Efficacy of cabergoline in non-irradiated patients with acromegaly: a multi-centre cohort study.

OBJECTIVE: Elucidate the efficacy (as per current biochemical criteria) of cabergoline monotherapy or as addition to long-acting somatostatin receptor ligand (SRL) in patients with acromegaly and no previous pituitary radiotherapy. DESIGN: Multi-centre, retrospective, cohort study (four UK Pituitary centres: Birmingham, Bristol, Leicester, Oxford). METHODS: Clinical, laboratory, imaging data were analysed. RESULTS: Sixty-nine patients on cabergoline monotherapy were included [median IGF-1 xUpper Limit of Normal (ULN) pre-cabergoline 2.13 (1.02-8.54), median treatment duration 23 months, median latest weekly dose 3 mg]. 31.9% achieved normal IGF-1 (25% GH-secreting, 60% GH+prolactin co-secreting tumours); median weekly cabergoline dose was similar between responders and non-responders. IGF-1 normalisation was related with GH+prolactin co-secreting adenoma (B 1.50, p=0.02) and lower pre-cabergoline IGF-1 xULN levels (B -0.70, p=0.02). Both normal IGF-1 and GH<1 mcg/L were detected in 12.9% of cases and tumour shrinkage in 29.4% of GH-secreting adenomas.Twenty-six patients on SRL+cabergoline were included [median IGF-1 xULN pre-cabergoline 1.7 (1.03-2.92), median treatment duration 36 months, median latest weekly dose 2.5 mg]. 23.1% achieved normal IGF-1 (15.8% GH-secreting, 33.3% GH+prolactin co-secreting tumours). Normal IGF-1 and GH<1 mcg/L were detected in 17.4%. CONCLUSIONS: In non-irradiated patients, cabergoline normalises IGF-1 in around one-third and achieves both IGF-1 and GH targets in approximately one out of ten cases. SRL+cabergoline is less efficient than previously reported possibly due to differences in studies methodology and impact of confounding factors.

Point-of-care ultrasound is a useful adjunct tool to a clinician's assessment in the evaluation of severe hyponatraemia.

INTRODUCTION: Hyponatraemia is the most common electrolyte disorder in inpatients resulting mainly from an imbalance in water homeostasis. Intravascular fluid status assessment is pivotal but is often challenging given multimorbidity, polypharmacy and diuretics use. We evaluated the utility of point-of-care ultrasound (POCUS) as an adjunct tool to standard practice for fluid assessment in severe hyponatraemia patients. METHODS: Patients presenting with severe hyponatremia (Serum Sodium [Na] < 120 mmol/L; Normal range: 135-145 mol/L), managed by standard care were included. Hyponatraemia biochemistry work-up and POCUS examination were undertaken. Both clinician and POCUS independently assigned one of the three fluid status groups of hypovolaemia, hypervolaemia or euvolaemia. The final diagnosis of three fluid status groups at admission was made at the time of discharge by retrospective case review. Clinician's (standard of care) and POCUS fluid assessments were compared to that of the final diagnosis at the time of discharge. RESULTS: n = 19 patients were included. Median Na on admission was 113 mmol/L (109-116), improved to 129 ± 3 mmol/L on discharge. POCUS showed the higher degree of agreement with the final diagnosis (84%; n = 16/19), followed by the clinician (63%; n = 12/19). A trend towards higher accuracy of POCUS compared to clinician assessment of fluid status was noted (84% vs. 63%, p = 0.1611). Biochemistry was unreliable in 58% (n = 11/19) likely due to renal failure, polypharmacy or diuretic use. Inappropriate emergency fluid management was undertaken in 37% (n = 7/19) of cases based on initial clinician assessment. Thirst symptom correlated to hypovolaemia in 80% (4/5) cases. CONCLUSION: As subjective clinical and biochemistry assessments of fluid status are often unreliable due to co-morbidities and concurrent use of medications, POCUS can be a rapid objective diagnostic tool to assess fluid status in patients with severe hyponatraemia, to guide accurate emergency fluid management.

Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps.

