Innate immune cells have recently been identified as novel thyroid hormone (TH) target cells in which intracellular TH levels appear to play an important functional role. The possible involvement of TH receptor alpha (TRα), which is the predominant TR in these cells, has not been studied to date. Studies in TRα0/0 mice suggest a role for this receptor in innate immune function. The aim of this study was to determine whether TRα affects the human innate immune response. We assessed circulating interleukin-8 concentrations in a cohort of 8 patients with resistance to TH due to a mutation of TRα (RTHα) and compared these results to healthy controls. In addition, we measured neutrophil and macrophage function in one of these RTHα patients (mutation D211G). Circulating interleukin-8 levels were elevated in 7 out of 8 RTHα patients compared to controls. These patients harbor different mutations, suggesting that this is a general feature of the syndrome of RTHα. Neutrophil spontaneous apoptosis, bacterial killing, NAPDH oxidase activity and chemotaxis were unaltered in cells derived from the RTHαD211G patient. RTHα macrophage phagocytosis and cytokine induction after LPS treatment were similar to results from control cells. The D211G mutation did not result in clinically relevant impairment of neutrophil or pro-inflammatory macrophage function. As elevated circulating IL-8 is also observed in hyperthyroidism, this observation could be due to the high-normal to high levels of circulating T3 found in patients with RTHα.
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Anne H van der Spek, Olga V Surovtseva, Saskia Aan, Anton T J Tool, Annemarie van de Geer, Korcan Demir, Anja L M van Gucht, A S Paul van Trotsenburg, Timo K van den Berg, Eric Fliers and Anita Boelen
Xuan Luo, Tingting Zheng, Chaoming Mao, Xin Dong, Xiao Mou, Chengcheng Xu, Qingyan Lu, Baocui Liu, Shengjun Wang and Yichuan Xiao
Myeloid-related protein 14 (MRP14) is responsible for inflammatory reactions. However, the correlation between MRP14 and Hashimoto’s thyroiditis (HT) is still not clear. In this study, we examined the status of MRP14 in thyroid tissues and sera of HT patients and explored the mechanism of IL-1β-mediated regulation of MRP14 expression, as well as the effects of MRP14 on pro-inflammatory chemokine secretion in thyroid follicular cells (TFCs), to elucidate the role of MRP14 in HT development. Our results showed dramatically increased MRP14 expression in thyroid tissues and sera from HT patients. In addition, IL-1β significantly promoted the expression of MRP14 in TFCs, which was mediated by activation of the MAPK/NF-κB signalling pathway. More importantly, IL-1β induced the secretion of the chemokines GRO-2, CXCL9 and CCL22, which was dependent on the regulation of MRP14 in TFCs. Therefore, these findings suggested that under pro-inflammatory conditions, TFCs secreted chemokines with the help of MRP14 regulation, which might suggest a potential pathological mechanism of lymphocyte infiltration into the thyroid gland in HT.
Wei Sun, Boyuan Zheng, Zhihong Wang, Wenwu Dong, Yuan Qin and Hao Zhang
In patients with papillary thyroid cancer (PTC) with clinical negative central lymph nodes (cN0), the use of prophylactic central lymph node dissection remains controversial. Contralateral central lymph node metastasis (CCLNM) occurs in 3.88–30.63% of patients with cN0 PTC. Therefore, the present meta-analysis aimed to obtain evidence for CCLNM risk factors in unilateral cN0 PTC.
Materials and methods
Relevant studies were identified in the PubMed, SCIE, and Wanfang databases up to Oct 31, 2019. The included patients had undergone lobectomy or total thyroidectomy with bilateral central lymph node dissection and were diagnosed pathologically with PTC. Revman 5.3 software was applied for statistical analysis.
