoscenze sul meccanismo d’azione degli inibitori del sistema reninaangiotensina, focalizzando l’attenzione sulle principali differenze biologiche e cliniche che esistono tra i vari farmaci di questo gruppo.

Noradrenaline and adrenaline are the final mediators of sympathoadrenal activity. They exert complex direct and indirect actions on glucose metabolism. Increases in plasma catecholamines - as in patients with pheochromocytoma - as well as in sympathetic activity, causing increased noradrenaline release by the sympathetic nerve terminals, cause an increase in blood glucose. Patients affected by pheochromocytoma are often affected by glucose intolerance or diabetes which generally ameliorates or disappears after surgery. These patients are characterized by a condition of insulin resistance while plasma insulin concentrations may be decreased or increased, depending on the type of adrenergic receptor, α or β - which are preferentially activated by circulating catecholamines. Activation of adrenergic receptors may also derive from a chronic increase in sympathoadrenal activity which is present in various conditions (i.e. obesity) associated with type 2 diabetes. Experimental evidence suggests that sympathetic hyperactivity may be a pathogenic factor for type 2 diabetes as well as for the occurrence of diabetic complications. Interestingly, dopamine agonists, which exert multiple actions including a decrease in sympathetic activation, have recently been found to be of benefit in the treatment of type 2 diabetes.

Hyponatremia is the most common electrolyte abnormality observed in clinical practice. Several studies have demonstrated that hyponatremia is associated with an increased length of hospital stay and of hospital resource utilization. To clarify the impact of hyponatremia on the length of hospitalization and costs, we performed a meta-analysis based on published studies that compared hospital length of stay and cost between patients with and without hyponatremia.An extensive Medline, Embase, and Cochrane search was performed to retrieve all studies published up to April 1, 2015 using the following words: "hyponatremia" or "hyponatraemia" AND "hospitalization" or "hospitalisation." A meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with and without hyponatremia.Of 444 retrieved articles, 46 studies satisfied the inclusion criteria, encompassing a total of 3,940,042 patients; among these, 757,763 (19.2%) were hyponatremic. Across all studies, hyponatremia was associated with a significantly longer duration of hospitalization (3.30 [2.90-3.71; 95% CIs] mean days; P.000). Similar results were obtained when patients with associated morbidities were analyzed separately. Furthermore, hyponatremic patients had a higher risk of readmission after the first hospitalization (odds ratio 1.32 [1.18-1.48; 95% CIs]; P.000). A meta-regression analysis showed that the hyponatremia-related length of hospital stay was higher in males (Slope = 0.09 [0.05-0.12; 95% CIs]; P = .000 and Intercept = -1.36 [-3.03-0.32; 95% CIs]; P = .11) and in elderly patients (Slope = 0.002 [0.001-0.003; 95% CIs]; P.000 and Intercept = 0.89 [0.83-0.97; 95% CIs]; P.001). A negative association between serum [Na(+)] cutoff and duration of hospitalization was detected. No association between duration of hospitalization, serum [Na(+)], and associated morbidities was observed. Finally, when only US studies (n = 8) were considered, hyponatremia was associated with up to around $3000 higher hospital costs/patient when compared with the cost of normonatremic subjects.This meta-analysis confirms that hyponatremia is associated with a prolonged hospital length of stay and higher risk of readmission. These observations suggest that hyponatremia may represent one important determinant of the hospitalization costs.

The syndrome of inappropriate ADH secretion (SIADH), also termed ''syndrome of inappropriate antidiuresis (SIAD)'', is an often unrecognized cause of hypotonic hyponatremia, arising from ectopic release of ADH in lung cancer or as a side effect of various drugs. In SIADH, hyponatremia results from selectively impaired water excretion by the kidney, whereas the external Na+ balance is normally regulated. Despite the increase in total body water, only a slight reduction of urine output and modest edema are usually seen. Renal function and acid-base balance are generally preserved, while subclinical neurological impairment may occasionally become life-threatening, when hyponatremia has an abrupt onset. The major clinical variants of SIADH are reviewed here, with particular emphasis on causes, iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH is based on water restriction, hypertonic saline plus loop diuretics, or aquaretics. Worsening of hyponatremia may result from parenteral isotonic fluid administration, emphasizing the importance of an early diagnosis and careful follow-up of these patients.