PURPOSE: Lower fat fraction (FF) in brown adipose tissue (BAT) than white adipose tissue (WAT) has been exploited using Dixon-based Magnetic Resonance Imaging (MRI) to differentiate these tissues in rodents, human infants and adults. We aimed to determine whether an optimal FF threshold could be determined to differentiate between BAT and WAT in adult humans in vivo. METHODS: Sixteen volunteers were recruited (9 females, 7 males; 44.2 ±â€¯19.2 years) based on BAT uptake on 18F-FDG PET/CT. Axial 3-echo TSE IDEAL sequences were acquired (TR(ms)/TE(ms)/matrix/NEX/FoV(cm) = 440/10.7-11.1/512 × 512/3/30-40), of the neck/upper thorax on a 3T HDxt MRI scanner (GE Medical Systems, Milwaukee, USA), and FF maps generated from the resulting water- and fat-only images. BAT depots were delineated on PET/CT based on standardized uptake values (SUV) >2.5 g/ml, and transposed onto FF maps. WAT depots were defined manually within subcutaneous fat. Receiver operating characteristic (ROC) analyses were performed, and optimal thresholds for differentiating BAT and WAT determined for each subject using Youden's J statistic. RESULTS: There was large variation in optimal FF thresholds to differentiate BAT and WAT between subjects (0.68-0.85), with great variation in sensitivity (0.26-0.84) and specificity (0.62-0.99). FF was excellent or good at separating BAT and WAT in four cases (area under the curve [AUC] 0.84-0.92), but poor in 10 (AUC 0.25-0.68). CONCLUSION: Although this technique was effective at differentiating BAT and WAT in some cases, no universal cut-off could be identified to reliably differentiate BAT and WAT in vivo in adult humans on the basis of FF.

Brown fat depots in adult humans remain static in their locations on PET/CT despite changes in seasonality.

Active brown adipose tissue (BAT) in humans has been demonstrated through use of positron emission tomography with 2-deoxy-2-(fluorine-18) fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) scans. The aim of our study was to determine whether active human BAT depots shown on 18F-FDG PET/CT scans remain static in their location over time. This was a retrospective study. Adult human subjects (n = 15) who had had 18F-FDG PET/CT imaging (n = 38 scans in total) for clinical reasons were included on the basis of 18F-FDG uptake patterns consistent with BAT activity. For each subject, 18F-FDG BAT uptake pattern on serial 18F-FDG PET/CT images was compared to an index 18F-FDG PET/CT image with the largest demonstrable BAT volume. Object-based colocalization was expressed as Mander's correlation coefficient (where 1 = 100% overlap, 0 = no overlap). Distribution of 18F-FDG BAT activity over time and across multiple 18F-FDG BAT scans was equivalent in 60% (n = 9) of the subjects. The degree of consistency in the pattern of 18F-FDG BAT uptake in each subject over time was greater than expected by chance in 87% (n = 13) of the subjects (pair-wise agreement 75-100%, Fleiss' κ 0.4-1). The degree of BAT colocalization on serial scans was greater than that expected by chance in 93% (n = 14) of the subjects (mean Mander's coefficient 0.81 ± 0.21 [95% CI]). To our knowledge, our study provides the most conclusive evidence to date to support the notion that active BAT depots in humans (volumes and activities of which were measured through use of 18F-FDG PET/CT scans) remain static in location over sustained periods.

Enhanced thermic effect of food, postprandial NEFA suppression and raised adiponectin in obese women who eat slowly.

