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Katrien Benhalima, Paul Van Crombrugge, Carolien Moyson, Johan Verhaeghe, Sofie Vandeginste, Hilde Verlaenen, Chris Vercammen, Toon Maes, Els Dufraimont, Christophe De Block, Yves Jacquemyn, Farah Mekahli, Katrien De Clippel, Annick Van Den Bruel, Anne Loccufier, Annouschka Laenen, Caro Minschart, Roland Devlieger and Chantal Mathieu

Objective

Since many European countries use risk factor screening for gestational diabetes mellitus (GDM), we aimed to determine the performance of selective screening for GDM based on the 2013 WHO criteria.

Design and methods

Overall, 1811 women received universal screening with a 75 g oral glucose tolerance test (OGTT) with GDM in 12.5% (n = 231) women based on the 2013 WHO criteria. We retrospectively applied different European selective screening guidelines to this cohort and evaluated the performance of different clinical risk factors to screen for GDM.

Results

By retrospectively applying the English, Irish, French and Dutch guidelines for selective screening, respectively 28.5% (n = 526), 49.7% (n = 916), 48.5% (n = 894) and 50.7% (n = 935) had at least one risk factor, with GDM prevalence of respectively 6.5% (n = 120), 7.9% (n = 146), 8.0% (n = 147) and 8.4% (n = 154). Using maternal age ≥30 and/or BMI ≥25 for screening, positive rate was 69.9% (n = 1288), GDM prevalence 10.2% (n = 188), sensitivity 81.4% (CI: 75.8–86.2%) and specificity 31.8% (CI: 29.5–34.1%). Adding other clinical risk factors did not improve detection. GDM women without risk factors had more neonatal hypoglycemia (14.4 vs 4.0%, P = 0.001) and labor inductions (39.7 vs 25.9%, P = 0.020) than normal-glucose tolerant women, and less cesarean sections than GDM women with risk factors (13.8 vs 31.0%, P = 0.010).

Conclusions

By applying selective screening by European guidelines, about 50% of women would need an OGTT with the lowest number of missed cases (33%) by the Dutch guidelines. Screening with age ≥30 years and/or BMI ≥25, reduced the number of missed cases to 18.6% but 70% would need an OGTT.

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Elodie Fiot, Delphine Zénaty, Priscilla Boizeau, Jérémie Haignere, Sophie Dos Santos, Juliane Léger and the French Turner Syndrome Study Group

Objective

Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.

Design and methods

This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).

Results

Median age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders.

Conclusion

These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.

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Esben Thyssen Vestergaard, Niels Moller, René Frydensbjerg Andersen, Søren Rittig and Jens Otto L. Jorgensen

Objective

Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies.

The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients.

Design

Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double blind and placebo controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analogue Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis, and urinary excretion of sodium and creatinine were measured.

Results

In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time x treatment Analysis of Variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water.

Conclusions

We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

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Sergio Valdés, Viyey Doulatram-Gamgaram, Ana Lago, Francisca García Torres, Rocío Badía-Guillén, Gabriel Olveira, Albert Goday, Alfonso Calle-Pascual, Luis Castaño, Conxa Castell, Elías Delgado, Edelmiro Menendez, Josep Franch-Nadal, Sonia Gaztambide, Joan Girbés, Ramón Gomis, Emilio Ortega, José L Galán-García, Gabriel Aguilera-Venegas, Federico Soriguer and Gemma Rojo-Martínez

Objective

The activity of brown adipose tissue is sensitive to changes in ambient temperature. A lower exposure to cold could result in an increased risk of developing diabetes at population level, although this factor has not yet been sufficiently studied.

Design

We studied 5072 subjects, participants in a national, cross-sectional population-based study representative of the Spanish adult population (Di@bet.es study). All subjects underwent a clinical, demographic and lifestyle survey, a physical examination and blood sampling (75 g oral glucose tolerance test). Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). The mean annual temperature (°C) in each individual municipality was collected from the Spanish National Meteorology Agency.

