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Presents information on the association of lymphatics with substernal goiters. What are the respiratory systems associated with substernal goiters; Reference to a case report of a patient with goiters; Details on the types of procedures used on the patient.

Purpose: This study aimed to develop and psychometrically evaluate a patient-reported outcome measure (PROM), SAlivary, LAcrimal, NaSal (SALANS), to document patients' symptoms after radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC)., Methods: We generated and iteratively revised SALANS items based on expert input, focus group discussions and feedback from cognitive testing (n = 17). We administered an initial SALANS measure with 39 items to patients diagnosed with DTC in the past two years (n = 105). Exploratory factor analysis (EFA) examined the factor structure of the SALANS items. We assessed the consistency reliability and related the total and subscale scores of the final SALANS to existing PROMs to assess validity., Results: The final SALANS consisted of 33 items and six subscales (sialadenitis, taste, xerostomia, dry eyes, epiphora, and nasal) with six factors extracted by EFA. The six subscales demonstrated good internal reliability (α range = 0.87-0.92). The SALANS total score showed good convergent validity with the Xerostomia Inventory (r = 0.86) and good discriminant validity with a measure of spirituality (r =  - 0.05). The mean SALANS total score was significantly higher (d = 0.5, p < 0.04) among patients who had RAI compared to those who did not have RAI., Conclusion: Preliminary evidence suggests that SALANS is a novel and reliable PROM to assess the type and frequency all symptoms experienced after RAI treatment for DTC. Future work is needed to further validate and develop the scale., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Hypothyroidism is a relatively common endocrine disorder and is well documented to be associated with lipid abnormalities., Methods: A narrative review was conducted of studies describing the alterations in the lipid profile accompanying both subclinical and overt hypothyroidism., Results: Lipid abnormalities are seen with TSH values in the upper end of the accepted reference range, as well as with subclinical and overt hypothyroidism. The degree of lipid derangement is generally proportional to the degree of TSH elevation. Other factors such as age, sex, and body mass index can also influence the pattern of the lipid abnormalities seen. The most robust finding with TSH elevation is increases in the low density lipoprotein cholesterol. Thyroid hormone treatment is efficacious in reversing the lipid abnormalities in both subclinical and overt hypothyroidism., Conclusion: Given the association of lipid abnormalities with metabolic and cardiovascular disease, consideration of hypothyroidism as an important non-communicable disease may facilitate studies that test the hypothesis that thyroid hormone treatment to reverse hypothyroidism-associated lipid abnormalities may improve metabolic and cardiovascular outcomes., (© 2023. The Author(s).)

Objective: There is no universal approach to the management of subclinical hypothyroidism (SCH). This study was designed to determine the impact of patient characteristics on management decisions in SCH amongst physician faculty members and trainees., Methods: An online survey was distributed to faculty members and medical trainees (ie, interns, residents, and fellows) at multiple academic medical centers. The survey included 9 clinical scenarios describing women with SCH with 5 management options sequenced from most "conservative" (no further treatment or monitoring) to most "aggressive" (treatment with levothyroxine)., Results: Of the 194 survey respondents, 95 (49.0%) were faculty members and 99 (51.0%) were trainees. Faculty members were more likely to report being "confident" or "very confident" in making the diagnosis of SCH compared to trainees (95.8% vs 46.5%, P < .001). Faculty members were also more likely to consider patient preference for treatment (60.0% vs 32.3%, P < .001). Among all respondents, the clinical factors that resulted in the highest predicted probability of treatment were hypothyroid symptoms (predicted probability [PP] 68.8%, 95% CI [65.7%-71.9%]), thyroid stimulating hormone >10 mIU/L in a 31-year-old (PP 63.9%, 95% CI [60.3%-67.3%]), and the desire for fertility (PP 52.2%, 95% CI [48.6%-56.0%]). In general, faculty members favored more aggressive treatment across all clinical scenarios., Conclusion: The presence of symptoms, thyroid stimulating hormone >10 mIU/L, and desire for fertility were most predictive of the decision to treat in SCH. In several clinical scenarios, both trainee and faculty decision-making demonstrated discordance with general SCH management principles., Competing Interests: Disclosure Dr Jiang, Dr Wolf, Dr Kaakati, Dr Oh, Dr Yip, Dr Jonklaas, Dr Laiteerapong, and Dr Ettleson have nothing to disclose. Dr Bianco reports consulting fees from AbbVie, Allergan, Sention Therapeutics, Synthonics and Thyron. These are not relevant to the content of this manuscript., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

