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Samuel Backman, Duska Bajic, Joakim Crona, Per Hellman, Britt Skogseid and Peter Stålberg

Objective: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1.

Design: Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included.

Methods: Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model.

Results: Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson’s two-hit model.

Conclusion: These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

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Jaap Deinum, Hans Groenewoud, Gert Jan van der Wilt, Livia Lenzini and Gian Paolo Rossi

Notwithstanding the high prevalence of primary aldosteronism (PA), probably the most common form of secondary hypertension, the diagnosis of PA is often neglected or delayed, thus precluding target treatment, which is curative in many cases. For selection of the most appropriate treatment, a fundamental step is the distinction between a lateralized form, mainly aldosterone-producing adenoma (APA), and bilateral adrenocortical hyperplasia (BAH), also known as idiopathic hyperaldosteronism (IHA). To this aim all current guidelines recommend adrenal vein sampling (AVS), a technically challenging procedure that often fails, particularly in non-experienced hands. Cosyntropin (synthetic ACTH) is administered in the attempt to maximize adrenal cortisol secretion and avoid pulsatile adrenocortical hormone secretion in about 40% of the referral centres around the world. However, the Endocrine Society guidelines do not advise about the use or not of cosyntropin as stimulus during AVS, as there are arguments in favour and against its use. These arguments are presented in this debate article reflecting the views of groups that currently use and do not use cosyntropin.

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Muhamad Badarna, Ruth Percik, Genya Aharon-Hananel, Inbal Uri and Amit Tirosh

Objective

Patients with pancreatic neuroendocrine tumors (PNET) have variable prognosis, even with comparable tumor grade and stage. In the current study we aimed to evaluate the prognostic utility of the intrapancreatic PNET anatomical site.

Design

Cohort study based on the Surveillance Epidemiology and End Results database.

Methods

Patients diagnosed with non-functioning PNET between 2004 and 2015 were compared by anatomic site for disease-specific mortality and all-cause mortality, using log-rank test and by multivariable cox regression analysis.

Results

Overall, 4171 patients (1839 women (44.1%), median age strata 60–64 years, range 10–14 to ≥85 years) were included in our analysis. Patients with PNETs located at the head vs body/tail of the pancreas had comparable tumor diameter, as well as ethnicity, gender and age distributions, but had higher rates of grade III and IV NET (13.2 vs 6.6% and 4.4 vs 1.9%, respectively, P < 0.001). NETs located at the head vs body/tail of pancreas were more likely to be locally advanced (32.2 vs 19.9%) with no difference in distant metastases (36.4 vs 33.5%, respectively, P < 0.001). Patients with NETs of the head vs. body/tail of the pancreas had higher disease-specific mortality risk in univariate (log-rank test, P < 0.001) and multivariable analysis (hazard ratio (HR): 1.34, 95% confidence interval: 1.10–1.65, P = 0.004). Multivariable analysis for all-cause mortality also showed increased risk for patients with pancreatic head vs. body/tail PNET (HR: 1.23, P = 0.013).

Conclusions

PNET anatomical location is associated with the mortality risk and should be considered as a prognostic factor, and as an additional consideration in directing patients management.

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Shunming Zhang, Yeqing Gu, Liu Wang, Qing Zhang, Li Liu, Min Min Lu, Ge Meng, Zhanxin Yao, Hongmei Wu, Yang Xia, Xue Bao, Honglei Wang, Hongbin Shi, Shaomei Sun, Xing Wang, Ming Zhou, Qiyu Jia, Kun Song, Huiling Xiang and Kaijun Niu

Background and Aims: The protective effect of garlic against nonalcoholic fatty liver disease (NAFLD) has been reported in animal studies. However, in humans, the association between garlic consumption and NAFLD are unclear. The study sought to explore the association between habitual raw garlic intake and newly diagnosed NAFLD among Chinese adults.

Methods: We performed a study of 11,326 men and 12,780 women aged 20 to 90 years. Habitual food intake was assessed using a validated and standardized 100-item food frequency questionnaire. Diagnosis of NAFLD was based on the liver ultrasonography and self-reported alcohol intake. Multiple logistic regression was used to evaluate the association of raw garlic intake with newly diagnosed NAFLD.

