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M D S A Dilrukshi, Marcus Vickars, Christine J H May, Taffy Makaya, Fiona Ryan, Bahram Jafar-Mohammadi, John A H Wass, Aparna Pal, and Aoife Garrahy

Objective

There is growing recognition of morbidity and mortality that can occur in patients with cranial diabetes insipidus (CDI) during hospitalisation, due to prescribing errors and dysnatraemia, often related to confusion between CDI and diabetes mellitus among non-specialists. We aimed to investigate this.

Methods

Data for each hospitalisation in patients with CDI attending Oxford University Hospital (OUH) were collected retrospectively. The same cohort were invited to complete a questionnaire by telephone.

Results

One hundred and nine patients were included, median age was 42 (range: 6–80) years. Route of desmopressin was tablet, melt and nasal spray in 74%, 7% and 17% of patients, respectively, while two patients used a combination of tablet and nasal spray. There were 85 admissions to OUH by 38 patients between 2012 and 2021. Daily measurement of serum sodium was performed in 39% of admissions; hyponatraemia and hypernatraemia occurred in 44 and 15% of admissions, respectively. Endocrine consultation was sought in 63% of admissions post-2018. Forty-five of 78 patients (58%) self-reported ≥1 admission to any hospital since diagnosis. Of these, 53% felt their medical team did not have a good understanding of the management of CDI during hospital admission. Twenty-four per cent reported delay in administration of desmopressin, while 44% reported confusion between CDI and diabetes mellitus, often leading to unnecessary blood glucose monitoring.

Conclusion

Dysnatraemia is common in hospitalised patients with CDI. More than half of patients perceived their medical team’s understanding of CDI to be poor when admitted with intercurrent illness. A coordinated approach, including early consultation of specialists, frequent serum sodium monitoring, and education of hospital specialists is needed to address this.

Free access

Katerina Saltiki, George Simeakis, Olga Karapanou, and Maria Alevizaki

During the last decades, knowledge of the molecular biology in medullary thyroid carcinoma (MTC) and specifically on the role of rearranged during transfection (RET)-activating mutations in tumorigenesis has led to the evolution of novel targeted therapies, mainly tyrosine kinase inhibitors (TKIs). Vandetanib and cabozantinib have been approved for the management of metastatic progressive MTC. Two novel, highly selective RET inhibitors, selpercatinib and pralsetinib, have recently been approved for the treatment of RET-mutant MTCs and RET-fusion differentiated thyroid cancer. The administration of targeted therapies in MTC patients has changed the therapeutic strategies; however, in the majority of cases, there are no real data showing an improvement of prognosis by TKIs in MTC. Drug resistance remains the main reason for treatment failure. Thus, the understanding of the molecular landscape of tumorigenesis and the mechanisms underlying resistance to targeted therapies is of paramount importance for the further development of more efficient therapies for MTC. The present review focuses on the molecular pathways implicated in MTC tumorigenesis, the approved targeted therapies, the tumoral escape mechanisms, as well as the future perspectives for targeted therapy.

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Ariadni Spyroglou, Laura Handgriff, Lisa Müller, Paul Schwarzlmüller, Mirko Parasiliti-Caprino, Carmina Teresa Fuss, Hana Remde, Anna Hirsch, Samuel Matthew O’Toole, Moe Thuzar, Luigi Petramala, Claudio Letizia, Elisa Deflorenne, Laurence Amar, Rok Vrckovnik, Tomaz Kocjan, Catherine D Zhang, Dingfeng Li, Sumitabh Singh, Takuyuki Katabami, Takashi Yoneda, Masanori Murakami, Norio Wada, Nobuya Inagaki, Marcus Quinkler, Ezio Ghigo, Mauro Maccario, Michael Stowasser, William M Drake, Martin Fassnacht, Irina Bancos, Martin Reincke, Mitsuhide Naruse, and Felix Beuschlein

Background

Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics.

Methods

We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed.

Results

As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients.

Conclusions

Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Open access

Irina Chifu, Andreas Max Weng, Stephanie Burger-Stritt, Thorsten Alexander Bley, Martin Christa, Herbert Köstler, and Stefanie Hahner

Objective

Replacement therapy in primary adrenal insufficiency (PAI) with corticosteroids modulates sodium homeostasis. Serum sodium is, however, prone to osmotic shifts induced by several additional factors besides corticosteroids and does not always reliably reflect treatment quality. Non-osmotic tissue storage can be visualized by sodium MRI (23Na-MRI) and might better reflect corticosteroid activity.