Thirteen studies comprising 2449 patients were included. The factors associated with increased CCLNM risk in patients with cN0 disease were: age <45 years (odds ratio (OR) = 1.89, 95% CI = 1.43–2.49, P < 0.00001), male sex (OR = 1.67, 95% CI = 1.24–2.24, P = 0.0007), extrathyroidal extension (OR = 1.63; 95% CI = 1.17–2.28; P = 0.004), tumor size ≥1 cm (OR = 2.63, 95% CI 1.85–3.74, P < 0.00001), lymphovascular invasion (OR = 4.27, 95% CI = 2.47–7.37, P < 0.00001), and ipsilateral central lymph node metastasis (OR = 11.42, 95% CI = 5.25–24.86, P < 0.00001). However, no association was found for capsular invasion, multifocality, or Hashimoto thyroiditis.
The meta-analysis identified that age <45 years, tumor ≥1 cm, male sex, lymphovascular invasion, extrathyroidal extension, and ipsilateral central lymph node metastasis are related to CCLNM in patients with unilateral CN0 PTC. These factors should influence the use of prophylactic central lymph node dissection in this group of patients.
Changjiao Yan, Meiling Huang, Xin Li, Ting Wang and Rui Ling
To investigate the mutant status of BRAF gene and analyze its relationship to epidemiological risk factors and clinical outcomes among patients with papillary thyroid cancer (PTC) in the largest, single-institution Chinese cohort to date.
The medical records of 2048 PTC patients were reviewed in this retrospective study. Single-factor and multiple logistic regression analyses were applied to identify risk factors for BRAF V600E mutation. Survival outcomes including distant metastatic and persistent or recurrent PTC were examined, with a mean follow-up time of 23.4 (5–47) months.
The BRAF V600E mutation was present in 83.7% of patients (1715 of 2048). Correlation was found between BRAF V600E mutation and several epidemiological features, including age, concomitant hypertension and Hashimoto thyroiditis (HT). For the clinicopathological features, BRAF V600E was significantly associated with bilateral multifocality (odds ratio (OR) 1.233, 95% confidence interval (CI) 1.063–1.431, P < 0.01) and less lateral lymph node metastases (OR 0.496, 95% CI 0.357–0.689, P < 0.01). Smaller tumor size and advanced disease stage were significant in single-factor analyses but became insignificant after multivariate adjustment. No association was found between BRAF V600E mutation and extrathyroidal invasion, distant metastatic and disease persistence or recurrence.
Part of epidemiological features are independent risk or protective factors for BRAF V600E mutation. The presence of BRAF V600E mutation is not an aggressive prognosis on poor clinical outcomes in PTC. However, the high prevalence of BRAF V600E may provide guidance for surgery strategy and opportunity for targeted treatment in recurrent and advanced stage disease.
C Sui, Q He, R Du, D Zhang, F Li, G Dionigi, N Liang and H Sun
This study examined the clinicopathological characteristics of 6279 N1 differentiated thyroid cancer (DTC) patients who underwent operations in our center.
This was a retrospective longitudinal analysis. We categorized the DTC patients on the basis of various lymph node (LN) characteristics. Logistic regression models and multiple linear regression models were used for the correlation analysis.
A total of 3693 (58.8%) N1a patients and 2586 (41.2%) N1b patients were included. Patients with N1b disease had larger metastatic foci (0.5 vs 0.15 cm), a greater number of metastatic LNs (5 vs 2), a greater number of dissected LNs (25 vs 7), and a smaller lymph node ratio (NR, number of positive LNs/number of sampled LNs) (23.1% vs 28.6%) than patients in stage N1a. Comparing the clinicopathological features, we found that male, increased tumor size, multifocality, and thyroiditis increased the risk of stage N1b disease (P < 0.05). Sex, multifocality, capsular infiltration, and tumor size were associated with the size of the metastatic LNs (P < 0.05). Sex, capsular infiltration, and nodular goiter were associated with the NR (P < 0.05). Female sex, tumor located in inferior lobe, maximal tumor diameter (MTD) < 1 cm, and nodular goiter were independent predictors for skip metastases (P < 0.05). MTD > 1 cm, central neck metastasis and age were independent predictors for bilateral lateral neck metastasis (BLNM) (P < 0.05).
The LN characteristics of stage N1a and N1b disease were associated with significantly different features, such as sex, tumor size, multifocality, capsular infiltration, and nodular goiter.
