European Thyroid Journal最新文献

Thyroid hormone receptor α1 (TRα1) regulates body temperature and heart rate in humans and mice. In addition to its direct actions in target tissues, it also affects peripheral functions indirectly through the brain. While these central actions on peripheral tissues have been demonstrated for liver and brown fat, the consequences for cardiac functions are still enigmatic. Recently, a population of parvalbumin neurons has been discovered in the anterior hypothalamic area that depends on TRα1 for correct development and controls heart rate in a temperature-dependent manner. Here we test the hypothesis that not only developmental but also acute actions of TRα1 in hypothalamic parvalbumin neurons affect the central control of cardiovascular functions. We used an AAV-mediated stereotaxic approach to express a mutant TRα1R348C conditionally in hypothalamic parvalbumin cells, thus impairing TRα1 action specifically in these neurons. While this had no effect on metabolism or thermoregulation, using non-invasive radiotelemetry we observed a reduced heart rate both at 22°C and 30°C. Interestingly, heart rate was normalized when the animals were measured by ECG, which requires prior handling, suggesting that the impairment caused by the mutant TRα1 can be compensated in more stressful situations. Taken together, our data show that TRα1 signaling in hypothalamic parvalbumin neurons acutely affects the central control of heart rate, adding a novel mechanism to bradycardia in hypothyroidism. Furthermore, the data underline the importance of non-invasive recordings of in vivo functions in animal models with alterations in central thyroid hormone action.

Background: A substantial proportion of patients taking thyroid hormone replacement for hypothyroidism show persistent symptoms. We sought to explore the prevalence and degree of fatigue in this patient group.

Methods: An online survey including the FACIT-F fatigue scale was distributed by two UK patient support organisations, the British Thyroid Foundation (BTF) and The Thyroid Trust (TTT). Overall, 1,334 responses were received, of which 1,251 were complete, unique and from patients with primary hypothyroidism/Hashimoto thyroiditis who reported taking thyroid hormone replacements.

Results: Ninety eight percent of respondents were women and the mean duration of treatment was 10.8 years (SD: 9.74). The mean fatigue score on the FACIT-F scale was 20.5 (SD: 10.5), with 89% of respondents fulfilling criteria for abnormal fatigue. Fatigue scores were not significantly different between respondents of different ages, gender, treatment type or treatment duration. FACIT-F scores were positively correlated with self-declared overall health state (Pearson r = 0.576, P < 0.001).

Conclusions: Fatigue in treated hypothyroidism is very common, and the FACIT-F scores reported are comparable or worse than those recorded for many other chronic conditions. This study suggests that addressing fatigue in this patient group will be key to improving wellbeing and quality of life.

Objective: Hyperthyroidism is characterized by weight fluctuations and overshoot of weight regain following treatment. We aimed to identify parameters predicting peak percentage weight gain (PWG) in the post-treatment period.

Methods: We included 110 patients (73 (66.4%) women) with hyperthyroidism 6-36 months after treatment initiation. The primary outcome was PWG of ≥10% (group A) or <10% (group B). We performed adjusted analyses by logistic regression with age, sex, disease-related weight loss, hypothyroidism occurrence, free T4 at diagnosis (fT4-t0) and disease duration as independent variables.

Results: Post-treatment mean (SD) weight gain was 7.4 (5.22) kg, whereas disease-related weight loss was 5.3 (5.15) kg. Group A (52.7% participants) compared to group B had significantly higher median (IQR) fT4-t0 at 47.4 (36.2, 97.2) vs 29.3 (22.8, 40.4) ng/dL (P < 0.001) and disease-related weight loss at 6.8 (3, 10) vs 2.5 (0, 4.8) kg (P < 0.001) and non-significantly higher presentation free triiodothyronine at 19.6 (10.4, 44.1) vs 11.8 (8.7, 22.9) pg/mL (P = 0.078) and TRAb at 6.3 (3, 16.1) vs 4.2 (2.4, 8.7) IU/L (P = 0.093), respectively. Significant predictor variables of post-treatment PWG in logistic regression were disease-related weight loss (OR = 1.23, P = 0.002) and fT4-t0 (OR = 1.04, P = 0.008).

Conclusion: More than half the patients with hyperthyroidism had ≥10% PWG post-treatment. Indicators of disease severity, namely disease-related weight loss and baseline thyroid hormones, were predictive of excessive weight gain post-treatment and could be utilized for risk stratification and early intervention.

Background: Tumor deposits (TDs), nodules in the peritumoral adipose tissue with no architectural residue of lymph node, have previously been described in colorectal adenocarcinomas with poor prognosis. However, the significance of TD has not been fully investigated in patients with papillary thyroid carcinoma (PTC).