Design

Longitudinal study of 8 patients with newly diagnosed PAI and cross-sectional study in 22 patients with chronic PAI is reported here. Comparison was made with matched healthy controls.

Methods

Using a 23Na-MRI protocol on a 3T scanner, relative sodium signal intensities (rSSI) to signal intensities of the reference vial with 100 mmol/L of sodium were determined in the muscle and skin of the lower calf.

Results

In newly diagnosed patients, tissue rSSI (median, range) were reduced and significantly increased after treatment initiation reaching levels similar to healthy controls (muscle: from 0.15 (0.08, 0.18) to 0.18 (0.14, 0.27), P = 0.02; skin: from 0.12 (0.09, 0.18) to 0.18 (0.14, 0.28), P < 0.01). Muscle rSSI was significantly higher in patients with chronic PAI compared to controls (0.19 (0.14, 0.27) vs 0.16 (0.12, 0.20), P < 0.01). In chronic PAI, skin rSSI significantly correlated with plasma renin concentration.

Conclusion

23Na-MRI provides an additional insight into sodium homeostasis, and thus the quality of replacement therapy in PAI, as tissue sodium significantly changes once therapy is initiated. The increased tissue sodium in patients with chronic PAI might be an indication of over-replacement.

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Faidon Magkos, Elisa Fabbrini, Bruce W Patterson, Bettina Mittendorfer, and Samuel Klein

Objective

Increased triglyceride (TG) and apolipoprotein B-100 (apoB-100) concentrations in plasma are important risk factors for cardiovascular disease in women. Administration of some estrogen preparations raises plasma TG and apoB-100 concentrations by increasing hepatic very low-density lipoprotein (VLDL) TG and apoB-100 secretion rates. However, the influence of physiological variation in endogenous estradiol on VLDL-TG and VLDL-apoB-100 metabolism and on free fatty acid (FFA) release into plasma (the major source of fatty acids for VLDL-TG production) is not known.

Design and methods

We measured basal VLDL-TG, VLDL-apoB-100, and plasma FFA kinetics by using stable isotopically labeled tracers in 36 eumenorrheic, premenopausal women (age: 33 ± 2 years, BMI: 31 ± 1 kg/m2; mean ± s.e.m.) during the follicular phase of the menstrual cycle; participants were divided into two groups based on low (n = 18) or high (n = 18) plasma estradiol concentrations (defined as below or above the median value of 140 pmol/L in the whole group).

Results

Mean plasma estradiol concentration was >3-fold higher in the high-estradiol than in the low-estradiol group (299 ± 37 and 96 ± 7 pmol/L, P < 0.001); there was no difference in plasma progesterone concentrations between the two groups (P = 0.976). There were no significant differences in plasma FFA concentration, FFA rate of appearance in plasma, VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, VLDL-TG and VLDL-apoB-100 plasma clearance rates, and mean residence times (all P ≥ 0.45). No significant associations were found between plasma estradiol concentration and FFA, VLDL-TG, and VLDL-apoB-100 concentrations and kinetics (all P > 0.19).

Conclusions

Plasma estradiol concentration is not an important correlate of basal plasma FFA, VLDL-TG, and VLDL-apoB-100 kinetics in premenopausal women.

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Joe Balmain, Meshal Jarebi, Abdallah Al-Salameh, Patrick Toussaint, Marine Timmerman, Louis Chenin, Jean-Marc Constans, and Rachel Desailloud

Objective

Since the outbreak of the COVID-19 pandemic, several cases of pituitary apoplexy (PA) following a SARS-CoV-2 infection have been described in several countries. Here, we describe a case series of PA occurring in the aftermath of a SARS-CoV-2 infection to alert physicians about possible neuro-endocrinological damage caused by the virus that can lead to visual sequelae and hypopituitarism.

Design and methods

We retrospectively identified all the adult patients treated at Amiens University Hospital between March 2020 and May 2021 for PA confirmed by cerebral imaging and following an RT-PCR-confirmed SARS-CoV-2 infection.