Xuechao Jiang, Yonghui Wang, Xiaoying Li, Leqi He, Qian Yang, Wei Wang, Jun Liu and Bingbing Zha
B lymphocytes are the source of autoantibodies against the thyroid-stimulating hormone receptor (TSHR) in Graves’ disease (GD). Characterization of autoimmune B-cell expression profiles might enable a better understanding of GD pathogenesis. To reveal this, the expression levels of long noncoding RNAs (lncRNAs) and mRNAs (genes) in purified B cells from patients with newly diagnosed GD and healthy individuals were compared using microarrays, which elucidated 604 differentially expressed lncRNAs (DE-lncRNAs) and 410 differentially expressed genes (DEGs). GO and pathway analyses revealed that the DEGs are mainly involved in immune response. A protein–protein interaction network presented experimentally validated interactions among the DEGs. Two independent algorithms were used to identify the DE-lncRNAs that regulate the DEGs. Functional annotation of the deregulated lncRNA–mRNA pairs identified 14 pairs with mRNAs involved in cell proliferation. The lncRNAs TCONS_00022357-XLOC_010919 and n335641 were predicted to regulate TCL1 family AKT coactivator A (TCL1A), and the lncRNA n337845 was predicted to regulate SH2 domain containing 1A (SH2D1A). TCL1A and SH2D1A are highly involved in B-cell proliferation. The differential expression of both genes was validated by qRT-PCR. In conclusion, lncRNA and mRNA expression profiles of B cells from patients with GD indicated that the lncRNA–mRNA pairs n335641–TCL1A, TCONS_00022357-XLOC_010919–TCL1A, and n337845–SH2D1A may participate in GD pathogenesis by modulating B-cell proliferation and survival. Therefore, the identified lncRNA and mRNA may represent novel biomarkers and therapeutic targets for GD.
Xiao-Ping Qi, Jian-Zhong Peng, Xiao-Wei Yang, Zhi-Lie Cao, Xiu-Hua Yu, Xu-Dong Fang, Da-Hong Zhang and Jian-Qiang Zhao
Cutaneous lichen amyloidosis (CLA) has been reported in some multiple endocrine neoplasia type 2A (MEN 2A) families affected by specific germline RET mutations C634F/G/R/W/Y or V804M, as a characteristic of the clinical manifestation in ‘MEN 2A with CLA’, one of four variants of MEN 2A, which was strictly located in the scapular region of the upper back.
This study reports a large south-eastern Chinese pedigree with 17 individuals carrying the MEN 2A-harboring germline C611Y (c.1832G>A) RET mutation by Sanger sequencing. One individual presented MEN 2A-related clinical features, including typical CLA in the interscapular region; another individual exhibited neurological pruritus and scratching in the upper back but lacked CLA skin lesions. Both subjects presented with CLA or pruritic symptoms several years before the onset of medullary thyroid carcinoma (MTC) and/or pheochromocytoma. The remaining 15 RET mutation carriers did not exhibit CLA; of these, one presented with MTC and pheochromocytoma, nine with MTC only, two with elevated serum calcitonin and three younger subjects with normal serum calcitonin levels. This family’s clinical data revealed a later diagnosis of MTC (mean age, 45.9 (range: 23–73) years), a lower penetrance of pheochromocytoma (2/17, 11.8%) and CLA (1/17, 5.9%). However, no hyperparathyroidism and Hirschsprung disease were reported in this family.
Summary and Conclusions
This is the first description of a family with MEN 2A-related CLA due to a germline RET C611Y mutation, which might exhibit a novel and diversified genotype–phenotype spectrum in MEN 2A.
Lauren Bell, Ann Louise Hunter, Angelos Kyriacou, Annice Mukherjee and Akheel A Syed
TSH receptor antibody (TRAb) is considered the gold standard diagnostic test for the autoimmunity of Graves’ disease (GD), which is commonly diagnosed clinically.
To evaluate the true positive (sensitivity) and true negative (specificity) rates of clinical diagnosis of GD or non-GD hyperthyroidism compared to the TRAb test.
