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Abstract Context Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable. Objective To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD. Design, Patients, and Methods A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality. Results Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome. Conclusion Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health. Patients with CD in remission have a more than twofold increased mortality, mainly due to cardiovascular diseases, but also due to infections and suicide.

Prolactin is a peptide hormone produced in the anterior pituitary, which increase in several physiological and pathological situations. It is unclear if hyperprolactinaemia may affect glycosylation of immunoglobulin G (IgG). Twenty-five patients with hyperprolactinemia and 22 healthy control subjects were included in the study. The groups had similar age and gender distribution. A panel of hormonal and haematological analyses, creatinine, glucose, liver enzymes and immunoglobulins were measured by routine clinical methods. IgG was purified from serum by Protein G Sepharose. Sialic acid was released from IgG by use of neuraminidase followed by quantification on high performance anion-exchange chromatography with pulsed amperometric detection. Tryptic glycopeptides of IgG was analysed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Hormone and immunoglobulin levels were similar in the two groups, except for IgA and prolactin. Significantly higher IgG1 and IgG2/3 galactosylation was found in the patient group with hyperprolactinaemia compared to controls. (A significant correlation between prolactin and IgG2/3 galactosylation (Rs 0.61, p<0.001) was found for samples with prolactin values below 2000 mIU/L. The relative amount of sialylated and bisecting glycans on IgG did not differ between patients and controls. The four macroprolactinaemic patients showed decreased relative amount of bisecting IgG2/3 glycans. Hyperprolactinaemia was found to be associated with increased galactosylation of IgG1and IgG2/3. This may have impact on IgG interactions with Fc-receptors, complement and lectins, and consequently lead to an altered immune response.

Of 1324 women diagnosed with gestational diabetes mellitus (GDM) in Sweden, 25% reported >10 years after the delivery that they had developed diabetes mellitus. We assessed the long-term risk of all glucose metabolic abnormalities in a subgroup of these women. Women (n = 51) previously diagnosed with GDM by capillary blood glucose ≥9.0 mmol/L (≈plasma glucose ≥10.0 mmol/L) after a 2 h 75 g oral glucose tolerance test (OGTT) were included. All underwent a clinical and biochemical evaluation, including a second 2 h 75 g OGTT. Individuals with known type 1 diabetes were excluded. At the follow-up, 12/51 (24%) reported previously diagnosed type 2 diabetes. Another four cases were diagnosed after the second OGTT, increasing the prevalence to 16/51 cases (31%). Impaired fasting plasma glucose (IFG) was diagnosed in 13/51 women and impaired glucose tolerance (IGT) in 10/51 women, leaving only 12 women (24%) with normal glucose tolerance. In addition, 2/51 women had high levels of glutamic acid decarboxylase (GAD) antibodies; of these, one woman classified as type 2 diabetes was reclassified as type 1 diabetes, and the second GAD-positive woman was diagnosed with IGT. Of the women diagnosed with GDM by a 2 h 75 g OGTT, a large proportion had impaired glucose metabolism a decade later, including type 1 and type 2 diabetes.

BackgroundStudies on the incidence of Cushing’s disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden.MethodsPatients registered with a diagnostic code for Cushing’s syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data.ResultsOf 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4–1.8) cases per million. 1987–1995, 1996–2004, and 2005–2013, the mean annual incidence was 1.5 (1.1–1.8), 1.4 (1.0–1.7) and 2.0 (1.7–2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P < 0.05).ConclusionThe incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987–2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.

Turner syndrome (TS) is a genetic condition characterized by partial or complete monosomy X. A reduced life expectancy has been shown in TS, depending on an increased risk of aortic dissection, and ischemic heart disease. Studies covering the occurrence of psychiatric conditions are sparse within TS. Several case reports describe concomitant TS and neuropsychiatric abnormalities that may represent a pathogenetic link to genetics, as well as feature correlates of TS. The aim of this study was to determine the presence, and the frequency of psychiatric diagnosis in women with TS in a Swedish cohort followed during 25 years’ time. Statistics from the entire female population in Sweden of corresponding age was used as reference. Data were retrieved from clinical examinations and validated from the National Board of Health and Welfare registries for women with TS ( n  = 487), aged 16 to 84 years, with respect to mental health disorders. The most common diagnoses in TS were mood and anxiety disorders. There was no increase in psychiatric diagnosis within the group with time, nor correlation to specific karyotype or somatic comorbidity as congenital heart disease and hypothyroidism, hormonal treatment, or childbirth. In addition, the frequency of psychiatric diagnosis in TS was lower than in the population-based data. Further investigations are needed in the view of the fact that women with Turner syndrome should not be burdened with more severe diagnoses.