OBJECTIVE: Meal duration may influence cardiometabolic health. The aim of this study was to explore postprandial effects of meal duration on human metabolism and appetite. DESIGN: Postprandial comparisons following a standard meal eaten slowly over 40 min ('D40') and the same meal eaten quickly over 10 min ('D10') on a different day. Each participant therefore acted as their own control, thereby limiting confounding factors. PATIENTS: Obese premenopausal Caucasian women (n = 10) with confirmed normoglycaemia were recruited from an obesity clinic at UHCW, Coventry UK. Subjects underwent whole-body calorimetry (8-h) on two separate days. MEASUREMENTS: Following standard lunch (D40 vs D10), 4-h postprandial analysis included thermic effect of food (TEF) and bloods taken at predefined times (including baseline fasting). Analytes included lipid profile, adiponectin, insulin, glucose, ghrelin, leptin, endotoxin, gut and pancreatic hormones. Appetite was measured using visual-analogue scales and ad libitum food intake at subsequent meal. Paired sample t-tests [including area under the curve (AUC)] were used to compare D40 and D10 trials. RESULTS: Postprandial TEF (over 240-min) was significantly greater for D40 than D10 [mean (SEM): 80·9 kcal (3·8) vs 29·9 kcal (3·4); 10·6% vs 3·9%, respectively, P = 0·006; AUC 71·7 kcal.h vs 22·4 kcal.h, respectively, P = 0·02]. Postprandial plasma NEFA was significantly lower, and adiponectin levels were significantly higher for D40 than D10 [AUC (SEM): NEFA 627 µmol.h/l (56) vs 769 µmol.h/l (60), respectively, P = 0·02; adiponectin 33·4 µg.h/ml (3·9) vs 27·3 µg.h/ml (3·8), respectively, P = 0·04]. Other postprandial analytes and appetite measures were equivalent. CONCLUSIONS: In obese women, eating slowly associates with enhanced TEF, elevated serum adiponectin and suppressed NEFA.

Identification of brown adipose tissue using MR imaging in a human adult with histological and immunohistochemical confirmation.

OBJECTIVE: Manipulation of human brown adipose tissue (BAT) represents a novel therapeutic option for diabesity. The aim of our study was to develop and test a novel magnetic resonance (MR) imaging-based method to identify human BAT, delineate it from white adipose tissue, and validate it through immunohistochemistry. DESIGN: A 25-year old Caucasian female with hyperparathyroidism-jaw tumor syndrome underwent parathyroidectomy. An (18)fluoro-2-deoxyglucose positron emission tomography (PET)-computed tomography (CT) scan performed after surgery ruled out malignancy but showed avid uptake within the mediastinum, neck, supraclavicular fossae, and axillae, consistent with BAT. Immunohistochemical staining using uncoupling protein-1 antibody was performed on one fat sample obtained from the suprasternal area during parathyroidectomy. Subsequently, serial MR scans were performed. Retrospectively, regions of interest (ROIs) were identified on MR corresponding to areas of high uptake on PET-CT. Prospectively, ROIs were identified on MR based on signal intensity and appearance and compared with PET-CT. RESULTS: Of 111 retrospectively identified ROIs from PET-CT, 93 (83.8%) showed corresponding low MR signal: 25 of 25 mediastinum (100%), 29 of 31 neck (93.5%), 31 of 41 supraclavicular (75.6%), and 8 of 14 axillae (57%). Prospectively, 47 of 54 ROIs identified on MR (87%) showed a corresponding increased uptake on PET-CT. Serendipitously, the sample obtained at surgery corresponded with high uptake and low signal on subsequent PET and MR, respectively, and immunohistochemistry confirmed BAT. CONCLUSION: We provide the first report for the reliable use of MR to identify BAT in a living human adult, with histological/immunohistochemical confirmation. Our data demonstrate proof of concept to support the development of MR as a safe, reproducible imaging modality for human BAT.

Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity.

INTRODUCTION: Recent observation of brown adipose tissue (BAT) being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through 'adaptive thermogenesis' for an anti-obesity strategy. Many endocrine dysfunctions are associated with changes in metabolic rate that over time may result in changes in body weight. It is likely that human BAT plays a role in such processes. REVIEW: In this brief review article, we explore the endocrine determinants of BAT activity, and discuss how these insights may provide a basis for future developments of novel therapeutic strategies for obesity management. A review of electronic and print data comprising original and review articles retrieved from PubMed search up to December 2013 was conducted (Search terms: brown adipose tissue, brown fat, obesity, hormone). In addition, relevant references from the articles were screened for papers containing original data. CONCLUSION: There is promising data to suggest that targeting endocrine hormones for BAT modulation can yield a cellular bioenergetics answer for successful prevention and management of human obesity. Further understanding of the physiological link between various endocrine hormones and BAT is necessary for the development of new therapeutic options.