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Alex Faje, Kerry Reynolds, Leyre Zubiri, Donald Lawrence, Justine Cohen, Ryan Sullivan, Lisa B Nachtigall and Nicholas Tritos

Objective: Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients, and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI, and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients.

Design and methods: We conducted a multi-center retrospective review utilizing the Research Patient Database registry to evaluate individuals diagnosed with hypophysitis following treatment with nivolumab/pembrolizumab (n=22), ipilimumab (n=64), and combo (n=20). Encounter notes, radiologic imaging, and laboratory results for these patients were comprehensively reviewed.

Results: Hypophysitis was rare following treatment with nivolumab/pembrolizumab (0.5%, 17/3,522) compared to ipilimumab (13.6%, 34/250), p <0.0001. Hypophysitis was diagnosed later in nivolumab/pembrolizumab (median 25.8 weeks, interquartile range[IR] 18.4-44.0) compared to ipilimumab (9.3, IR 7.2-11.1) or combo patients (12.5, IR 7.4-18.6), p <0.0001 for both. Headache and pituitary enlargement occurred less commonly in nivolumab/pemrolizumab patients (23% and 5/18, respectively) compared to ipilimumab (75%, 60/61) and combo (75%, 16/17) treatment groups (p<0.0001 versus ipilimumab and p=0.001 versus combo for headache and p<0.0001 for both for enlargement).

Conclusions: This study represents the first comprehensive cohort analysis of nivolumab or pembrolizumab-associated hypophysitis in a large patient group. Hypophysitis occurs rarely with these medications, and these patients have a distinct phenotype compared to hypophysitis after treatment with ipilimumab or ipilimumab plus nivolumab.

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Leonie H.a. Broersen, Femke M. Van Haalen, Tina Kienitz, Olaf Dekkers, Christian J Strasburger, Alberto M Pereira and N R Biermasz

Background: Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing’s syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown.

Methods: Cohort study including consecutive patients with Cushing’s syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000-2015. We summarized incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence, and assessed the effect of better education in time on incidence of adrenal crisis.

Results: We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval [CI]: 6.7-12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2-4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies.

Conclusions: The incidence of adrenal crises after treatment for Cushing’s syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing’s syndrome, which is probably the period of severest HPA-axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.

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Dong Hyun Sinn, Danbee Kang, Soo Jin Cho, Seung Woon Paik, Eliseo Guallar, Juhee Cho and Geum-Youn Gwak

Objective: Non-alcoholic fatty liver disease (NAFLD), a condition associated with multiple metabolic abnormalities, is frequently observed in normal weight individuals (lean NAFLD). The metabolic consequences of lean NAFLD, however, are not well characterized. Thus, this study aimed to evaluate the risk of incident diabetes in lean NAFLD.

Methods: This is a cohort study of 51,463 adults without diabetes, history of liver disease or cancer at baseline who participated in a regular health screening exam. Fatty liver was diagnosed by ultrasonography. The study outcome was the development of diabetes during follow-up.

Results: During 236,446.6 person-years of follow-up (median follow-up of 4.0 years), 5,370 participants developed diabetes. In fully-adjusted models, the hazard ratios (HRs) for incident diabetes comparing lean participants with NAFLD, overweight/obese participants without NAFLD, and overweight/obese participants with NAFLD to lean participants without NAFLD, were 1.18 (95% CI 1.03–1.35), 1.06 (0.98–1.14), and 1.45 (1.34–1.57), respectively. The fully-adjusted HR for incident diabetes for lean NAFLD participants with low NAFLD fibrosis score (NFS) (〈-1.455) and with intermediate to high NFS (≥-1.455) compared to lean participants without NAFLD were 1.32 (1.14–1.53) and 2.73 (2.10–3.55), respectively.

Conclusions: In this large cohort study, the presence and severity of NAFLD in normal-weight adults was associated with an increased incidence of diabetes independently of established risk factors. Indeed, isolated lean NAFLD was a stronger risk factor for incident diabetes than the presence of overweight/obesity without NAFLD. Subjects with lean NAFLD require careful monitoring for the development of metabolic abnormalities.

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Jens Bollerslev, Camilla Schalin-Jantti, Lars Rejnmark, Heide Siggelkow, Hans Morreau, Rajesh V Thakker, Antonio Sitges-Serra, Filomena Cetani and Claudio Marcocci

PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed.

PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the

natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy.

HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy.

Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field.

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Chin-Hsiao Tseng

Background

Whether metformin might affect the risk of benign nodular goiter in patients with type 2 diabetes mellitus has not been investigated.

Methods

Patients with new-onset type 2 diabetes mellitus during 1999–2005 were enrolled from Taiwan’s National Health Insurance database. Analyses were conducted in a propensity score matched-pairs of 20,048 ever users and 20,048 never users of metformin. The patients were followed until December 31, 2011, for the incidence of benign nodular goiter. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the propensity score.

Results

Among the never users and ever users of metformin, 392 and 221 cases were diagnosed of benign nodular goiter during follow-up, with incidence of 457.88 and 242.45 per 100,000 person-years, respectively. The overall hazard ratio for ever versus never users was 0.527 (95% confidence interval: 0.447–0.621). When cumulative duration of metformin therapy was divided into tertiles, the hazard ratios for the first (<25.3 months), second (25.3–57.3 months) and third (>57.3 months) tertiles were 0.815 (0.643–1.034), 0.648 (0.517–0.812) and 0.255 (0.187–0.348), respectively. Sensitivity analyses estimating the overall hazard ratios for patients enrolled in each specific year from 1999 to 2005 consistently showed a lower risk of benign nodular goiter among users of metformin.