There are many thyroid-related factors that combine with non-thyroid-related factors in order to affect the patient response to treatment of hypothyroidism, in terms of their satisfaction with therapy. Some of the thyroid-derived factors include the etiology of the hypothyroidism and the amount of residual thyroid function that the patient retains. These two factors may be intertwined and affected by a third influence, the presence of thyroid peroxidase antibodies. The downstream consequences of the interactions between these three factors may influence both free thyroxine and free triiodothyronine levels, TSH concentrations, and various thyroid biomarkers. Evidence of the widespread importance of thyroid hormones can be inferred from the multiple genes that are regulated, with their regulation affecting multiple serum biomarkers. Thyroid biomarkers may extend from various well-known serum markers such as lipids and sex hormone-binding globulin to serum levels of thyroid hormone metabolites. Moreover, the interplay between thyroid hormones and biomarkers and their relative ratios may be different depending on the hypothyroidism etiology and degree of residual thyroid function. The ultimate significance of these relationships and their effect on determining patient-reported outcomes, quality of life, and patient satisfaction is, as yet, poorly understood. However, identification of better biomarkers of thyroid function would advance the field. These biomarkers could be studied and correlated with patient-reported outcomes in future prospective studies comparing the impact of various thyroid hormone therapies., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer ACB is currently organizing a Research Topic with the author., (Copyright © 2022 Jonklaas.)

Objective: A personalized simulation tool, p-THYROSIM, was developed (1) to better optimize replacement LT4 and LT4+LT3 dosing for hypothyroid patients, based on individual hormone levels, BMIs, and gender; and (2) to better understand how gender and BMI impact thyroid dynamical regulation over time in these patients., Methods: p-THYROSIM was developed by (1) modifying and refining THYROSIM, an established physiologically based mechanistic model of the system regulating serum T3, T4, and TSH level dynamics; (2) incorporating sex and BMI of individual patients into the model; and (3) quantifying it with 3 experimental datasets and validating it with a fourth containing data from distinct male and female patients across a wide range of BMIs. For validation, we compared our optimized predictions with previously published results on optimized LT4 monotherapies. We also optimized combination T3+T4 dosing and computed unmeasured residual thyroid function (RTF) across a wide range of BMIs from male and female patient data., Results: Compared with 3 other dosing methods, the accuracy of p-THYROSIM optimized dosages for LT4 monotherapy was better overall (53% vs. 44%, 43%, and 38%) and for extreme BMI patients (63% vs. ~51% low BMI, 48% vs. ~36% and 22% for high BMI). Optimal dosing for combination LT4+LT3 therapy and unmeasured RTFs was predictively computed with p-THYROSIM for male and female patients in low, normal, and high BMI ranges, yielding daily T3 doses of 5 to 7.5 μg of LT3 combined with 62.5-100 μg of LT4 for women or 75-125 μg of LT4 for men. Also, graphs of steady-state serum T3, T4, and TSH concentrations vs. RTF (range 0%-50%) for untreated patients showed that neither BMI nor gender had any effect on RTF predictions for our patient cohort data. Notably, the graphs provide a means for estimating unmeasurable RTFs for individual patients from their hormone measurements before treatment., Conclusions: p-THYROSIM can provide accurate monotherapies for male and female hypothyroid patients, personalized with their BMIs. Where combination therapy is warranted, our results predict that not much LT3 is needed in addition to LT4 to restore euthyroid levels, suggesting opportunities for further research exploring combination therapy with lower T3 doses and slow-releasing T3 formulations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cruz-Loya, Chu, Jonklaas, Schneider and DiStefano.)

Diverse causes potentially underlie decreased quality of life in biochemically euthyroid patients treated for hypothyroidism with levothyroxine. Once these contributing factors are addressed, if symptoms persist, there may be benefit to personalized use of combination therapy adding liothyronine. This approach should be carefully monitored: avoiding overtreatment and ensuring that therapy is only continued if it improves patient-reported quality of life. Most randomized clinical trials have not shown benefits, perhaps because of not targeting the most symptomatic patients. Sustained-release liothyronine preparations may soon be available for optimally designed studies assessing whether combination therapy provides superior therapy for hypothyroidism in select patients., Competing Interests: Disclosure J. Jonklaas has nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We examined relationships between thyroid hormone (TH) metabolites in humans by measuring 3,5-diiodothyronine (3,5-T2) and 3-iodothyronamine (3-T1AM) levels after liothyronine administration. In secondary analyses, we measured 3,5-T2 and 3-T1AM concentrations in stored samples from two clinical trials. In 12 healthy volunteers, THs and metabolites were documented for 96 h after a single dose of 50 mcg liothyronine. In 18 patients treated for hypothyroidism, levothyroxine therapy was replaced by daily dosing of 30-45 mcg liothyronine. Analytes were measured prior to the administration of liothyronine weekly for 6 weeks, and then hourly for 8 h after the last liothyronine dose of the study. In the weekly samples from the hypothyroid patients, 3,5-T2 was higher by 0.033 nmol/L with each mcg/dL increase in T4 and 0.24 nmol/L higher with each ng/dL increase in FT4 ( p -values = 0.007, 0.0365). In hourly samples after the last study dose of liothyronine, patients with T3 values higher by one ng/dL had 3-T1AM values that were lower by 0.004 nmol/L ( p -value = 0.0473); patients with 3,5-T2 higher by one nmol/L had 3-T1AM values higher by 2.45 nmol/L ( p -value = 0.0044). The positive correlations between weekly trough levels of 3,5-T2 and T4/FT4 during liothyronine therapy may provide insight into 3,5-T2 production, possibly supporting some production of 3,5-T2 from endogenous T4, but not from exogenous liothyronine. In hourly sampling after liothyronine administration, the negative correlation between T3 levels and 3-T1AM, but positive correlation between 3,5-T2 levels and 3-T1AM could support the hypothesis that 3-T1AM production occurs via 3,5-T2 with negative regulation by T3.

