A nationwide registry-based observational study of thyroid disease incidence in the Faroe Islands.

OBJECTIVE: The occurrence of thyroid disease varies among populations. While the iodine nutrition level of the Faroese seems to have been decreasing over the past decades, there is no systematic evaluation of the thyroid disease pattern in the Faroe Islands. Such knowledge of thyroid disease occurrence in the North Atlantic region may support healthcare planning and prevention. To investigate incidence rates, including subtypes of thyroid diseases, and demographic characteristics of thyroid disease patients in the Faroe Islands, to improve understanding of the patterns and trends of these disorders. DESIGN AND METHOD: A registry-based observational study was conducted over 10 years, encompassing all adult Faroese individuals. PATIENTS AND MEASUREMENTS: Health records from general practitioners and hospitals were used to identify incident cases of thyroid diseases. Validation was performed using multiple data sources. The incidence rates were standardised using population data from the middle of the study period 2006-2018. RESULTS: Among the 1152 individuals diagnosed with thyroid disease, the standardised incidence rates per 100,000 person-years were 55 for hyperthyroidism and 112 for hypothyroidism, and around four times higher in women than in men. Hashimoto's thyroiditis was the dominant cause of hypothyroidism, while Graves' disease was the leading cause of hyperthyroidism. The incidence of hypothyroidism increases with age. A decreasing trend was observed over time for both hypothyroidism and hyperthyroidism. CONCLUSION: Considering the decrease in iodine nutrition levels over the past decades, we were surprised by the high incidence of autoimmune thyroid disease. The findings highlight the need for continuous monitoring of thyroid disease occurrence in coastal areas of the North Atlantic Ocean.

Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Polyautoimmunity in Patients With Anticyclic Citrullinated Peptide Antibody-Positive and -Negative Rheumatoid Arthritis: a Nationwide Cohort Study From Denmark.

OBJECTIVE: This study aimed to compare the prevalence and incidence of polyautoimmunity between anticyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative patients with rheumatoid arthritis (RA). METHODS: In a nationwide register-based cohort study, patients with RA (disease duration ≤ 2 yrs) in the DANBIO rheumatology register with an available anti-CCP test in the Register of Laboratory Results for Research were identified. The polyautoimmunity outcome included 21 nonrheumatic autoimmune diseases identified by linkage between the Danish Patient Registry and Prescription Registry. The age- and sex-adjusted prevalence ratio (PR) was calculated by modified Poisson regression to estimate the prevalence at diagnosis in anti-CCP-positive vs anti-CCP-negative patients. The hazard ratio (HR) of polyautoimmunity within 5 years of entry into DANBIO was estimated in cause-specific Cox regression models. RESULTS: The study included 5839 anti-CCP-positive and 3799 anti-CCP-negative patients with RA. At first visit, the prevalence of prespecified polyautoimmune diseases in the Danish registers was 11.1% and 11.9% in anti-CCP-positive and anti-CCP-negative patients, respectively (PR 0.93, 95% CI 0.84-1.05). The most frequent autoimmune diseases were autoimmune thyroid disease, inflammatory bowel disease, and type 1 diabetes mellitus. During a mean follow-up of 3.5 years, only a few (n = 210) patients developed polyautoimmunity (HR 0.6, 95% CI 0.46-0.79). CONCLUSION: Polyautoimmunity as captured through the Danish National Patient Registry occurred in approximately 1 in 10 patients with RA at time of diagnosis regardless of anti-CCP status. In the years subsequent to the RA diagnosis, only a few and mainly anti-CCP-negative patients developed autoimmune disease.

Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes.

BACKGROUND: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear. METHODS: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated. RESULTS: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations. CONCLUSIONS: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs.

Respiratory impairments in patients suffering from Fabry disease - A cross-sectional study.

BACKGROUND: The inherited X-linked disorder, Fabry disease, is caused by deficient lysosomal enzyme α-galactosidase A, with progressive accumulation of globotriaosylceramide in multiple organs including the upper and lower airways. OBJECTIVES: To assess pulmonary function at the time of the first pulmonary function test (PFT) performed among the National Danish Fabry cohort and define the prevalence of affected lung function variables. MATERIALS AND METHOD: A cross-sectional retrospective cohort study of 86 adult patients enrolled in one or both international patient registry databases for Fabry disease, Fabry Registry or FollowME with at least one PFT. The Mainz Severity Score Index (MSSI) was calculated to determine the disease severity. Lung function variables were examined by multivariate regression adjusted for important variables for developing airway illness. RESULTS: Seventeen patients (20%) showed obstructive airflow limitation and 7 (8%) a restrictive lung deficiency. Smoking status (p = .016) and MSSI (p < .001) were associated with increasing obstructive airway limitation. CONCLUSION: The prevalence of affected lung function among the National Danish Fabry cohort was 28%. Patients with classic gene variants frequently developed a decrease in lung function regardless of their smoking status, with significant relationship with disease severity.

Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs).

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.

Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry.

BACKGROUND: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). METHODS: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. RESULTS: Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were -1.18 (Pfrom 0 <0.001) and -0.92 mL/min/1.73 m2/year (Pfrom 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of -2.39 mL/min/1.73 m2/year (Pfrom 0 <0.001; Pdifference = 0.055, as compared with the slope of -1.18 mL/min/1.73 m2/year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. CONCLUSIONS: During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.

Sex difference in patients with controlled acromegaly-A multicentre survey.

OBJECTIVE: Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF-I) patterns as well as clinical features but whether this also pertains to controlled disease is unclear. DESIGN: In a cross-sectional, multi-centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined. METHODS: Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF-I and completion of two HR-Qol questionnaires (acromegaly quality of life questionnaire [AcroQol] and Patient-assessed Acromegaly Symptom Questionnaire [PASQ]). RESULTS: The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF-I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF-I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04). CONCLUSION: In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF-I levels, which also translated into impaired metabolic health and well-being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease-specific sex differences prevail after treatment.

Anti-Müllerian hormone and live birth in unexplained recurrent pregnancy loss.

RESEARCH QUESTION: Is anti-Müllerian hormone (AMH) associated with live birth rate (LBR) in women with unexplained recurrent pregnancy loss (RPL)? DESIGN: Cohort study of women with unexplained RPL attending the RPL Unit, Copenhagen University Hospital, Denmark, between 2015 and 2021. AMH concentration was assessed upon referral, and LBR in the next pregnancy. RPL was defined as three or more consecutive pregnancy losses. Regression analyses were adjusted for age, number of previous losses, body mass index, smoking, treatment with assisted reproductive technology (ART) and RPL treatments. RESULTS: A total of 629 women were included; 507 (80.6%) became pregnant after referral. Pregnancy rates were similar for women with low and high AMH compared to women with medium AMH (81.9, 80.3 and 79.7%, respectively) (low AMH: adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.84-2.47, P = 0.18; high AMH: aOR 0.98, 95% CI 0.59-1.64, P = 0.95). AMH concentrations were not associated with live birth. LBR was 59.5% in women with low AMH, 66.1% with medium AMH and 65.1% with high AMH (low AMH: aOR 0.68, 95% CI 0.41-1.11, P = 0.12, high AMH: aOR 0.96, 95% CI 0.59-1.56, P = 0.87). Live birth was lower in ART pregnancies (aOR 0.57, 95% CI 0.33-0.97, P = 0.04) and with higher numbers of previous losses (aOR 0.81, 95% CI 0.68-0.95, P = 0.01). CONCLUSION: In women with unexplained RPL, AMH was not associated with the chances of live birth in the next pregnancy. Screening for AMH in all women with RPL is not supported by current evidence. The chance of live birth among women with unexplained RPL achieving pregnancy by ART was low and needs to be confirmed and explored in future studies.

Survival and long-term socioeconomic consequences of childhood and adolescent onset of brain tumours.

AIM: To evaluate survival distributions, long-term socioeconomic consequences, and health care costs in patients with childhood and adolescent onset of brain tumours in a Danish nationwide prospective cohort study. METHOD: A search of national registries identified 2283 patients (1198 males, 1085 females; mean age 9 years 6 months [SD 5 years 7 months]) diagnosed with a brain tumour between 1980 and 2015 and aged no older than 18 years at diagnosis. These were compared with sex-, age-, and residency-matched comparison individuals. Patients with malignant tumours were compared with those with benign tumours. Survival distributions were estimated by the Kaplan-Meier method and hazard ratio by the Cox proportional hazard model. Socioeconomic data at age 20 and 30 years were assessed. RESULTS: The probability of mortality was highest during the first year after tumour diagnosis. In young adulthood, the patients were generally less likely to be married, had lower grade-point averages, educational levels, and income, were less likely to be in employment, and had higher health care costs than comparison individuals. Patients with malignant tumours had worse outcomes with respect to education, employment, and health care costs than those with benign tumours. INTERPRETATION: A diagnosis of brain tumour in childhood and adolescence adversely affects survival and has negative long-term socioeconomic consequences, especially in patients with malignant tumours. These patients require continuous social support.

