Background: Before the development of antithyroid drugs in the 1940s, treatment of Graves' hyperthyroidism was primarily surgical. Surgical mortality was quite variable, but a significant minority of patients died during or after surgery. Summary: In 1936, Karl Compton, President of the Massachusetts Institute of Technology, in a lecture attended by Massachusetts General Hospital physicians, suggested that artificially radioactive isotopes might be useful for studying metabolism. By 1942, Hertz and Roberts reported on the successful use of radioactive iodine (RAI) to treat Graves' hyperthyroidism. RAI uptake was subsequently demonstrated in well-differentiated thyroid cancer metastases. In 1948, Seidlin demonstrated stimulation of uptake in thyroid cancer metastases by thyrotropin (TSH). By 1990, 69% of endocrinologists in North America recommended RAI for Graves' hyperthyroidism. Currently RAI is less frequently used for Graves' hyperthyroidism, related to concerns about exacerbation of thyroid eye disease, about radiation exposure, and about potential adverse consequences of permanent hypothyroidism. Similarly, RAI was administered to the majority of patients with thyroid cancer for decades, but its use is now more selective. Conclusions: RAI is a remarkable example of interinstitutional cooperation between physicians and scientists to transition from bench to bedside in only three years. It is the model for a theranostic approach to disease (the simultaneous use of a radioactive drug for diagnosis and therapy). The future of RAI is less certain; inhibition of TSH receptor stimulating antibodies in Graves' disease and more precise targeting of genes that drive thyroid oncogenesis may diminish the use of RAI. Alternatively, redifferentiation techniques may improve the efficacy of RAI in RAI-refractory thyroid cancer.

Background: Fetal development is crucially dependent on thyroid hormone (TH). Maternal-to-fetal transfer of TH is a prerequisite for fetal TH availability, particularly in the first half of pregnancy. The mechanisms of transplacental transport of TH, however, are yet poorly understood. We, therefore, investigated the TH transport processes across human placentas using an ex vivo perfusion system. Methods: Intact cotyledons from term placentas of uncomplicated pregnancies were cannulated within 30 minutes after delivery and the maternal and fetal circulations were re-established. One hundred nanomolar thyroxine (T4) was added to either the maternal or fetal circulation and perfusions run up to three hours during which samples were taken from both circulations at different time points. Variables included addition of iopanoic acid (IOP) to block activity of the deiodinase type 3 (D3) and bovine serum albumin (BSA) to trap released T4. T4 and 3,3',5'-triiodothyronine concentrations in the perfusates were measured by radioimmunoassays. Results: Maternal-to-fetal transfer was slow, with T4 barely detectable in the fetal circulation unless D3 was blocked by IOP. Fetal T4 was detected after three hours perfusion (10.6 ± 0.6 nM) when BSA (34 g/L) was added in the fetal circulation to trap the released T4. In contrast, fetal-to-maternal transfer of T4 was rapid and maternal T4 increased to 43.6 ± 5.5 nM. Conclusions: Maternal-to-fetal T4 transport is limited, whereas fetal-to-maternal transport is rapid indicating that T4 transport across human term placenta is an asymmetrical process. With the high D3 activity, our observations are compatible with a protective role of the placental barrier. Future studies should reveal how the placenta exerts its gatekeeper function in ensuring optimal TH passage to the fetus.

Background: Fetal overgrowth (large for gestational age, LGA) is associated with an increased risk of maternal and fetal morbidity and adverse health outcomes. Thyroid hormones are key regulators of metabolism during pregnancy and fetal development. Lower maternal free thyroxine (fT4) and higher maternal triglyceride (TG) levels during early pregnancy are associated with higher birth weight. We aimed at examining the mediating role of maternal TG in the association between maternal fT4 and birth weight. Methods: We performed a large prospective cohort study including pregnant Chinese women who were treated at a tertiary obstetric center during the period of January 2016 to December 2018. We included 35,914 participants with complete medical records. We performed causal mediation analysis to decompose the overall effect of fT4 on birth weight and LGA with maternal TG as the mediator. Results: We observed statistically significant associations between maternal fT4, TG levels, and birth weight (all p < 0.0001). Using a four-way decomposition model, we identified a controlled direct effect (coefficient [confidence interval, CI], -0.038 [-0.047 to -0.029], p < 0.0001) that accounted for 63.9% of the total effect, in addition to the other three estimated effects (reference interaction, coefficient [CI] = -0.006 [-0.009 to -0.001], p = 0.008; mediated interaction, coefficient [CI] = 0.0004 [0.000 to 0.001], p = 0.008; and pure indirect effect, coefficient [CI] = -0.009 [-0.013 to -0.005], p < 0.0001) of TG on the association between fT4 and birth weight Z score. Moreover, maternal TG accounted for 21.6% and 20.7% (via mediation) and 13.6% and 41.6% (via maternal fT4 and TG interaction) of the total effect of maternal fT4 on fetal birth weight and LGA, respectively. The proportions of the total associations that could be reduced by "eliminating" the effect of maternal TG were 36.1% for birth weight and 65.1% for LGA, respectively. Conclusions: High maternal TG levels may play substantial mediating roles in the relationship between low fT4 levels in early pregnancy and increased birth weight and a higher risk of LGA. Further, the occurrence of fetal overgrowth may also be influenced by possible synergistic effects between fT4 and TG.

