The Effects of Patient Characteristics on the Management of Subclinical Hypothyroidism: A Survey of Faculty and Trainees.

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.

Hypothyroidism, lipids, and lipidomics.

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.

Optimized Replacement T4 and T4+T3 Dosing in Male and Female Hypothyroid Patients With Different BMIs Using a Personalized Mechanistic Model of Thyroid Hormone Regulation Dynamics.

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.

Restoration of euthyroidism with levothyroxine: implications of etiology of hypothyroidism and the degree of residual endogenous thyroid function.

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.

Role of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism.

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.

Changes in Thyroid Metabolites after Liothyronine Administration: A Secondary Analysis of Two Clinical Trials That Incorporated Pharmacokinetic Data.

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.

Immunotherapy-Associated Hypothyroidism: Comparison of the Pre-Existing With De-Novo Hypothyroidism.

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.

Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for 131I Administration.

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.

Primary hypothyroidism and quality of life.

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.

Brain Fog in Hypothyroidism: Understanding the Patient's Perspective.

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.

Optimal Thyroid Hormone Replacement.

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.

COVID-19 and Thyroid Diseases: A Bidirectional Impact.

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.

A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the European Thyroid Association, the Society of Nuclear Medicine and Molecular Imaging on Current Diagnostic and Theranostic Approaches in the Management of Thyroid Cancer.

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.

Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.

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.

Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

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.