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Gerald Raverot, Alexandre Vasiljevic, Emmanuel Jouanneau and Hélène Lasolle

Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine-resistant or aggressive prolactinomas. We discussed the two published cases and describe another case of poorly differentiated plurihormonal PIT-1-positive adenoma with moderate SSTR2 expression and intense STTR5 expression successfully treated with PAS-LAR 40 mg/month.

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Selvetta S van Santen, Daniel S Olsson, Casper Hammarstrand, Mark Wijnen, Marry M van den Heuvel-Eibrink, Aart J van der Lely, Gudmundur Johannsson, Joseph A M J L Janssen and Sebastian J C M M Neggers

Objective

Craniopharyngioma patients often have poor metabolic profiles due to hypothalamic–pituitary damage. Previously, using BMI as obesity marker, the occurrence of the metabolic syndrome in these patients was estimated at 46%. Our aim was to determine if dual X-ray absorptiometry (DXA) scan in evaluation of obesity and metabolic syndrome would be superior.

Design

Retrospective study of craniopharyngioma patients for whom DXA scan results were available.

Methods

BMI, fat percentage and fat mass index were used to evaluate obesity and as components for obesity in metabolic syndrome.

Results

Ninety-five craniopharyngioma patients were included (51% female, 49% childhood-onset disease). Metabolic syndrome occurred in 34–53 (45–51%) subjects (depending on the definition of obesity, although all definitions occurred in higher frequency than in the general population). Metabolic syndrome frequency was higher if obesity was defined by fat percentage (52 vs 42%) or fat mass index (51 vs 43%) compared to BMI. Misclassification appeared in 9% (fat percentage vs BMI) and 7% (fat mass index vs BMI) for metabolic syndrome and 29 and 13% for obesity itself, respectively. For metabolic syndrome, almost perfect agreement was found for BMI compared with fat percentage or fat mass index. For obesity, agreement was fair to moderate (BMI vs fat percentage).

Conclusion

Using BMI to evaluate obesity underestimates the true prevalence of metabolic syndrome in patients with craniopharyngioma. Furthermore, fat percentage contributes to a better evaluation of obesity than BMI. The contribution of DXA scan might be limited for identification of the metabolic syndrome.

Free access

E Diamanti-Kandarakis, L Duntas, G A Kanakis, E Kandaraki, N Karavitaki, E Kassi, S Livadas, G Mastorakos, I Migdalis, A D Miras, S Nader, O Papalou, R Poladian, V Popovic, D Rachoń, S Tigas, C Tsigos, T Tsilchorozidou, T Tzotzas, A Bargiota, M Pfeifer and COMBO ENDO TEAM: 2018

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

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

Purpose

To evaluate the accuracy of 18F-FDG-PET/CT for the 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 databases were 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 Deeks 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 were compared pairwise 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 (I 2 = 80% for sensitivity, I 2 = 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, 18F-FDG-PET/CT has high diagnostic accuracy for the 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.

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Kristina E Almby, Niclas Abrahamsson, Martin H Lundqvist, Ulf Hammar, Ketan Thombare, Amalia Panagiotou, F Anders Karlsson, Magnus Sundbom, Urban Wiklund and Jan W Eriksson

Objectives

The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

Design

Experimental hyperinsulinemic–hypoglycemic clamp study.

Methods

Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

Results

No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

Conclusions/interpretation

Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

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Eva C Coopmans, Sebastiaan W F van Meyel, Kay J Pieterman, Jolique A van Ipenburg, Leo J Hofland, Esther Donga, Adrian F Daly, Albert Beckers, Aart-Jan van der Lely and Sebastian J C M M Neggers

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy, a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis or both in prolactinomas.

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Leonie H A Broersen, Femke M van Haalen, Tina Kienitz, Olaf M Dekkers, Christian J Strasburger, Alberto M Pereira and Nienke 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 included consecutive patients with Cushing’s syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the 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), 5370 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.

Free access

Gherardo Mazziotti, Andrea G A Lania and Ernesto Canalis

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) exert physiological actions on the skeleton throughout life, by stimulating longitudinal bone growth in children, the acquisition of bone mass during adolescence and the maintenance of skeletal architecture in adults. When GH and IGF-I are secreted in excess, bone remodeling is enhanced leading to deterioration of bone microstructure and impairment of bone strength. Indeed, acromegaly causes skeletal fragility, and vertebral fractures are reported in a remarkable number of subjects exposed to GH and IGF-I excess. The management of skeletal fragility in acromegaly is a challenge, since the awareness of this complication is low, the prediction of fracture risk is difficult to ascertain, the risk of fractures remains after the control of acromegaly and the effectiveness of bone-active drugs is unknown. This review is an update on bone disorders associated with acromegaly and provides a perspective of possible therapeutic approaches based on emerging pathophysiological and clinical information.

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Jens Bollerslev, Ansgar Heck and Nicoleta Cristina Olarescu

Acromegaly is a rare and challenging disease calling for management in highly specialised multidisciplinary teams (MDTs). Untreated disease has severe morbidity and a clearly increased mortality. Major attainments have been gained over the latest decades, and therefore, the aim of this review is to discuss recent achievements in modern multimodal therapy of acromegaly performed by MDTs, with an emphasis on an individualised, proactive management from the time of diagnosis to long-term outcome. Treatment by surgery is the only potential curative treatment, however, even with modern techniques still with modest cure rates, leaving the patients to often long-term medical treatment. Treatment strategies have changed dramatically in the Western world over recent years, implying a more proactive treatment algorithm often with a shorter or longer pre-surgical treatment period with somatostatin receptor ligands (SRLs). Not all patients will however respond to primary treatment with conventional SRLs and there has recently been a development of potential biomarkers for response that has been implemented in the clinical routine. By today, multimodal treatment can bring every patient in remission, but still almost a third of all patients are undertreated according to large, international registries. On the other hand, it might be a challenge not to over treat thereby bringing the patient into a state of relative or absolute growth hormone deficiency. Clinical series published during the last decade on treatment of patients with acromegaly have indicated a normalisation of mortality, most probably reflecting the proactive and individualised modern treatment. In conclusion, modern, multimodal treatment seems to have normalised mortality, but still the patients suffer from a high multi-organ morbidity and often multi-pharmacy. Every patient should receive an individualised, proactive treatment in order to improve long-term outcome and to reduce costs for the society.