ThyroidVol. 33, No. 5 CorrectionFree AccessCorrection to: Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity by Soheili-Nezhad et al. Thyroid 2023;33(2):159–168; doi: 10.1089/thy.2022.0304is erratum ofExploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune ComorbidityPublished Online:4 May 2023https://doi.org/10.1089/thy.2022.0304.correxAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In the February 2023 issue of Thyroid (vol. 33, no. 2; pp. 159–168) the article entitled “Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity” by Soheili-Nezhad et al. (doi: 10.1089/thy.2022.0304) requires correction.This article was originally published under the copyright of Mary Ann Liebert, Inc. publishers. It has now been updated to reflect Open Access, with copyright transferring to the author(s), and a Creative Commons License (CC-BY) added (http://creativecommons.org/licenses/by/4.0). The CC-BY license goes into effect April 27, 2023.The online version of this article has been corrected to reflect this.FiguresReferencesRelatedDetailsRelated articlesExploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity14 Feb 2023Thyroid Volume 33Issue 5May 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Correction to: Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity by Soheili-Nezhad et al. Thyroid 2023;33(2):159–168; doi: 10.1089/thy.2022.0304.Thyroid.May 2023.656-656.http://doi.org/10.1089/thy.2022.0304.correxPublished in Volume: 33 Issue 5: May 4, 2023PDF download

Background: Sonographic evaluation is fundamental to thyroid nodule assessment. The American Thyroid Association (ATA) ultrasound risk stratification system (USRSS) is widely used, but the appearance of some nodules has been considered nonclassifiable (NC-ATA). The risk of malignancy (RoM) of NC-ATA nodules varies widely between studies, leading to uncertainty in clinical management. The aim of this study was to comprehensively evaluate the prevalence and malignancy risk of NC-ATA nodules. Methods: A systematic review was performed searching PubMed/MEDLINE and EMBASE to identify original studies of thyroid nodules classified using the ATA USRSS from 2016 to 2022 and reporting the outcome of NC-ATA nodules. Meta-analysis was conducted to obtain pooled RoM estimates and meta-regression sensitivity analyses were used to explore sources of between-study heterogeneity. Results: Of 6377 screened studies, 135 underwent full-text review, and 16 studies reporting 21,271 nodules were included. Within these, the pooled prevalence of NC-ATA nodules was 7.8% (1872 nodules; [confidence interval; CI 5.1-11.1]). The pooled RoM estimate for NC-ATA nodules was 20.3% [CI 13.0-28.7] and there was significant heterogeneity between studies (I2 = 92.8%, p < 0.001). NC-ATA nodule RoM estimates were significantly different by study type: single-center versus multicenter studies (24.8% vs. 12.3%, respectively, p = 0.031) and study design: retrospective versus prospective studies (25.1% vs. 8.5%, respectively, p = 0.003). No significant difference was observed in RoM based on inclusion of <1 cm nodules or geographic region. Meta-regression analysis showed study design and use of surgical histology for diagnostic criteria contributed significantly to differences in the reported RoM estimates. Conclusion: In this first meta-analysis comprehensively assessing the RoM of NC-ATA nodules, the malignancy risk was found to be comparable with the current ATA USRSS intermediate suspicion category. Significant heterogeneity was observed between studies and limits the interpretation of these results. In future iterations of the ATA USRSS that seek into incorporate categorization of NC-ATA nodules, these meta-analysis data may help to inform proper malignancy risk stratification. The study protocol was registered on PROSPERO, the international prospective register of systematic reviews (CRD42020182498), on July 14, 2020.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

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There have been significant advancements in the understanding of maternal-fetal disease over the past century. This narrative review summarizes the landmark studies that have advanced the understanding of thyroid pathophysiology and thyroid disease during preconception, pregnancy, and postpartum, written to commemorate the 100th year anniversary of the founding of the American Thyroid Association.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes. Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis. Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 ± 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 ± 17.4 mm versus 23 ± 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size ≤10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153). Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

Background: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked disease where patients exhibit peripheral hyperthyroidism and cerebral hypothyroidism, which results in severe neurological impairments. These brain defects arise from a lack of thyroid hormones (TH) during critical stages of human brain development. Treatment options for MCT8-deficient patients are limited and none have been able to prevent or ameliorate effectively the neurological impairments. This study explored the effects of the TH agonist sobetirome and its CNS-selective amide prodrug, Sob-AM2, in the treatment of pregnant dams carrying fetuses lacking Mct8 and deiodinase type 2 (Mct8/Dio2 KO), as a murine model for MCT8 deficiency. Methods: Pregnant dams carrying Mct8/Dio2 KO fetuses were treated with 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for 7 days, starting at embryonic day 12.5 (E12.5). As controls, pregnant dams carrying wild-type and pregnant dams carrying Mct8/Dio2 KO fetuses were treated with daily subcutaneous injections of vehicle. Dams TH levels were measured by enzyme-linked immunosorbent assay (ELISA). Samples were extracted at E18.5 and the effect of treatments on the expression of triiodothyronine (T3)-dependent genes was measured in the placenta, fetal liver, and fetal cerebral cortex by real-time polymerase chain reaction. Results: Maternal sobetirome treatment led to spontaneous abortions. Sob-AM2 treatment, however, was able to cross the placental as well as the brain barriers and exert thyromimetic effects in Mct8/Dio2 KO fetal tissues. Sob-AM2 treatment did not affect the expression of the T3-target genes analyzed in the placenta, but it mediated thyromimetic effects in the fetal liver by increasing the expression of Dio1 and Dio3 genes. Interestingly, Sob-AM2 treatment increased the expression of several T3-dependent genes in the brain such as Hr, Shh, Dio3, Kcnj10, Klf9, and Faah in Mct8/Dio2 KO fetuses. Conclusions: Maternal administration of Sob-AM2 can cross the placental barrier and access the fetal tissues, including the brain, in the absence of MCT8, to exert thyromimetic actions by modulating the expression of T3-dependent genes. Therefore, Sob-AM2 has the potential to address the cerebral hypothyroidism characteristic of MCT8 deficiency from fetal stages and to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain.