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Open access

Hippolyte Dupuis, Emilie Merlen, Arnaud Jannin, Philippe Jamme, Alexandre Fagart, Marie-Christine Vantyghem, and Miriam Ladsous

Introduction

Immune checkpoint inhibitors (ICI) are used to treat cancers including metastatic melanomas and can induce endocrine side effects. The thyroid is frequently affected with classically transient thyrotoxicosis followed by hypothyroidism. The evolution of thyroid nodules and goiters under ICI therapy is poorly described.

Case presentation

A 72-year-old male presenting with hyperthyroidism due to a toxic nodule in a multinodular goiter (MNG) started ICI therapy combining ipilimumab and nivolumab to treat metastatic melanoma. After an initial worsening of thyrotoxicosis, treated with carbimazole, he developed profound hypothyroidism, persisting after carbimazole discontinuation, needing a long-term levothyroxine supplementation. Ultrasound control performed 6 months after ICIs treatment initiation revealed diffuse thyroid atrophy with involution of all nodules. 123I-scintigraphy confirmed a destructive mechanism.

Discussion

The evolution of MNG and toxic nodules is poorly described in patients treated with ICI since systematic US evaluations are lacking. We describe for the first time a toxic nodule cured by ICI therapy inducing destructive thyroiditis.

Conclusion

Pre-existing nodules and MNG, even if toxic, are not a contraindication for ICI treatment provided the patients are carefully monitored.

Open access

Zohar Steinberg Ben-Zeev, Marina Peniakov, Clari Felszer, Scott A Weiner, Avishay Lahad, Shlomo Almashanu, and Yardena Tenenbaum Rakover

Introduction

Maternal thyroid disease is considered as a risk factor for abnormal thyroid function at birth, as well as for long-term morbidity in offspring. The potential harmful effects on the neonate had led to the clinical practice of thyroid function assessment in infants born to mothers with thyroid disease during pregnancy. In this study, we evaluated the usefulness of routine thyroid function tests for every newborn of a mother with thyroid dysfunction.

Methods

Data were collected retrospectively from the medical files of mothers diagnosed with thyroid disease and their infants (496 mother–neonate pairs). All mothers with diagnosed thyroid disease who gave birth in the years 2016–2019 at our medical center were included.

Results

Hypothyroidism was the most common maternal diagnosis (91.4%), among which 48.7% had Hashimoto’s thyroiditis. Hyperthyroidism was diagnosed in 8.6% of the cohort – 71.6% of them with Graves’ disease. None of the newborns was diagnosed with congenital hypothyroidism in the screening program. Thyroid-stimulating hormone was >10 mIU/L in 14.6% and >20 mUI/L in 2.2%; all had free thyroxine within normal range. Serum thyroid function test identified four infants with thyroid disease; two had congenital hypothyroidism not related to maternal thyroid disease, one had transient familial congenital hypothyroidism and one had neonatal Graves’ disease.

Conclusions

Thyroid function testing for all newborns of mothers with thyroid dysfunction seems redundant. However, in cases of congenital hypothyroidism in siblings, thyroid function test, in addition to newborn thyroid screening, is recommended, and more careful follow-up is indicated. In maternal Graves’ disease, thyroid function test on days 2–3 of life is recommended.

Open access

Liyuan Liu, Yang Yu, Lei Chen, Yang Zhang, Guizhi Lu, Ying Gao, and Junqing Zhang

Background

Hashimoto’s thyroiditis (HT) can be divided into IgG4 HT and non-IgG4 HT based on IgG4 and IgG immunohistochemical staining. In clinical practice, it is often necessary to identify diseases such as primary thyroid lymphoma (PTL) and IgG4 HT when a patient presents with a rapidly enlarged thyroid. The aim of our study was to uncover the differential points between the two diseases.

Methods

Clinical information from 19 IgG4 HT and 10 PTL patients was obtained from the patients’ medical records, including age, sex, main clinical manifestation, thyroid functional status, the presence of serum anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies, and thyroid ultrasonography results. Thyroid sections from all patients were collected to detect IgG4 and IgG expression by immunohistochemical staining.