In the 1970s, treatment with thyroid extract was superseded by levothyroxine, a synthetic L form of tetraiodothyronine. Since then, no major innovation has emerged for the treatment of hypothyroidism. The biochemical definition of subclinical hypothyroidism is a matter of debate. Indiscriminate screening for hypothyroidism has led to overdiagnosis and treatment initiation at lower serum levels of thyroid-stimulating hormone (TSH) than previously. Adverse health effects have been documented in individuals with hypothyroidism or hyperthyroidism, and these adverse effects can affect health-related quality of life (QOL). Levothyroxine substitution improves, but does not always normalize, QOL, especially for individuals with mild hypothyroidism. However, neither studies combining levothyroxine and liothyronine (the synthetic form of tri-iodothyronine) nor the use of desiccated thyroid extract have shown robust improvements in patient satisfaction. Future studies should focus not only on a better understanding of an individual's TSH set point (the innate narrow physiological range of serum concentration of TSH in an individual, before the onset of hypothyroidism) and alternative thyroid hormone combinations and formulations, but also on autoimmunity and comorbidities unrelated to hypothyroidism as drivers of patient dissatisfaction. Attention to the long-term health consequences of hypothyroidism, beyond QOL, and the risks of overtreatment is imperative., (© 2022. Springer Nature Limited.)

Background: Immunotherapy has revolutionized the treatment of solid malignancies, but is associated with endocrine-related adverse events. This study aims to dissect the natural course of immunotherapy-induced hypothyroidism and provide guidance regarding diagnosis and management in patients with and without pre-existing hypothyroidism., Methods: A retrospective analysis was conducted using patients who received immunotherapy between 2010-2019 within a multicenter hospital system. Participants were separated in three groups-those with pre-existing hypothyroidism, those who developed primary hypothyroidism and those with hypophysitis within a year of their first immunotherapy. Serial effects of immunotherapy on thyroid function tests (TFTs) and levothyroxine dosing were evaluated., Results: 822 patients were screened, with 85 determined to have pre-existing hypothyroidism, 48 de-novo primary hypothyroidism and 12 de-novo hypophysitis. All groups displayed fluctuations in TFTs around weeks 6-8 of treatment. In the pre-existing hypothyroidism group, the levothyroxine dose was higher at 54 weeks than at baseline with the difference showing a trend towards statistical significance (p=0.06). The observed mean levothyroxine dose was significantly lower than the mean calculated weight-based dose for all groups. This finding was most clinically significant for the de-novo hypophysitis group (mean difference: -58.3 mcg, p<0.0001). The mean 0.9 mcg/kg levothyroxine dose at week 54 for the de-novo hypophysitis group was statistically lower than the other groups (p=0.009)., Conclusion: It is reasonable to screen with TFTs every 4 weeks, and space out TFTs surveillance to every 12 weeks after week 20. Our findings suggest a more conservative approach for levothyroxine dosing in those developing de-novo hypothyroidism, especially hypophysitis, such as initiating at 0.9-1.2 mcg/kg., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kristan, Toro-Tobon, Francis, Desale, Bikas, Jonklaas and Goyal.)