The discovery of incidental adrenal masses during imaging procedures has become progressively more frequent. In such situations a correct clinical and biochemical approach have to be performed in order to obtain information on the biological and functional nature of the adrenal mass. Clinicians are asked to establish whether the adrenal mass is an adenoma, a pheochromocytoma, an adrenal carcinoma or a metastasis, and to perform a correct laboratory evaluation to search for even mild derangements in adrenal secretion. Recognition of mild signs and symptoms related to slight adrenal hypersecretion may permit a precocious identification of diseases associated with significant morbidity and mortality. Indeed cardiovascular events represent the most frequent complications due to catecholamine release by a pheochromocytoma, or to chronic hypercortisolism as in Cushing’s syndrome. Finally, the early recognition of an adrenal carcinoma is of utmost importance to improve the outcome and the prognosis of this biologically aggressive tumor.

Item does not contain fulltext Phaeochromocytomas and paragangliomas are neural crest-derived tumours. Autopsy studies indicate that relatively large numbers of these tumours remain undiagnosed during life. This may reflect non-specific signs and symptoms and low medical alertness in evaluating the clinical picture or it may reflect a silent clinical presentation - the subclinical phaeochromocytoma. The associated clinical picture depends on the capacity of the tumours to release catecholamines and sometimes biologically active peptides. Hypertension is the hallmark of catecholamine release, but the amount, type and pattern of catecholamine secretion is extremely variable. Some tumours have low or intermittent secretory activity, some produce mainly or solely dopamine, while others very rarely do not synthesize or release any catecholamines (non-secretory or non-functional tumours). Such tumours may present with mild or even absent signs and symptoms of catecholamine excess. Low secretory activity may reflect small tumour size or differences in secretory phenotypes associated with the biochemical and genetic background of the tumours. Tumours due to succinate dehydrogenase subunit B mutations are often subclinical, poorly differentiated, contain low amounts of catecholamines, and are usually malignant at diagnosis. Adrenoceptor desensitization can result in a subclinical presentation, even when catecholamine levels are high. Subclinical phaeochromocytomas are often discovered as incidentalomas during radiological procedures or during routine screening for phaeochromocytoma in carriers of mutations in one of the ten currently identified tumour susceptibility genes. Undiagnosed phaeochromocytomas, whether or not subclinical and even if biologically benign, may cause extremely deleterious consequences or even death, following abrupt release of catecholamines. 01 augustus 2012

Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected.

Malignant pheochromocytomas/paragangliomas are rare tumors with a poor prognosis. Malignancy is diagnosed by the development of metastases as evidenced by recurrences in sites normally devoid of chromaffin tissue. Histopathological, biochemical, molecular and genetic markers offer only information on potential risk of metastatic spread. Large size, extraadrenal location, dopamine secretion,SDHBmutations, a PASS score higher than 6, a high Ki-67 index are indexes for potential malignancy. Metastases can be present at first diagnosis or occur years after primary surgery. Measurement of plasma and/or urinary metanephrine, normetanephrine and metoxytyramine are recommended for biochemical diagnosis. Anatomical and functional imaging using different radionuclides are necessary for localization of tumor and metastases. Metastatic pheochromocytomas/paragangliomas is incurable. When possible, surgical debulking of primary tumor is recommended as well as surgical or radiosurgical removal of metastases. I-131-MIBG radiotherapy is the treatment of choice although results are limited. Chemotherapy is reserved to more advanced disease stages. Recent genetic studies have highlighted the main pathways involved in pheochromocytomas/paragangliomas pathogenesis thus suggesting the use of targeted therapy which, nevertheless, has still to be validated. Large cooperative studies on tissue specimens and clinical trials in large cohorts of patients are necessary to achieve better therapeutic tools and improve patient prognosis.