University teaching hospital in North West England.
Patients in the Endocrinology service who had a TRAb measurement between December 2009 and October 2015.
Electronic patient records were studied retrospectively for a pre-TRAb clinical diagnosis of GD or non-GD hyperthyroidism. We examined descriptive statistics and binary classification tests; Fisher exact test was used to analyse contingency tables.
We identified 316 patients with a mean age of 45 (range, 17–89) years; 247 (78%) were women. Compared to the TRAb result, clinical diagnosis had a sensitivity of 88%, specificity 66%, positive predictive value 72%, negative predictive value 84%, false negative rate 12%, false positive rate 34%, positive likelihood ratio 2.6 and negative likelihood ratio 0.2 (P < 0.0001).
Clinicians were liable to both over- and under-diagnose GD. The TRAb test can help reduce the number of incorrect or unknown diagnoses in the initial clinical assessment of patients presenting with hyperthyroidism.
Marco Marino, Valentina Cirello, Valentina Gnarini, Carla Colombo, Elisa Pignatti, Livio Casarini, Chiara Diazzi, Vincenzo Rochira, Katia Cioni, Bruno Madeo, Cesare Carani, Manuela Simoni and Laura Fugazzola
Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with a steadily increasing incidence in the last few decades worldwide. The predisposition to developing this carcinoma by the heterozygous state of rs2910164 within the precursor of the miR-146a has been reported, but recently not confirmed. Interestingly, on the same chromosome, almost 50 kb separate the pre-miR-146a from the pituitary tumor-transforming gene 1 (PTTG1), a proto-oncogene involved in several tumors, including thyroid cancers. In this study, we analyzed, using a case–control design, the genetic association between PTC and the genomic region encompassing pre-miR-146a rs2910164 and PTTG1 rs1862391 and rs2910202. We enrolled 307 affected patients and 206 healthy controls. The possible presence of thyroid nodules in controls was excluded by ultrasonography. All the cases were submitted to single-nucleotide polymorphism (SNP) genotyping of pre-miR-146a and PTTG1, and risk association analyses were carried out. The genotypic and allelic frequencies of pre-miR-146a rs2910164 were not statistically different in the patients and controls, and this SNP was not in linkage disequilibrium with the investigated PTTG1 SNPs. Consistently, meta-analyses, the first including all the affected cases published to date, did not confirm the previously reported association of the heterozygous CG genotype with PTC. The PTTG1 SNPs exhibited the same allelic frequency in the patients and controls and were not associated with the disease. In conclusion, in a well-selected Italian population, neither pre-miR-146a rs2910164 nor PTTG1 rs1862391 and rs2910202 were found to be associated with the risk of developing PTC.
Thiago U Pantaleão, Andrea C F Ferreira, Maria C S Santos, Álvaro S P Figueiredo, Ruy A N Louzada, Doris Rosenthal, Denise P Carvalho and Vânia M Corrêa da Costa
Mercury seems to exert an inhibitory effect on deiodinases, but there are few studies using Thimerosal (TM) as the mercury source. We aimed to elucidate the effect of TM on thyroid hormones peripheral metabolism. Adult Wistar female rats received 0.25 µg or 250 µg TM/100 g BW, IM, twice a week, for a month. We evaluated serum total T3 and T4, D1 activity using 125I-rT3 as tracer, and D2 activity using 125I-T4. NADPH oxidase activity was measured by Amplex-red/HRP method and mRNA levels by real time PCR. Serum T4 was increased and T3 decreased by the greatest dose of TM. Even though D1 activity in pituitary and kidney was reduced by the highest dose of TM, hepatic D1 activity and D1 mRNA levels remained unchanged. D2 activity was also significantly decreased by the highest dose of TM in all CNS samples tested, except cerebellum, but D2 mRNA was unaltered. mRNA levels of the tested NADPH oxidases were not affected by TM and NADPH oxidase activity was either unaltered or decreased. Our results indicate that TM might directly interact with deiodinases, inhibiting their activity probably by binding to their selenium catalytic site, without changes in enzyme expression.