Results

The IgG4 HT patients were significantly younger than those in the PTL group (39.68 ± 10.95 vs 66.20 ± 10.23 years, P < 0.001). There were no significant differences in the sex distribution or TgAb- or TPOAb-positive rates. The PTL group had a higher prevalence of clinical hypothyroidism than the IgG4 HT group (P = 0.016). In the PTL group, thyroid lesions were more likely to exhibit hypoechogenicity (6/6 vs 1/19, P < 0.001) on ultrasound images. In the PTL group, two patients met the immunohistochemical cut-off value of the criteria for IgG4 HT.

Conclusions

Simply relying on immunohistochemistry for IgG4 cannot diagnose IgG4 HT correctly when a patient presents with rapid thyroid enlargement. A combination of clinical and pathological analyses will help distinguish IgG4 HT from PTL which may be with abundant IgG4-positive plasma cells.

Open access

Sofia Macedo, Ana Pestana, Liliana Santos, Celestino Neves, Susana Guimarães, Amaro Duarte-Neto, Marisa Dolhnikoff, Paulo Saldiva, Georgina Alves, Rute Oliveira, Didier Cabanes, Fátima Carneiro, Manuel Sorinho-Simoes, and Paula Soares

Objective: To understand whether thyroid cells can be directly infected by the SARS-CoV-2 virus and to establish a putative correlation with the expression of the host entry machinery: ACE-2, TMPRSS2, and Furin.

Methods: We assessed the presence of SARS-CoV-2 virus at the gene level by RT-PCR, viral RNA transcripts localization by in situ hybridization, and by detecting viral proteins by immunohistochemistry for the nucleocapsid and the spike proteins. Furthermore, we also describe the immunoexpression of key host factors for virus entry in the COVID-19 thyroid samples.

Results: We performed RT-PCR for SARS-CoV-2 in all autopsy specimens and detected viral genome positivity in 13 of 15 thyroid tissues and in a lung specimen. In nine of the 14 positive samples, we were also able to confirm SARS-CoV-2 signal by in situ hybridization. Immunohistochemistry for the viral nucleocapsid and spike protein was also positive for 10 and nine of the RT-PCR positive cases, respectively, but revealed a lower sensitivity. We also described, for the first time in a COVID-19 series, the immunohistochemical expression of ACE-2, TMPRSS2, and Furin in the thyroid.

Conclusions: Our results obtained in thyroid specimens from deceased COVID-19 patients indicate that thyrocytes can be directly infected by SARS-CoV-2, since we detected the presence of SARS-CoV-2 genome in follicular cells. Nevertheless, we did not find a clear correlation between the presence of viral genome and the expression of the host factors for virus entry, namely ACE-2, TMPRSS2, and Furin.

Open access

Alessia Cozzolino, Tiziana Filardi, Ilaria Simonelli, Giorgio Grani, Camilla Virili, Ilaria Stramazzo, Maria Giulia Santaguida, Pietro Locantore, Massimo Maurici, Daniele Gianfrilli, Andrea M Isidori, Cosimo Durante, Carlotta Pozza, and on behalf of TALENT Group

Context

Significant uncertainty exists about the diagnostic accuracy of ultrasonographic (US) features used to predict the risk of thyroid cancer in the pediatric population. Moreover, there are no specific indications for thyroid nodule evaluation in patients during the transition age.

Objective

The meta-analysis aimed to address the following question: which thyroid nodule US features have the highest accuracy in predicting malignancy in the transition age.

Methods

We performed a meta-analysis of observational/cohort/diagnostic accuracy studies dealing with thyroid nodule sonography, reporting US features, and using histology as a reference standard for the diagnosis of malignancy and histology or cytology for the diagnosis of benignity in the transition age (mean/median age 12–21 years).

Results

The inclusion criteria were met by 14 studies, published between 2005 and 2020, including 1306 thyroid nodules (mean size 17.9 mm) from 1168 subjects. The frequency of thyroid cancer was 36.6%. The US features with the highest diagnostic odds ratio (DOR) for malignancy were the presence of suspicious lymph nodes (DOR: 56.0 (95% CI: 26.0–119.0)), a ‘taller than wide’ shape of the nodule (6.0 (95% CI: 2.0–16.0)), the presence of microcalcifications (13.0 (95% CI: 6.0–29.0)) and irregular margins (9.0 (95% CI: 5.0–17.0)). Heterogeneity among the studies was substantial.

Conclusions

Following the diagnosis of a thyroid nodule in the transition age, a thorough US examination of the neck is warranted. The detection of suspicious lymph nodes and/or thyroid nodules with a ‘taller than wide’ shape, microcalcifications, and irregular margins is associated with the highest risk of malignancy in the selection of nodules candidates for biopsy.

