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Camilo Fuentes Peña C Fuentes Peña, Nuclear Medicine, Hopital Erasme, Bruxelles, 1070, Belgium

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María Cecilia Opazo M Opazo, Instituto de Ciencias Naturales, Facultad de Medicina Veterinaria y Agronomía , Universidad de Las Americas, Santiago, Chile

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Luis Méndez L Méndez, Millennium Institute on Immunology and Immunotherapy, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile

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Claudia Riedel C Riedel, Millennium Institute on Immunology and Immunotherapy, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile

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Bernard Hauquier B Hauquier, Nuclear Medicine, Hopital Erasme, Bruxelles, Belgium

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Lionel Marcelis L Marcelis, Laboratory of Paediatric Research, Hopital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium

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Frederic Cotton F Cotton, Clinical Chemestry - LHUB-ULB, Universite Libre de Bruxelles, Bruxelles, Belgium

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Rodrigo Moreno-Reyes R Moreno-Reyes, Nuclear Medicine, Hopital Erasme, Bruxelles, Belgium

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Background: Thyroglobulin (Tg) is a biomarker of iodine status. Newborn Tg is a more sensitive marker than neonatal TSH in detecting variations in iodine intake. This study aims to validate a Tg enzyme-linked immunosorbent assay (ELISA) for Tg determination on dried blood spots (DBS) in newborns. This study also set out to assess the stability of Tg and the influence of newborns’ hematocrit on Tg determination.

Methods: A commercially available ELISA Tg assay was adapted for use on DBS. DBS-Tg in cord blood were measured in 209 newborns delivered from healthy euthyroid pregnant women. Sensitivity, linearity, repeatability, and intermediate fidelity were determined using the appropriate standards and quality control materials.

Results: The limit of detection (LoD) of the DBS-Tg assay was 2.4 µg/L, and the limit of quantification (LoQ) was 5.8 µg/L. Repeatability and intermediate fidelity were 7.7-8.3% and 11.0-11.2%, respectively. The median cord plasma Tg and DBS-Tg values in newborns were not significantly different, 30.2 (21.3-44.4) µg/L and 31.6 (19.3-48.7) µg/L (p=0.48) with the ELISA respectively, and 76.5 (40.0-101.5) µg/L with the Elecsys assay with an R=0.88. DBS-Tg concentrations decrease with increasing hematocrit values (p<0.05). DBS-Tg values were stable at a concentration of 25 µg/L for 12 months at -20ºC and 4ºC.

Conclusion: This DBS-Tg assay demonstrated good analytical performances over a wide range of Tg concentrations, suggesting it is well suited to detecting variations in Tg concentrations. Studies comparing populations with different prevalence of anemia should consider the effect of hematocrit on DBS-Tg determination. The availability of a DBS-Tg assay for newborns makes it possible to integrate iodine status monitoring with newborn screening for inherited metabolic diseases.

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Omar Elghawy O Elghawy, Department of Hematology Oncology, University of Pennsylvania, Philadelphia, United States

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Adam Barsouk A Barsouk, Department of Hematology and Oncology, University of Pennsylvania, Philadelphia, United States

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Jessica Xu J Xu, Department of Hematology and Oncology, University of Pennsylvania, Philadelphia, United States

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Simon Chen S Chen, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States

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Roger B. Cohen R Cohen, Department of Hematology Oncology, University of Pennsylvania, Philadelphia, United States

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Lova Sun L Sun, Department of Medicine, University of Pennsylvania, Philadelphia, 19104-6243, United States

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Objective: Poorly differentiated thyroid carcinomas (PDTCs) are rare and aggressive head and neck malignancies with a poor prognosis. Systemic treatment for incurable PDTC consists of multi-kinase inhibitors (MKIs) based on extrapolation from the experience with radioiodine refractory differentiated thyroid cancer (DTC). Cabozantinib is an approved second line MKI therapy for DTC, but there are limited data regarding safety and efficacy of cabozantinib for PDTC.

Methods: We conducted a single institution, retrospective analysis of patients with PDTC who received cabozantinib in any line of therapy. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record. Median PFS and OS were primary endpoints and estimated using Kaplan-Meier methodology.

Results: Seven patients with PDTC who received cabozantinib, were included. 4/7 (57%) patients had a partial response to cabozantinib, while 2/7 (29%) had SD as their best response. Median time on treatment for cabozantinib was 10.53 months. Median PFS from start of cabozantinib was 12.9 months and median OS was 14.21 months. Most adverse events to treatment (5/6) were low grade. Two (29%) patients were alive at date of last follow up.

Conclusion: Cabozantinib is an effective and reasonably well-tolerated treatment option for patients with PDTC. Prospective studies are needed to further investigate the role of cabozantinib in the treatment of PDTC, alone and in combination with other agents including checkpoint inhibitors.

