Visceral Adiposity Is an Independent Determinant of Hypercoagulability as Measured by Thrombin Generation in Morbid Obesity.

Introduction Increased visceral adipose tissue (VAT) has been shown to be associated with the development of insulin resistance, type 2 diabetes, stroke, and ischemic heart disease. It remains unknown whether fat distribution impacts on coagulation markers and/or the risk of venous thrombosis. This study evaluates markers of hypercoagulability in class III obesity (body mass index [BMI] >40 kg/m 2 ) compared with nonobese controls. We further investigated whether hypercoagulability was influenced by VAT, metabolic syndrome, and metabolic markers, including adiponectin. Patients and Methods Ninety patients were recruited from the obesity clinic at King's College Hospital from November 2009 to December 2011. The inclusion criteria were class III obesity (BMI ≥40 kg/m 2 ) and age 18 to 65 years. A control group (healthy ambulatory participants, with a BMI < 30 kg/m 2 ) was recruited from volunteers responding to advertisement. Abdominal VAT and subcutaneous adipose tissue surface areas were determined by evaluation of a single-slice CT at spinal vertebra L4. Results Thrombin generation revealed a significantly increased peak and endogenous thrombin potential in patients compared with controls. Lag time and time to peak (ttP) were also significantly prolonged in patients. VAT was found to have the strongest association with thrombin generation parameters: lag time (ß = 0.378; p < 0.001), peak thrombin (0.378; p = 0.04), and ttP (ß = 0.373; p = 0.001). BMI was found to be a predictor for lag time only (ß = 0.313; p = 0.003). SAT was not associated with any of the thrombin generation parameters (data not shown). VAT was found to be an independent determinant of peak thrombin, lag time, and ttP. The study suggests not only fat mass but also fat distribution, particularly visceral adiposity, mediates hypercoagulability in obesity.

Importance of cannulated prolactin test in the definition of hyperprolactinaemia.

PURPOSE: Recent guidelines suggest that a single prolactin measurement is adequate to confirm hyperprolactinaemia. This may lead to unnecessary investigation of artefactual hyperprolactinaemia. Prolactin measurement drawn from an indwelling cannula after rest removes stress as a confounding variable. The objective was to determine the frequency of true hyperprolactinaemia amongst patients referred following a single prolactin measurement. METHODS: A cannulated study was considered if prolactin on referral ('Referral Prolactin') was <5,500 mU/L (260 ng/mL) but >410 mU/L (19 ng/mL) in males or >510 mU/L (24 ng/mL) in females, irrespective of clinical context. Case-notes of 267 patients undergoing cannulated prolactin measurement over a 10-year period (2000-2010) were reviewed. Pre-existing pituitary disease, dopamine antagonist use, and macroprolactinaemia were excluded. Morning ante-cubital vein cannulation was followed immediately by withdrawal of 'Repeat Prolactin' sample. After 120-min bed-rest, 'Resting Prolactin' was withdrawn through the cannula. RESULTS: 235 patients were included for analysis. 64 (27%) were within normal range; following Repeat Prolactin in 41 (17%) and Resting Prolactin in 23 (9%) cases. Referral Prolactin was higher in patients with true hyperprolactinaemia, 1,637 ± 100 mU/L (77.2 ± 4.7 ng/mL) than with artefactual hyperprolactinaemia, 1,122 ± 68 mU/L (52.9 ± 3.2 ng/mL; P < 0.001) but there was substantial overlap. 21 out of 171 cases (12%) with true hyperprolactinaemia had a macroadenoma. Presenting symptoms did not predict true hyperprolactinaemia. Referral Prolactin of 2,000 mU/L (94 ng/mL) had 97% specificity to identify true hyperprolactinaemia. CONCLUSIONS: Reliance on a single, non-rested prolactin value may lead to over-diagnosis of hyperprolactinaemia. A resting sample should be considered with random values <2,000 mU/L (94 ng/mL).

Disease severity and staging of obesity: a rational approach to patient selection.

