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Eline Sofia van der Valk, Bibian van der Voorn, Anand M. Iyer, Sjoerd van den Berg, Mesut Savas, Yolanda B de Rijke, Erica van den Akker, Olle Melander, and Elisabeth F.C. van Rossum

Context. Obesity and cardiometabolic diseases are associated with higher long-term glucocorticoid levels, measured as scalp hair cortisol (hairF) and cortisone (hairE). Cardiometabolic diseases have also been associated with copeptin, a stable surrogate marker for the arginine-vasopressin (AVP) system. Since AVP is, together with corticotropin-releasing hormone (CRH) an important regulator of the hypothalamic- pituitary adrenal axis (HPA-axis), we hypothesize that AVP contributes to chronic hypercortisolism in obesity.

Objective. To investigate whether copeptin levels are associated with higher hairF and hairE levels in obesity.

Design. A cross-sectional study in 51 adults with obesity (body mass index ≥30 kg/m2).

Methods. Associations and interactions between copeptin, hairF, hairE, and cardiometabolic parameters were cross-sectionally analyzed.

Results. Copeptin was strongly associated with body mass index (BMI) and waist circumference (WC), (rho=0.364 and 0.530, p=0.008 and <0.001 respectively), also after correction for confounders. There were no associations between copeptin and hairF or hairE on a continuous or dichotomized scale, despite correction for confounders.

Conclusion. In patients with obesity, AVP seems not a major contributor to the frequently observed high cortisol levels. Other factors which stimulate the HPA-axis or affect cortisol synthesis or breakdown may be more important than the influence of AVP on long-term glucocorticoid levels in obesity.

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Teresa Porcelli, Filippo Maffezzoni, Letizia Chiara Pezzaioli, Andrea Delbarba, Carlo Cappelli, and Alberto Ferlin

Male osteoporosis has been neglected for too long time and there is need for a change. This condition is clearly under-estimated, under-diagnosed and under-treated. The diagnosis is often made late in the natural history of the pathology or even after a fracture event. Guidelines on screening politics do not agree whether and when men should be considered, and clinical trials are far less performed in men with respect to women. Actually, most of our knowledge on male osteoporosis, especially regarding treatment, is extrapolate from the female counterpart. Male osteoporosis is frequently secondary to other conditions and often associated with comorbidities. Therefore, identification of specific causes of male osteoporosis is essential to drive a correct and personalized treatment. Moreover, men have more osteoporosis-related complications and higher mortality rate associated with fractures. Furthermore, not only fewer men receive a correct and timely diagnosis, but also fewer men receive adequate treatment, and adherence to therapy is far less in men than in women. Of note, very few studies assessed the effect of antiosteoporotic treatments in men and most of them considered only bone density as primary endpoint. This review focuses on the areas that are still nebulous in male osteoporosis field, from identification of subjects who need to be evaluated for osteoporosis and screening programs dealing with primary prevention to diagnostic procedures for good estimates of bone quantity and quality and precise calculation of fracture risk and personalized treatment that take into account the pathophysiology of osteoporosis.

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Bruno Lapauw and Jean-Marc Kaufman

Overt hypogonadism in men adversely affects body composition and metabolic health, which generally improve upon testosterone (T) therapy. As obese men often display lower serum T levels, in particular when they present with the metabolic syndrome (MetS) or type 2 diabetes (T2DM), there have been claims that androgen therapy prevents or reverses obesity and improves metabolic health. This has contributed to the increase of T prescriptions during the past two decades. In this narrative review, based on findings from larger observational studies and randomized controlled intervention trials, we evaluate whether low T predicts or predisposes to obesity and its metabolic consequences, and whether obese men with low T are truly hypogonadal. We further describe the mechanisms underlying the bidirectional relationships of T levels with obesity and metabolic health, and finally assess the evidence for T therapy in men with obesity, MetS and/or T2DM, considering efficacy, safety concerns and possible alternative approaches. It is concluded that low serum SHBG and total T levels are highly prevalent in obese men, but that only those with low free T levels and signs or symptoms of hypogonadism should be considered androgen deficient. These alterations are reversible upon weight loss. Whether low T is a biomarker rather than a true risk factor for metabolic disturbances remains unclear. Considering the limited number of sound T therapy trials having shown beneficial effects, the modest amplitude of these effects, and unresolved safety issues, one cannot in the present state-of-the-art advocate T therapy to prevent or reverse obesity-associated metabolic disturbances. Instead, focus should remain on lifestyle measures and management of obesity-related consequences.