Results

Eight cases (six women, two men) occurred between March 2020 and May 2021 and were reviewed in this study. The mean age at diagnosis was 67.5 ± 9.8 years. Only one patient had a ‘known’ non-functional pituitary macroadenoma. The most common symptom of PA was a sudden headache. Brain imaging was typical in all cases. Only two patients required decompression surgery, whereas the others were managed conservatively. The clinical outcome was favorable for all patients but without recovery of their pituitary deficiencies. There was no diabetes insipidus.

Conclusion

This case series, the largest in the literature, reinforces the strength, consistency, and coherence of the association between SARS-CoV-2 infection and PA. Our study provides support for the hypothesis that SARS-CoV-2 may be a new precipitating factor for PA. It is essential that practitioners be alerted about possible pituitary disease due to the virus so that such patients are recognized and appropriately managed, hence improving their prognosis.

Open access

Philippe Touraine, Yempabou Sagna, Anders F Mattsson, Pia Burman, André P Van Beek, Martin Ove Carlsson, Ferah Aydin, Ulla Feldt-Rasmussen, and Cecilia Camacho-Hübner

Objective

To analyze the effectiveness and safety of growth hormone (GH) replacement treatment in adult patients with Langerhans cell histiocytosis (LCH) and GH deficiency (GHD) enrolled in KIMS (Pfizer International Metabolic Database).

Patients and methods

Patients with LCH and GHD were studied at baseline and some of them after 1 year of GH treatment. The effectiveness of GH is presented as change after 1 year of treatment (mean, 95% CI). The LCH population was compared to two other groups of patients enrolled in KIMS, granulomatous and lymphocytic hypophysitis.

Results

At baseline, 81 adults with LCH (27 with childhood onset, 56% females), mean age at GHD onset of 29 () years were studied. Diabetes insipidus was diagnosed in 86% of patients. Analysis of 1 year of GH treatment was possible in 37 patients. One-year cross-sectional values for the GH dose were 0.39 (s.d.± 0.21) mg and −0.5 (−1.2 to 0.2) for insulin-like growth factor-1 s.d. Total cholesterol decreased 0.9 (−1.5 to −0.3 (mmol/L); P < 0.05); AGHDA-QoL-score (n = 20) was improved by 2.8 points (−5.6 to 0.0; P < 0.05), while mean BMI increased 0.6 ± 3 kg/m2 (95% CI: −0.2 to 1.4). All these effects did not differ from the two other groups after adjusting for age, gender, and baseline values. In 20 of 77 patients included in the safety analysis, 36 serious adverse events were reported during 435 patient-years (82.8/1000); no new safety signals were reported.

Conclusion

After 1 year of GH treatment in patients with LCH, metabolic variables and quality of life improved, with no new safety signals.

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Fatma Dursun, Hulya Maras Genc, Ayşe Mine Yılmaz, Ibrahim Tas, Metin Eser, Cemile Pehlivanoglu, Betul Karademir Yilmaz, and Tulay Guran

Background

Biallelic QRSL1 mutations cause mitochondrial ‘combined oxidative phosphorylation deficiency-40’ (COXPD40). COXPD40 has been reported to be invariably lethal in infancy. Adrenal insufficiency was weakly reported and investigated among seven previously reported patients with COXPD40.

Objective

We report the clinical, biochemical, molecular, and functional characteristics of a patient with adrenal insufficiency due to COXPD40.

Methods

The medical history and adrenal function tests were examined. Genetic analysis was performed using whole-exome sequencing. Mitochondrial function was tested using mitochondrial membrane potential (MMP) and superoxide dismutase (SOD) enzyme assays.

Results

An 8-year-old boy was investigated for adrenal insufficiency. He also had mild developmental delay, sensorineural hearing loss, hypertrophic cardiomyopathy, nephrocalcinosis, elevated parathyroid hormone and creatine kinase, and lactic acidosis. Biallelic novel QRSL1 variants (c.300T>A;Y100* and c.610G>A;G204R) were identified. Oxidative damage in mitochondria was shown by reduced MMP and SOD assays in the patient compared to controls (P < 0.0001). Adrenal function tests revealed a ‘primary adrenal insufficiency other than congenital adrenal hyperplasia’ (non-CAH PAI) with an isolated glucocorticoid deficiency. In the 8-year follow-up, having the longest survival of reported COXPD40 patients, he had preserved mineralocorticoid functions and gonadal steroidogenesis.

