Copeptin in the differential diagnosis of hypotonic polyuria.

COPEPTIN: Copeptin is secreted in equimolar amount to Arginine Vasopressin (AVP) but can easily be measured with a sandwich immunoassay. Both peptides, copeptin and AVP, show a high correlation. Accordingly, copeptin mirrors the amount of AVP in the circulation and its measurement provides an attractive marker in the differential diagnosis of diabetes insipidus. THE POLYURIA POLYDIPSIA SYNDROME: Diabetes insipidus-either central or nephrogenic-has to be differentiated from primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since many decades, the "gold standard" for differential diagnosis has been the classical water deprivation test, which has several limitations leading to an overall limited diagnostic accuracy. In addition, the test has a long duration of 17 hours and is cumbersome for patients. Clinical signs and symptoms as well as MRI characteristics overlap between patients with diabetes insipidus and primary polydipsia. Direct measurement of AVP upon osmotic stimulation was first shown to overcome these limitations, but failed to enter clinical practice mainly due to technical limitations of the AVP assay. COPEPTIN AS DIAGNOSTIC TOOL IN THE POLYURIA POLYDIPSIA SYNDROME: We have recently shown that copeptin, without prior water deprivation, identifies patients with nephrogenic diabetes insipidus. On the other hand, for the more difficult differentiation between central diabetes insipidus and primary polydipsia, a copeptin level of 4.9 pmol/L stimulated with hypertonic saline infusion differentiates between these two entities with a high diagnostic accuracy, and is superior to the water deprivation test. It is important to note that close sodium monitoring during the hypertonic saline test is a prerequisite. CONCLUSION: Therefore, we propose that copeptin upon hypertonic saline infusion should become the new standard test in the differential diagnosis of diabetes insipidus.

Radiation exposure of adrenal vein sampling: a German Multicenter Study

Objective: Adrenal vein sampling (AVS) represents the current diagnostic standard for subtype differentiation in primary aldosteronism (PA). However, AVS has its drawbacks. It is invasive, expensive, requires an experienced interventional radiologist and comes with radiation exposure. However, exact radiation exposure of patients undergoing AVS has never been examined. Design and Methods: We retrospectively analyzed radiation exposure of 656 AVS performed between 1999 and 2017 at four university hospitals. The primary outcomes were dose area product (DAP) and fluoroscopy time (FT). Consecutively the effective dose (ED) was approximately calculated. Results: Median DAP was found to be 32.5 Gy*cm2 (0.3­3181) and FT 18 min (0.3­184). The calculated ED was 6.4 mSv (0.1­636). Remarkably, values between participating centers highly varied: Median DAP ranged from 16 to 147 Gy*cm2, FT from 16 to 27 min, and ED from 3.2 to 29 mSv. As main reason for this variation, differences regarding AVS protocols between centers could be identified, such as number of sampling locations, frames per second and the use of digital subtraction angiographies. Conclusions: This first systematic assessment of radiation exposure in AVS not only shows fairly high values for patients, but also states notable differences among the centers. Thus, we not only recommend taking into account the risk of radiation exposure, when referring patients to undergo AVS, but also to establish improved standard operating procedures to prevent unnecessary radiation exposure.

[Hyponatremia in emergency admissions - often dangerous]. / Hyponatriämie in der Notaufnahme ­ häufig gefährlich.

Hyponatremia is the most common electrolyte disorder in clinical practice and associated with increased morbidity and mortality, independent of underlying disease. Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema whilst over rapid correction of chronic hyponatremia can cause serious neurologic impairment and death resulting from osmotic demyelination. Still hyponatremia is often neglected and insufficiently addressed, most likely due to limited understanding of its pathophysiological mechanisms. Being familiar with only few basic principles of body fluid regulation may be a worthwhile investment into the clinical career and save patients' lives.

Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity.

A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine-phosphate-guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.

A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also referred to as syndrome of inappropriate antidiuresis (SIAD), is the most common cause of hyponatremia characterized by extracellular hypotonicity and impaired urine dilution in the absence of any recognizable nonosmotic stimuli for the antidiuretic hormone arginine vasopressin (AVP). Hyponatremia in SIADH is primarily the result of excessive water retention caused by a combination of inappropriate antidiuresis and persistent fluid intake in the presence of impaired osmoregulated inhibition of thirst. It is sometimes aggravated by a sodium deficiency caused by a decreased intake or a secondary natriuresis in response to elevated extracellular volume. Inappropriate antidiuresis usually results from endogenous production of AVP that can be either ectopic (from a malignancy) or eutopic (from the hypothalamus/neurohypophysis). Regardless of its origin, different types of osmotic dysregulation of AVP have been reported with possibly fundamental deviations in treatment need and efficacy. A recent quantitative analysis of 50 patients with SIADH, which underwent serial measurements of copeptin during hypertonic saline infusion, revealed five distinct types of osmoregulatory defect ("type A to E") without affiliation to specific underlying diseases. In addition to apparently impaired osmoregulated inhibition of AVP release in the majority of patients, 12% of patients showed an AVP-independent mechanism of inappropriate antidiuresis, whilst 20% of them presented a reverse relation between hormone release and serum osmolality, presumably related to interrupted nonosmotic inhibitory pathways. The interference of these different types of SIAD with clinical presentation and therapy response will be a relevant subject for future research.