Method: We retrospectively enrolled 541 patients undergoing surgery between 2015 and 2021. The patients were classified into two groups according to TD status (TD vs non-TD), and the clinicopathologic characteristics and disease-free survival (DFS) were compared. Associations of TD presence with other clinicopathologic factors were evaluated by logistic regression analysis. Univariate and multivariate Cox regression analyses were performed to determine the primary cohort's prognostic factors for DFS. A nomogram was constructed for clinicians as a quantitative tool for estimating DFS.

Result: In our cohort, TD were identified in 16.1% of patients and had higher rate of aggressive features, including microscopic and gross extrathyroidal extension, invasion of the recurrent laryngeal nerve and esophagus, prevertebral fascia involvement or encasement of the carotid artery/internal jugular vein, extranodal extension, advanced clinical stage, tumor recurrence and distant metastasis (all P < 0.05). Univariate and multivariate Cox regression analyses confirmed TD as an independent prognostic factor for DFS, with a 2.501-fold increased risk of recurrence (P < 0.001). The nomogram, incorporating TD and other significant factors, demonstrated good discrimination and calibration (C-index = 0.79).

Conclusion: The presence of TD was significantly associated with poor prognosis in PTC patients. TD showed promising efficacy as a potential prognostic indicator for PTC patients.

Objective: Mammalian acid chitinase (AMCase; CHIA) has potential as a biomarker and drug target in the fields of medicine and pharmacology, and its role in inhibiting tumor growth and Th2 cell-mediated asthma-related inflammation has become a research hotspot. However, the role of CHIA in thyroid cancer is unclear.

Methods: Tissue microarrays and thyroid cancer cell lines were used to detect CHIA expression and determine its clinical relevance. CHIA gene expression was altered in thyroid cancer cells to examine the effects of CHIA expression on the biological behavior of thyroid cancer cells, and the related molecular mechanisms involved were explored.

Results: We first examined CHIA expression in a thyroid tissue microarray using immunohistochemistry. We found that CHIA was significantly upregulated in thyroid cancer tissues relative to paired thyroid cancer adjacent tissues. After correlation analysis, we found that upregulated CHIA expression correlated with the tumor-node-metastasis (TNM) stage of patients with thyroid cancer. Similarly, CHIA expression was significantly higher in the thyroid cancer cell lines BCPAP, TPC-1, KTC-1 and FTC133 than in the human normal thyroid epithelial cell line Nthy-ori-3-1. CHIA promotes proliferation, migration and invasion; inhibits thyroid cancer cell apoptosis; and regulates markers of proliferation and epithelial-mesenchymal transition. Mechanistically, CHIA activated the JAK2/STAT3 signaling pathway in thyroid cancer cells.

Conclusions: CHIA upregulation promoted the proliferation, migration and invasion of thyroid cancer cells through JAK2/STAT3 signaling pathway activation. Therefore, CHIA could represent a potential new oncoprotein for patients with thyroid cancer.

Objective: Maternal thyroid peroxidase antibody (TPOAb) positivity has been associated with a variety of pregnancy complications and has potential neuropsychological developmental implications for the offspring. The aim of our study was to explore the effect of maternal TPOAb levels on emotional and behavioral problems in children.

Design: The study was designed as a cohort study.

Participants: Based on the Ma'anshan birth cohort in China, 2,464 mother-infant pairs were included in this study.

Measurements: Repeated blood samples were collected from pregnant women, and TPOAb and FT4 were measured retrospectively by electrochemiluminescence immunoassay (ECLIA). The strengths and difficulties questionnaire was used to assess the emotional and behavioral problems of 4-year-old preschoolers.

Results: After adjusting for potential confounders, maternal TPOAb positivity during the third trimester of pregnancy was found to be associated with an elevated risk of conduct problems in girls, with an odds ratio (OR) of 2.190 (95% confidence interval (CI): 1.137-4.219). Conversely, maternal TPOAb positivity in the first trimester was linked to a decreased incidence of prosocial behavior in boys, with an OR of 0.451 (95% CI: 0.237-0.861).

Conclusions: Maternal TPOAb positivity during pregnancy may be associated with emotional and behavioral problems in preschool-aged children.

Introduction: Little is known about sex differences in lenvatinib treatment safety and efficacy.

Methods: Real-word retrospective Italian multicenter study enrolling patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib.

