Year in Thyroidology: Clinical Science (2021

Abstract

Introduction

From my lens through serving the American Thyroid Association (ATA) in several roles, I have framed this opportunity to highlight select studies published between October 2021 and August 2022 in the clinical thyroid literature. I have selected 16 articles to review (Table 1), with the goal of looking back at historical work shaping the field, summarizing some of the unanswered questions in clinical thyroidology at present, with an eye toward what may be on the horizon for researchers, clinicians, and our patients. It is an impossible task to fully cover this vast topic in its entirety—many more well-designed, carefully conducted studies have made significant advancements in our field through their results. This is a summary of the Clinical Year in Thyroidology talk given at the ATA Annual Meeting in Montreal on October 20, 2022.

Table 1.

Highlighted Publications from the Clinical Thyroid Literature, October 2021–August 2022

Iodine nutrition
Li et al (2022)¹
Thyroid and pregnancy
Yang et al (2022)²
Osinga et al (2022)⁴
Hypothyroidism
Ettleson et al (2022)⁶	Reviewed by: Ref. 24
Brito et al (2022)⁷	Reviewed by: Ref. 25
Dumitrescu et al (2022)¹⁰	Reviewed by: Ref. 26
Evron et al (2022)¹¹	Reviewed by: Ref. 27
Hyperthyroidism
Chee et al (2022)¹²
Thyroid eye disease
Douglas et al (2022)¹⁵
Thyroid autoimmunity
McLeod et al (2022)¹⁶	Reviewed by: Ref. 28
Thyroid cancer
Morton et al (2021)¹⁷	Reviewed by: Ref. 29
Lee et al (2021)¹⁹	Reviewed by: Ref. 30
Robenshtok et al (2022)²⁰	Reviewed by: Ref. 31
Chou et al (2022)²¹	Reviewed by: Ref. 32
Chou et al (2022)²²	Reviewed by: Ref. 33
Thyroid nodules
Orloff et al (2022)²³

Iodine Nutrition

Although significant public health progress has been achieved in the eradication of endemic iodine deficiency over the past several decades, it is important to look back at what we have learned with an eye toward ensuring continued work to this field. In a report by Li and colleagues,¹ a group of adolescents residing in a historically iodine-deficient region of northeast China (where ∼10% of the villagers were severely iodine deficient during the late 1970s) were surveyed in 1979, 1 year after salt iodization had begun. This study describes follow-up findings of the surviving 31 adults (median age 59.52 ± 9.63 years, 55% men) with a history of neurologic cretinism (marked intellectual disability) now 42 years later. All adults remained with persistent intellectual disabilities (6 severe, 13 moderate, 12 mild), sobering findings underscoring the important role of adequate iodine nutrition, particularly in very early life.

Thyroid and Pregnancy

A study by Yang and colleagues is the largest available analysis of preconception maternal thyroid function and adverse obstetric outcomes² (accompanied by an invited commentary by Alexander in the same issue).³ This population-based cohort study was conducted in China from 2013 to 2016 of 11,194,002 women (mean ± standard deviation age, 27.56 ± 5.10 years), of whom 42.34% became pregnant within 1 year. The median overall serum thyrotropin (TSH) concentration was normal (1.73 mIU/L [interquartile range, 1.16–2.52]), but those with abnormally decreased or increased TSH concentrations had greater risks of decreased fecundability (hazard ratio [HR] ranging 0.78–0.90) and spontaneous abortion (HR range, 1.25–1.33), depending on the severity of the abnormal TSH. However, there are currently no prospective, blinded trials to support the benefit of universal maternal thyroid function screening, and these findings still do not formally define the optimal thyroid hormone status for women wishing to conceive.