Results

Linear regression analysis showed a significant positive association between mean annual temperature and fasting plasma glucose (β: 0.087, P < 0.001), 2 h plasma glucose (β: 0.049, P = 0.008) and HOMA-IR (β: 0.046, P = 0.008) in multivariate adjusted models. Logistic regression analyses controlled by multiple socio-demographic variables, lifestyle, adiposity (BMI) and geographical elevation showed increasing odds ratios for prediabetes (WHO 1999), ORs 1, 1.26 (0.95–1.66), 1.08 (0.81–1.44) and 1.37 (1.01–1.85) P for trend = 0.086, diabetes (WHO 1999) ORs 1, 1.05 (0.79–1.39), 1.20 (0.91–1.59) and 1.39 (1.02–1.90) P = 0.037, and insulin resistance (HOMA-IR ≥75th percentile of the non-diabetic population): ORs 1, 1.03 (0.82–1.30), 1.22 (0.96–1.55), 1.26 (0.98–1.63) (P for trend = 0.046) as the mean annual temperature (into quartiles) rose.

Conclusions

Our study reports an association between ambient temperature and the prevalence of dysglycemia and insulin resistance in Spanish adults, consistent with the hypothesis that a lower exposure to cold could be associated with a higher risk of metabolic derangements.

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Mirela Diana Ilie, Véronique Raverot, François Tronc, Alexandre Vasiljevic, Francoise Borson-Chazot and Gerald Raverot

Context: Cabergoline has been shown to have some effect in the treatment of moderate Cushing’s disease, but its effectiveness in Cushing’s syndrome of ectopic or occult origin remains to be investigated.

Case series: In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing’s syndrome of ectopic or occult origin. Cabergoline’s effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases.

Review of the literature: In the literature, we found only 11 cases of ectopic or occult Cushing’s syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded.

Conclusions: Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing’s syndrome.

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Orit Twito, Simona Grozinsky-Glasberg, Sigal Levy, Gideon Bachar, David Gross, Carlos A Benbassat, Alon Rozental and Dania Hirsch

Objective: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short and long-term disease outcomes in sporadic and familial MTC.

Methods: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1-year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality.

Results: The study enrolled 193 patients (mean age 48.9±18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1±9.4 years (8.5±8.1 in sporadic and 16.9±11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1% and 60.4% patients, respectively. All-cause and DRM were 28.5% and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1-year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, p<0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, p<0.001).

Conclusions: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision-making.

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Katharina Schilbach, Christina Gar, Andreas Lechner, Shiva Sophia Nicolay, Laura Schwerdt, Michael Haenelt, Jakob Dal, Jens Otto L. Jorgensen, Sylvere Störmann, Jochen Schopohl and Martin Bidlingmaier

Objective: Growth hormone (GH) nadir (GHnadir) during oral glucose tolerance test (OGTT) is an important tool in diagnosing acromegaly, but data evaluating the need to adjust cut-offs to biological variables utilizing todays assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22kD-GH specific assay.

Design: Multicenter study with prospective and retrospective cohorts (525 healthy adults; 405 females, 120 males).

Methods: GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75g glucose.

Results: GHnadir concentrations (µg/L) were significantly higher in lean and normal weight subjects (group A) compared to overweight and obese subjects (group B); (males (M): A vs. B, mean: 0.124 vs. 0.065, P=0.0317; premenopausal females without estradiol-containing OC (OC-EE) (FPRE): A vs. B, mean: 0.179 vs. 0.092, P<0.0001; postmenopausal women (FPOST): A vs. B, mean: 0.173 vs. 0.078, P<0.0061). Age, glucose metabolism and menstrual cycle had no impact on GHnadir. However, premenopausal females on OC-EE (FPREOC) exhibited significantly higher GHnadir compared to all other groups (all P<0.0001). BMI had no impact on GHnadir in FPREOC (A vs. B, mean: 0.624 vs. 0.274, P=0.1228).

Conclusions: BMI, sex and OC-EE intake are the major determinants for the GHnadir during OGTT in healthy adults. Using a modern sensitive GH assay, GHnadir concentrations in healthy subjects are distinctly lower than cut-offs used in previous guidelines for diagnosis and monitoring of acromegaly.