Hypothyroidism is a common endocrinopathy, and levothyroxine is frequently prescribed. Despite the basic tenets of initiating and adjusting levothyroxine being agreed on, there are many nuances and complexities to consistently maintaining euthyroidism. Understanding the impact of patient weight and residual thyroid function on initial levothyroxine dosage and consideration of age, comorbidities, thyrotropin goal, life stage, and quality of life as levothyroxine is adjusted can be challenging and continually evolving. Because levothyroxine is a lifelong medication, it is important to avoid risks from periods of overtreatment or undertreatment. For the subset of patients not restored to baseline health with levothyroxine, causes arising from all aspects of the patient's life (coexistent medical conditions, stressors, lifestyle, psychosocial factors) should be broadly considered. If such factors do not appear to be contributing, and biochemical euthyroidism has been successfully maintained, there may be benefit to a trial of combination therapy with levothyroxine and liothyronine. This is not supported by the majority of randomized clinical trials, but may be supported by other studies providing lower-quality evidence and by animal studies. Given this discrepancy, it is important that any trial of combination therapy be continued only as long as a patient benefit is being enjoyed. Monitoring for adverse effects, particularly in older or frail individuals, is necessary and combination therapy should not be used during pregnancy. A sustained-release liothyronine preparation has completed phase 1 testing and may soon be available for better designed and powered studies assessing whether combination therapy provides superior therapy for hypothyroidism., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Recombinant human thyrotropin (rhTSH) is currently not Food and Drug Administration approved for the treatment of high-risk patients with differentiated thyroid cancer (DTC)., Objective: The goal of our study was to compare the outcomes in higher-risk patients with metastatic DTC prepared for radioiodine (RAI) therapy with rhTSH vs thyroid hormone withdrawal (THW)., Methods: A retrospective chart review was performed of patients with metastatic DTC in follow-up at MedStar Washington Hospital Center and MedStar Georgetown University Hospital from 2009 to 2017. Patients were divided according to their preparation for RAI therapy, with assessment of progression-free survival (PFS) and overall survival (OS)., Results: Fifty-five patients with distant metastases (16 men, 39 women) were prepared for RAI therapy exclusively either with rhTSH (n = 27) or with THW (n = 28). There were no statistically significant differences between the groups regarding clinicopathological features and history of RAI therapies. The median follow-up time for patients with rhTSH-aided therapies was 4.2 years (range, 3.3-5.5 years) and for patients with THW-aided therapies was 6.8 years (range, 4.2-11.6 years) ( P  = .002). Multivariate analysis showed that the method of thyrotropin stimulation was not associated with a difference in PFS or OS., Conclusion: As has been shown previously for low-risk DTC, this study indicates that the mode of preparation for RAI therapy does not appear to influence the outcomes of patients with metastatic DTC. PFS and OS were similar for patients with THW-aided or rhTSH-aided RAI therapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Patient-centered studies have shown that several patients on thyroid hormone replacement therapy for hypothyroidism exhibit persistent symptoms, including "brain fog." Here, we aimed to determine which of these specific symptoms are associated with brain fog, identify patient-reported factors that modify these symptoms, and identify patient concerns related to brain fog not included in thyroid-specific questionnaires., Methods: A survey on brain fog symptoms adapted from thyroid-specific patient-reported outcome was distributed online. Textual data analysis was performed to identify common areas of concern from open-ended survey responses., Results: A total of 5170 participants reporting brain fog while being treated for hypothyroidism were included in the analysis. Of these, 2409 (46.6%) participants reported symptom onset prior to the diagnosis of hypothyroidism, and 4096 (79.2%) participants experienced brain fog symptoms frequently. Of the symptoms listed, participants associated fatigue and forgetfulness most frequently with brain fog. More rest was the most common factor provided for improving symptoms. The textual data analysis identified areas of concern that are not often included in thyroid-specific quality of life questionnaires, including a focus on the diagnosis of hypothyroidism, the types and doses of medications, and the patient-doctor relationship., Conclusion: Brain fog in patients treated for hypothyroidism was associated most frequently with fatigue and cognitive symptoms. Several additional areas of patient concern were found to be associated with brain fog, which are not typically addressed in thyroid-specific questionnaires., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Background: The American Thyroid Association (ATA), the European Association of Nuclear Medicine, the European Thyroid Association, and the Society of Nuclear Medicine and Molecular Imaging have established an intersocietal working group to address the current controversies and evolving concepts in thyroid cancer management and therapy. The working group annually identifies topics that may significantly impact clinical practice and publishes expert opinion articles reflecting intersocietal collaboration, consensus, and suggestions for further research to address these important management issues. Summary: In 2019, the intersocietal working group identified the following topics for review and interdisciplinary discussion: (i) perioperative risk stratification, (ii) the role of diagnostic radioactive iodine (RAI) imaging in initial staging, and (iii) indicators of response to RAI therapy. Conclusions: The intersocietal working group agreed that (i) initial patient management decisions should be guided by perioperative risk stratification that should include the eighth edition American Joint Committee on Cancer staging system to predict disease specific mortality, the modified 2009 ATA risk stratification system to estimate structural disease recurrence, with judicious incorporation of molecular theranostics to further refine management recommendations; (ii) diagnostic RAI scanning in ATA intermediate risk patients should be utilized selectively rather than being considered mandatory or not necessary for all patients in this category; and (iii) a consistent semiquantitative reporting system should be used for response evaluations after RAI therapy until a reproducible and clinically practical quantitative system is validated.

