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Open access

Wiebke Schloetelburg, Ines Ebert, Bernhard Petritsch, Andreas Max Weng, Ulrich Dischinger, Stefan Kircher, Andreas Konrad Buck, Thorsten Alexander Bley, Timo Deutschbein, and Martin Fassnacht

Objective

Reliable results of wash-out CT in the diagnostic workup of adrenal incidentalomas are scarce. Thus, we evaluated the diagnostic accuracy of delayed wash-out CT and determined thresholds to accurately differentiate adrenal masses.

Design

Retrospective, single-center cohort study including 216 patients with 252 adrenal lesions who underwent delayed wash-out CT. Definitive diagnoses based on histopathology (n = 92) or comprehensive follow-up.

Methods

Size, average attenuation values of the adrenal lesions in all CT scan phases, and absolute and relative percentage wash-out (APW/RPW) were determined by an expert radiologist blinded for clinical data. Adrenal lesions with unenhanced attenuation values >10 Hounsfield units (HU) built a subgroup (n = 142). Diagnostic accuracy was calculated.

Results

The study group consisted of 171 adenomas, 32 other benign tumors, 11 pheochromocytomas, 9 adrenocortical carcinomas, and 29 other malignant tumors. All (potentially) malignant and 46% of benign lesions showed unenhanced attenuation values >10 HU. In this most relevant subgroup, the established thresholds of 60% for APW and 40% for RPW misclassified 35.9 and 35.2% of the masses, respectively. When we applied optimized cutoffs (APW >83%; RPW >58%) and excluded pheochromocytomas, we missed only one malignant tumor by APW and none by RPW. However, only 11 and 15% of the benign tumors were correctly identified.

Conclusions

Wash-out CT with the established thresholds for APW and RPW is insufficient to reliably diagnose adrenal masses. Using the proposed cutoff of 58% for RPW, malignant tumors will be correctly identified, but the added value is limited, namely 15% of patients with benign tumors can be prevented from additional imaging or even unnecessary surgery.

Open access

Jens Bollerslev, Lars Rejnmark, Alexandra Zahn, Ansgar Heck, Natasha M Appelman-Dijkstra, Luis Cardoso, Fadil M Hannan, Filomena Cetani, Tanja Sikjaer, Anna Maria Formenti, Sigridur Björnsdottir, Camilla Schalin-Jäntti, Zhanna Belaya, Fraser Gibb, Bruno Lapauw, Karin Amrein, Corinna Wicke, Corinna Grasemann, Michael Krebs, Eeva Ryhänen, Özer Makay, Salvatore Minisola, Sébastien Gaujoux, Jean-Philippe Bertocchio, Zaki Hassan-Smith, Agnès Linglart, Elizabeth M Winter, Martina Kollmann, Hans-Georg Zmierczak, Elena Tsourdi, Stefan Pilz, Heide Siggelkow, Neil Gittoes, Claudio Marcocci, Peter Kamenický, and the 2021 PARAT Working Group

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders in 2019 were discussed during two virtual workshops in 2021 and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosis of familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represents areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborn children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed at a broader clinical audience and were developed with the focus on endocrinologists in training.

Open access

Roberta Armignacco, Anne Jouinot, Lucas Bouys, Amandine Septier, Thomas Lartigue, Mario Neou, Cassandra Gaspar, Karine Perlemoine, Leah Braun, Anna Riester, Fidéline Bonnet-Serrano, Anne Blanchard, Laurence Amar, Carla Scaroni, Filippo Ceccato, Gian Paolo Rossi, Tracy Ann Williams, Casper K Larsen, Stéphanie Allassonnière, Maria-Christina Zennaro, Felix Beuschlein, Martin Reincke, Jérôme Bertherat, and Guillaume Assié

Objective

Cushing’s syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing’s syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing’s syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers.

Design

We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing’s syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation.

Methods

Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850 000 CpG sites). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features.

Results

Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing’s syndrome correction. In Cushing’s syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts.

Conclusions

Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assessment of glucocorticoid action beyond hormone assays.

Open access

Sara Santini, Nathalie Vionnet, Jérôme Pasquier, Michel Suter, Didier Hans, Elena Gonzalez-Rodriguez, Nelly Pitteloud, and Lucie Favre

Objective

Bariatric surgery (BS) induces loss of body fat mass (FM) with an inexorable loss of lean mass (LM). Menopause leads to deleterious changes in body composition (BC) related to estrogen deficiency including LM loss and increase in total and visceral adipose tissue (VAT). This study aims to describe the long-term weight evolution of post-menopausal women after Roux-en-Y gastric bypass (RYGB) and to compare the BC between BS patients vs post-menopausal non-operated women.

Design

Cross-sectional study of 60 post-menopausal women who underwent RYGB ≥2 years prior to the study with nested case–control design.

Methods

Post-menopausal BS women were matched for age and BMI with controls. Both groups underwent DXA scan, lipids and glucose metabolism markers assessment.

Results

Median follow-up was 7.5 (2–18) years. Percentage of total weight loss (TWL%) was 28.5 ± 10%. After RYGB, LM percentage of body weight (LM%) was positively associated with TWL% and negatively associated with nadir weight. Forty-one post-BS women were age- and BMI-matched with controls. Post-BS patients showed higher LM% (57.7% (±8%) vs 52.5% (±5%), P  = 0.001), reduced FM% (39.4% (±8.4%) vs 45.9% (±5.4%), P  < 0.01) and lower VAT (750.6 g (±496) vs 1295.3 g (±688), P  < 0.01) with no difference in absolute LM compared to controls. While post-BS women showed a better lipid profile compared to controls, no difference was found in glucose markers.