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Nicole Prinz, Katja Konrad, Christoph Brack, Eva Hahn, Antje Herbst, Andrea Icks, Juergen Grulich-Henn, Norbert Jorch, Christian Kastendieck, Kirsten Mönkemöller, Oliver Razum, Claudia Seigleder-Schweiger, Michael Witsch and Reinhard Holl

Objective: With increasing migration to Europe, diabetes diagnosis and treatment of refugees became challenging. To describe current experience with pediatric refugees in Germany and Austria.

Design and Methods: 43,137 patients (<21 years) with type 1 diabetes from the diabetes patient follow-up registry (DPV) were studied, and divided by refugee status into patients born in Middle East (n=365) or Africa (n=175) and native patients (child and parents born in Germany/Austria; G/A: n=42,597). Groups were compared using multivariable regression adjusted for age, sex and diabetes duration (SAS 9.4). In refugees the first year after arrival was studied, and for native children the most recent year of care.

Results: After adjustment, HbA1c was highest in refugees (ME vs. AFR vs. G/A: 72.3±1.0 vs. 75.0±1.4 vs. 66.0±0.1 mmol/mol, each p<0.001) and microalbuminuria (9.9 vs 13.6 vs. 6.5%, each p<0.05) was more prevalent. African children experienced severe hypoglycemia (17.8±4.3 vs. 25.4±8.7 vs. 11.5±0.3 per 100 patient years) significantly more often, whereas hypoglycemia with coma (5.1±1.1 vs. 4.1±1.6 vs. 2.6±0.1 per 100 patient years) and retinopathy (2.1 vs. n/a vs. 0.2%) were significantly more common in children from Middle East compared to natives. Insulin pumps were used in a markedly larger proportion of native patients (7.4 vs. 13.2 vs. 43.0%, each p<0.001).

Conclusions: A relevant number of pediatric refugees with type 1 diabetes are treated in German/Austrian diabetes clinics. Refugee children, parents and caregivers are faced with several problems in diabetes therapy and outcome that should be addressed more intensively by pediatric diabetes teams.

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Mario Rotondi, Andrea Carbone, Francesca Coperchini, Rodolfo Fonte and Luca Chiovato

IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel’s thyroiditis, Hashimoto’s thyroiditis and its fibrotic variant, Graves’ disease and Graves’ orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.

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QiChang Wan, Lin Bai, Gege Zhao, Youjia Zhang, Qingjie Ma, Renjie Wang and Bin Ji

Purpose: To evaluate the accuracy of 18F-FDG-PET/CT for detection of recurrent and/or metastatic diseases in differentiated thyroid cancer (DTC) patients with thyroglobulin elevation and negative iodine scintigraphy. Whether PET/CT with TSH stimulation (sPET/CT) had better diagnostic performance than PET/CT without TSH stimulation (nsPET/CT) in this scenario was also evaluated.

Methods: PubMed and Embase was searched for eligible studies from January 2001 to December 2018. Only studies with clearly stated reference standard (histopathology confirmation and/or clinical/imaging follow-up) were included. Publication bias was assessed by funnel plot. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristics curve (AUC) for PET/CT was determined by random-effect analysis, respectively. sPET/CT and nsPET/CT was compared pair-wisely for all diagnostic estimate indexes using Z-test.

Results: We included 17 studies with 1195 patients in this meta-analysis. The pooled sensitivity, specificity, DOR, and AUC for PET/CT on patient-based data were 0.86 (95% CI; 0.79-0.91), 0.84 (95% CI; 0.72-0.91), 31.00 (95% CI; 12.00-80.00), and 0.91 (95% CI; 0.88-0.93), respectively. There was high heterogeneity (I2=80% for sensitivity, I2=82% for specificity) and possible publication bias (P=0.01). Z-test did not detect statistically significant difference between sPET/CT and nsPET/CT for all the diagnostic estimate indexes (All P>0.05).

Conclusions: On patient-based analysis, 18-FDG-PET/CT has high diagnostic accuracy for detection of recurrent and/or metastatic diseases in DTC patients with thyroglobulin elevation and negative iodine scintigraphy, but existing studies were limited by high heterogeneity and possible publication bias. The diagnostic performance of sPET/CT may be not superior to nsPET/CT.