Results: The prevalence of newly diagnosed NAFLD was 28.9% in men and 10.1% in women, respectively. In men, the fully adjusted odds ratios (95% confidence interval) of having NAFLD across increasing frequency of raw garlic intake were 1.00 (reference) for 〈1 time/week, 0.81 (0.73, 0.90) for 1-3 times/week, 0.66 (0.54, 0.80) for 4-6 times/week, and 0.71 (0.55, 0.90) for ≥7 times/week (P for trend 〈 0.0001). The odds ratio for NAFLD associated with each 1 g of raw garlic/1000 kcal was 0.93 (0.90, 0.97) in men. In women, no significant association between raw garlic intake and NAFLD was identified. These associations between raw garlic intake and NAFLD were consistent in several sensitivity analyses.

Conclusions: Frequent consumption of raw garlic is inversely associated with NAFLD in Chinese men. Further investigations are needed to confirm this finding.

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Giulia Gava, Ilaria Mancini, Isabella Orsili, Silvano Bertelloni, Stefania Alvisi, Renato Seracchioli and Maria Cristina Meriggiola

Objectives. To assess bone health in adult women with complete androgen insensitivity syndrome (CAIS) and removed gonads compared with age-matched healthy controls. To evaluate the effects of transdermal estradiol 2 mg or oral estradiol valerate 2 mg on bone, biochemical and clinical characteristics. Design. Cohort study. Methods. Bone, body composition and anthropometric parameters were assessed in 32 adult CAIS and 32 healthy controls. In 28 CAIS evaluations of metabolic, bone and body composition were performed also after a maximum of six years of therapy. Results. Lumbar, femoral and total body bone mineral density (BMD) were significantly lower in those with CAIS when compared with controls. The prevalence of vertebral osteoporosis and osteopenia was significantly higher in the CAIS group (p=0.038 OR=9.67, 95% CI 1.13-82.83 and p=0.012 OR 3.85, 95% CI 1.34-11.16, respectively). Prevalence of femoral osteopenia was significantly higher in the CAIS group (p=0.0012, OR=7.93 95% CI 2.26-27.9). During follow-up, lumbar BMD significantly increased suggesting a significant effect of treatment on BMD (p=0.0016), while femoral and total body BMD did not show any significant change. Total body BMD values were positively associated to the duration and route of estrogen administration and to serum estradiol levels. Transdermal administration of estrogens was associated with better total body BMD in comparison to oral administration. Conclusions. Our results reinforce the importance of adequate hormonal treatment in women living with CAIS, suggesting a better effect from the transdermal route over the oral route.

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Katrine Hygum, Jakob Starup-Linde, Torben Harsløf, Niklas Rye Jørgensen, Bolette Hartmann, Jens Juul Holst and Bente L Langdahl

Objective

Bone turnover has a diurnal variation influenced by food intake, incretin hormones, the sympathetic nervous system and osteocyte function. The aim of the study was to compare diurnal variation in bone turnover in patients with diabetes and controls.

Design

A clinical 24-h study with patients with type 1 diabetes (n = 5), patients with type 2 diabetes (n = 5) and controls (n = 5).

Methods

Inclusion criterion: age >50 years. Exclusion criteria: diseases/medication that affect bone metabolism or recent use of incretin-based drugs. We drew blood samples hourly during the day and every 3 h during the night. We served an identical diet on all study days. We used repeated-measures one-way ANOVA to compare the levels of the investigated markers, and we quantified the effect of time by comparing group mean standard deviations.

Results

The bone formation marker procollagen type 1 N-terminal propeptide showed a significant interaction between time and group (P = 0.01), and the mean standard deviation was lower in patients with type 2 diabetes compared with controls (P = 0.04) and patients with type 1 diabetes (P = 0.02). Other markers of bone formation and resorption showed significant effect of time. Levels of glucagon-like peptide-2, glucose-dependent insulinotropic peptide and sclerostin only showed significant effect of time (all P values 0.01), but levels of sclerostin tended to being highest in type 2 diabetes and lowest in controls.

Conclusions

The diurnal variation in bone formation is attenuated in patients with type 2 diabetes. This is not explained by changes in incretin hormone levels, but possibly mediated by sclerostin.

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Patricia Lemieux, S John Weisnagel, Annabelle Z Caron, Anne-Sophie Julien, Anne-Sophie Morisset, Anne-Marie Carreau, Jonathan Poirier, André Tchernof, Julie Robitaille, Jean Bergeron, André Marette, Marie-Claude Vohl and Claudia Gagnon

Objective

To determine whether vitamin D3 supplementation improves insulin sensitivity, using the hyperinsulinemic-euglycemic clamp.

Design

This single-centre, double-blind, placebo-controlled trial randomised 96 participants at high risk of diabetes or with newly diagnosed type 2 diabetes to vitamin D3 5000 IU daily or placebo for 6 months.

