European Thyroid Journal最新文献

Alemtuzumab is a powerful anti-CD52 drug that is an established treatment option in patients with multiple sclerosis due to its proven efficacy. However, in about 50% of patients, the use of alemtuzumab is burdened by the development of secondary autoimmune thyroid diseases, constituting a range of alemtuzumab-induced autoimmune thyroid diseases (AIATDs). Graves' disease (GD) is the most common AIATD, with an incidence of approximately 60%, and presents different characteristics from the conventional form. Indeed, GD with a fluctuating course is significantly more prevalent (15-50%), which poses a major challenge for physicians in its management. Other AIATDs also exhibit distinct features compared to their conventional counterparts; notably, hypothyroidism is frequently associated with TSH-receptor blocking antibodies, and alemtuzumab-induced GD demonstrates a higher rate of fluctuating course and potential for spontaneous remission. Alemtuzumab-induced thyroid eye disease (TED) is less common than conventional TED, with similar clinical and management characteristics. In this review, we summarize the latest evidence, also from real-world studies, with a focus on clinical management and possible predictors of AIATDs.

Introduction: Mutations of RAS genes are detected in a spectrum of follicular-patterned thyroid tumors. Preoperative prediction of invasive cancers based on the presence of RAS mutation alone is challenging because non-invasive and invasive tumors tend to have similar sonographic and cytologic features. The aim of this study was to perform clinicopathologic and molecular analyses of RAS-mutant tumors, identify molecular and clinical markers associated with invasiveness, and determine their diagnostic and therapeutic potentials.

Methods: We collected clinicopathologic characteristics and performed RNA-seq on 48 surgically resected RAS-mutant thyroid tumors (23 non-invasive and 25 invasive). A classifier using expression data of selected invasiveness markers and clinical parameters was applied to an independent set of 54 RAS-mutant fine-needle aspiration (FNA) samples to predict invasion. Selected markers were investigated in vitro and in vivo.

Results: On RNA-seq analysis, invasive RAS-mutant tumors showed different gene expression profiles compared to non-invasive tumors. Expression levels of six selected genes (CA12, CD44, LRP4, ECM1, FN1, and CRABP1) were associated with invasiveness on qRT-PCR. Expression levels of these genes plus nodule size predicted invasion in RAS-mutant FNA samples with 95% sensitivity and 89% specificity. siRNA silencing and chemical inhibition of CA12 reduced invasion of RAS-mutant human thyroid cells. Treatment of RAS-mutant xenografts with CA12 inhibitors arrested tumor growth.

Conclusions: Development of invasion in RAS-mutant tumors is associated with significant alteration in gene expression. Expression levels of six genes and nodule size may predict invasion in RAS-mutant thyroid nodules, whereas chemical inhibition of CA12 may have a potential therapeutic effect in RAS-mutant tumors.

The incidence of differentiated thyroid cancer (DTC) has increased significantly in recent decades. Following initial diagnosis, DTC patients are classified according to the American Thyroid Association (ATA) as low, intermediate, and high risk for recurrence. Patients in the ATA low recurrence-risk category have a recurrence risk of ≤5%, with 20-year disease-specific mortality of <1%. Accordingly, there has been a shift to de-escalating initial treatment, including the relaxation of thyroid-stimulating hormone suppression. In addition, fewer low-risk patients undergo total thyroidectomy or radioactive iodine therapy. However, the optimal long-term surveillance strategy remains unclear, with many patients continuing follow-up in speciality clinics for many years. In addition, emerging evidence suggests that long-term surveillance can be effectively managed in primary care settings. To enhance understanding among Canadian thyroid practitioners and to improve care for Canadian patients diagnosed with low-risk DTC, we developed this consensus statement by collecting feedback from a multidisciplinary team led by one chairperson (endocrinologist), an additional eight endocrinologists, two surgeons, and one patient partner. This consensus statement reflects current evidence and expert opinion regarding initial management and long-term surveillance of low-risk DTC patients. This work is valuable to Canadian thyroid practitioners as it provides standardized guidelines to ensure optimal care and improved outcomes for low-risk DTC patients.

