Year in Thyroidology—Recent Developments and Future Challenges: Clinical Science Review

Introduction

There were many outstanding publications in the past two years. The 2021 Year in Thyroidology—Recent Developments and Future Challenges: Clinical Science Review featured key clinical research within five categories: Thyroid Nodules and Cancer, Thyroid Function and Thyroid Eye Disease, Thyroid and Pregnancy, Thyroid and Pediatrics, and Disparities in Thyroid.

Materials and Methods

The focus was on articles published since the 2019 Year in Thyroidology: Clinical Science Review. This includes articles published between November 1, 2019, and August 31, 2021. Meta-analysis, reviews, consensus statements, and clinical guidelines were excluded. Articles that focused on surgery and procedures were avoided as they were included in the Year in Thyroidology: Surgery Review.

A PubMed review was performed and the search terms included: “thyroid neoplasms” (N = 5842), “thyroid cancer” (N = 9620), “thyroid nodule” (N = 1498), “hypothyroid” (N = 3329), “hyperthyroid” (N = 2157), “thyroid and eye” (N = 653), “thyroid and pregnancy” (N = 893), “thyroid and children” (N = 2044), “thyroid and adolescents” (N = 1345), and “thyroid and disparities” (N = 72). The focus was on peer-reviewed articles published in English, with human subjects, and that met one or more of the following criteria: potential to change clinical practice, focus on a novel topic, and/or use of strong methodology.

Faculty affiliated with Clinical Thyroidology, Drs. Leung and Papaleontiou, as well as faculty with expertise in pediatric endocrinology, Dr. Dinauer, provided additional independent feedback on key publications from their perspective. Drs. Leung, Papaleontiou, and Dinauer were not asked to perform a literature review or to review Dr. Haymart's literature review. They were asked to relay their opinions on articles published between November 1, 2019, and August 31, 2021, that they perceived as groundbreaking, practice changing, or highly innovative.

The final selection of the nominees as well as featured articles was made by Dr. Haymart. Dr. Haymart selected 15 finalists (3 per category) based on the 3 criteria: potential to change clinical practice, focus on a novel topic, and/or use of strong methodology. The final featured article per category was selected if it was especially strong in one or more of the three criteria.

Results

As shown in Table 1, there were three nominees for each of the five categories and one featured article per category. The category with the largest number of publications was Thyroid Nodules and Cancer. The three nominees for this category included: Livhits et al. (1), Pitt et al. (2), and Wirth et al. (3). These nominees represented a range of methodology, including a qualitative study and clinical trials, as well as topics ranging from nodules to medullary thyroid cancer. Ultimately, the featured article was by Wirth et al., chosen because of its potential to change practice patterns and because of its strong methodology (3).

The nominees for Thyroid Function and Thyroid Eye Disease featured article included two comparative effectiveness studies: Brito et al. (4) and Shakir et al. (5). These articles were selected because of their potential to impact a broad range of patients from a variety of clinic settings, including primary care clinics. The third article nominated was a phase 3 trial of Douglas et al. (6). Selected for the potential to change practice and the strong methodology, the featured article was by Douglas et al. (6).

The nominees for Thyroid and Pregnancy included a range of patient cohorts: women with a history of miscarriage, women on thyroid hormone replacement during pregnancy, and women without thyroid disease who had a singleton pregnancy. The nominees were Lemieux et al. (7), Dhillon-Smith et al. (8), and Lee et al. (9). Since most of the past focus has been on avoiding hypothyroidism, not hyperthyroidism, during pregnancy, the article by Lemieux et al. was chosen because of the clinically relevant, and potentially practice changing findings related to a suppressed thyrotropin (TSH) (7).

The nominees for Thyroid and Pediatrics featured article ranged from a focus on nodules to thyroid cancer to thyroid function in adolescence. The three nominees were as follows: Richman et al. (10), Vaccarella et al. (11), and Campbell et al. (12). The featured article was by Richman et al. (10). Since most of the studies on the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) focus on adults, the focus on children was innovative and led to results that suggest modifications to TI-RADS may be needed for pediatric patients.

An understudied but important area of research in thyroidology is Disparities in Thyroid. This final category included publications focused on disparities in the management of benign thyroid disease, thyroid cancer, and pediatric thyroid cancer. The nominees were as follows: Ettleson et al. (13), Ullmann et al. (14), and Gruszczynski et al. (15). Ultimately, the featured article was Ettleson et al., chosen because existing disparities research in thyroid more commonly focuses on surgery or cancer (13). Therefore, this article had a novel focus and should stimulate additional studies on treatment disparities for hypothyroidism.

Discussion

The five featured articles are all important additions to the field of thyroidology.