Conclusion

Biallelic QRSL1 mutations can cause non-CAH PAI. Adrenal functions should be monitored in mitochondrial disorders to improve clinical outcomes.

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Mario Detomas, Barbara Altieri, Irina Chifu, Hanna Remde, Xiang Zhou, Laura-Sophie Landwehr, Silviu Sbiera, Matthias Kroiss, Martin Fassnacht, and Timo Deutschbein

Objective

Endogenous hypercortisolism predisposes to impaired immune function and infections. To date, however, it is unknown whether there is a subtype-specific pattern in white blood cell (WBC) and WBC differential (WBCD) count.

Methods

A retrospective monocentric cohort study was carried out in patients with overt endogenous Cushing’s syndrome (CS) or adrenal incidentalomas and autonomous cortisol secretion (ACS), with WBC/WBCD analysis at initial diagnosis and after biochemical remission. Cut-offs were obtained by receiver-operating characteristics analysis.

Results

In total, 253 patients were analyzed (Cushing’s disease (CD); n  = 88; ectopic CS (ECS), n  = 31; cortisol-producing adrenal adenomas (CPA), n  = 40; ACS, n  = 45; adrenocortical carcinomas (ACC), n  = 49). Total leukocytes and neutrophils correlated positively with serum cortisol after 1-mg dexamethasone (r = 0.314 and r = 0.428), while a negative correlation was observed for lymphocytes and eosinophils (r = −0.374 and r= −0.380) (each P < 0.0001). Similar observations were made for 24 h-urinary free cortisol. CD and ECS differed in numbers of neutrophils and lymphocytes (P < 0.0001) and were well differentiated at a cut-off of 6.1 for the neutrophil/lymphocyte ratio (sensitivity 90.0%, specificity 89.4%, and areas under the curve (AUC) 0.918). For adrenocorticotropic hormone (ACTH)-independent CS, the best diagnostic outcome was obtained for the discrimination of CPA and ACC at a cut-off of 187.9 for the platelet/lymphocyte ratio (sensitivity 59.6%, specificity 80.6%, and AUC 0.713). For ECS, CPA, and CD, neutrophils decreased (delta −47.0, −29.7, and −26.2%) and lymphocytes increased (+123.2, +78.1, and +17.7%) already 3 months after remission.

Conclusion

Most immune cells correlate with the degree of hypercortisolism and differ among CS subtypes. WBCD changes are already identified 3 months after remission from endogenous hypercortisolism.

Open access

Linda Kujanpää, Riikka K Arffman, Eeva Vaaramo, Henna-Riikka Rossi, Jaana Laitinen, Laure Morin-Papunen, Juha Tapanainen, Leena Ala-Mursula, and Terhi T Piltonen

Objective

Polycystic ovary syndrome (PCOS) presents with multiple comorbidities potentially affecting function. This was the first general population-based study to evaluate work ability, participation in working life, and disability retirement in middle-aged women with and without PCOS.

Design

This is a cohort study.

Methods

Women with PCOS (n = 280) and women without PCOS symptoms or diagnosis (n = 1573) were identified in the Northern Finland Birth Cohort in 1966 and were evaluated for self-rated work ability and potential confounders at age 46. Next, incidence rate ratios (IRRs) for disability and unemployment days were extracted from national registers during a prospective 2-year follow-up. Lastly, we assessed hazard ratios (HRs) for disability retirement between 16 and 52 years of age from national registers.

Results

The women with PCOS reported poorer ability to work at age 46, especially due to poorer health. During the 2-year follow-up period, the affected women gained on average an additional month of disability and unemployment days, corresponding to an approximately 25% higher risk for both disability (IRR (95% CI): 1.25 (1.22–1.27)) and unemployment days (IRR (95% CI): 1.26 (1.23–1.28)) in models adjusted for health and socioeconomic factors. Lastly, we found a two-fold higher cumulative risk for disability retirement by age 52 compared to non-PCOS women (HR (95% CI): 1.98 (1.40–2.80)), which remained after adjusting for confounding factors (aHR (95% CI): 1.55 (1.01–2.38)).

Conclusions

PCOS is associated with lower participation in working life already in midlife. Acknowledging PCOS-related multimorbidity, concerted efforts are needed to support sustainable careers for women with PCOS.