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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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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.

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Jessica Boyd, Alexander A Leung, Hossein SM Sadrzadeh, Christina Pamporaki, Karel Pacak, Timo Deutschbein, Stephanie Fliedner and Gregory A Kline

Objective

Determine rate of high plasma normetanephrine or metanephrine (PNM-PMN) in a large sample of patients according to PNM-PMN posture and age-adjusted references.

Design

Retrospective re-analysis of PNM-PMN from a Canadian reference laboratory (n = 5452), 2011–2015; most were in seated position (n = 5112) rather than supine (n = 340). An international PPGL database demonstrated expected distribution of supine PNM-PMN in PPGL patients.

Methods

All PNM-PMN from a tertiary referral laboratory were reviewed. Any PNM-PMN result greater than 2× upper reference limit (URL) was considered likely true PPGL. Results 1–2× URL were uncertain, requiring additional testing/follow-up despite most being false positive given the rarity of PPGL. The rate of results in the 1–2× URL category were calculated for each group according to collection posture and differing published URL: seated, supine or supine age adjusted.

Results

When collected and interpreted by seated URL, 19.6% of PNM required additional testing; only 4.6% being >2× URL. For patients over age 50 years, the abnormal rate was 24.9%. When collected supine, interpreted by supine age-adjusted URL, only 5.3% of PNM were mildly elevated. Possible false positives may be even lower when considering PMN or plasma methoxytyramine which were commonly high in true PPGL despite mild PNM elevations.

Conclusions

In a general medical population, seated PNM has a high rate of abnormal results, far exceeding expected prevalence. Supine measurement with supine, age-adjusted interpretation is strongly preferred prior to costly or invasive PPGL investigations.

Summary

Review of 5452 plasma normetanephrine measurements showed 20% to be high, likely false positives for most. Supine, age-adjusted measures were half as likely to be elevated.

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Alexander Faje, Kerry Reynolds, Leyre Zubiri, Donald Lawrence, Justine V Cohen, Ryan J Sullivan, Lisa 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%, 17/3522) 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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Frédérique Albarel, Frédéric Castinetti and Thierry Brue

In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

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Grigoris Effraimidis

Prediction models are of a great assistance for predicting the development of a disease, detecting or screening undiagnosed patients, predicting the effectiveness of a treatment and helping toward better decision-making. Recently, three predictive scores in the field of autoimmune thyroid disease (AITD) have been introduced: The Thyroid Hormones Event Amsterdam (THEA) score: a predictive score of the development of overt AITD, the Graves’ Events After Therapy (GREAT) score: a prediction score for the risk of recurrence after antithyroid drugs withdrawal and the Prediction Graves’ Orbitopathy (PREDIGO) score: a prediction score for the development of Graves’ orbitopathy in newly diagnosed patients with Graves’ hyperthyroidism. Their construction, clinical applicability, the possible preventative measurements which can be taken to diminish the risks and the potential future developments which can improve the accuracy of the predictive scores are discussed in this review.