Copeptin as a biomarker and a diagnostic tool in the evaluation of patients with polyuria-polydipsia and hyponatremia.

Copeptin is part of the 164 amino acid precursor protein preprovasopressin together with vasopressin and neurophysin II. During precursor processing, copeptin is released together with vasopressin. Copeptin concentrations respond as rapidly as vasopressin to changes in osmolality, a decrease in blood pressure or stress and there is a close correlation of vasopressin and copeptin concentrations. For these reasons, copeptin is propagated as a surrogate marker for vasopressin in the differential diagnosis of the polyuria-polydipsia syndromes and hyponatremia. Results of prospective studies show that a baseline copeptin level without prior fluid deprivation >20 pmol/L is able to identify patients with nephrogenic diabetes insipidus, whereas osmotically stimulated copeptin levels differentiate between patients with partial central diabetes insipidus and primary polydipsia with a high sensitivity and specificity >94%. In hyponatremia, low copeptin levels point to primary polydipsia and high levels to hypovolemic hyponatremia. The copeptin to urinary sodium ratio differentiates accurately between volume-depleted and normovolemic disorders.

Interaction of thyroid hormone with brown adipose tissue. Lessons learned from PET-CT.

Brown adipose tissue (BAT) plays an important role in regulating core-body temperature in various species including man. [18F]FDG-PET/CT imaging first revealed the presence of metabolically active BAT depots and that decreased BAT function is associated with various metabolic conditions. Thyroid hormone (TH) in concert with sympathetic nervous system signalling (SNS) stimulates BAT thermogenesis and thyroid disorders result in dysfunctional BAT. Currently, research is focussing not only on BAT regulation but also on browning of white adipose tissue (WAT) to BAT beige adipose tissue (BeAT) in order to develop novel treatments for human obesity and related conditions. While [18F]FDG-PET/CT imaging is continuing to provide valuable insights into BAT and BeAT function in health and disease, there is a pressing need to develop alternative radiotracers that reliably track their activity in vivo. As a result it is expected that preclinical micro PET/CT investigations of BAT and BeAT will gain in prominence. The aim of this short review is to i) describe fundamentals in BAT biology, ii) highlight some of the clinical and preclinical studies performed on humans and rodents with a focus on TH, BAT and PET/CT, and iii) bridge these data with our own studies within the DFG thyroid transact priority program.

Argument for a non-linear relationship between severity of human obesity and dopaminergic tone.

Alterations in the dopaminergic system have been implicated in both animal and human obesity. However, to date, a comprehensive model on the nature and functional relevance of this relationship is missing. In particular, human data remain equivocal in that seemingly inconsistent reports exist of positive, negative or even no relationships between dopamine D2/D3 receptor availability in the striatum and measures of obesity. Further, data on receptor availability have been commonly interpreted as reflecting receptor density, despite the possibility of an alternative interpretation, namely alterations in the basal levels of endogenous dopaminergic tone. Here, we provide a unifying framework that is able to explain the seemingly contradictory findings and offer an alternative and novel perspective on existing data. In particular, we suggest (i) a quadratic relationship between alterations in the dopaminergic system and degree of obesity, and (ii) that the observed alterations are driven by shifts in the balance between general dopaminergic tone and phasic dopaminergic signalling. The proposed model consistently integrates human data on molecular and behavioural characteristics of overweight and obesity. Further, the model provides a mechanistic framework accounting not only for the consistent observation of altered (food) reward-responsivity but also for the differences in reinforcement learning, decision-making behaviour and cognitive performance associated with measures of obesity.

Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery.

BACKGROUND/OBJECTIVES: Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear. SUBJECTS/METHODS: We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. RESULTS: The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. CONCLUSIONS: The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting.

[German adrenocortical carcinoma registry. Surgical therapy results and follow-up treatment]. / Deutsches Nebennierenrindenkarzinom-Register. Chirurgische Therapieergebnisse und Nachbehandlung.

