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Urszula Razny, Anna Polus, Joanna Goralska, Anna Zdzienicka, Anna Gruca, Maria Kapusta, Maria Biela, Aldona Dembinska-Kiec, Bogdan Solnica and Malgorzata Malczewska-Malec

Objective

To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance.

Design

Cross-sectional study.

Methods

Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls.

Results

Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling – β catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load.

Conclusions

Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.

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Elena Valassi, Antoine Tabarin, Thierry Brue, Richard A Feelders, Martin Reincke, Romana Netea-Maier, Miklós Tóth, Sabina Zacharieva, Susan M Webb, Stylianos Tsagarakis, Philippe Chanson, Marija Pfeiffer, Michael Droste, Irina Komerdus, Darko Kastelan, Dominique Maiter, Olivier Chabre, Holger Franz, Alicia Santos, Christian J Strasburger, Peter J Trainer, John Newell-Price, Oskar Ragnarsson and the ERCUSYN Study Group

Objective

Patients with Cushing’s syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality.

Methods

In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2–5.5) years.

Results

Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment.

Conclusion

Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.

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Ana Claudia Keselman, Ayelen Martin, Paula Alejandra Scaglia, Nora María Sanguineti, Romina Armando, Mariana Gutiérrez, Débora Braslavsky, María Gabriela Ballerini, María Gabriela Ropelato, Laura Ramirez, Estefanía Landi, Sabina Domené, Julia F Castro, Hamilton Cassinelli, Bárbara Casali, Graciela del Rey, Ángel Campos Barros, Julián Nevado Blanco, Horacio Domené, Héctor Jasper, Claudia Arberas, Rodolfo A Rey, Pablo Lapunzina-Badía, Ignacio Bergadá and Patricia A Pennisi

Background

IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation.

Results

We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from −1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth.

Conclusion

The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.

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S Kos, C M Cobbaert, T M Kuijper, W Oostdijk, S E Hannema, J M Wit, N Biermasz and B E P B Ballieux

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Seung Hyun Ko, Kyung Do Han, Jae Seung Yun, Sungjin Chung and Eun Sil Koh

Objective

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide and are both associated with the increased incidence of kidney and bladder cancers. However, previous reports have provided conflicting results. We investigated the impact of body mass index (BMI) and diabetes on the incidence of both cancers in the general population.

Methods

Using nationally representative data from the Korean National Health Insurance System, 9,777,133 subjects without any malignancy who underwent health examinations in 2009 were followed to the end of 2017.

Results

After a median follow-up period of 8.32 years, 12,544 incidents of kidney cancer and 15,137 incidents of bladder cancer were identified. The hazard ratio (HR) for kidney cancer was the lowest in people with a BMI <18.5 kg/m2 (HR: 0.82, 95% confidence interval (CI): 0.72–0.94) and the highest in those with a BMI ≥30 kg/m2 (HR: 1.71, 95% CI: 1.57–1.87) compared to a reference BMI group (18.5–23 kg/m2). In subjects with diabetes, obesity was associated with increased risk of kidney cancer, although the HRs were lower than observed in those without diabetes. Otherwise, there was a reduction in risk of bladder cancer with obesity in men and the HR for bladder cancer was not affected by BMI increase in women. There was a strongly positive association between diabetes and bladder cancer in the total study population.

Conclusions

Obesity was a strong risk factors for kidney cancer, whereas the association between obesity and bladder cancer differed by gender. The subjects with diabetes had a higher risk for both cancers than those without diabetes.

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Lee S Nguyen, Nathalie Rouas-Freiss, Christian Funck-Brentano, Monique Leban, Edgardo D Carosella, Philippe Touraine, Shaida Varnous, Anne Bachelot and Joe-Elie Salem

Background

HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represents an adequate model to study the hormonal influence on biomarkers as it leads to impaired cortisol biosynthesis and increased progesterone and androgens production due to 21-hydroxylase enzyme deficiency.

Methods

In a cross-sectional study of CAH patients matched on sex and age with healthy control, the association between circulating levels of soluble HLA-G and hormones was assessed by use of non-parametric analyses tests. Multivariable linear regressions were performed on normalized data.