Open access

Min Ren, Qianlan Yao, Longlong Bao, Zhiting Wang, Ran Wei, Qianming Bai, Bo Ping, Cai Chang, Yu Wang, Xiaoyan Zhou, and Xiaoli Zhu

Objective

The data regarding the mutation landscape in Chinese patients with thyroid cancer are limited. The diagnostic performance of thyroid nodules by fine-needle aspiration (FNA) cytology needs optimization, especially in indeterminate nodules.

Methods

A total of 1039 FNA and surgical resection samples tested using the targeted multigene next-generation sequencing (NGS) panel were retrospectively collected. The features of gene alterations in different thyroid tumors were analyzed, and the diagnostic efficacy was evaluated.

Results

Among 1039 samples, there were 822 FNA and 217 surgical FFPE samples. Among 207 malignant thyroid resections, a total of 181 out of 193 papillary thyroid carcinomas (PTCs) were NGS-positive (93.8%), with a high prevalence of BRAF mutations (81.9%, 158/193) and a low prevalence of RAS (1.0%, 2/193) and TERT promoter mutations (3.6%, 7/193). Gene fusions, involving the RET and NTRK3 genes, were present in 20 PTCs (10.4%) and mutually exclusive with other driver mutations. Two of three follicular thyroid carcinomas harbored multiple mutations. RET gene point mutations were common in medullary thyroid carcinoma (8/11, 72.7%). The combination of cytology and DNA–RNA-based NGS analysis demonstrated superior diagnostic value (98.0%) in FNA samples. For indeterminate thyroid nodules, the diagnostic sensitivity and specificity of NGS testing were 79.2 (38/48) and 80.0% (8/10), respectively. Two mutation-positive benign cases harbored NRAS and TSHR mutations, respectively.

Conclusions

Our study revealed the distinct molecular profile of thyroid tumors in the Chinese population. The combination of NGS testing and FNA cytology could facilitate the accurate diagnosis of thyroid nodules, especially for indeterminate nodules.

Open access

Laura Tosatto and Francesca Coscia

Thyroid hormones are essential for the metabolism of vertebrates and their synthesis, storage and release in the thyroid gland are orchestrated by their large protein precursor thyroglobulin (Tg). Alterations of Tg structure and localisation often correlate with major thyroid disorders. Namely, Tg is the main antigen in autoimmune thyroid diseases, and mutations in its gene are one of the causes of congenital hypothyroidism. Post-translational modifications (PTMs) are crucial for Tg surface properties and may be affected by the disease microenvironment; yet, their role in thyroid homeostasis and pathogenesis remains elusive. The advance of electron cryo-microscopy (cryo-EM) has recently enabled the structure of Tg to be revealed in the un-iodinated and iodinated states. Moreover, ad hoc proteomic analyses have lately identified new PTMs in Tg. Here, we provide an overview of the Tg cryo-EM models obtained so far, and we build a three-dimensional map of known PTMs in Tg. Based on their location, we suggest the potential implication of each PTM in hormonogenesis, interactions with cellular partners, colloid cross-linking and hormone release. In addition, several PTMs overlap with immunogenic regions and pathogenic gene mutations. Hence, our analysis reveals a possible cross-talk between PTMs and alteration of Tg function in these disorders. In perspective, multi-omics analyses from patients, interpreted with structural and functional data, may generate more robust models to correlate phenotypes with classes of Tg functional alterations. This integrative approach will likely provide more targeted strategies to restore specific Tg functions in different thyroid pathologies.

Open access

X Y Hu, J Wu, P Seal, S A Ghaznavi, C Symonds, S Kinnear, and R Paschke

Objectives

There has been slow adoption of thyroid ultrasound guidelines with adherence rates as low as 30% and no population-based studies investigating adherence to guideline-based malignancy risk assessment. We therefore evaluated the impact of adherence to the 2015 ATA guidelines or 2017 ACR-TIRADS guidelines on the quality of thyroid ultrasound reports in our healthcare region.

Methods

We reviewed 899 thyroid ultrasound reports of patients who received fine-needle aspiration biopsy and were diagnosed with Bethesda III or IV nodules or thyroid cancer. Ultrasounds were reported by radiology group 1, group 2, or other groups, and were divided into pre-2018 (before guideline adherence) or 2018 onwards. Reports were given a utility score (0–6) based on how many relevant nodule characteristics were included.

Results

Group 1 had a pre-2018 utility score of 3.62 and 39.4% classification reporting rate, improving to 5.77 and 97.0% among 2018-onwards reports. Group 2 had a pre-2018 score of 2.8 and reporting rate of 11.5%, improving to 5.58 and 93.3%. Other radiology groups had a pre-2018 score of 2.49 and reporting rate of 32.2%, improving to 3.28 and 61.8%. Groups 1 and 2 had significantly higher utility scores and reporting rates in their 2018-onward reports when compared to other groups’ 2018-onward reports, pre-2018 group 1 reports, and pre-2018 group 2 reports.

Conclusions

Dedicated adherence to published thyroid ultrasound reporting guidelines can lead to improvements in report quality. This will reduce diagnostic ambiguity and improve clinician’s decision-making, leading to overall reductions in unnecessary FNA biopsy and diagnostic surgery.

Open access

Ying Sun, Di Teng, Lei Zhao, Xiaoguang Shi, Yongze Li, Zhongyan Shan, and Weiping Teng

Objective

Central sensitivity of thyroid hormone refers to the sensitivity of hypothalamic–pituitary–thyroid (HPT) axis to the change in circulating free thyroxine (fT4). A complex relationship exists between thyroxine levels and iodine nutritional status. To explore the relationship between thyroid hormone sensitivity and iodine nutritional status in elevated thyrotropin (TSH), we used national data to assess the relationship between thyroid hormone sensitivity and iodine nutritional status with contrasting demographic characteristics in China.

Methods

We enrolled 12,197 participants with TSH > 4.2 mIU/L from China. Serum and urine samples were collected, and we measured serum fT4, TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) levels and urinary iodine concentration (UIC). The thyroid hormone sensitivity indices were calculated based on fT4 and TSH. The thyroid feedback quantile-based index (TFQI) is a new index to reflect thyroid hormone sensitivity. Higher TFQI quartiles indicated lower thyroid hormone sensitivity.

Results

The odds ratios (ORs) for the fourth versus first TFQI quartile were 0.84 (95% CI 0.72–0.99) for iodine deficiency, 1.24 (95% CI 1.05–1.47) for TPOAb+, and 0.44 (95% CI 0.40–0.50) for females. The OR of the fourth and first TFQI quartiles for age <30 years and >60 years was 2.09 (95% CI 1.82–2.41) and 1.19 (95% CI 1.05–1.36), respectively (P  < 0.05). Other thyroid sensitivity indices also yielded similar results.

Conclusion

Thyroid hormone sensitivity and age have a U-shaped association in individuals with elevated TSH. Increased thyroid hormone sensitivity is associated with iodine deficiency and the female gender. Decreased thyroid hormone sensitivity is associated with TPOAb+. These findings are interesting and potentially useful for understanding the interaction between iodine nutrition and the hypothalamic–pituitary–thyroid axis.

Open access

J Karmisholt, S L Andersen, I Bulow-Pedersen, A Krejbjerg, B Nygaard, and A Carlé

Purpose

In this prospective multicenter study with patients newly diagnosed with Graves’ hyperthyroidism (GH), we studied the timing and characteristics of adverse drug reactions in patients treated with anti-thyroid drugs (ATD) for up to 48 months.

Methods

Patients with GH were treated with ATD until remission and hereafter with a low-dose regime to keep the patients in remission. The patients were followed with blood samples and recording of adverse events approximately every second month for the first 2 years and every third month for the following 2 years.

Results

We included 208 patients and the patients were treated for a median of 22 (range: 0.5–49) months. Ten percent of the patients experienced adverse drug reactions and 75% of the cases occurred during the first 6 months. After 24 months, the methimazole dose was lowered to 5 mg/day, and after this time point, no further adverse drug reactions were recorded. Skin reactions were the most prominent reaction, comprising 68% of the registered reactions, and no hepatic and bonemarrow affection was recorded.

Conclusion

With this study, we report the frequency, timing of occurrence, and characteristics of adverse drug reactions when treating GH with the ATD drug methimazole for up to 48 months. Long-term low-dose methimazole treatment can be a cost-effective and straightforward treatment option if adverse drug reactions such as severe hepatic and bone marrow affection are kept in mind.