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Merel M Ruissen, Anne Linde Mak, Ulrich Beuers, Maarten E Tushuizen, and Adriaan G Holleboom

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem with a global prevalence of over 25% and prevalence rates of over 60% in high-risk populations. It is considered the hepatic component of the metabolic syndrome and is associated with an increased risk of the development of various liver-associated and cardiometabolic complications. Given the complexity of NAFLD and associated comorbidities and complications, treatment requires interventions from a variety of different healthcare specialties. However, many clinicians are currently insufficiently aware of the potential harm and severity of NAFLD and associated comorbidities, complications and the steps that should be taken when NAFLD is suspected. Recognizing which patients suffer from non-progressive simple steatosis, metabolically active NASH with high risk of developing cardiovascular disease and which patients have a high risk of developing cirrhosis and hepatocellular carcinoma is important. Unfortunately, this can be difficult and guidelines towards the optimal diagnostic and therapeutic approach are ambivalent. Here we review the pathogenesis, diagnostics and treatment of NAFLD and discuss how multidisciplinary care path development could move forward.

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Martin Overgaard, Dorte Glintborg, Henrik Thybo Christesen, Tina Kold Jensen, and Marianne Skovsager Andersen

Objective:

Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS).

Design:

Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included.

Methods:

Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L.

Results:

The median (IQR) prolactin increased from 633 (451–829) mIU/L in first–second trimester to 5223 (4151–6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = −0.19, P < 0.001) and third trimester (r = −0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051).

Conclusions:

Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.

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Rolf H H Groenwold and Olaf M Dekkers

The validity of any biomedical study is potentially affected by measurement error or misclassification. It can affect different variables included in a statistical analysis, such as the exposure, the outcome, and confounders, and can result in an overestimation as well as in an underestimation of the relation under investigation. We discuss various aspects of measurement error and argue that often an in-depth discussion is needed to appropriately assess the quality and validity of a study.

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Alessia Cozzolino, Tiziana Feola, Ilaria Simonelli, Giulia Puliani, Valeria Hasenmajer, Marianna Minnetti, Elisa Giannetta, Daniele Gianfrilli, Patrizio Pasqualetti, Andrea Lenzi, and Andrea M. Isidori

Objective: Neurosurgery is the first-line treatment for acromegaly. Whether metabolic disorders are reversible after neurosurgery is still debated. The meta-analysis aimed to address the following questions: 1) Does neurosurgery affect glycolipid metabolism? 2) Are these effects related to disease control or follow-up length?

Design: a meta-analysis and systematic review of the literature.

Methods: Three reviewers searched up databases until August 2019 for prospective trials reporting glycometabolic outcomes after neurosurgery. Three other extracted outcomes, all assessed the risk of bias.

Results: Twenty studies were included. Neurosurgery significantly reduced fasting plasma glucose (FPG) [effect size (ES) -0.57 mmol/L, 95% CI -0.82 to -0.31; P<0.001], glucose load [ES -1.10 mmol/L, 95% CI -1.66 to -0.53; p<0.001], glycosylated haemoglobin (HbA1c) [ES -0.28%, 95% CI -0.42 to -0.14; P<0.001], fasting plasma insulin (FPI) [ES -10.53 mU/L, 95% CI -14.54 to -6.51; P<0.001], homeostatic model assessment of insulin resistance (HOMA-IR) [ES -1.98, 95% CI -3.24 to -0.72; P=0.002], triglycerides (TGDs) [ES -0.28 mmol/L, 95% CI -0.36 to -0.20; P<0.001] and LDL-cholesterol (LDL-C) [ES -0.23 mmol/L, 95% CI -0.45 to -0.02 mmol/L); P=0.030] and increased HDL-cholesterol (HDL-C) [ES 0.21 mmol/L, 95% CI 0.14 to 0.28; P<0.001]. Meta-regression analysis showed that follow-up length - not disease control - had a significant effect on FPG, with the greatest reduction in the shortest follow-up (beta=0.012, SE=0.003; P=0.001).

Conclusions: Neurosurgery improves metabolism with a significant decrease in FPG, glucose load, HbA1c, FPI, HOMA-IR, TGDs, and LDL-C and increase in HDL-C. The effect on FPG seems to be more related to follow-up length than to disease control.

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Nathalie Oliveira Santana, Antonio Marcondes Lerario, Claudia Kliemann Schmerling, Suemi Marui, Venancio Avancini Ferreira Alves, Ana O. Hoff, Peter Kopp, and Debora Lucia Seguro Danilovic

Objective: Genomic alterations in Hürthle cell carcinomas (HCC) include chromosomal losses, mitochondrial DNA mutations, and changes in the expression profile of the PI3K-AKT-mTOR and Wnt/β-catenin pathways. This study aimed at characterizing the mutational profile of HCC.

Methods: Next-generation sequencing (NGS) of 40 HCC using a 102-gene panel including, among others, the MAPK, PI3K-AKT-mTOR, Wnt/β-catenin, and Notch pathways. HCC was widely invasive in 57.5%, and lymph node and distant metastases were diagnosed in 5% and 7.5% of cases. During follow-up, 10% of patients presented with persistent/recurrent disease, but there were no cancer-related deaths.