The featured article for Thyroid Nodules and Cancer was a pivotal study by Wirth et al. (3). It is important to identify treatment options for advanced, progressive thyroid cancer that improve outcomes and yet minimize harms. Targeted therapy offers promise. However, the efficacy and safety of selective rearranged during transfection (RET) inhibition for advanced medullary thyroid cancers with RET mutations and select other advanced thyroid cancers with RET fusions was previously unknown. Wirth et al. conducted a phase 1–2 trial in 65 centers in 12 countries and enrolled 162 patients, including adolescents and adults. Selpercatinib was administered orally in 28-day cycles.

Phase 1 patients received doses in range of 20 mg/day to 240 mg b.i.d. and phase 2 enrollees received 160 mg b.i.d. Primary end point was complete or partial response (as determined by independent review panel according to the RECIST), and secondary end points were duration of response, progression-free survival, and safety. Key findings were that of the 55 RET-mutant medullary thyroid cancer (MTC) who previously received vandetanib and/or cabozantinib 69% had a response (9% complete and 60% partial) and 1 year progression-free survival was 82%. Of the 88 RET-mutant MTC without prior vandetanib and/or cabozantinib, 73% had a response (11% complete and 61% partial) and 1 year progression-free survival was 92%.

Of the 19 patients with previously treated RET fusion-positive cancer, 79% had a response and 1 year progression-free survival was 64%. Impressively, the risks of study drug were low as most adverse events were grade 1 or 2 and treatment discontinuation due to treatment-related adverse events only occurred in 2%. Strengths of the study include the strong methodology and clinically relevant research question. A limitation is that radiographic tumor progression was not an explicit inclusion criterion. However, for select patients with medullary thyroid cancer or other thyroid cancers with RET fusions, selective RET inhibitors have potential to alter their disease course.

Active thyroid eye disease can be disabling. There had been little progress in treatment options until the last five years. The featured Thyroid Function and Thyroid Eye Disease article was a phase 3 study on teprotumumab in patients with active thyroid eye disease (6). Douglas et al. performed a randomized, double-masked, placebo-controlled, phase 3 multicenter trial in 13 sites in the United States and Europe. In the trial, patients with Graves' and active, moderate-to-severe thyroid eye disease, defined as lid retraction of ≥2 mm, moderate-to-severe soft tissue involvement, proptosis of ≥3 mm above normal for race/ethnicity and sex, periodic or constant diplopia, were assigned in a 1:1 ratio to intravenous infusion of insulin-like growth factor type 1 receptor inhibitor teprotumumab or placebo once every 3 weeks for 21 weeks.

Primary outcome was reduction in proptosis of ≥2 mm at week 24. Secondary outcomes included Clinical Activity Score indicating no or minimal inflammation, mean change in proptosis, diplopia response, mean change in Graves' ophthalmopathy-specific quality of life (QOL), and overall response. A total of 41 subjects were assigned to teprotumumab and 42 to placebo. Of those treated with teprotumumab, 83% had proptosis response compared with 10% with placebo (p < 0.001). Additional secondary outcomes were also significantly better including Clinical Activity Score of no or minimal inflammation 59% versus 21% for placebo and mean change in Graves' ophthalmopathy-specific QOL 13.79 points compared with 4.43 points.

Most of the adverse events were grade 1 or 2. There were five patients who developed hearing impairments, five with weight loss and two with mild hyperglycemia. There were two infusion reactions with one patient withdrawing from the trial. Strengths of the study include the clinically relevant topic and strong methodology. However, long-term follow-up is needed. Regardless, this study suggests that teprotumumab may help many patients with moderate-to-severe thyroid eye disease.

Most clinicians are aware of the adverse effects of undertreatment with thyroid hormone during pregnancy. However, few studies have addressed overtreatment. The featured Thyroid and Pregnancy article by Lemieux et al. evaluated treatment patterns and relationship between overtreatment and undertreatment with adverse pregnancy outcomes in women on thyroid hormone replacement (7). This was a retrospective cohort study from Alberta, Canada, of women aged 15 to 49 years on thyroid hormone replacement with delivery between October 2014 and September 2017. TSH values before conception and during pregnancy were assessed. Of 10,680 deliveries, 82.2% underwent TSH testing at least once, meaning close to 20% did not receive testing.

A total of 43.7% had a levothyroxine dose adjustment. Of the 44% who had a TSH measurement 4 months before conception, 66% had a preconception TSH measurement in the goal range of 0.10–4.00 mIU/L and 43.6% between 0.10 and 2.50 mIU/L. Among the 8774 pregnancies with TSH testing performed during pregnancy, a total of 351 pregnancies (4%) had at least one TSH <0.10 mIU/L. Multiple logistic regression was used to determine if TSH <0.10 mIU/L (overtreatment) or ≥10.00 mIU/L (undertreatment) were associated with adverse pregnancy or neonatal outcome. TSH <0.10 mIU/L increased odds of preterm delivery compared with control (16.5% vs. 8.2%; adjusted OR 2.14 [CI 1.51–2.78]).

