Hyponatraemia diagnosis and treatment clinical practice guidelines.

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic.

Copeptin Associates with Cause-Specific Mortality in Patients with Impaired Renal Function: Results from the LURIC and the 4D Study.

Background: In chronic kidney disease (CKD) arginine vasopressin (AVP) cannot efficiently act via renal V2-receptors. AVP is upregulated leading to augmented activation of V1a- and V1b-receptors, which might contribute to the increase in cardiovascular and infectious complications in CKD. Here, we evaluate copeptin, a surrogate of AVP, and its association with cause specific mortality among patients within the whole spectrum of renal function.

Lack of Ubiquitin Specific Protease 8 (USP8) Mutations in Canine Corticotroph Pituitary Adenomas.

Purpose: Cushing's disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism.

Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline.

Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency.

Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members.

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas.

Context: Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively.

High evening salivary cortisol is an independent predictor of increased mortality risk in patients with systolic heart failure.

Aims: Serum cortisol independently predicts mortality risk in patients with systolic heart failure. Salivary cortisol may provide advantages as it better reflects the biologically active free compound. Furthermore, sampling is non-invasive and may easily be performed in outpatients.

The New Molecular Landscape of Cushing's Disease.

Cushing's disease (CD) is caused by corticotropin-secreting pituitary adenomas and results in substantial morbidity and mortality. Its molecular basis has remained poorly understood until the past few years, when several proteins and genes [such as testicular orphan nuclear receptor 4 (TR4) and heat shock protein 90 (HSP90)] were found to play key roles in the disease. Most recently, mutations in the gene of ubiquitin-specific peptidase 8 (USP8) increasing its deubiquination activity were discovered in a high percentage of corticotroph adenomas.

Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn's Registry.

Design: Abnormalities in glucose homeostasis have been described in patients with primary aldosteronism (PA) but most studies show inconsistent results. Therefore, we aimed to compare the prevalence of type 2 diabetes mellitus and metabolic syndrome (MetS) in newly diagnosed PA patients to a matched control cohort of the background population.

Methods: In total, 305 PA patients of the prospective German Conn's Registry were compared to the population-based Study of Health In Pomerania (SHIP1; n=2454).

Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells.

Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades.

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome.

Previous SNP array analyses have revealed genomic alterations of the Notch pathway as being the most frequent abnormality in adrenocortical tumors (ACTs). The aim of the present study was to evaluate the expression of components of Notch signaling in ACTs and to correlate them with clinical outcome. The mRNA expression of JAG1, NOTCH1, and selected target genes of NOTCH1 (HES1, HES5, and HEY2) was evaluated in 80 fresh frozen samples (28 normal adrenal glands (NAGs), 24 adenomas (ACAs), and 28 carcinomas (ACCs)) by quantitative RT-PCR.

High incidence of hyponatremia in rowers during a four-week training camp.

Purpose: To investigate the incidence of hyponatremia and its relationship to plasma copeptin, a surrogate marker for arginine vasopressin (AVP) during 28 days of high-volume rowing training.

Methods: Thirty rowers from the German junior national team (21 male) were studied during a training camp. Serum sodium ([Na(+)]), osmolality, and copeptin were measured before the beginning of the camp (day 0), and at days 7, 13, 18, 24, and 28.

Diagnostic Accuracy of Copeptin in the Differential Diagnosis of the Polyuria-polydipsia Syndrome: A Prospective Multicenter Study.

Context: The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, given that inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity.

Post-saline infusion test aldosterone levels indicate severity and outcome in primary aldosteronism.

Objective: The saline infusion test (SIT) is widely used as a confirmatory test for primary aldosteronism (PA). SIT results are judged as follows: post-test aldosterone levels <50 ng/l exclude PA, whereas levels >50 ng/l confirm PA. We hypothesized that post-SIT aldosterone concentrations indicate the severity of PA and might predict outcome.

Mineralocorticoid substitution and monitoring in primary adrenal insufficiency.

Patients with primary adrenal insufficiency usually show pronounced impairment of aldosterone secretion and, therefore, require also mineralocorticoid replacement for full recovery. Clinical signs of mineralocorticoid deficiency comprise hypotension, weakness, salt craving and electrolyte disturbances (hyperkalemia, hyponatremia). Mineralocorticoid deficiency is confirmed by demonstration of profoundly decreased aldosterone and highly elevated plasma renin activity (PRA).

Computed tomography criteria for discrimination of adrenal adenomas and adrenocortical carcinomas: analysis of the German ACC registry.

Objective: Thresholds of 2-20 hounsfield units (HU) in unenhanced computed tomography (CT) are suggested to discriminate benign adrenal tumors (BATs) from malignant adrenal tumors. However, these studies included only low numbers of adrenocortical carcinomas (ACCs). This study defines a HU threshold by inclusion of a large cohort of ACCs.

Prognostic value of aldosterone and cortisol in patients hospitalized for acutely decompensated chronic heart failure with and without mineralocorticoid receptor antagonism.

Background: Serum aldosterone and cortisol independently predict an increased mortality risk in heart failure (HF), and mineralocorticoid receptor antagonism (MRA) improves survival. The prognostic relevance of aldosterone and cortisol with MRA is unclear.

Methods And Results: In this post hoc analysis of a prospective cohort, study serum levels of aldosterone and cortisol were measured at baseline in 842 patients with systolic HF.

Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently.

Objective: The aim of this study was to identify markers with prognostic value for patients in this clinical setting.

Design, Setting, And Participants: From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified.

Mutations in the deubiquitinase gene USP8 cause Cushing's disease.

Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas.

PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit.

We recently identified a high prevalence of mutations affecting the catalytic (Cα) subunit of protein kinase A (PKA) in cortisol-secreting adrenocortical adenomas. The two identified mutations (Leu206Arg and Leu199_Cys200insTrp) are associated with increased PKA catalytic activity, but the underlying mechanisms are highly controversial. Here we utilize a combination of biochemical and optical assays, including fluorescence resonance energy transfer in living cells, to analyze the consequences of the two mutations with respect to the formation of the PKA holoenzyme and its regulation by cAMP.

High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study.

Objective: Adrenal crisis (AC) is a life-threatening complication of adrenal insufficiency (AI), which according to retrospective data represents a significant clinical complication. Here we aimed to prospectively assess incidence of AC and mortality associated with AC in patients with chronic AI.

Methods: A total of 423 patients with AI (primary AI, n = 221; secondary AI, n = 202) were prospectively followed up for 2 years.

Extensive expertise in endocrinology. Adrenal crisis.

Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5-10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years.

Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma.

Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear.

Timelines in the management of adrenal crisis - targets, limits and reality.

Objective: To evaluate current management timelines in adrenal crisis (AC) and to establish time targets and time limits for emergency treatment.

Design/patients: Patients from a prospective study who had reported an AC (n = 46) were contacted and asked about management of their AC. A survey among 24 European endocrinologists collected expert recommendations concerning time targets and time limits for contact-arrival time of emergency health professionals and presentation of emergency card-glucocorticoid (GC) injection time.

CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma.

Background: Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.

Objective: To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.