The increasing prevalence of obesity places ever-increasing cost demands on healthcare systems. One million individuals are eligible for bariatric surgery in the UK, and yet less than 6000 bariatric procedures are performed annually. Bariatric surgery reverses or improves almost all the medical and psychosocial co-morbidities associated with obesity. Although the BMI is a simple method to estimate adiposity at a population level, it is relatively inaccurate within an individual and provides little-to-no indication of overall health status or disease severity. Staging systems overcome the inherent limitations of BMI and allow highly informed decision-making for an individual. At a societal level, this helps to identify those most likely to gain and maximise economic benefit. This review summarises the co-morbidities associated with obesity and the evidence for their improvement following surgery. The rationale for new staging criteria and appropriate patient selection are discussed.

Phaeochromocytoma [corrected] crisis.

Phaeochromocytoma [corrected] crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma [corrected] crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma [corrected] crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved.

Temozolomide in the management of dopamine agonist-resistant prolactinomas.

BACKGROUND: The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment. CASE SERIES: We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16-year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT). LITERATURE REVIEW AND DISCUSSION: A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT-negative staining and a good response to temozolomide (OR 9.35, P = 0.0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.

Assessment of obesity beyond body mass index to determine benefit of treatment.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Weight or weight loss per se may not indicate health status or health benefit. • There is no gold standard for assessing which patients would benefit most from weight-loss interventions. • The King's Criteria is one of several recently proposed obesity classification systems. WHAT THIS STUDY ADDS: • The King's Criteria can capture health problems related to obesity and health benefits after weight loss. • The King's Criteria is a reproducible scoring system. • Using the King's Criteria may help shift the focus of patients and clinicians from weight loss to health gain. SUMMARY: Body mass index (BMI) alone does not reflect health status in individuals. The King's Obesity Staging Criteria is a clinical tool for the assessment of patients with complex obesity. We assessed the performance of a modified version of the King's Criteria by scoring 144 obese patients before and 1 year after bariatric surgery. We also evaluated inter-observer variability by having 11 clinicians score the same 12 patients. The King's Obesity Staging Criteria comprise nine health domains: Airways, Body mass index, Cardiovascular disease, Diabetes, Economic complications, Functional limitations, Gonadal axis, Health status (perceived), and body Image. For each domain, a person's health is assigned a score of 0 ('normal health'), 1 ('at risk'), 2 ('established disease') or 3 ('advanced disease'). The patient's mean BMI decreased from 48 ± 7 to 37 ± 7 kg m(-2) post surgery. Before surgery, 84% of patients were either in stage 2 ('established disease') or stage 3 ('advanced disease') for one or more domains other than BMI. The modified King's Criteria showed significant health improvements after surgery, with a higher proportion of patients scored in stage 0 ('normal health') within each health domain (P < 0.001 for all). Observers assigned the same score in >75% of cases for all domains except Health status perceived (71%) and body Image (65%). In conclusion the King's Criteria captured morbidity in obese patients and health gains after weight loss. Different clinicians mostly assigned similar scores. The King's Criteria is a clinical tool that may help shift the focus of patients and clinicians towards improving health and not only losing weight. REGISTRATION NUMBER: NCT01112228 (http://www.clinicaltrials.gov).

Visceral adiposity is closely correlated with neck circumference and represents a significant indicator of insulin resistance in WHO grade III obesity.