Methods

We assessed at baseline and 6 months: (1) primary aim: peripheral insulin sensitivity (M-value using a 2-h hyperinsulinemic-euglycemic clamp); (2) secondary aims: other insulin sensitivity (HOMA2%S, Matsuda) and insulin secretion (insulinogenic index, C-peptide area under the curve, HOMA2-B) indices using a 2-h oral glucose tolerance test (OGTT); β-cell function (disposition index: M-value × insulinogenic index); fasting and 2-h glucose post OGTT; HbA1c; anthropometry.

Results

Baseline characteristics were similar between groups (% or mean ± s.d.): women 38.5%; age 58.7 ± 9.4 years; BMI 32.2 ± 4.1 kg/m2; prediabetes 35.8%; diabetes 20.0%; 25-hydroxyvitamin D (25(OH)D) 51.1 ± 14.2 nmol/L. At 6 months, mean 25(OH)D reached 127.6 ± 26.3 nmol/L and 51.8 ± 16.5 nmol/L in the treatment and placebo groups, respectively (P < 0.001). A beneficial effect of vitamin D3 compared with placebo was observed on M-value (mean change (95% CI): 0.92 (0.24–1.59) vs −0.03 (−0.73 to 0.67); P = 0.009) and disposition index (mean change (95% CI): 267.0 (−343.4 to 877.4) vs −55.5 (−696.3 to 585.3); P = 0.039) after 6 months. No effect was seen on other outcomes.

Conclusions

In individuals at high risk of diabetes or with newly diagnosed type 2 diabetes, vitamin D supplementation for 6 months significantly increased peripheral insulin sensitivity and β-cell function, suggesting that it may slow metabolic deterioration in this population.

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Yempabou Sagna, Carine Courtillot, Joseph Y Drabo, Abdellatif Tazi, Jean Donadieu, Ahmed Idbaih, Fleur Cohen, Zahir Amoura, Julien Haroche and Philippe Touraine

Objective

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH.

Design

Single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital.

Method

Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients: 40, CO patients: 23). Fifty-eight patients underwent follow-up assessments.

Results

Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least one anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (P = 0.003) but was not systematically associated with DI regardless of the age of onset. Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up.

Conclusion

The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.

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Giuseppa Patti, Saverio Scianguetta, Domenico Roberti, Alberto Di Mascio, Antonio Balsamo, Milena Brugnara, Marco Cappa, Maddalena Casale, Paolo Cavarzere, Sarah Cipriani, Sabrina Corbetta, Rossella Gaudino, Lorenzo Iughetti, Lucia Martini, Flavia Napoli, Alessandro Peri, Maria Carolina Salerno, Roberto Salerno, Elena Passeri, Mohamad Maghnie, Silverio Perrotta and Natascia Di Iorgi

Background

Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone.

Aim

To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus.

Patients and methods

We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating.

Results

Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype–phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case.

Conclusion

adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

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Kristina Laugesen, Jens Otto Lunde Jørgensen, Irene Petersen and Henrik Toft Sørensen

Objective

Glucocorticoid treatment of inflammatory disorders is associated with significant adverse effects related to glucocorticoid excess as well as adrenal insufficiency. This necessitates awareness of its use. We therefore investigated trends in systemic glucocorticoid use as well as morbidity and comedications among users.

Design

Cross-sectional drug utilisation study.

Methods

We conducted a population-based study of 926,314 users of systemic glucocorticoids (oral and injectable formulations) from 1999 to 2014 using Danish nationwide registries. We computed annual prevalence and incidence of systemic glucocorticoid use and prevalence of comedications and morbidity. Further, we assessed the annual amount of disease-modifying drug use.

Results

Of the 926,314 users of systemic glucocorticoids, 54% were female and median age at first-time use was 55 years. The annual prevalence was ≈ 3%, while the incidence was ≈ 1.4/100 person years (p-y). Both figures remained constant from 1999 to 2014. In the elderly, the annual prevalence was 6.7–7.7% (60–79 years of age) and 9.7–11% (≥80 years of age). Incidence increased among persons aged ≥80 years from 3.0/100 p-y in 1999 to 3.6/100 p-y in 2014. Concomitantly, the annual amount of for example methotrexate, azathioprine and tumour necrosis factor (TNF)-alpha agents increased and new biological agents emerged. The most frequent comedications were antibiotics (49%), cardiovascular drugs (38%) and NSAIDs (37%).

Conclusions

Our findings confirm a widespread use of systemic glucocorticoids, especially in the elderly, which prevails despite increased use of disease-modifying drugs. The continuously prevalent use of glucocorticoid use constitutes a challenge for the endocrine community.