Adrenocortical carcinoma (ACC) is a highly aggressive endocrine disease with an incidence of 1-2 cases per million population per year. Due to the low incidence of ACC knowledge concerning the surgical management is mainly based on retrospective studies or recommendations of isolated experts. Cancer databases, such as the German ACC registry are prerequisite to collect and evaluate clinical data from a large number of patients. For non-metastatic tumor stages, complete tumor resection is the only treatment with curative intent. Open surgery remains the recommended approach for ACC. However, in small tumors with uncertain malignancy a laparoscopic resection by an expert surgeon can be considered. A loco-regional lymphadenectomy should be part of the primary surgical treatment of ACC. Tumor recurrence is common even after an apparently complete primary resection. Therefore, based on the individual risk (tumor size, resection status, proliferation index) adjuvant mitotane treatment is recommended in most patients. Patients with low-risk should be included in the ADIUVO trial. In case of tumor relapse indications for a reoperation should be strongly considered, especially when the time interval since the primary surgery is long (> 12 months) and a complete resection of the recurrent disease seems to be feasible.

Exogenous peptide YY3-36 and Exendin-4 further decrease food intake, whereas octreotide increases food intake in rats after Roux-en-Y gastric bypass.

BACKGROUND: Patients show an elevated postprandial satiety gut hormone release after Roux-en-Y Gastric bypass (gastric bypass). The altered gut hormone response appears to have a prominent role in the reduction of appetite and body weight (BW) after gastric bypass. Patients with insufficient BW loss after gastric bypass have an attenuated postprandial gut hormone response in comparison with patients who lost an adequate amount of BW. The effects of additional gut hormone administration after gastric bypass are unknown. METHODS: The effects of peripheral administration of peptide YY3-36 (PYY3-36; 300 nmol kg(-1)), glucagon-like peptide-1 (GLP-1) analogue Exendin-4 (20 nmol kg(-1)) and somatostatin analogue octreotide (10 µg kg(-1)) on feeding and BW were evaluated in rats after gastric bypass. RESULTS: Gastric bypass rats weighed (P<0.01) and ate less on postoperative day 5 (P<0.001) and thereafter, whereas postprandial plasma PYY and GLP-1 levels were higher compared with sham-operated controls (P<0.001). Administration of both PYY3-36 and Exendin-4 led to a further decrease in food intake in bypass rats compared with saline treatment (P=0.02 and P<0.0001, respectively). Similar reduction in food intake was observed in sham rats (P=0.02 and P<0.001, respectively). Exendin-4 treatment resulted in a significant BW loss in bypass (P=0.03) and sham rats (P=0.04). Subsequent treatment with octreotide led to an increase in food intake in bypass (P=0.007), but not in sham rats (P=0.87). CONCLUSION: Peripheral administration of PYY3-36 and Exendin-4 reduces short-term food intake, whereas octreotide increases short-term food intake in rats after gastric bypass. The endogenous gut hormone response after gastric bypass can thus potentially be further enhanced by additional exogenous therapy with pharmacological doses of gut hormones in patients with insufficient weight loss or weight regain after surgery.

Alterations of sucrose preference after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naïve rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naïve rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass.

The syndrome of inappropriate secretion of antidiuretic hormone: diagnostic and therapeutic advances.

Hyponatremia is the most common electrolyte disorder and its presence predicts poor prognosis. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is among the most frequent causes of hyponatremia and is caused by a variety of disorders and pathomechanisms, mostly related to malignancy, pulmonary, or neurologic disorders. The introduction of small molecule vasopressin receptor-2 (VR2) antagonists, so called vaptans, into clinical medicine for the treatment of SIADH makes a reliable diagnosis of SIADH mandatory. This requires structured assessment of essential and supplemental criteria of SIADH, an approach that is currently frequently neglected in clinical routine. Hypertonic saline remains the gold standard in the initial treatment of symptomatic SIADH with severe neurological deficits. However, correction of hyponatremia needs to be slow (<10-12 mmol/l within the first 24 h, and <18 mmol/l within the first 48 h, respectively) to avoid osmotic myelinolysis. Fluid restriction and demeclocyclin have been the most widely used treatments for chronic hyponatremia in SIADH. However, fluid restriction suffers from poor long-term acceptance and demeclocyclin lacks broad availability and has been associated with safety concerns. In controlled clinical trials vaptans have been shown to be efficacious both during short-term and long-term administration (up to 12 months) for mild to moderate SIADH with an acceptable safety profile. However, clinical experience with vaptans in SIADH outside of carefully monitored clinical trials remains still rather limited. Thus, careful postmarketing surveillance will be crucial to fully appreciate the risks and benefits of this new class of drugs in SIADH.