OBJECTIVE: Although associations between visceral adiposity (intra-abdominal fat mass) and insulin resistance are well established, previous data include few subjects with WHO grade III obesity [body mass index (BMI) > 40 kg/m(2)]. We have investigated the relationship between visceral adiposity and insulin resistance using computed tomography (CT)-quantified fat mass and the homeostasis model assessment for insulin resistance (HOMA-IR) in patients with severe obesity. PATIENTS AND METHODS: Eighteen nondiabetic subjects with BMI > 40 kg/m(2) were recruited. BMI, and waist, hip and neck circumferences were measured. Fasting plasma insulin and glucose were measured to calculate HOMA-IR. A single slice CT scan was taken at L4 and visceral and abdominal subcutaneous adipose tissue (VAT and ASAT, respectively) quantified using 'SliceOmatic' image analysis software. RESULTS: A close correlation was demonstrated between VAT and HOMA-IR (r(2) = 0.46, P = 0.002), whereas ASAT showed no relationship. Neck circumference correlated with both VAT (r(2) = 0.67, P < 0.0001) and HOMA-IR (r(2) = 0.35, P = 0.01). Waist circumference only correlated significantly with VAT (r(2) = 0.25, P = 0.03). CONCLUSIONS: Visceral adiposity remains a strongly significant indicator of insulin resistance in WHO grade III obesity. Neck circumference surpasses other anthropometric measurements as a powerful marker of both VAT and insulin resistance.

Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety.

BACKGROUND: Bariatric surgery is the most effective treatment for achieving long-term weight loss in morbidly obese patients. This study investigated prospective changes in gut hormones and metabolic indices after Roux-en-Y gastric bypass (RYGB). METHODS: Six patients were seen before, and at 1, 3 and 6 months after operation. Blood was collected after a 12-h fast and at regular intervals after a mixed 420-kcal meal. Hormonal responses were determined, and comparisons between basal levels and areas under the curve were made. Visual analogue scores were used to assess satiety, hunger and nausea. RESULTS: Mean body mass index decreased from 48.3 kg/m(2) before surgery to 36.4 kg/m(2) 6 months after RYGB. This was accompanied by a decrease in fasting leptin (P < 0.001) and insulin (P = 0.021) levels. At 1, 3 and 6 months after operation, progressively increasing peptide YY (P < 0.001), enteroglucagon (P = 0.045) and glucagon-like peptide 1 (P = 0.042) responses were observed. There was no change in fasting ghrelin levels (P = 0.144). Postprandial satiety was significantly increased by 1 month after surgery and this was maintained until the end of the study (P < 0.001). CONCLUSION: RYGB resulted in substantial weight loss with enhanced postprandial satiety, a sustained weight plateau, and proportionate reduction in fasting insulin and leptin levels. Lack of the expected increase in appetite and food intake as components of a counter-regulatory response may be explained by gut adaptation and the consequent graded rise in the levels of gut hormones that promote satiety.

Attenuated peptide YY release in obese subjects is associated with reduced satiety.

The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY(1-36) to PYY(3-36) was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY(3-36) was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY(3-36) in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY(3-36) on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY(3-36). Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY(3-36) infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.

The nadir growth hormone after an octreotide test dose predicts the long-term efficacy of somatostatin analogue therapy in acromegaly.

OBJECTIVE: In the treatment of acromegaly, a 'test dose' of octreotide is recommended prior to the use of depot somatostatin analogue (SSA) therapy. However, there remains no consensus regarding the criteria that predict a response to treatment. The ability to select patients who may benefit most from medical therapy is potentially of great value in clinical practice. The aim of the study was to determine the predictive value of both the nadir GH and the mean GH following an octreotide test dose in identifying patients who subsequently achieved disease remission with depot SSA therapy. Remission was defined as a mean GH < 5 mU/l (< 2 microg/l). DESIGN: Retrospective case-control study. PATIENTS: A group of 41 patients with acromegaly underwent an octreotide test dose where GH was measured hourly for a total of 6 h following an injection of octreotide 50 microg subcutaneously. Nadir GH and mean GH following the octreotide test dose were determined. Thirty-three patients were subsequently treated with depot SSA therapy and mean GH and IGF-I levels were determined at follow-up. RESULTS: The nadir GH demonstrated superior predictive power to that of mean GH across a range of GH cut-off values. A nadir GH < 5 mU/l demonstrated 80% sensitivity and 83% specificity in predicting remission with depot SSA therapy. A nadir GH < 10 mU/l demonstrated 100% sensitivity and 56% specificity. CONCLUSIONS: The nadir GH following an octreotide test dose is a useful predictive marker of achieving disease remission with depot SSA therapy used as either a primary or an adjuvant agent.