ObjectiveA delayed diagnosis of pituitary adenomas (PAs) can lead to increased morbidity and reduced quality of life. The aim was to estimate diagnostic delay and investigate the concordance between patient-reported symptoms and the medical record documentation in patients with PA.DesignCross-sectional study.SettingSeven university hospitals.Participants654 patients: non-functioning PA (NFPA, 314), prolactinoma (118), acromegaly (164) and Cushing’s Disease (CD, 58).Data collectionQuestionnaires and medical record extraction.Primary and secondary outcomesType of first healthcare contact, delay of PA diagnosis and patient-reported symptoms and symptoms documented in medical records.ResultsFirst healthcare contact was usually a general practitioner. Estimated time from symptoms to diagnosis varied from <1 year (66%), 1–5 years (12%), 5–9 years (13%) and >10 years (9%). The longest diagnostic delays were observed in acromegaly and CD. A longer delay was observed in women compared with men (p<0.001). The most frequent patient-reported symptoms among NFPA were headache and visual disturbances; for prolactinomas, menstrual irregularities and headache; for acromegaly, change in appearance and snoring; and for CD, weight gain and tiredness. Concordance between patient-reported symptoms at diagnosis and medical records was found for visual disturbances in NFPA and prolactinomas (Cohen’s kappa >0.6) and for menstrual irregularities in prolactinomas (Cohen’s kappa >0.7).ConclusionWe report a large variation in symptom duration before diagnosis with a substantial diagnostic delay in patients with CD and acromegaly. An increased awareness about endocrine diseases in the general population and health professionals may contribute to earlier diagnosis of pituitary adenomas.

Gestational diabetes mellitus (GDM) is a common complication with negative impacts on mother and child. The primary aim of this study was to examine whether plasma glucose cutoffs for GDM diagnosis based on venous sampling can be replaced by cutoffs based on capillary sampling. A prospective cross-sectional study was performed at an antenatal care clinic including 175 pregnant women undergoing an oral glucose tolerance test (OGTT). Duplicate samples were collected by capillary and venous puncture while fasting and 1 h and 2 h after an OGTT. Both samples were analyzed on Accu-Chek Inform II. The cutoffs for a GDM diagnosis using capillary samples were corrected from 5.1 to 5.3 mmol/L for the fasting sample, from 10.0 to 11.1 mmol/L for the 1 h sample, and from 8.5 to 9.4 mmol/L for the 2-h sample using half of the dataset. Applying these cutoffs to the remaining dataset resulted in a sensitivity, specificity, and accuracy of 85.0%, 95.0%, and 90.3%, respectively, with a positive predictive value (PPV) of 83%, an negative predictive value (NPV) of 96%, and a positive negative likelihood ratio (LHR) of 16.4 using capillary sampling for the GDM diagnosis at fasting and 2-h after. Corrected cutoffs and capillary samples can be used for the diagnosis of GDM with maintained diagnostic accuracy using Accu-Chek Inform II.

PurposeBilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development.Data sourcesSystematic literature search in four databases.Study SelectionObservational studies reporting the prevalence of NS after BA in adult patients with CD.Data extractionData extraction and risk of bias assessment were performed by three independent investigators.Data synthesisThirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)].ConclusionsEvery fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

One of the most critical decisions that emergency department (ED) physicians make is the discharge versus admission of patients. We aimed to study the association of the decision in the ED to admit patients with chest pain and/or breathlessness to a ward with risk assessment using the Rapid Emergency Triage and Treatment System (RETTS), the National Early Warning Score (NEWS), and plasma levels of the biomarkers copeptin, midregional proadrenomedulin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP). Patients presenting at the ED with chest pain and/or breathlessness with less than one week onset were enrolled. Patients were triaged according to RETTS. NEWS was calculated from the vital signs retrospectively. Three hundred and thirty-four patients (167 males), mean age 63.8 ± 16.8 years, were included. Of which, 210 (62.8%) patients complained of chest pain, 65 (19.5%) of breathlessness, and 59 (17.7%) of both. Of these, 176 (52.7%) patients were admitted to a ward, and 158 (47.3%) patients were discharged from the ED. In binary logistic models, age, gender, vital signs (O saturation and heart rate), NEWS class, and copeptin were associated with admission to a ward from the ED. In receiver-operating-characteristics (ROC) analysis, copeptin had an incremental predictive value compared to NEWS alone ( = 0.002). Emergency physicians' decisions to admit patients with chest pain and/or breathlessness from the ED to a ward are related to age, O saturation, heart rate, NEWS category, and copeptin. As an independent predictive marker for admission, early analysis of copeptin might be beneficial when improving patient pathways at the ED.

Background Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93–140/million), secondary AI (estimated prevalence, 150–280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387). Methods Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy. Results Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands. Conclusions EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.