Conclusions

Post-menopausal women after RYGB have a lower FM and VAT, preserved LM and a better lipid profile compared to controls. Weight loss after RYGB seems to have a persistent positive impact on metabolic health.

Open access

Zimin Song, Meng Gao, Jun Lv, Canqing Yu, Yu Guo, Zheng Bian, Yuxia Wei, Ling Yang, Huaidong Du, Yiping Chen, Jianqiang Zhang, Jvying Yao, Junshi Chen, Zhengming Chen, Tao Huang, Liming Li, and the China Kadoorie Biobank (CKB) Collaborative Group

Objectives

To prospectively assess the association of metabolic health status and its transition with incident diabetes risk across BMI categories.

Design

Cohort study based on the China Kadoorie Biobank (CKB).

Methods

The CKB study enrolled 512 715 adults aged 30–79 years from ten diverse areas in China during 2004–2008. After exclusion, 432 763 participants were cross-classified by BMI categories and the metabolic status was followed up for incident diabetes disease. The changes in BMI and metabolic health status were defined from baseline to the second resurvey.

Results

Type 2 diabetes risk is higher for metabolically healthy obese (MHO) subjects than metabolically healthy normal weight (MHN) individuals (HR: 3.97, 95% CI: 3.64–3.66), and it is highest for those affected by metabolically unhealthy obese (MUO) (HR: 6.47, 95% CI: 6.17–6.79). About 15.26% of participants with MHN converted to metabolically healthy overweight or obesity (MHOO), whereas 48.40% of MHOO remained unconverted throughout the follow-up. In obese or overweight people, the conversion from metabolically healthy to unhealthy might increase the chances of developing diabetes as compared to those with a stable metabolic healthy state (HR: 3.70, 95% CI: 2.99–4.59), while those with persistent metabolic disorders are most likely to have diabetes (HR: 8.32, 95% CI: 7.08–9.78).

Conclusions

Metabolic healthy is a transient state, and individuals converted from metabolically healthy status to unhealthy phenotypes across all BMI categories might raise the risk of diabetes.

Open access

Mikiko Okazaki-Hada, Eijun Nishihara, Mako Hisakado, Takumi Kudo, Mitsuru Ito, Shuji Fukata, Mitsushige Nishikawa, Takashi Akamizu, and Akira Miyauchi

Objective

Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations.

Design and methods

We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital.

Results

Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P  = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD.

Conclusions

The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Open access

Dilek Cicek, Nick Warr, Gozde Yesil, Hatice Kocak Eker, Firdevs Bas, Sukran Poyrazoglu, Feyza Darendeliler, Gul Direk, Nihal Hatipoglu, Mehmet Eltan, Zehra Yavas Abali, Busra Gurpinar Tosun, Sare Betul Kaygusuz, Tuba Seven Menevse, Didem Helvacioglu, Serap Turan, Abdullah Bereket, Richard Reeves, Michelle Simon, Matthew Mackenzie, Lydia Teboul, Andy Greenfield, and Tulay Guran

Context

Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (Myo-Ectodermo-Gonadal Dysgenesis (MEGD) syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD).

Method

We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory, and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing.

Results

A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low anti-Müllerian hormone, and high follicle-stimulating hormone and luteinizing hormone concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5, and 8.5 days post coitum(dpc) revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier.

Conclusion

Our data indicate the essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

Open access

Alessandro Prete, Richard J Auchus, and Richard J Ross

Background

Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.

Methods

Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.

Summary

Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.

Conclusions

CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Open access

Yongze Li, Zhongyan Shan, and Weiping Teng

Objective

Longitudinal studies have investigated the effects of changing iodine status on thyroid disorders, but the effect of a transition from more than adequate iodine to adequate iodine on national changes in prevalence adjusted for changing risk factors remains unclear.

Design

Two repeat nationwide surveys were conducted from 2009–2010 to 2015–2017 to assess changes in thyroid disorder prevalence and iodine status in China.

Methods

A multistage stratified random sampling method was used to obtain a nationally representative sample of urban adults aged 18 and older in mainland China in 2009 (n = 14 925) and 2015 (n = 12 553). Changes in thyroid disorder prevalence, urinary iodine concentration (UIC), and thyroid-stimulating hormone (TSH) levels were assessed. Logistic regression models were used to examine changes in prevalence over time.

Results

The median UIC decreased significantly from 219.7 to 175.9 μg/L (P < 0.0001). The weighted prevalence of overt hyperthyroidism, subclinical hyperthyroidism, Graves’ disease, and goitre decreased between 2009 and 2015 in the overall population (P < 0.05 for all). Despite no significant changes in subclinical hyperthyroidism or hypothyroidism or anti-thyroid peroxidase or anti-thyroglobulin antibody positivity prevalence, a significant increase in thyroid nodule prevalence (P < 0.0001) was found in the overall population. The 2.5th TSH percentile increased by 0.15 mIU/L (95% CI: 0.01 to 0.30 mIU/L, P = 0.04) from 2009 to 2015.

Conclusions

With the iodine status transition from more than adequate to adequate, thyroid disorder (except for thyroid nodules) prevalence remained stable or even decreased after adjusting for confounding factors among adults in mainland China between 2009 and 2015. Additional studies are needed to explore the reasons for the increased thyroid nodule prevalence.

Open access

Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio, Claudia Battista, Alessandro Bozzao, Marco Caputo, Enrica Ciccarelli, Laura De Marinis, Ernesto De Menis, Marco Faustini-Fustini, Franco Grimaldi, Andrea Lania, Giovanni Lasio, Francesco Logoluso, Marco Losa, Pietro Maffei, Davide Milani, Maurizio Poggi, Michele Zini, Laurence Katznelson, Anton Luger, and Catalina Poiana

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts.

The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology.

In the last century prolactinomas represented the paradigm of pituitary tumors for whom the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.