Glucose metabolism, gut-brain hormones, and acromegaly treatment: an explorative single centre descriptive analysis.

PURPOSE: Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment options include surgery, medical therapy with somatostatin analogues (SSA) and Pegvisomant (PEG), and irradiation. The objective of the study was to describe the differential effect of various treatment regimens on the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) in patients with acromegaly. METHODS: 23 surgically treated, non-diabetic patients with acromegaly and 12 healthy controls underwent an oral glucose tolerance test (OGTT) and subsequently isoglycaemic intravenous glucose infusion on a separate day. Baseline hormone concentrations, time-to-peak and area under the curve (AUC) on the OGTT-day and incretin effect were compared according to treatment regimens. RESULTS: The patients treated with SSA (N = 15) had impaired GIP-response (AUC, P = 0.001), and numerical impairment of all other hormone responses (P > 0.3). Patients co-treated with PEG (SSA + PEG, N = 4) had increased secretion of insulin and glucagon compared to patients only treated with SSA (SSA ÷ PEG, N = 11) (insulinAUC mean ± SEM, SSA + PEG 49 ± 8.3 nmol/l*min vs SSA ÷ PEG 25 ± 3.4, P = 0.007; glucagonAUC, SSA + PEG 823 ± 194 pmol/l*min vs SSA ÷ PEG 332 ± 69, P = 0.009). GIP secretion remained significantly impaired, whereas GLP-1 secretion was numerically increased with PEG (SSA + PEG 3088 ± 366 pmol/l*min vs SSA ÷ PEG 2401 ± 239, P = 0.3). No difference was found in patients treated with/without radiotherapy nor substituted or not with hydrocortisone. CONCLUSION: SSA impaired the insulin, glucagon, and incretin hormone secretions. Co-treatment with PEG seemed to counteract the somatostatinergic inhibition of the glucagon and insulin response to OGTT. We speculate that PEG may exert its action through GH-receptors on pancreatic δ-cells. Clinical trial registration NCT02005978.

Effect of near infrared autofluorescence guided total thyroidectomy on postoperative hypoparathyroidism: a randomized clinical trial.

PURPOSE: The purpose of this single-blinded, 2-centre, randomized controlled trial was to test if near-infrared (NIR) autofluorescence image guidance for parathyroid gland (PG) detection during total thyroidectomy can reduce the incidence of hypoparathyroidism in both malignant and benign cases. METHOD: Patients admitted for primary or completion total thyroidectomy were randomized to either the NIR intervention group or the standard care NONIR (no near infrared) group. The primary endpoint was the rate of hypoparathyroidism at the 3-month follow-up, defined as hypocalcemia and inappropriately low parathyroid hormone levels and/or continuous treatment with active vitamin D. The secondary endpoint was the PG identification rate. RESULTS: A total of 147 patients were included of whom 73 were allocated to NIR. Primary or completion thyroidectomy was conducted in 84 and 63 cases, respectively. A total of 130 completed 3 months follow-up. Postoperative hypoparathyroidism in the NIR group at 12 h, 1 month and 3 months was, respectively, 31.8, 14.1, 6.5% compared with 35.9, 18.9, 11.8% in the NONIR group (all p > 0.46). In the NIR group, the identification rate of PGs was 69.5% (146 of 210 PGs), and 9% (19 of 210 PGs) were identified only due to additional use of NIR. For 15 out of 69 patients (21.7%) additionally PGs was found. CONCLUSION: Hypoparathyroidism was nominally less frequent in the NIR group, although not statistically significant. Further studies are needed to confirm if NIR may be a supportive PG identification tool to minimize the number of PG which would have been otherwise missed, especially during more complicated thyroid procedures. TRIAL REGISTRY: ClinicalTrials.gov: NCT04193332. Registration date: 16.08.2019.

Withdrawal of dopamine agonist treatment in patients with hyperprolactinaemia: A systematic review and meta-analysis.