Results: A total of 138 patients (64 females) were included, with a median follow-up of 26 months (2-72). More men performed physical activities (34% vs 17%, P = 0.024). The frequency of smoking and alcohol consumption was higher in men (58% vs 33%, P = 0.003; 45% vs 17%, P = 0.001). We did not find sex differences in lenvatinib dose reduction due to adverse events (AEs) (78% females vs 85% males). Ninety-nine percent of patients developed at least one adverse event (AE), with no sex difference in their number and the time to first AE. Severe AEs occurred in 74% of males and 66% of females (P = 0.398), with a mean dose of 18.2 mg (±5.7), and a median time to the first serious AE of 9 weeks (1-154). Stomatitis/mucositis and hematological disorders were more frequent in females (48% vs 30%, P = 0.016; 17% vs 4%, P = 0.011). Gastrointestinal disorders were higher in males (15% vs 2%, P = 0.010). Eighty-seven patients interrupted lenvatinib due to AEs (median time: 3 months (0-48), mean dose: 17 mg ±5.5). Discontinuation occurred in 21 patients, five for severe AEs. No sex differences were found in progression-free survival, overall survival or disease control rate. Liver metastases were associated with disease progression (HR: 3.73, 95% CI: 1.06-13.12, P = 0.040) or death (HR: 4.82, 95% CI: 1.75-13.25, P = 0.002) only in females.

Conclusion: Lenvatinib is effective in both sexes and exhibits a good safety profile, with a sex difference in the frequencies of some adverse events.

Objective: The optimal treatment with antithyroid drugs (ATDs) for a first episode of Graves' disease (GD) remains controversial.

Methods: Retrospective, two academic centres study of newly diagnosed GD between 1990 and 2022, treated with ATD in block-and-replace (B+R) regimen for at least 12 months and followed up for at least 1 year after ATD discontinuation or until disease relapse. Sixty patients received high-dose B+R (HD) with fixed ATD dose maintained during the study, and 60 patients received low-dose B+R (LD) with lower ATD dose adjusted during the study.

Results: Baseline characteristics were similar in both groups. The point-prevalence of euthyroidism was not different between HD and LD (38 vs 47%, P = 0.460 at 6 months, 69 vs 82%, P = 0.194 at 12 months, 70 vs 78%, P = 0.370 at 18 months, respectively). At 18 months, 27% HD vs 38% LD (P = 0.242) had thyroid eye disease. There were no differences in the number or type of ATD-related adverse events (AE) (no AE 73 vs 78%, P = 0.707). LD received mean lower ATD dose (15.3 ± 4.2 vs 30.0 ± 0.0 mg/day, P < 0.001) and lower levothyroxine dose (72.6 ± 16.7 vs 100.6 ± 24.5 μg/day, P < 0.001). After a first course of ATD, 63% of HD patients and 60% of LD patients relapsed (P = 0.707) after a median time (interquartile range) of 11.0 (18) vs 7.0 (19) months (P = 0.109).

Conclusion: We observed similar relapse rates in patients with a first episode of GD receiving up to 50% less ATD and 30% less levothyroxine dose than high-dose B+R regimen.

Anaplastic thyroid cancer is one of the rarest subtypes of thyroid cancer, accounting for only 1-2% of all thyroid cancer cases. It is also one of the most aggressive: prognosis remains dismal and the disease-specific mortality rate is close to 100%. This rarity has markedly limited the availability of prospective trial results, and no standard chemotherapeutic option for unresectable or metastatic anaplastic thyroid cancer has yet been established. Nevertheless, combination therapy with a BRAF inhibitor and MEK inhibitor has shown encouraging efficacy in patients with BRAF V600E-mutated anaplastic thyroid cancer. Other novel treatments such as immune checkpoint inhibitors have also shown promising results. Owing to these therapeutic advances, the prognosis of anaplastic thyroid cancer appears to be gradually improving. However, further development of novel treatments for this rare malignancy requires the development of substantial infrastructure for international collaborative study.

Objectives: Total thyroidectomy is the treatment of choice for medullary thyroid cancer (MTC), although the sporadic forms are usually monocentric. Aim of the present study was to evaluate i) the performance of calcitonin (Ct) levels, ultrasound scans (US) and cytology in the preoperative identification of MTC and ii) the number of total thyroidectomies that could have been avoided being the location of the MTC diagnosed preoperatively.

Materials and methods: We retrospectively analyzed 89 RET germline negative patients diagnosed with MTC in the past 30 years, treated with total thyroidectomy ± lymphadenectomy, and followed in our Tertiary Care Center. In a subgroup of 55 patients, divided in those with a mono- or bi-lateral goiter, we applied ex-post criteria for the presurgical identification of the lobe holding the MTC nodule.

Results: Only 2/89 patients (2.2%) had a bilateral MTC at histology. A strongly significant correlation was found between preoperative basal Ct levels and MTC size. According to the ex-post identification criteria, the 84.4 and 56.5% of the nodules would have been identified preoperatively as MTC in monolateral and bilateral goiters, respectively.

Conclusions: This is the first European study that aims to evaluate the feasibility of lobectomy as first-line therapy for MTC based on the evaluation of thyroid US and serum Ct levels. These tools have been shown to have a good accuracy in detecting the affected lobe and strongly support the possibility to perform a more conservative surgery to treat RET-negative patients with suspicious MTC and nodular goiter.