Conclusion

Metformin use is associated with a lower risk of benign nodular goiter in patients with type 2 diabetes mellitus.

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Jordan Sibeoni, Emilie Manolios, Laurence Verneuil, Philipe Chanson and Anne Revah-Levy

Context

Acromegaly has a substantial diagnostic delay associated with an increased risk of comorbidities and psychosocial deterioration. Qualitative methods which focus on the ways that individuals understand and relate to what they are experiencing are the best methods for exploring patients’ perspectives. To the best of our knowledge, they have not been developed in the context of acromegaly.

Objectives

This study aimed to explore the experience of the diagnostic pathway of patients with acromegaly.

Design

We conducted a qualitative study, based on 20 face-to-face unstructured interviews in a third referral Endocrinology center. Participants, purposively selected until data saturation, were patients with acromegaly with diverse disease durations, types of treatment or associated comorbidities. The data were examined by thematic analysis.

Results

Our analysis found four themes: (i) what happened for patients before the diagnosis; (ii) what happened after; (iii) the style or type of doctor involved and (iv) patients’ suggestions for limiting diagnostic delay. Our findings underlined the direct associations between diagnostic delay and the doctor–patient encounter, and the truly catastrophic experience of this disease, both before and after the diagnosis.

Conclusions

Diagnosis of acromegaly requires active medical involvement and awareness. Intervention of patient-experts in medical schools may help to be more aware of this disease. Endocrinologists caring for patients with acromegaly should also address the catastrophic dimension of the patient’s experience and initiate the narrative to help them to put it into words for preventing harmful consequences such as social isolation and QoL impairment, but also anxiety or depression.

Open access

Julia Otten, Mats Ryberg, Caroline Mellberg, Tomas Andersson, Elin Chorell, Bernt Lindahl, Christel Larsson, Jens Juul Holst and Tommy Olsson

Objective

To investigate how weight loss by different diets impacts postprandial levels of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon.

Methods

In this single-centre, parallel group 2-year trial, 70 healthy postmenopausal obese women were randomised to the Paleolithic diet or a healthy control diet based on Nordic Nutrition Recommendations. Both diets were without calorie restriction. The primary outcome was the change in fat mass. Here, secondary analyses on GLP-1, GIP and glucagon measured during an OGTT are described.

Results

In the Paleolithic diet group, mean weight loss compared to baseline was 11% at 6 months and 10% at 24 months. In the control diet group, mean weight loss was 6% after 6 and 24 months (P = 0.0001 and P = 0.049 for the comparison between groups at 6 and 24 months respectively). Compared to baseline, the mean incremental area under the curve (iAUC) for GLP-1 increased by 34 and 45% after 6 and 24 months in the Paleolithic diet group and increased by 59% after 24 months in the control diet group. The mean iAUC for GIP increased only in the Paleolithic diet group. The area under the curve (AUC) for glucagon increased during the first 6 months in both groups. The fasting glucagon increase correlated with the β-hydroxybutyrate increase.

Conclusions

Weight loss caused an increase in postprandial GLP-1 levels and a further rise occurred during weight maintenance. Postprandial GIP levels increased only after the Paleolithic diet. Reduced postprandial glucagon suppression may be caused by a catabolic state.

Open access

Irina Bancos, Jon Hazeldine, Vasileios Chortis, Peter Hampson, Angela E Taylor, Janet M Lord and Wiebke Arlt

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Maria Othelie Underdal, Øyvind Salvesen, Anne Schmedes, Marianne Skovsager Andersen and Eszter Vanky

Objective

To explore whether gestational prolactin and breast increase are markers of metabolic health in pregnancy and on long-term, in PCOS.

Design

Follow-up study. Women with PCOS, according to the Rotterdam criteria (n = 239), former participants of the randomized controlled trial (RCT) PregMet were invited, 131 participated in the current follow-up study, at mean 8 years after pregnancy.

Methods

Metformin 2000 mg/day or placebo from first trimester to delivery in the original RCT. No intervention in the current study.

Prolactin was analyzed in the first trimester and at gestational week 32 and metabolic characteristics which are part of the metabolic syndrome and measures of glucose homeostasis were examined. Metabolic health was also evaluated according to breast increase versus lack of breast increase during pregnancy.

Results

Prolactin increase in pregnancy was negatively correlated to BMI (P = 0.007) and systolic blood pressure (P ≤ 0.001) in gestational week 32. Prolactin at gestational week 32 was negatively correlated to BMI (P = 0.044) and visceral fat area (P = 0.028) at 8-year follow-up in an unadjusted model. Prolactin at gestational week 32 showed no associations to metabolic health at follow-up when baseline BMI was adjusted for. Women who reported lack of breast increase during pregnancy, had higher BMI (P = 0.034), waist-hip ratio (P = 0.004), visceral fat area (P = 0.050), total cholesterol (P = 0.022), systolic (P = 0.027) and diastolic blood pressure (P = 0.011) at 8-year follow-up.

Conclusion

High prolactin levels and breast increase in pregnancy were associated with a more favorable long-term metabolic health in women with PCOS. Both prolactin and breast increase may be mediated by gestational BMI.

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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.