In the last decades discoveries of adrenal masses incidentally during the course of diagnostic procedures for unrelated disorders (incidentalomas) have become progressively more frequent. The clinician in this position must answer two main questions: Is the mass benign or malignant?, and To what extent is the adrenal secretion altered? To come to a clinical decision, several diagnostic tools need to be engaged, starting with an accurate and correct radiological evaluation and a hormonal assessment of the adrenal function. When necessary, other diagnostic procedures such as functional imaging and fine-needle biopsy (FNB) can be considered in selected cases. Surgical removal is recommended for clinically relevant hypersecretory masses, as well as for masses suspected to be malignant. Most frequently, adrenal incidentalomas (AIs) are represented by benign cortical adenomas, a subset of which causes a mild hypercortisolism, known as subclinical Cushing's syndrome (SCS). The criteria to define this syndrome, as well as its treatment, are still debated and controversial. AIs that are not surgically removed should be re-examined in time to exclude a supervening increase in size or function. Follow-up criteria have not been established. Laparoscopic surgery is the recommended procedure to remove benign masses. The surgical procedure for adrenal malignancies is still debated.

The syndrome of inappropriate ADH secretion (SIADH), also recently referred to as the "syndrome of inappropriate antidiuresis", is an often underdiagnosed cause of hypotonic hyponatremia, resulting for instance from ectopic release of ADH in lung cancer or as a side-effect of various drugs. In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external Na+ balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest edema are usually seen. Renal function and acid-base balance are often preserved, while neurological impairment may range from subclinical to life-threatening. Hypouricemia is a distinguishing feature. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH with water restriction, aquaretics, or hypertonic saline + loop diuretics, as opposed to worsening of hyponatremia during parenteral isotonic fluid administration, underscores the importance of an early accurate diagnosis and careful follow-up of these patients.

OBJECTIVES: In about 15-20% of patients with ACTH-dependent Cushing's syndrome the source of ACTH is outside the pituitary gland. Pulmonary tumours are the most frequent, yet not unique, source of ectopic ACTH. In some instances the localisation of an ACTH-secreting tumour may be problematic. Occult ectopic ACTH secretion indicates the occurrence of ACTH-dependent hypercortisolism with an unknown origin. Another peculiarity of Cushing's syndrome may reside in the episodic cortisol hypersecretion, which can determine a pattern characterised by hypercortisolism together with periods of remission (cyclic Cushing's syndrome). We describe a very challenging case of Cushing's syndrome due to ectopic ACTH hypersecretion, showing virtually all of the most unusual features of the disease. DESIGN: A 55-year-old woman affected by Cushing's syndrome, presenting with biochemical features of ectopic ACTH secretion, has been followed for 7 years. METHODS: Thorough basal and dynamic hormonal assessment through the past 7 years is reported. In addition, the results of extensive imaging studies are presented. RESULTS: The source of ACTH secretion has not been identified so far, and hypercortisolism has been controlled by octreotide treatment. In addition, the patient showed a cyclic pattern of hypercortisolism with a long-term remission period. A unique feature of this case is represented by the fact that we observed a temporary, yet dramatic, short-lasting remission of ACTH and cortisol hypersecretion during a pulmonary infection, which occurred while the patient was hospitalised for a periodic hormonal assessment. CONCLUSIONS: This case well represents the wide spectrum of clinical variability of Cushing's syndrome. Most interestingly, to our knowledge, this is the first report of a case of Cushing's syndrome showing a remission during an acute infection.

PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine‐secreting chromaffin tumours has been reported to date. We report the case of a 15‐year‐old girl with hypertension and a norepinephrine‐secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.