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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.
Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, South Korea
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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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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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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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Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, South Korea
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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.
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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.
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Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.
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Objective:
Hyperthyroidism increases cardiovascular morbidity and mortality, but the underlying mechanisms are not fully understood. In this study we compared non-invasive haemodynamics between 20 hyperthyroid patients and 60 euthyroid subjects.
Methods:
The measurements were performed median 6 days after the initiation of antithyroid medication when the patients were still hyperthyroid. Three controls matched for age, sex, body mass index, and smoking status were selected for each patient. Recordings were performed during rest and passive head-up tilt using whole-body impedance cardiography, radial pulse wave analysis, and finger blood pressure measurements.
Results:
Systolic and diastolic blood pressures in the aorta and radial artery were similar in hyperthyroid and euthyroid subjects, while finger blood pressure was 16/12 mmHg lower in hyperthyroidism (p<0.001). Pulse wave velocity and aortic pulse pressure were similar, but radial pulse pressure was ~5 mmHg higher in hyperthyroidism (p=0.040) due to augmented amplification (p=0.045). Systemic vascular resistance was reduced (-18%), whereas heart rate (+19 beats/min), cardiac index (+28%), and left cardiac work (+31%) were increased in hyperthyroidism (p<0.001). Subendocardial viability ratio, reflecting the balance between coronary perfusion and pressure load, was reduced by 19% in hyperthyroidism (p<0.001). Compared with euthyroid subjects, hyperthyroid patients presented with reductions in systolic and diastolic finger blood pressures (p<0.001), and higher increase in heart rate (p=0.014) during upright posture.
Conclusions:
Hyperthyroid patients exhibited hyperdynamic circulation, reduced vascular resistance, reduced peripheral but not central blood pressure, and higher pulse pressure amplification. Furthermore, left cardiac workload was increased in parallel with unfavourable changes in coronary perfusion conditions.
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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 down regulated 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 was 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, 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 thyroid hormone TH action.
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Objective: As thionamide is associated with various adverse effects, we reevaluated the practical efficacy of potassium iodide (KI) therapy for Graves’ hyperthyroidism (GD).
Methods: We administered KI (mainly 100 mg/day) to 324 untreated GD patients, and added methimazole (MMI) only to those remaining thyrotoxic even at 200 mg/day. When the patient became hypothyroid, MMI if taken was stopped, then levothyroxine (LT4) was added without reducing the KI dose. Radioactive iodine (RI) therapy or thyroidectomy was performed whenever required. We evaluated the early effects of KI at 2-4 weeks, and followed patients for 2 years.
Results: At 2 weeks, serum thyroid hormone decreased in all 324 patients. At 4 weeks, fT4, fT3, and both fT4 and fT3 levels became normal or low in 74.7%, 50.6%, and 50.6%, respectively. In a cross-sectional survey over 2-years, GD was well-controlled with KI or KI+LT4 (KI-effective) in >50% of patients at all time points. Among 288 patients followed for 2 years, 42.7% remained ‘KI-effective’ throughout 2 years (KI Group), 30.9% were well-controlled with additional MMI given for 1-24 months, and 26.4% were successfully treated with ablative therapy (mainly RI). Among ‘KI-effective’ patients at 4 weeks, 76.5% were classified into KI Group. No patients experienced adverse effects of KI.
Conclusion: KI therapy was useful in the treatment of GD. A sufficient dose of KI was effective in >50% of GD patients from 4 weeks to 2 years, and 42.7% (76.5% of ‘KI effective’ patients at 4 weeks) remained ‘KI-effective’ throughout 2 years.
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Background: To explore whether IgG4 is involved in the pathogenesis of IgG4 HT.
Methods: Serum TgAb IgG4 and TPOAb IgG4 were measured in IgG4 HT and non-IgG4 HT. C1q, mannose-binding lectin (MBL), Bb, C3d, C4d and membrane attack complex (MAC) in thyroid tissues from IgG4 HT, non-IgG4 HT and controls were examined by immunohistochemistry. We assessed IgG4 and MAC deposition in mouse thyroid by immunohistochemistry after injecting purified IgG4 into mice. The glycosylation patterns of TgAb IgG4 from IgG4 HT were identified by MALDI-TOF-MS. The ability of IgG4 binding to MBL before and after deglycosylation was assessed by ELISA. MBL and MAC fluorescence were detected in thyrocytes after the addition of IgG4 or deglycosylated IgG4.
Results: Serum TgAb IgG4 and TPOAb IgG4 levels were higher in IgG4 HT. MBL, Bb, C3d, C4d and MAC levels were higher in thyroid tissues of IgG4 HT than in non-IgG4 HT (all P < 0.001). IgG4 colocalized with MBL by immunofluorescence. In mice, follicular cell structure disruption was observed after the injection of IgG4 from IgG4 HT, as well as the colocalization of IgG4 with MAC. High levels of TgAb IgG4 glycosylation patterns, including monogalactose glycan (G1F), galactose-deficient glycan (G0F), and high-mannose glycan (M5), were detected in IgG4 HT. After deglycosylation, IgG4 reduced its ability binding to MBL, and there was low MBL and MAC activation in thyrocytes.
Conclusion: High levels of IgG4 glycosylation patterns, including G1F, G0F and M5, may activate the complement lectin pathway, thereby participating in the pathogenesis of IgG4 HT.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy
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Endocrine Section, Beacon Hospital, Dublin, Ireland.
School of Medicine, University College Dublin, Ireland
Endocrinology Department, St Vincent’s University Hospital, Dublin, Ireland
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Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.
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Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
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Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Objective
Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC.
Methods
Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies.
Results
Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial.
Conclusion
Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.
