Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β.

CONTEXT: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity. OBJECTIVE: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4. METHODS: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed. RESULTS: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4. CONCLUSIONS: Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling

Serum immunoglobulins and biomarkers of dementia:a population-based study

Background: Inflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia. Methods: Between 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-β40 (Aβ-40), amyloid-β42 (Aβ-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex. Results: Of 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5–72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7–60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aβ-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029−-0.002], p = 2.8 × 10–2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046−-0.008], p = 6.0 × 10–3) and more white matter hyperintensities (0.047 [0.016 – 0.077], p = 3.0 × 10–3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aβ-40, and Aβ-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women. Conclusions: While associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.</p

Active Surveillance for Papillary Thyroid Microcarcinoma in a Population with Restrictive Diagnostic Workup Strategies

Background: The worldwide incidence of papillary thyroid carcinoma (PTC) has increased. Efforts to reduce overtreatment follow two approaches: limiting diagnostic workup of low-risk thyroid nodules and pursuing active surveillance (AS) after diagnosis of microscopic PTC (mPTC). However, most studies on AS have been performed in countries with a relatively high proportion of overdiagnosis and thus incidental mPTC. The role of AS in a population with a restrictive diagnostic workup protocol for imaging and fine-needle aspiration remains unknown. Therefore, the aim of this study was to describe the proportion and characteristics of patients with mPTC in the Netherlands and to describe the potential candidates for AS in a situation with restrictive diagnostic protocols since 2007. Methods: All operated patients with an mPTC in the Netherlands between 2005 and 2015 were identified from the Netherlands Cancer Registry database. Three groups were defined: (Group 1) mPTC with preoperative distant or lymph node metastases, (Group 2) mPTC in pathology report after thyroid surgery for another indication, and (Group 3) patients with a preoperative high suspicious thyroid nodule or proven mPTC (Bethesda 5 or 6). Only patients in Group 3 were considered potential candidates for AS. Results: A total of 1018 mPTC patients were identified. Group 1 consisted of 152 patients with preoperatively discovered metastases. Group 2 consisted of 667 patients, of whom 16 (2.4%) had lymph node metastases. There were 199 patients in Group 3, of whom 27 (13.6%) had lymph node metastases. After initial treatment in Group 3, 3.5% (7/199) of the patients had recurrence. Conclusions: Restrictive diagnostic workup strategies of patients with small thyroid nodules lead to limited patients eligible for AS and a higher incidence of lymph node metastases. We believe that there is limited additive value for AS in countries with restrictive diagnostic workup guidelines such as in the Netherlands. However, if an mPTC is encountered, AS can be offered on an individual basis

Deescalating Follow-up after Hemithyroidectomy for Patients with Low-risk Papillary Thyroid Microcarcinoma

Importance: Structural recurrent disease (RD) after surgical treatment of papillary thyroid microcarcinoma (mPTC) is rare. We hypothesized that the RD rate after hemithyroidectomy in low-risk patients with mPTC is low.Objective: To assess the occurrence of RD in Dutch patients with mPTC who received surgical treatment according to the Dutch guidelines.Design, Setting, and Participants: This nationwide retrospective cohort study included all patients who had undergone surgery with a diagnosis of cN0/cNx mPTC in the Netherlands between January 2000 and December 2020 were identified from the Netherlands Cancer Registry database. Patients with preoperative lymph node metastases were excluded. Two groups were defined: group 1 (incidental), mPTC in pathology report after thyroid surgery for another indication; and group 2 (nonincidental), patients with a preoperative highly suspect thyroid nodule (Bethesda 5) or proven mPTC (Bethesda 6). Dutch guidelines state that a hemithyroidectomy is sufficient in patients with unifocal, intrathyroidal mPTC. Main Outcomes and Measures: The occurrence of RD in patients with low-risk mPTC after hemithyroidectomy.Results: In total, 1636 patients with mPTC were included. Patients had a median (IQR) follow-up time of 71 (32-118) months. Median (IQR) age at time of diagnosis was 51 (41-61) years and 1292 (79.0%) were women. Overall, RD after initial treatment was seen in 25 patients (1.5%). The median (IQR) time to RD was 8.2 (3.6-16.5) months and 22 of the 25 (88%) patients developed RD within 2 years. Recurrent disease was not significantly different between both groups (group 1, n = 15 [1.3%]; group 2, n = 10 [2.1%]; difference, 0.8%; 95% CI, -0.5% to 2.5%). Of the 484 patients with nonincidental mPTC (group 2), 246 (50.8%) patients were treated with a hemithyroidectomy and follow-up in accordance with Dutch guidelines. Lymph node metastases were found in 1 of 246 (0.4%) patients after hemithyreoidectomy, and new mPTC in the contralateral thyroid was detected in 3 of 246 (1.2%) patients. Median (IQR) follow-up of this patient group was 37 (18-71) months. The 10-year probability of RD was 1.3% for patients without vascular invasion and 24.4% for patients with vascular invasion. Conclusions and Relevance: This nationwide cohort study found that overall, RD after hemithyroidectomy for patients with low-risk mPTC was rare (&lt;2%). Based on these results, it seems reasonable to deescalate follow-up of patients with low-risk mPTC without vascular invasion after hemithyroidectomy. From a health care perspective, deescalation of follow-up may contribute to increased sustainability and accessibility to health care, both large challenges for the future..</p

Preferences of patients, clinicians, and healthy controls for the management of a Bethesda III thyroid nodule

Background: Active surveillance is propagated as an alternative for hemithyroidectomy in the management of Bethesda III thyroid nodules. Methods: A cross-sectional survey questioned respondents on their willingness to accept risks related to active surveillance and hemithyroidectomy. Results: In case of active surveillance, respondents (129 patients, 46 clinicians, and 66 healthy controls) were willing to accept a risk of 10%–15% for thyroid cancer and 15% for needing more extensive surgery in the future. Respondents were willing to accept a risk of 22.5%–30% for hypothyroidism after hemithyroidectomy. Patients and controls were willing to accept a higher risk on permanent voice changes compared with clinicians (10% vs. 3%, p < 0.001). Conclusion: Real-life risks associated which active surveillance and hemithyroidectomy for Bethesda III nodules are equivalent or less than the risks people are willing to accept. Clinicians accepted less risk for permanent voice changes