Results

Overall, 83 CAH patients and 69 healthy controls were included. Among CAH patients, all were under glucocorticoid and 52 (62.6%) were under mineralocorticoid supplementation. Compared to controls, CAH patients had increased HLA-G levels (15 vs 8 ng/mL, P = 0.02). In controls, HLA-G level was independently associated with progesterone and estradiol (β = 0.44 (0.35–1.27) and −0.44 (−0.94, −0.26) respectively, both P values = 0.001). In CAH patients, HLA-G level was independently associated with mineralocorticoid supplementation dosage (β = 0.25 (0.04–0.41), P = 0.001) and estradiol (β = −0.22 (−0.57, −0.02), P < 0.001).

Conclusion

CAH patients had higher HLA-G levels than healthy controls. HLA-G level was positively associated with progesterone and corticosteroid supplementation, and negatively with estradiol. The association between mineralocorticoid, renin and HLA-G levels may suggest a role of the renin-angiotensin system in the expression of soluble HLA-G.

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Kirstie Lithgow, Ruchika Batra, Tim Matthews and Niki Karavitaki

Visual dysfunction is an important element in the morbidity encountered in patients with pituitary adenoma leading to functional impairment and compromised quality of life. It consists of many parameters (even in the absence of reported symptomatology) as a result of tumour growth in proximity to structures critical for vision (anterior visual pathway, cranial nerves within cavernous sinuses), and as an adverse consequence of therapeutic interventions. Adenoma resection leads to high rates of visual improvement and possibly continues beyond a year post surgery, but the exact timing of maximum effect requires elucidation. Retinal nerve fibre layer measurement may be a reliable, objective parameter predicting favourable visual outcomes, although its prognostic value when pathological, needs to be confirmed. For compromised vision after pituitary apoplexy, early surgical decompression remains usual practice until evidence-based guidance becomes available. The risk of radiation-induced visual toxicity is mainly influenced by total and per fraction dose of radiation and treatment modality. Careful selection of cases and of radiotherapy technique/planning are of major importance in minimising this risk. Dopamine agonists lead to visual recovery in a considerable number of prolactinoma patients. Visual morbidity should be considered a vital indicator in the metrics of quality of service/care in pituitary disease making regular, full ophthalmic examination an essential component of modern management of pituitary pathology at all time points of patient pathway. Well-designed studies minimising effects of bias and using tools and scoring systems reliably reflecting visual status will provide robust evidence on valid prognostication and patient stratification guiding clinical decision making.

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F Bolfi, A F Neves, C L Boguszewski and V S Nunes-Nogueira

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Irene Campi, Giovanni B Perego, Antonella Ravogli, Antonella Groppelli, Gianfranco Parati, Luca Persani and Laura Fugazzola

Objectives

Amiodarone-induced thyrotoxicosis (AIT) affects up to 3% of treated patients. Type 2 AIT (AIT2) is a destructive thyroiditis and is usually treated with medium-high oral doses of prednisone. As AIT may worsen the underlying heart disease, a rapid control of thyroid function is desirable. We aimed to determine whether a combined intravenous methylprednisolone (IVMP) pulses therapy associated to prednisone in the interpulse period can represent an efficient and safe alternative to urgent total thyroidectomy in patients with AIT2 not responsive to prednisone alone.

Design and methods

Patients presenting with a severe AIT2 studied in a tertiary referral Center from August 2018 to April 2019. We included four patients requiring a rapid improvement of thyroid function for their underlying cardiac disorders. The baseline doses of oral prednisone (range: 5–12.5 mg/day) and IVMP (range: 250–500 twice a week) were determined according to the severity of the thyrotoxicosis and were titrated based on clinical response.

Results

Combined treatment was effective in all patients in the prompt restoration of euthyroidism and no major adverse events were reported during the follow-up. In all cases, FT4 and FT3 levels normalized at 3–5 weeks of treatment. A permanent hypothyroidism was observed in one patient, 3 months after the discontinuation of treatment.

Conclusions

We report for the first time that the combined intravenous and oral steroid therapy is effective in patients with AIT2. The treatment is well tolerated and leads to a rapid improvement of thyroid function, avoiding urgent total thyroidectomy and favoring a quick functional recovery and rehabilitation of cardiac patients.

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Ravi Kumar Dutta, Thomas Arnesen, Anette Heie, Martin Walz, Piero Alesina, Peter Söderkvist and Oliver Gimm

Objective

To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs).

Description

Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured.

Conclusion

In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.