FSH secretion predominates in vivo and in vitro in patients with non-functioning pituitary adenomas.

OBJECTIVE: Non-functioning pituitary adenomas (NFPAs) are characterised by the lack of symptoms of hormone hypersecretory syndromes but in vitro studies have demonstrated that tumour cells may stain for gonadotrophins and/or their alpha- or beta-subunits. In this study, we aimed to examine the pattern of secretion of LH and FSH from a series of pituitary adenomas cultured in vitro and where data were available to relate the results to pre-operative serum gonadotrophin levels. METHODS: The in vitro secretion of LH and FSH was measured from 46 cultured NFPAs and compared with pre-operative serum gonadotrophin levels in 38 patients. Peritumorous 'normal' pituitary cell cultures from 20 additional pituitary tumour patients were used for comparison with the NFPA group. RESULTS: A median pre-operative LH:FSH ratio of 0.33:1 was found in 38 patients with NFPAs. Preferential secretion of FSH was also documented from media of 46 NFPAs cultured in vitro with a median LH:FSH ratio of 0.32:1. A significant correlation (r = 0.43, P < 0.01) was observed between serum and media levels of FSH but not LH. Peritumorous 'normal' pituitary cells released LH and FSH in a reversed ratio (median LH:FSH ratio = 3.6:1, P < 0.01 compared with NFPAs). CONCLUSIONS: This study has evaluated pre-operative serum gonadotrophin levels and in vitro release of hormones in cultures of surgically removed tissue from patients with NFPAs. The data suggest preferential secretion of FSH occurs both in vitro and in vivo. By demonstrating that NFPAs cultured in vitro reflect the in vivo situation of preferential secretion of FSH, it may be possible in future to perform functional studies using this system to elucidate the cellular and molecular mechanisms involved in the development of an imbalance in gonadotroph cells preferentially overproducing FSH in NFPAs.

The relationship between pituitary tumour transforming gene (PTTG) expression and in vitro hormone and vascular endothelial growth factor (VEGF) secretion from human pituitary adenomas.

OBJECTIVE: Pituitary tumour transforming gene (PTTG) is a recently identified protooncogene, ubiquitously expressed in pituitary tumours at levels higher than those detected in normal pituitary. Although the precise function of PTTG protein is unknown, in vitro experiments have shown that it induces angiogenesis. In this study, we have examined the potential relationship between the level of PTTG expression and tumour phenotype, tumour size, in vitro pituitary hormone secretion and release of vascular endothelial growth factor (VEGF), a potent angiogenic factor. METHODS: Pituitary tumours (12 somatotroph, five lactotroph, five corticotroph and 18 non-functioning) were studied by cell culture, measuring the basal secretion of anterior pituitary hormones and VEGF in vitro. Immunocytochemistry was used to confirm the clinical diagnosis and tumour phenotype. PTTG mRNA expression was investigated by comparative RT-PCR. Tumour Volume was quantitated from pre-operative MRI scans. RESULTS: PTTG expression was significantly increased 2.7-fold in somatotroph tumours compared with non-functioning adenomas (P<0.01, ANOVA). A positive correlation was demonstrated between PTTG expression and in vitro GH secretion (r=0.41, P<0.01, Spearman) but no correlations were found for any of the other pituitary hormones. In 16 out of 40 pituitary tumours, we were able to determine the in vitro secretion of VEGF and relate this to PTTG expression. All of the adenomas tested secreted measurable VEGF but there was no correlation between the amount of VEGF secreted and either the tumour phenotype or PTTG expression. Neither PTTG expression nor VEGF secretion correlated with tumour Volume. CONCLUSIONS: Our studies have confirmed the presence of PTTG in pituitary adenomas and demonstrated a higher level of expression in somatotroph tumours and a significant correlation with GH secretion. We failed to demonstrate a relationship between PTTG expression and production of the angiogenic factor, VEGF, or tumour Volume. Thus, although PTTG induces angiogenesis experimentally, it seems unlikely that a VEGF-mediated angiogenic mechanism occurs during pituitary tumour progression.