Anaplastic thyroid carcinoma (ATC) is among the most daunting entities in clinical oncology. Large-scale genomic studies of thyroid cancer within the last decade have uncovered a distinct set of recurrent somatic alterations implicated in the development, aggressiveness, and treatment resistance of ATC. The sequence of events leading to the development of ATC commonly begins with a tumorigenic mutation that constitutively activates the mitogen-activated protein kinase (MAPK) pathway, giving rise to indolent entities such as well-differentiated papillary or follicular thyroid carcinomas. This is followed by recurring alterations that drive oncogenic properties such as enhanced proliferation, genomic instability, replicative immortality, and dedifferentiation, culminating in the emergence of highly aggressive ATC tumors. The truncal MAPK-activating events present therapeutic opportunities, as small molecule inhibitors against key components of this pathway are available. Indeed, genotype-guided targeting of the MAPK pathway is now the standard of care for subgroups of ATC patients, and further efforts exploring additional MAPK inhibitors and the combination of immune checkpoint blockade with MAPK inhibition are overcoming resistance to the current targeted therapies in the clinic and expanding our arsenal against this disease. In this review, we summarize the current understanding of the genomic landscape of ATC, discuss the biological and clinical ramifications of recurring aberrations, and provide an overview of the opportunities and challenges in the clinical management of this lethal malignancy.

Objective: The monocarboxylate transporter (MCT) 8 is a specific transporter for thyroid hormones. Pathogenic variants in MCT8 lead to a severe psychomotor disorder called MCT8 deficiency. A recently published patient carries a MCT8V235 to leucine substitution that was incapable of T3 transport. Analyses of our MCT8 homology model predicted steric clashes between Leu235 and Phe285 as well as Gln288, possibly affecting another transport-sensitive phenylalanine at position 287.

Methods: We analyzed the occurrence of potential van der Waals (VDW) interactions between Leu235 and Phe285 as well as Gln288 in the homology model. We overexpressed MCT8V235 and MCT8F287 mutants with altered side-chain properties in cells to assess their role in T3 transport function. In addition, we created an MCT8V235L,F285A double mutant.

Results: Mutations of MCT8V235 to alanine, threonine or isoleucine, as well as the analysis of potential VDW interactions, helped us to identify Phe285, but not Gln288, as the amino acid responsible for the inactivity of MCT8V235L. The hypothesis was supported by activity measurements of an MCT8V235L,F285A double mutant that showed rescued T3 transport with KM values similar to wild-type MCT8. The analyses of MCT8F287 mutated to tyrosine, tryptophan and valine revealed that the size and/or the aromatic properties of the amino acid side chain are crucial for proper membrane expression and T3 transport.

Conclusion: We were able to restore transport activity of MCT8V235L by introducing a second mutation (MCT8V235L,F285A). We speculate that the additional mutation prevents a shift of Phe287 into the potential transport cavity, eventually restoring T3 transport.

Background: Early diagnosis of medullary thyroid cancer (MTC) when basal calcitonin (CT) levels are <100 pg/mL remains a clinical challenge. The calcium stimulation test is a unique tool for stimulating CT. However, standardized and sex-specific cutoff values are lacking. Therefore, this study aimed to investigate whether the calcium stimulation test for CT is adequate for diagnosing MTC in both sexes and to identify sex-specific cutoff values.

Methods: This was an individual patient data (IPD) meta-analysis. A literature search was performed using Scopus, PubMed, and Web of Science until September, 2024, to identify articles on the calcium stimulation test for diagnosing MTC.

Results: A total of five studies involving 243 patients (148 females and 95 males) who underwent total thyroidectomy were included in this study. Before surgery, all patients underwent the calcium stimulation test with calcium gluconate (25 mg/kg) for CT assessed by chemiluminescence assay. In females, a global threshold of 162 pg/mL was identified, with a pooled sensitivity of 0.90 (95% confidence interval (95% CI): 0.79-0.97) and specificity of 0.66 (95% CI: 0.56-0.75). The pooled area under the curve (AUC) was 0.87 (95% CI: 0.76-0.97). In males, a global threshold of 562 pg/mL was identified, with a pooled sensitivity of 0.79 (95% CI: 0.60-0.92) and specificity of 0.89 (95% CI: 0.79-0.96). The pooled AUC was 0.94 (95% CI: 0.90-0.99).

Conclusions: The calcium stimulation test for CT for the diagnosis of MTC showed better performance in males than in females, with a suggested cutoff value of 562 pg/mL in males.

Significance statement: The management of indeterminate calcitonin (CT) values is still challenging in the early diagnosis of MTC, lacking general recommendations, which can help clinicians in these cases. This is the first IPD meta-analysis that underscores the sex-based disparity in the diagnostic accuracy of the calcium stimulation test for CT in suspected MTC cases, showing better performance in diagnosing MTC in male versus female patients, with a cutoff value of 562 pg/mL in male subjects. In the context of the limited literature, this paper provides added value for the clinical endocrine practitioner, suggesting the use of the calcium stimulation test in highly selected cases with indeterminate CT values (10-100 pg/mL) with a sex-oriented and personalized approach.

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.