OBJECTIVE: To estimate the proportion of patients with persistent normoprolactinaemia following dopamine agonist (DA) withdrawal and to identify predictors of successful withdrawal in patients with hyperprolactinaemia. DESIGN, PATIENTS, AND MEASUREMENTS: A systematic review of observational eligible studies were identified by searching PubMed and Embase. The primary outcome was the proportion of patients with normoprolactinaemia after cessation of DA treatment. Secondary outcome included the proportion of patients with normoprolactinaemia after DA withdrawal using individual patient data. Risk of bias was assessed by using Newcastle-Ottawa Scale. Pooled proportions were estimated using a random effects model in case I2 ≤ 75% or by reporting range of effects if I2 > 75%. RESULTS: Thirty-two observational studies enroling 1563 patients were included. The proportion of patients with persistent normoprolactinaemia ranged from 0% to 75% (I2 = 84%). Heterogeneity was partly explained by age with more successful withdrawal in patients of higher age. Individual patient data analyses suggested that the proportion of patients with persistent normoprolactinaemia 6 months after DA withdrawal with a low maintenance dose and full regression of the prolactinoma was 87.7% (95% confidence interval [CI] = 60.7-97.1; I2 = 0%) and 58.4% (95% CI = 23.8-86.3; I2 = 75%) for microadenomas and macroadenomas, respectively. CONCLUSIONS: The proportion of patients with persistent normoprolactinaemia following DA withdrawal treatment varied greatly, partly explained by the mean age of participants of the individual studies. Individual patient data analysis suggested that successful withdrawal was likely in patients with full regression of prolactinomas using a low maintenance dose before cessation.

Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort.

INTRODUCTION: Recent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb3) and related analogues, deacylated forms of globotriaosylceramide (Gb3), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease. METHODS: We evaluated Gb3, lyso-Gb3 and analogues using tandem mass spectrometry in 57 women with Fabry disease followed during a period of 15.4 years. Twenty-one women were never treated and 36 received treatment (agalsidase-beta, n=30; agalsidase-alfa, n=5; or migalastat, n=1). Lyso-Gb3 and analogues at m/z (-28), (-2), (+16), (+34) and (+50) were analysed in plasma and urine. Total Gb3 and lyso-Gb3 analogues at m/z (-12) and (+14) were evaluated in urine while the analogue at m/z (+18) was evaluated in plasma. RESULTS: A strong correlation between plasma and urine lyso-Gb3 and analogue levels was revealed. Plasma and urine lyso-Gb3 and analogue levels were not statistically different between patients carrying missense (n=49), nonsense (n=6) or deletion mutations (n=2). Never treated patients had lower plasma lyso-Gb3 and analogues at m/z (-28), (-2), (+16), (+34) and the seven urinary lyso-Gb3 analogues compared with pretreatment levels of the treated patients. A significant reduction of plasma lyso-Gb3 and five analogues, as well as urine Gb3 and six lyso-Gb3 analogues, but not lyso-Gb3 and lyso-Gb3 at m/z (+50), was observed post-treatment with agalsidase-beta. The same tendency was observed with agalsidase-alfa. CONCLUSION: Women with Fabry disease who started treatment based on clinical manifestations had higher lyso-Gb3 and analogue biomarker levels than never treated women. This indicates that a biomarker cut-off could potentially be a decision tool for treatment initiation in women with Fabry disease.

Sex differences in acromegaly at diagnosis: A nationwide cohort study and meta-analysis of the literature.

OBJECTIVE: Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies. DESIGN: A nationwide cohort study including all incident cases of acromegaly (1978-2010, n = 596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed. METHOD: Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated. RESULTS: The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R2  = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF-ISDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females. In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I2  = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable. CONCLUSION: There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay.

Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study.

PURPOSE: Pasireotide is an effective treatment for acromegaly and Cushing's disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. METHODS: Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing's disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. RESULTS: Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was - 0.28% (95% CI - 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. CONCLUSION: Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

Brain tumours in children and adolescents may affect the circadian rhythm and quality of life.

AIM: Children with brain and cervical medulla tumours may experience circadian abnormalities and poor health. We aimed to examine their circadian rhythm, fatigue and quality of life (QoL). METHODS: Children with a brain or cervical medulla tumour were recruited from the Paediatric Department, Rigshospitalet, Copenhagen, Denmark, between 2016 and 2020. They were grouped by tumour location involving the circadian regulatory system, defined as diencephalon, pineal gland, brain stem and cervical medulla, or other areas. Saliva melatonin and cortisol concentrations were measured. Sleep diaries and actigraphy assessed sleep-wake patterns. The Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale measured fatigue and QoL. RESULTS: We included 68 children (62% males) with a median age (25th-75th percentiles) of 12.2 (7.7-16.3) years. Children with tumours involving the circadian regulatory system typically had a lower melatonin peak (p=0.06) and experienced significantly more fatigue and poorer QoL. Low melatonin profiles were observed in 31% and 4% had a phase-shifted daytime peak, compared with 14% and 0%, respectively, in children with tumours located elsewhere. Children with low melatonin profiles had significantly lower inter-daily stability than those with normal profiles. CONCLUSION: Tumours involving the circadian regulatory system adversely affected circadian function, fatigue and QoL.

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study.

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.