Results: Genetic alterations were identified in 47.5% of HCC and comprised 190 single-nucleotide variants and 5 insertions/deletions. The Wnt/β-catenin pathway was most frequently affected (30%), followed by MAPK (27.5%) and PI3K-AKT-mTOR (25%). FAT1 and APC were the most frequently mutated genes and present in 17.5%. RAS mutations were present in 12.5% but no BRAF mutation was found. There was no association between the mutational profile and clinicopathological features.

Conclusions: This series of HCC presents a wide range of mutations in the Wnt/β-catenin, MAPK and PI3K-AKT-mTOR pathways. The recurrent involvement of Wnt/β-catenin pathway, particularly mutations in APC and FAT1, are of particular interest. The data suggest that mutated FAT1 may represent a potential novel driver in HCC tumorigenesis and that the Wnt/β-catenin pathway plays a critical role in this distinct thyroid malignancy.

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Mario Rotondi, Gloria Groppelli, Laura Croce, Francesco Latrofa, Giuseppe Ancona, Francesca Coperchini, Daniela Pasquali, Carlo Cappelli, Alessandro Fugazza, Valeria Guazzoni, Giorgio Radetti, and Luca Chiovato

Objective:

The association between chronic autoimmune thyroiditis (CAT) and differentiated thyroid cancer (DTC) remains controversial. The incidence of DTC increases when screening procedures are implemented, as typically occurs in CAT patients being routinely submitted to thyroid ultrasound (US). The aim of this study was to longitudinally evaluate the long-term development of DTC in patients with CAT.

Design and methods:

A retrospective longitudinal cohort study was designed. For the study, 510 patients with chronic autoimmune thyroiditis (CAT) with a 10-year follow-up were enrolled. Patients were divided in two groups according to the presence (CAT+ NOD+; n = 115) or absence (CAT+ NOD−; n = 395) of co-existent nodules at diagnosis. The main outcome measures were appearance of new thyroid-nodules and development of DTC during follow-up.

Results:

During a 10-year median follow-up period, new thyroid-nodules were detected in 34/115 (29.5%) patients in the CAT+ NOD+ group and in 41/395 (10.3%) in the CAT+ NOD− group (P < 0.001). Logistic regression analysis showed that thyroid-volume at diagnosis and belonging to the CAT+ NOD+ group significantly predicted the appearance of a new thyroid nodule during follow-up, independently of baseline age and sex. Among the 75 patients experiencing the appearance of a new nodule, 27 (39%) met the criteria for fine-needle-aspiration-cytology (FNAC). A benign cytological diagnosis was rendered in all cases.

Conclusions:

In our series of CAT patients, the appearance of new thyroid-nodules was frequent, but none of them were found to be malignant. The presence of CAT appears to be associated with a negligible risk of developing clinically overt DTC.

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Marco Castellana, Giorgio Grani, Maija Radzina, Vito Guerra, Luca Giovanella, Maurilio Deandrea, Rose Ngu, Cosimo Durante, and Pierpaolo Trimboli

Objective:

Several thyroid imaging reporting and data systems (TIRADS) have been proposed to stratify the malignancy risk of thyroid nodule by ultrasound. The TIRADS by the European Thyroid Association, namely EU-TIRADS, was the last one to be published.

Design:

We conducted a meta-analysis to assess the prevalence of malignancy in each EU-TIRADS class and the performance of EU-TIRADS class 5 vs 2, 3 and 4 in detecting malignant lesions.

Methods:

Four databases were searched until December 2019. Original articles reporting the performance of EU-TIRADS and adopting histology as reference standard were included. The number of malignant nodules in each class and the number of nodules classified as true/false positive/negative were extracted. A random-effects model was used for pooling data.

Results:

Seven studies were included, evaluating 5672 thyroid nodules. The prevalence of malignancy in each EU-TIRADS class was 0.5% (95% CI: 0.0–1.3), 5.9% (95% CI: 2.6–9.2), 21.4% (95% CI: 11.1–31.7), and 76.1% (95% CI: 63.7–88.5). Sensitivity, specificity, PPV, NPV, LR+, LR− and DOR of EU-TIRADS class 5 were 83.5% (95% CI: 74.5–89.8), 84.3% (95% CI: 66.2–93.7), 76.1% (95% CI: 63.7–88.5), 85.4% (95% CI: 79.1–91.8), 4.9 (95% CI: 2.9–8.2), 0.2 (95% CI: 0.1–0.3), and 24.5 (95% CI: 11.7–51.0), respectively. A further improved performance was found after excluding two studies because of limited sample size and low prevalence of malignancy in class 5.

Conclusions:

A limited number of studies generally conducted using a retrospective design was found. Acknowledging this limitation, the performance of EU-TIRADS in stratifying the risk of thyroid nodules was high. Also, EU-TIRADS class 5 showed moderate evidence of detecting malignant lesions.