In contrast, 9.1% had at least one TSH >10.0 mIU/L during pregnancy, and in this cohort, TSH >10.0 mIU/L was not associated with adverse pregnancy or neonatal outcome. Strengths of the study include the large cohort size and the clinically relevant topic. Limitations include variability in practice patterns and risk for unmeasured confounders. Previously, attention was devoted to avoiding an elevated TSH in pregnant women on thyroid hormone replacement. However, this study suggests that a suppressed TSH could also be harmful.

Nodule risk stratification systems such as the American College of Radiology TI-RADS have altered the care of adults with thyroid nodules. However, it is not known if TI-RADS can be applied to nodules in the pediatric population. Richman et al. assessed TI-RADS retrospectively in a pediatric cohort (10). This was a retrospective, single-institution cohort study of patients aged <19 years who underwent fine needle aspiration (FNA) between 2004 and 2017. The number of nodules that would be biopsied based on TI-RADS was compared with the number of nodules biopsied in clinic. Per the authors, biopsies were performed according to the American Thyroid Association guidelines for management of pediatric thyroid nodules; in general, nodules 1 cm or larger in diameter or 0.5 cm or larger with suspicious appearance on ultrasound underwent biopsy.

There were a total of 314 patients with the mean age of the patients 14.9 years (range 2–18 years) and 82.8% of the cohort female. A total of 19.1% of the nodules were cancer. The use of TI-RADS would have missed 17 (22%) of the cancers. Of clinical relevance, eight of the cancers would have fallen into the TI-RADS management recommendation of “no follow up or FNA.” On further review of these 8 patients, 1 patient had a suspicious lymph node and would have undergone biopsy for another reason. The average diameter of the 8 cancers was 4.0 cm, with 6 of the 8 cancers >4.0 cm.

This study suggests that perhaps regardless of TI-RADS, large nodules in children should undergo biopsy or surgery. A strength of this study is the focus on pediatrics and TI-RADS, an understudied topic. A limitation is the retrospective study design, which is a disadvantage for TI-RADS. Further studies are needed, but this innovative study implies that there may need to be modifications to TI-RADS for the pediatric population.

Most of the research on disparities in thyroid has focused on thyroid cancer and/or the surgical population. There has been limited assessment of disparities in the treatment of benign thyroid disease. In the featured Disparities in Thyroid article, Ettleson et al. evaluated disparities between those with adequately and inadequately treated hypothyroidism. The study participants were 20 years or older, underwent thyroid function testing as part of the National Health and Nutrition Examination Survey between 2007 and 2012, and had hypothyroidism. Of the 698 patients, 536 had treated hypothyroidism, 115 untreated subclinical hypothyroidism, and 47 untreated clinical hypothyroidism.

Patients who were pregnant or with history of thyroid cancer were excluded. Treated patients were categorized as undertreated (TSH >5.6 mIU/L), overtreated (TSH <0.3 mIU/L), and adequately treated. The study found that male gender and age <45 correlated with untreated subclinical hypothyroidism, whereas age <45 and lack of access to routine health care were associated with untreated clinical hypothyroidism. Race/ethnicity, education level, and income were not associated with differences in whether treated or untreated hypothyroidism. However, of the 536 participants with treated hypothyroidism, 10.4% were undertreated and 12.7% overtreated. In analysis, overtreated and undertreated were combined as inadequately treated (23.1%).

In multivariate regression, Hispanic ethnicity was associated with increased risk of inadequate treatment compared with non-Hispanic Whites (OR 2.42 [CI 1.14–5.14]). A strength of the study is the underexplored research focus. A limitation is the relatively small sample size and the inability to explore upstream drivers or downstream implications. Further research is needed to both understand the upstream drivers, that is, systems-level barriers, communication barriers, or potential differences in language preferences, as well as downstream implications on patient health. If Hispanic Americans are more likely to be overtreated or undertreated with thyroid hormone, are they also more at risk for pregnancy-related complications in young women or bone and cardiovascular health risks in older adults? Additional research is needed.

In conclusions, there were many strong publications between November 2019 and August 2021, making it very difficult to select nominees and featured articles for the five topic areas. The 15 nominees and 5 featured articles spanned a breadth of topics and methodological approaches. All five featured articles have the potential to change practice patterns or stimulate further research that will ultimately change practice patterns.