Context: COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has become the most lethal and rapidly moving pandemic since the Spanish influenza of 1918-1920, is associated with thyroid diseases., Methods: References were identified through searches of PubMed and MEDLINE for articles published from Jan 1, 2019 to February 19, 2021 by use of the MeSH terms " hypothyroidism ", " hyperthyroidism ", " thyroiditis ", " thyroid cancer ", " thyroid disease ", in combination with the terms " coronavirus " and " COVID-19 ". Articles resulting from these searches and references cited in those articles were reviewed., Results: Though preexisting autoimmune thyroid disease appears unlikely to render patients more vulnerable to COVID-19, some reports have documented relapse of Graves' disease (GD) or newly diagnosed GD about 1 month following SARS-CoV-2 infection. Investigations are ongoing to investigate molecular pathways permitting the virus to trigger GD or cause subacute thyroiditis (SAT). While COVID-19 is associated with non-thyroidal illness, it is not clear whether it also increases the risk of developing autoimmune hypothyroidism. The possibility that thyroid dysfunction may also increase susceptibility for COVID-19 infection deserves further investigation. Recent data illustrate the importance of thyroid hormone in protecting the lungs from injury, including that associated with COVID-19., Conclusion: The interaction between the thyroid gland and COVID-19 is complex and bidirectional. COVID-19 infection is associated with triggering of GD and SAT, and possibly hypothyroidism. Until more is understood regarding the impact of coronavirus on the thyroid gland, it seems advisable to monitor patients with COVID-19 for new thyroid disease or progression of preexisting thyroid disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies., Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members., Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations., Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations., Competing Interests: J.J., A.R.C., H.H., E.A.M., L.C.M., A.M.S., and C.M.D. have no conflicts to discuss. A.C.B. is a consultant for Synthonics Inc., Allergan Inc., and BLA Technology LLC; F.S.C. is a consultant for IBSA and Acella; T.W. is a consultant for AbbVie, Allergan Inc., and developer of ThyPRO and ThyPRO-30. E.F. is a coinvestigator in a combination therapy trial funded by the Dutch government with funds provided to participating institutions (principal investigator [PI] Marco Medici). B.N. is the PI of a trial of synthetic combination therapy versus thyroid extract funded by the Danish government with funds provided to the institution. T.W. also serves as a volunteer consultant and steering committee member specifically with ThyPRO expertise for combination therapy trials with PIs Medici (above), B.N. (above), and Steen Bonnema (trial funded by the Danish government). C.M.D. serves as a volunteer external advisory board member for the trial with PI Medici (above)., (Copyright © 2021 by European Thyroid Association Published by S. Karger AG, Basel.)

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25-82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF , NRAS , HRAS , TP53 , ATM , MUTYH , POLE , and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention., Competing Interests: RF is employed by Caris Life Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gomes-Lima, Shobab, Wu, Ylli, Bikas, McCoy, Feldman, Lee, Rao, Jensen, Vasko, Castro, Jonklaas, Wartofsky and Burman.)

Clinicians often encounter thyroid function tests (TFT) comprising serum/plasma free thyroxine (FT4) and thyroid stimulating hormone (TSH) measured using different assay platforms during the course of follow-up evaluations which complicates reliable comparison and interpretation of TFT changes. Although interconversion between concentration units is straightforward, the validity of interconversion of FT4/TSH values from one assay platform to another with different reference intervals remains questionable. This study aims to establish an accurate and reliable methodology of interconverting FT4 by any laboratory to an equivalent FT4 value scaled to a reference range of interest via linear transformation methods. As a proof-of-concept, FT4 was simultaneously assayed by direct analog immunoassay, tandem mass spectrometry and equilibrium dialysis. Both linear and piecewise linear transformations proved relatively accurate for FT4 inter-scale conversion. Linear transformation performs better when FT4 are converted from a more accurate to a less accurate assay platform. The converse is true, whereby piecewise linear transformation is superior to linear transformation when converting values from a less accurate method to a more robust assay platform. Such transformations can potentially apply to other biochemical analytes scale conversions, including TSH. This aids interpretation of TFT trends while monitoring the treatment of patients with thyroid disorders.

Competing Interests: Declaration of competing interest No potential conflict of interest relevant to this article was reported.