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Boyka Markova B Markova, Dept. of Endocrinology, University Hospital Essen, Essen, Germany

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Steffen Mayerl S Mayerl, Dept. of Endocrinology, University Hospital Essen, Essen, 45147, Germany

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Heike Heuer H Heuer, Dept. of Endocrinology, University Hospital Essen, Essen, Germany

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Patients with an inactive thyroid hormone (TH) transporter MCT8 (Allan-Herndon-Dudley Syndrome, AHDS) display severe neurological impairments and motor disabilities indicating an indispensable function of MCT8 in facilitating TH access to the human brain. As a consequence, the CNS of AHDS patients appears to be in a TH deficient state which greatly compromises proper neural development and function. As another hallmark of this disease, patients exhibit elevated serum T3 levels leading to a hyperthyroid situation in peripheral tissues. Several treatment strategies have been developed and evaluated in preclinical mouse models as well as in patients. Here, we discuss these different therapeutic approaches to overcome MCT8 deficiency and summarize the current achievements and challenges in improving brain maturation in the absence of MCT8.

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Karel David Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium

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Paul Van Crombrugge Department of Endocrinology, OLV Hospital, Aalst, Belgium

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Anne-Marie Van der Biest Department of Endocrinology, AZ Glorieux, Ronse, Belgium

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Frederiek D’Hondt Department of Urology, OLV Hospital, Aalst, Belgium

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Frank Claessens Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Alexander Giesen Department of Urology, University Hospitals Leuven, Leuven, Belgium

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Steven Joniau Department of Urology, University Hospitals Leuven, Leuven, Belgium

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Brigitte Decallonne Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium

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The androgen receptor signaling inhibitor apalutamide is used successfully for the treatment of prostate cancer. An increased risk of hypothyroidism, mostly subclinical, has been reported in the SPARTAN and TITAN trials. We present three cases of subacute deterioration of previously known but well-controlled hypothyroidism treated with levothyroxine, occurring shortly after the initiation of treatment with apalutamide, resulting in severe hypothyroidism. These cases highlight the importance of awareness of thyroid dysfunction during treatment with apalutamide, particularly in patients with pre-existing thyroid disease, common in the general population. We provide practice recommendations for thyroid management prior to and during apalutamide treatment as well as after the interruption of this therapy.

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Hyunju Park Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

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Jung Heo Division of Endocrinology and Metabolism, Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang-si, Gyeonggi-do, Korea

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Hyun Jin Ryu Division of Endocrinology & Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Min-Ji Kim Statistics and Data Center, Samsung Medical Center, Research Institute for Future Medicine

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Young Lyun Oh Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Tae Hyuk Kim Division of Endocrinology & Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Sun Wook Kim Division of Endocrinology & Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jae Hoon Chung Division of Endocrinology & Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Objective

Previous reports suggest that a high body mass index (BMI) increases the risk of thyroid carcinoma. However, it remains unclear whether a high BMI is associated with the risk of the BRAFV600E mutation. We aimed to assess whether a high BMI is associated with an increased risk of the BRAFV600E mutation.

Design and Methods

We screened 6558 PTC patients who had undergone BRAFV600E mutation testing between January 2009 and December 2017. After exclusion, 6438 PTC patients were enrolled. We used logistic regression, and restricted cubic spline plots of the adjusted odds ratios (ORs) were illustrated to model the relationship between BMI and the BRAFV600E mutation.

Results

Of the 6438 patients, 5102 (79.2%) had the BRAFV600E mutation, and 4954 (76.9%) were female. The median BMI was 23.8 (21.6–26.2) kg/m2. The primary tumor size was ≤1 cm in 4226 patients (65.6%) and >1 cm in 2212 patients (34.4%). The BRAFV600E mutation was significantly associated with high BMI only in patients with a primary tumor size >1 cm (OR: 1.034; 95% CI: 1.003–1.065; P = 0.029), whereas no clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; 95% CI: 0.984–1.030; P = 0.570). Gender was not a significant factor in either group.

Conclusions

Our study found that a higher BMI was positively associated with the BRAFV600E mutation in patients with a primary tumor size >1 cm. These results suggest that the association between BMI and the BRAFV600E mutation status differs depending on primary tumor size.

Significance Statement

Obesity has been suggested as a potential risk factor for thyroid carcinoma. The aim of this study was to assess the association between BMI and the BRAFV600E mutation. In this study, the BRAFV600E mutation was significantly associated with a high BMI only in a primary tumor size >1 cm (OR: 1.034; P = 0.029). No clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; P = 0.570). The association between BMI and the BRAFV600E mutation status differs depending on the primary tumor size.

Open access
Hyun-Jin Lee Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, South Korea

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Young-Sool Hah Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea

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So Young Cheon Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea

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Seong Jun Won Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Chae Dong Yim Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Somi Ryu Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Seung-Jun Lee Department of Convergence of Medical Sciences, Gyeongsang National University, Jinju, South Korea

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Ji Hyun Seo Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, South Korea

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Jung Je Park Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Objective

This study examined the effect of sirtuin 4 (SIRT4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).

Methods

Data from The Cancer Genome Atlas (TCGA) were analyzed to identify SIRT4 expression in thyroid cancer. Subsequently, the correlation between SIRT4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated SIRT4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.

Results

Gene Expression Omnibus (GEO) and TCGA data indicated that SIRT4 expression is lower in thyroid cancer and SIRT4 downregulation is associated with poor overall survival. In PTC tissues, positive SIRT4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of SIRT4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. SIRT4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial–mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.

Conclusion

This study provides novel insight into the potential contribution of SIRT4 to the regulation of the pathological progression of PTC. The data suggest that SIRT4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of SIRT4.

Open access
Yalan Hu Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, the Netherlands
Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands

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Lorraine Soares De Oliveira Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, Massachusetts, USA.
Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, Massachusetts, USA.

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Kim Falize Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, the Netherlands

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A S Paul van Trotsenburg Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands
Department of Pediatric Endocrinology. Emma children’s hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

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Eric Fliers Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands
Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

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Joseph E Kaserman Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, Massachusetts, USA.
The Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA

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Andrew A Wilson Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, Massachusetts, USA.
The Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA

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Anthony N Hollenberg Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, Massachusetts, USA.

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Eveline Bruinstroop Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands
Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

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Anita Boelen Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, the Netherlands
Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands

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Background

Mutations in TBL1X, part of the NCOR1/SMRT corepressor complex, were identified in patients with hereditary X-linked central congenital hypothyroidism and associated hearing loss. The role of TBL1X in thyroid hormone (TH) action, however, is incompletely understood. The aim of the present study was to investigate the role of TBL1X on T3-regulated gene expression in two human liver cell models.

Methods

A human hepatoma cell line (HepG2) wherein TBL1X was downregulated using siRNAs, and human-induced pluripotent stem cell-derived hepatocytes (iHeps) generated from individuals with a TBL1X N365Y mutation. Both cell types were treated with increasing concentrations of T3. The expression of T3-regulated genes was measured by qPCR.

Results

KLF9, CPT1A, and PCK1 mRNA expression were higher upon T3 stimulation in the HepG2 cells with decreased TBL1X expression compared to controls, while DIO1 mRNA expression was lower. Hemizygous TBL1X N365Y iHeps exhibited decreased expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to cells with the heterozygous TBL1X N365Y allele, but KLF9 and HMGCS2 expression was unaltered.

Conclusion

Downregulation of TBL1X in HepG2 cells and the TBL1X N365Y variant in iHeps have differential effects on T3-regulated gene expression. This suggests that TBL1X may play a gene context role in TH action.

Open access
Karoly Rucz K Rucz, Department of Endocrinology, Siofok Hospital, Siofok, Hungary

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Laszlo Hegedus L Hegedus, Department of Endocrinology, , Odense University Hospital, Odense, Denmark

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Steen Joop Bonnema S Bonnema, Department of Endocrinology, , Odense University Hospital, Odense, Denmark

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Andrea Frasoldati A Frasoldati, Endocrinology Unit , Arcispedale S Maria Nuova, Reggio Emilia, Italy

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Laszlo Jambor L Jambor, Department of Radiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

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Gabor Laszlo Kovacs G Kovacs, 1st Department of Medicine, Flohr Ferenc Hospital, Kistarcsa, Hungary

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Enrico Papini E Papini, Regina Apostolorum Hospital in Albano, Rome, Italy

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Gilles Russ G Russ, Unité Thyroïde et Tumeurs Endocrines - Pr Leenhardt Hôpital La Pitie Salpetriere, Sorbonne Université, Paris, France

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Zsolt Karanyi Z Karanyi, Faculty of Medicine, Department of Medicine, University of Debrecen, Debrecen, 4010, Hungary

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Endre V. Nagy E Nagy, Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

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Tamas Solymosi T Solymosi, Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

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Objective. The ultrasound evaluation of thyroid nodules (TN) in patient selection for fine needle aspiration (FNA) requires both uniformly accepted definitions of each nodule characteristic and extensive experience of the examiner. We hypothesized that nodule echogenicity alone may provide comparable performance to the more complex approaches, in patient selection for FNA.

