High prevalence of severe sleep cycle disruption in de novo acromegaly and underdiagnosis by common clinical screening tools: A prospective, observational, cross-sectional study.

CONTEXT: Although sleep disordered breathing (SDB) is well-recognised in acromegaly, most studies have reported heterogeneous, often heavily treated, groups and few have performed detailed sleep phenotyping at presentation. OBJECTIVE: To study SDB using the gold standard of polysomnography, in the largest group of newly-diagnosed, treatment-naïve patients with acromegaly. SETTING AND PATIENTS: 40 patients [22 males, 18 females; mean age 54 years (range 23-78)], were studied to: (i) establish the prevalence and severity of SDB (ii) assess the reliability of commonly employed screening tools [Epworth Sleepiness Scale (ESS) and overnight oxygen desaturation index (DI)] to detect SDB (iii) determine the extent to which sleep architecture is disrupted. RESULTS: Obstructive sleep apnoea (OSA), defined by the apnoea-hypopnoea index (AHI), was present in 79% of subjects (mild, n = 12; moderate, n = 5; severe, n = 14). However, in these individuals with OSA by AHI criteria, ESS (positive in 35% [n = 11]) and DI (positive in 71%: mild, n = 11; moderate, n = 6; severe, n = 5) markedly underestimated its prevalence/extent. Seventy-eight percent of patients exhibited increased arousal, with marked disruption of the sleep cycle, despite most (82%) having normal total time asleep. Fourteen patients spent longer in stage 1 sleep. Deeper sleep stages were severely attenuated in many subjects (reduced stage 2, n = 18; reduced slow wave sleep, n = 24; reduced rapid eye movement sleep, n = 32). CONCLUSION: Our study provides strong support for clinical guidelines that recommend screening for sleep apnoea syndrome in patients with newly-diagnosed acromegaly. Importantly, however, it highlights shortcomings in commonly recommended screening tools (questionnaires, desaturation index) and demonstrates the added value of polysomnography to allow timely detection of obstructive sleep apnoea and associated sleep cycle disruption.

A novel mass spectrometry-based method for determining insulin-like growth factor 1: assessment in a cohort of subjects with newly diagnosed acromegaly.

OBJECTIVE: To develop an alternative method to immunoassay for the quantitative analysis of insulin-like growth factor 1 (IGF-1) using a mass spectrometry (MS)-based approach. STUDY DESIGN AND PATIENTS: A stable isotope dilution Ultra High Performance Liquid Chromatography tandem MS (uHPLC-MS/MS)-based method for the quantification of IGF-1 was developed. The method employed Selected Reaction Monitoring (SRM) of two tryptic peptides derived from IGF-1, and utilised solid phase extraction for enrichment of the peptide fraction containing IGF-1 rather than immunocapture, so was less susceptible to assay interference. Plasma samples from 25 consecutive unselected patients with newly diagnosed acromegaly, collected both before and after 24 weeks of primary medical therapy with Lanreotide Autogel(®), were analysed by a widely used commercial immunoassay (Siemens Immulite 2000(®)) and by uHPLC-MS/MS. RESULTS: The uHPLC-MS/MS method showed good correlation with the immunoassay over a wide range of IGF-1 concentrations. The Passing and Bablock regression was: uHPLC-MS/MS (nmol/l) = 1.37 (95% confidence interval: 1.26-1.46) × immunoassay (nmol/l) + 3.14 (95% confidence interval: -2.71 to 10.32). Six patients had discordant growth hormone (GH) and IGF-1 levels following primary medical therapy, and in all six the immunoassay and uHPLC-MS/MS platforms returned comparable results. The method was not affected by concentrations of IGFBP3 up to 12,500 ng/ml. CONCLUSIONS: uHPLC-MS/MS offers an independent method for determining/validating IGF-1 in subjects with acromegaly. Further studies, including the establishment of age- and sex-matched reference ranges and calibration to the new International IGF-1 standard IS 02/254, are now required to allow its introduction in to routine clinical use.

Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas.

CONTEXT: Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations. OBJECTIVE: To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI. SETTING AND PATIENTS: In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L). RESULTS: 29 patients (16%) were diagnosed with SH. Adrenocorticotropin was <10 pg/mL (<2.2 pmol/L) in all patients with SH. We calculated age- and sex-specific DHEAS ratios (derived by dividing the DHEAS by the lower limit of the respective reference range) for all patients. Receiver operating characteristic curve analyses demonstrated that a ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%). CONCLUSION: A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs.

Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI.

OBJECTIVE: To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS: Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS: Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS: In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).

A comprehensive study of clinical, biochemical, radiological, vascular, cardiac, and sleep parameters in an unselected cohort of patients with acromegaly undergoing presurgical somatostatin receptor ligand therapy.

CONTEXT: Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management. OBJECTIVE: The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort. STUDY DESIGN: This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy. RESULTS: Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 µg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged. CONCLUSIONS: Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.

Sitagliptin in glutamic acid decarboxylase antibody-positive diabetes mellitus.

OBJECTIVE: To describe a case illustrating the use of sitagliptin, an inhibitor of dipeptidyl-peptidase-4 (DPP-4), in anti-glutamic acid decarboxylase antibody-positive diabetes mellitus in association with a rare ataxic variant of stiff person syndrome. METHODS: We present our experience with use of the DPP-4 inhibitor sitagliptin for management of autoimmune diabetes in a elderly woman and highlight the association of diabetes with other autoimmune conditions. RESULTS: A 68-year-old Japanese woman presented with poorly controlled "type 2" diabetes mellitus, cerebral palsy, cerebellar ataxia, and hypothyroidism. She complained of stiffness and spasms, which had resulted in multiple falls and immobility. Antidiabetic medications included gliclazide, rosiglitazone, and acarbose; various insulins had been tried but discontinued because they worsened her stiffness and spasms. Her hemoglobin A1c values remained above 9% despite maximal doses of the aforementioned orally administered hypoglycemic agents. After sitagliptin therapy was initiated, her hemoglobin A1c level decreased from 9.3% (78 mmol/mol) to 7.3% (56 mmol/mol) in 5 months. Investigations confirmed the presence of an ataxic variant of stiff person syndrome. On repeated testing 18 months later, her anti-glutamic acid decarboxylase antibody levels had declined by more than 85%. CONCLUSION: Apart from the well-known mechanism of an increase in glucagonlike peptide-1, sitagliptin may exert its glucose-lowering effect by other mechanisms in patients with autoimmune diabetes. Further studies should be undertaken to address the effectiveness of DPP-4 inhibitors in non-type 2 diabetes.

Increased prevalence of gallbladder polyps in acromegaly.

INTRODUCTION: Several studies have suggested an increased prevalence of benign and malignant tumors in acromegaly, particularly colonic neoplasms. The gallbladder's epithelial similarity to the colon raises the possibility that gallbladder polyps (GBP) may occur more frequently in acromegaly. PATIENTS AND METHODS: Thirty-one patients with newly diagnosed acromegaly (14 females, 17 males; mean age 54.7 yr, range 27-76 yr) were referred to our center between 2004 and 2008. All had pituitary adenomas and were treated with somatostatin analogs prior to transsphenoidal surgery. Biliary ultrasonography was performed at the time of referral. In a retrospective case-cohort study, we compared the prevalence of GBP in these scans with those of 13,234 consecutive patients (age range 20-80 yr) presenting at the hospital for abdominal/biliary ultrasound during the same time interval. Associations between GH and IGF-I levels and GBP in acromegaly were also examined. RESULTS: There was a higher prevalence of GBP in patients with acromegaly compared with controls (29.03 vs 4.62%, P = 0.000008); relative risk was 6.29 (95% confidence interval 3.61-10.96). Eight of nine patients with acromegaly and GBP were older than 50 yr of age. GH levels were higher in those with GBP (median 30.8 µg/liter, interquartile range 10.9-39.1) than those without (8.2 µg/liter, interquartile range 6.0-16.0), but IGF-I levels were comparable. CONCLUSIONS: This is the first study to demonstrate an increased prevalence of GBP in patients with newly diagnosed acromegaly. Further studies are required to determine whether these patients are at increased risk of developing gallbladder carcinoma and to define the role, if any, of biliary ultrasound surveillance.