Purpose: Despite having a generally favorable prognosis, differentiated thyroid cancer is known to have a significant, long-term impact on the quality of life of survivors. We wished to investigate short- and long-term effects among thyroid cancer survivors following radioactive iodine therapy., Methods: We conducted eight focus groups (N = 47) to understand patients' experiences of short- and long-term effects after radioactive iodine treatment and the impact these treatment-related side effects had on patients' quality of life. We elicited responses regarding experiences with side effects following radioactive iodine treatment, particularly salivary, lacrimal, and nasal symptoms. We transcribed audiotapes and conducted qualitative analyses to identify codes and themes., Results: We identified eight broad themes from the qualitative analyses. Themes reflecting physical symptoms included dry mouth, salivary gland dysfunction, altered taste, eye symptoms such as tearing or dryness, and epistaxis. Psychosocial themes included lack of knowledge and preparation for treatment, regret of treatment, and distress that thyroid cancer is labeled as a "good cancer.", Conclusions: Thyroid cancer survivors reported a wide range of radioactive iodine treatment-related effects and psychosocial concerns that appear to reduce quality of life. The psychosocial concerns reported by participants underscore the significant unmet information and support needs prior to and following RAI treatment among individuals diagnosed with thyroid cancer., Implications for Cancer Survivors: Future research is needed to help both patients and physicians understand the effect of radioactive iodine on quality of life, and to better assess the benefits versus the risks of radioactive iodine therapy.

Background: Levothyroxine is a commonly prescribed medication. Some data suggest that levothyroxine may be initiated for mild degrees of hypothyroidism and used without considering age-specific reference ranges or individual patient factors when prescribing., Methods: The electronic medical record of a health care system operating in the Washington, DC and Maryland area was interrogated to determine the number of patients who were being prescribed levothyroxine during the time period 2008-2016, the number of prescriptions supplied to these individuals, an associated diagnosis of hypothyroidism, and whether the prescriptions were new or existing prescriptions. Information was also extracted about the age of patients receiving prescriptions and the thyroid stimulating hormone level documented prior to levothyroxine initiation., Results: Although the number of levothyroxine prescriptions provided annually increased over this time period, when corrected for the number of patients in the database, the percentage of patients receiving levothyroxine prescriptions showed a slight downward trend. Levothyroxine was both most frequently prescribed and frequently initiated in those of ages 50-59 years and 60-69 years. The doses of levothyroxine most commonly prescribed were 50 µg and 100 µg and the pattern of levothyroxine doses being used was unaffected by whether a diagnosis of hypothyroidism was documented or not. Levothyroxine prescription initiation was associated with mean thyroid stimulating hormone values that were modestly elevated and in the range of 7.5-13.8 mIU/L., Conclusion: This analysis showed that although the percentage of patients being prescribed levothyroxine is stable or slightly declining, with most decrement in those without a diagnosis of hypothyroidism, there is nevertheless continued initiation of levothyroxine in those with mild degrees of thyroid stimulating hormone elevation, and in those of older age, raising concerns about both unnecessary treatment and iatrogenic thyrotoxicosis. Such data suggest the need for great consideration of both the degree of thyroid stimulating hormone elevation and the patient context when considering whether treatment of an elevated thyroid stimulating hormone value, versus ongoing monitoring, is indicated., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: There has been a wide range of reference intervals proposed in previous literature for thyroid hormones due to large between-assay variability of immunoassays, as well as lack of correction for collection time. We provided the diurnal reference intervals for five thyroid hormones, namely total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), free triiodothyronine (FT3), and reverse T3 (rT3), measured in serum samples of healthy participants using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method., Methods: Couplet serum samples (a.m. and p.m.) were collected from 110 healthy females and 49 healthy males. Healthy volunteers were recruited from four participating centers between 2016 and 2018. Measurements of thyroid hormones were obtained by LC-MS/MS analysis., Results: Our study revealed significant uptrend in AM to PM FT4 ( p  < 0.0001) samples, downtrend in AM to PM TT3 ( p  = 0.0004) and FT3 samples ( p  < 0.0001), and AM to PM uptrend in rT3 samples ( p  < 0.0001). No difference was observed for TT4 between AM and PM. No significant sex differences were seen for any of the five thyroid hormones., Conclusion: When diagnosing thyroid disorders, it is important to have accurate measurement of thyroid hormones, and to acknowledge the diurnal fluctuation found, especially for FT3. Our study highlights the importance of standardization of collection times and implementation of LC-MS/MS in thyroid hormone measurement., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: There has been a trend for increased prescribing of levothyroxine (LT4) in many countries, including the United States. Several different factors have been suggested to be the cause of this practice pattern. These factors include increased size of the United States population, more diagnosis of hypothyroidism, more treatment of minimally elevated thyroid-stimulating hormone (TSH) levels, more use of LT4 in older patients, and use of LT4 for treatment of euthyroid patients with non-thyroidal conditions., Methods: The electronic databases of the MedStar Health system operating in the Washington, DC and Maryland areas were interrogated to determine the number of patients who were being prescribed levothyroxine during the time period 2008-2016, the number of prescriptions supplied to these individuals, the associated diagnosis, and whether the prescriptions were new or existing prescriptions. Regression analyses were also performed to determine the prescribing trends during this time period., Results: Although the annual number of levothyroxine prescriptions increased during this time period, the percentage of patients in the database receiving levothyroxine for hypothyroidism initially increased and then decreased over time (2.5% to 3.2% to 2.5%). The percentage of prescriptions written for patients who did not appear to carry a diagnosis of hypothyroidism steadily declined (3.5% to 1.0%). Although the percentage of patients with existing prescriptions for hypothyroidism initially increased and then were maintained at steady levels (1.4% to 2.4% to 2.2%), a smaller percentage of patients with existing prescriptions were documented over time when there was no diagnosis of hypothyroidism (1.45% to 0.89%). The percentage of patients with new prescriptions declined over time for all groups. The number of annual 90-day period prescriptions increased over the time for patients with a diagnosis of hypothyroidism, but down-trended starting over the latter part of the time period for those patients without a diagnosis of hypothyroidism., Conclusion: Taken together, these data suggest that there may be a stabilization, and even a down-trend in levothyroxine prescribing with the MedStar system. The decrease in levothyroxine prescribing appears to be accounted for by less use of levothyroxine without an established diagnosis of hypothyroidism, and less initiation of new prescriptions., Competing Interests: Conflict of interest: JJ has no disclosures. SD is a senior biostatistician for MedStar Health Research Institute., (© The Author(s), 2020.)