Patients and Methods. Seven highly experienced investigators from four countries evaluated, online, the ultrasound (US) video recordings of 123 histologically verified TN, by answering 17 nodule characteristics-related questions. The diagnostic performances of five TN image reporting and data systems (TIRADS) were compared to making decisions based alone on echogenicity of the nodule, for indicating FNA in 110 nodules ≥10 mm.

Results. In the 10 to 20 mm size range, the sensitivities and specificities of the five TIRADS systems in identifying malignant nodules was 80.5%-91.0%, and 31.4-50.9%, respectively. Had FNA been recommended in all hypoechoic nodules, disregarding other US characteristics, comparable sensitivity and specificity (87.5% and 43.4%, respectively) were obtained. Compared to nodules >20mm, a higher proportion of cancers were hypoechoic in the 10 to 20 mm size range (87.2% vs. 77.8%, p=0.05). In the 10-20 mm size range, compared to hypoechoic nodules, a significantly lower proportion of isoechoic nodules demonstrated suspicious findings (70.7% vs. 30.0%, p<0.05).

Conclusion. In contrast to >20 mm diameter nodules, the recommendation of FNA may rely on a single US feature, echogenicity, in the 10-20 mm size range. If independently confirmed in larger cohorts, this may simplify nodule evaluation in this size range.

Open access
Jeanette Carlqvist J Carlqvist, Department of Radiology, University of Gothenburg Institute of Clinical Sciences, Goteborg, Sweden

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Ulf Nyman U Nyman, Division of Medical Radiology, Lund University Department of Translational Medicine, Malmo, Sweden

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John Brandberg J Brandberg, Department of Radiology, University of Gothenburg Institute of Clinical Sciences, Goteborg, Sweden

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Helena Filipsson Nyström H Nyström, Department of Endocrinology, Sahlgrenska University Hospital, Goteborg, Sweden

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Mikael Hellström M Hellström, Department of Radiology, University of Gothenburg Institute of Clinical Sciences, Goteborg, Sweden

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Objectives: When exposed to iodine contrast medium (ICM), thyroid dysfunction may develop, due to excess amounts of iodide. The incidence of contrast-induced thyroid dysfunction has been difficult to interpret, because of the observational and retrospective designs of most previous studies. With the Swedish CArdioPulmonary bioImage Study (SCAPIS), where randomly selected individuals aged 50–65 years, underwent contrast-enhanced coronary CT angiography (CCTA), we were able to prospectively assess the incidence, magnitude and clinical impact of contrast-induced thyroid dysfunction.

Methods: In 422 individuals, thyroid hormone levels were analysed before and 4–12 weeks after CCTA. Thyroid-related patient-reported outcome questionnaires (ThyPRO) at the time of pre and post CCTA blood samplings were provided by 368 of those individuals. Thyroid peroxidase antibodies (TPOab) were analysed and ultrasound of the thyroid gland was performed to detect any thyroid nodules.

Results: There was a small statistically significant effect on thyroid hormone levels but no cases of overt hypo- or hyperthyroidism after ICM. Subclinical hypo- or hyperthyroidism or isolated low/high levels of free thyroxine (fT4) developed in 3.5% of the population with normal hormone levels pre-CCTA, but without any increased thyroid-related symptoms compared to the remaining cohort. Elevated TPOab and being born outside Sweden were risk factors of developing subclinical hypothyroidism. Presence of thyroid nodules was not associated with ICM-induced thyroid dysfunction.

Conclusion: The results of this prospective study support the notion that in iodine-sufficient countries, ICM associated thyroid dysfunction is rare, usually mild, self-limiting and oligo/asymptomatic in subjects aged 50–65 years.

Open access
Alison-Michelle Naujack Institute for Human Genetics, Department of Epigenetics & Metabolism, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany

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Christin Krause Institute for Human Genetics, Department of Epigenetics & Metabolism, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany

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Jan H Britsemmer Institute for Human Genetics, Department of Epigenetics & Metabolism, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany

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Natalie Taege Institute for Human Genetics, Department of Epigenetics & Metabolism, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany

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Jens Mittag Institute for Experimental Endocrinology, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany

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Henriette Kirchner Institute for Human Genetics, Department of Epigenetics & Metabolism, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany

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Objective

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis, and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signaling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized that epigenetic mechanisms may be involved in modulating hepatic TH action.

Methods

Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2 cells were used to validate the functional binding of miRNA to predicted targets. DNA methylation was analyzed by bisulfite pyrosequencing.

Results

miR-34a-5p was upregulated in MASH patients and correlated positively with the clinical parameters of MASH. Using in silico and in vitro analysis, we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by the functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2 cells reduced the expression of THRA, THRB, DIO1, and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As an additional regulatory mechanism, DNA methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression.

Conclusion

miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB-specific DNA methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.

Open access