Over the past few decades, there has been an unprecedented rise in off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Testosterone therapy is often promoted to men for the treatment of low energy, lower libido, erectile dysfunction, and other symptoms. Growth hormone is used in attempts to improve athletic performance in athletes and to attenuate aging in older adults. Thyroid hormone and/or thyroid supplements or boosters are taken to treat fatigue, obesity, depression, cognitive impairment, impaired physical performance, and infertility. Adrenal supplements are used to treat common nonspecific symptoms due to "adrenal fatigue," an entity that has not been recognized as a legitimate medical diagnosis. Several factors have contributed to the surge in off-label use and misuse of these hormones and supplements: direct-to-consumer advertising, websites claiming to provide legitimate medical information, and for-profit facilities promoting therapies for men's health and anti-aging. The off-label use and misuse of hormones and supplements in individuals without an established endocrine diagnosis carries known and unknown risks. For example, the risks of growth hormone abuse in athletes and older adults are unknown due to a paucity of studies and because those who abuse this hormone often take supraphysiologic doses in sporadic intervals. In addition to the health risks, off-label use of these hormones and supplements generates billions of dollars of unnecessary costs to patients and to the overall health-care system. It is important that patients honestly disclose to their providers off-label hormone use, as it may affect their health and treatment plan. General medical practitioners and adult endocrinologists should be able to begin a discussion with their patients regarding the unfavorable balance between the risks and benefits associated with off-label use of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Abbreviations: DHEA = dehydroepiandrosterone; FDA = U.S. Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LT3 = L-triiodothyronine; LT4 = levothyroxine; T3 = total triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Background: Non-thyroid malignancies that metastasize to the thyroid gland are relatively rare. At one end of the spectrum they may only be identified at the time of autopsy. At the other extreme, they may be identified during the evaluation of a progressive malignancy. Most patients who are identified as having metastases to their thyroid gland are euthyroid, but some patients may have associated hypothyroidism or hyperthyroidism. This review examines cases of hyperthyroidism associated with metastases affecting the thyroid gland., Results: Twenty four articles describing 26 cases of malignancy-associated hyperthyroidism were identified, with the cases presenting with features suggestive of a thyroiditis and with goiter. The solid malignancies (19 cases) were mostly breast and lung cancer. Hematologic malignancies (7 cases) were also reported with a similar thyroiditis-like presentation. Patients underwent the traditional work-up for a thyroiditis, but frequently underwent other radiographic studies, in addition to radioactive iodine imaging, and frequently also underwent thyroid biopsy. The course in most patients (22/26 cases) was progression from hyperthyroidism to hypothyroidism, as the underlying malignancy progressed or thyroidectomy was performed, or the patient succumbed to their malignancy. Some patients (4 cases) became euthyroid with successful treatment of their malignancy. A subset of patients (5 cases) initially presented with severe thyrotoxicosis. Many affected patients succumbed to their underlying malignancy., Conclusion: Malignancy-associated hyperthyroidism has a similar underlying mechanism to subacute thyroiditis, in so much as there is damage or destruction of thyroid tissue. In cases of subacute thyroiditis this damage is self-limited, and there is recovery of thyroid function. In some cases of thyroiditis associated with malignancy there may be thyroid gland recovery as the underlying malignancy is treated and controlled. However, if the malignancy progresses, eventual hypothyroidism is likely to ensue., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Published by Elsevier Inc.)

Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources., (Copyright © 2020 Köhrle, Lehmphul, Pietzner, Renko, Rijntjes, Richards, Anselmo, Danielsen and Jonklaas.)

Background: The 2015 American Thyroid Association (ATA) clinical practice guidelines (CPGs) on management of thyroid nodules (TNs) and differentiated thyroid cancer (DTC) in adults were developed to inform clinicians, patients, researchers, and health policy makers about the best available evidence, and its limitations, relating to management of these conditions. Methods: We conducted a cross-sectional electronic survey of ATA members' perspectives of these CPGs, using a standardized survey (Clinician Guidelines Determinant Questionnaire) developed by the Guidelines International Network. A survey link was electronically mailed to members in February of 2019, with reminders sent to nonrespondents 2 and 5 weeks later. Data were descriptively summarized, after excluding missing responses. Results: The overall response rate was 19.8% (348/1761). The effective response rate was 20.2% (348/1720), after excluding a recently deceased member and individuals who had either invalid e-mail addresses or whose e-mails were returned. Of the respondents, 37.9% (132/348) were female, 60.4% (209/346) were endocrinologists, 27.5% (95/346) were surgeons, and 3.5% (12/346) were nuclear medicine specialists. The majority of respondents (71.9%; 250/348) were at a mid- or advanced-career level, and more than half were in academia (57.5%; 195/339). The majority (69.8%; 243/348) practiced in North America. The vast majority of respondents indicated that the CPGs explained the underlying evidence (92.3%; 298/323) and 92.9% (300/323) agreed or strongly agreed with the content. Most respondents stated that they regularly used the CPGs in their practice (83.0%; 268/323). Most respondents (83.0%; 268/323) also agreed or strongly agreed that the recommendations were easy to incorporate in their practice. The most popular CPG format was an electronic desktop file (78.8%; 252/320). Shorter more frequent CPGs were favored by 55.0% (176/320) of respondents, and longer traditional CPGs were favored by 39.7% (127/320). Conclusions: The clinical content and evidence explanations in the adult TN and DTC CPGs are widely accepted and applied among ATA survey respondents. Future ATA CPG updates need to be optimized to best meet users' preferences regarding format, frequency, and length.

Objective: To gain insight into the mixed results of reported combination therapy studies conducted with levothyroxine (LT4) and liothyronine (LT3) between 1999 and 2016. Methods: We defined trial success as improved clinical outcome measures and/or patient preference for added LT3. We hypothesized that success depends strongly on residual thyroid function (RTF) as well as the LT3 added to sufficient LT4 dosing to normalize serum T4 and TSH, all rendering T3 levels to at least middle-normal range. The THYROSIM app was used to simulate "what-if" experiments in patients and study designs corresponding to the study trials. The app graphically provided serum total (T4) and free (FT4) thyroxine, total (T3) and free (FT3) triiodothyronine, and TSH responses over time, to different simulated LT4 and combination LT4 + LT3 dosage inputs in patients with primary hypothyroidism. We compared simulation results with available study response data, computed RTF values that matched the data, classified and compared them with trial success measures, and also generated nomograms for optimizing dosages based on RTF estimates. Results: Simulation results generated three categories of patients with different RTFs and T3 and T4 levels at trial endpoints. Four trial groups had >20%, four <10%, and five 10-20% RTF. Four trials were predicted to achieve high, seven medium, and two low T3 levels. From these attributes, we were able to correctly predict 12 of 13 trials deemed successful or not. We generated an algorithm for optimizing dosage combinations suitable for different RTF categories, with the goal of achieving mid-range normal T4, T3 and TSH levels. RTF is estimated from TSH, T4 or T3 measurements prior to any hormone therapy treatment, using three new nonlinear nomograms for computing RTFs from these measurements. Recommended once-daily starting doses are: 100 μg LT4 + 10-12.5 μg LT3; 100 μg LT4 + 7.5-10 μg LT3; and 87.5 μg LT4 + 7.5 μg LT3; for <10%, 10-20%, and >20% RTF, respectively. Conclusion: Unmeasured and variable RTF is a complicating factor in assessing effectiveness of combination LT4 + T3 therapy. We have estimated and partially validated RTFs for most existing trial data, using THYROSIM, and provided an algorithm for estimating RTF from accessible data, and optimizing patient dosing of LT4 + LT3 combinations for future combination therapy trials., (Copyright © 2019 DiStefano and Jonklaas.)