A study by Osinga and colleagues illustrates the complexities of defining reference intervals for serum maternal thyroid function tests during pregnancy.⁴ Using individual-participant level data from the Consortium on Thyroid and Pregnancy cohort (reflecting aggregate data from ∼80,000 women corresponding to ∼100,000 maternal–child pairs, contributed by over 50 collaborators in 25 countries), this systematic review searched until December 2021 reported that there are large methodological differences in the published cohorts reporting pregnancy-specific thyroid function reference intervals. Some studies had applied the 5th to 95th percentiles to define reference TSH and free thyroxine (FT4) levels during pregnancy (rather than the internationally recommended use of 2.5th to 97.5th percentiles),⁵ and not all cohorts had excluded serum thyroid peroxidase (TPO) antibody positivity, which may increase the upper TSH limit by up to 17.4% (first trimester) and up to 9.8% (second trimester). These findings highlight the pressing need to optimally characterize the normative thyroid function test ranges during gestation, which will be critical for thyroid and pregnancy studies that quantify thyroid dysfunction.

Hypothyroidism

A study by Ettleson and colleagues provides further insight into persistent symptoms in patients treated for hypothyroidism.⁶ Patient respondents to this online survey self-reported brain fog (n = 5170; mean age 50.6 ± 12.1 years; 95.9% women; 45.3% whose hypothyroidism was owing to Hashimoto's thyroiditis) and accompanying symptoms. Responses related to “memory/language” and “sleep/time,” or of aspects related to the medical condition or its treatment (such as “disease/diagnose,” “doctor/patient,” and “medication”) were common, insightful findings into patients' perspectives regarding the evaluation and treatment of their hypothyroidism.

Levothyroxine (LT4) is the most common form of thyroid hormone replacement in patients with hypothyroidism. A retrospective cohort study by Brito and colleagues examined the therapeutic interchange of different generic LT4 formulations in patients with hypothyroidism within the Optum Labs Data Warehouse, a large U.S. administrative insurance claims database linked to laboratory test results.⁷ Of 15,829 adults (mean age 58.9 ± 14.6 years, 73.4% women) with ≥1 filled prescription of generic LT4 between 2008 and 2019, there was a similar proportion of those with a normal-range serum TSH level 3 months later, regardless if they had been switched to another generic or continued with the same LT4 formulation (mean TSH 2.7 mIU/L in both groups). The findings raise the question of whether existing hypothyroidism guidelines recommending that LT4 usage from the same source⁸ should be revised.

The potential benefits of L-triiodothyronine (LT3) have been increasingly explored in recent years, and there was universal agreement in a 2021 consensus document from the American, European, and British Thyroid Associations that new formulations of LT3 are needed for future clinical trials assessing combination LT3/LT4 therapy.⁹ Dumitrescu et al published the findings of a phase I, double-blind, randomized, placebo-controlled trial of a long-acting form of LT3.¹⁰ Poly-zinc-liothyronine (PZL) is a zinc–triiodothyronine (T3) complex that adheres to intestinal mucosal lining and acts as a slow-release depot of LT3. In a crossover design, 12 healthy adults each received a single dose of either PZL, conventional LT3, or placebo. The PZL dose resulted in serum T3 levels with a more gradual peak and longer plateau period than LT3, and both PZL and LT3 provided higher serum T3 levels than placebo, which was sustained even 24 hours after the single treatment dose. These promising results show that metal coordination chemistry may deliver LT3 in a more sustained manner, potentially as a future once-daily dose.

The risks of treatment of hypothyroidism may not be without risks. In a retrospective cohort analysis of the U.S. Veterans Health Administration system, the largest integrated health care system in the United States, Evron and colleagues studied 705,307 patients (median age 67 years [range, 18–110]; 88.7% men) who had received thyroid hormone treatment between 2004 and 2017.¹¹ Over a median of 4 years, time-weighted serum TSH and FT4 levels that were both abnormally increased or decreased (signifying overtreatment or undertreatment of hypothyroidism) were associated with increased cardiovascular mortality risks (up to adjusted HR 2.67; 95% confidence interval, 2.55–2.80).

Hyperthyroidism

A publication by Chee et al explores the intersection between the SARS-Co-V2 pandemic and thyroid autoimmunity and dysfunction.¹² Although small, this case series (n = 12, mean age 35.5 years, 92% women) described a relapse of or new diagnosis of Graves' disease at a median of 17 days after mRNA vaccination against SARS-Co-V2. The authors postulate several mechanisms for this observation, including direct activation of angiotensin-converting enzyme 2 (ACE-2) receptors in the thyroid, molecular mimicry (cross-reactivity of SARS-CoV-2 mRNA vaccine components with thyroid antigens), genetic predisposition (the vaccine activates B lymphocytes to produce antibodies against the TSH receptor), and/or the induction of autoimmunity by vaccine adjuvants, resulting in an autoimmune/inflammatory syndrome induced by adjuvants. However, a large population-based epidemiologic study of 2.3 mRNA and inactivated SARS-CoV2 vaccine recipients in Hong Kong has since been published that showed no association between vaccination and incident thyroid dysfunction.¹³

Thyroid Eye Disease

Also recently published were the results of the extension study to OPTIC, the phase 3, randomized, double-masked, placebo-controlled, parallel-group, multicenter trial of teprotumumab for patients with moderate to severe, progressive, acute thyroid eye disease,¹⁴ one of the two clinical trials that resulted in U.S. Food and Drug Administration approval for the drug in 2020. The extension study (OPTIC-X) was reported by Douglas and colleagues of 37 subjects who had been in the placebo arm of OPTIC, and in the extension, received teprotumumab at a median of 12.9 months after diagnosis, compared with 6.3 months of those from the original trial.¹⁵ Despite the later treatment, there were significant improvements in proptosis (of ≥2 mm in 89%), diplopia in 61%, and clinical activity score in 66% after 6 months of therapy, providing evidence that even delayed teprotumumab treatment of appropriately selected patients with thyroid eye disease may provide benefit. In a consensus statement (accepted, in press) jointly prepared by the American and European Thyroid Associations, the task force cautioned that these findings should be interpreted in balance with the drug's relatively high cost, limited global availability, and absent cost-effectiveness data.

Thyroid Autoimmunity

The associations between thyroid autoimmunity and differentiated thyroid cancer were explored in a nested case–control study by McLeod et al.¹⁶ Among U.S. active duty military personnel who had available banked sera, there were 451 new cases (median age 36 years, 61% men) of papillary thyroid cancer (PTC) between 1996 and 2014. When matched to non-PTC controls, those with positive serum TPO and/or thyroglobulin (Tg) antibody titers measured at both 3–5 and 7–10 years prior had an increased incident risk of PTC. Although provocative, the authors caution that their findings should not necessarily be interpreted to universally screen for thyroid cancer in those with known positive thyroid antibody titers, given the still incompletely understood risks of thyroid cancer overdiagnosis with this approach.

Thyroid Cancer

A study by Morton et al (for which the senior author, Dr. Stephen J. Chanock, provided the keynote plenary lecture at the 2022 ATA Annual Meeting) provides insight on the topic of radiation-induced thyroid carcinogenesis.¹⁷ The authors studied 440 fresh-frozen PTC samples from 359 patients who had been exposed to the Chernobyl explosion in 1986 (median age at exposure, 7.2 years; 76% women; median latency to PTC diagnosis, 22.4 years). Samples were assessed by whole-genome sequencing, single nucleotide polymorphism microarray genotyping, mRNA and microRNA sequencing, methylation profiling, transcriptome analysis, and telomere-length quantification; molecular drivers were identified in 98% of the PTCs in those previously exposed to the Chernobyl fallout. There were significant associations seen between radiation doses and fusion drivers, small deletions, and balanced structural variants resulting from the nonhomologous end-joining repair of dsDNA damage, but no one unique biomarker signature was identifiable to define radiation-induced PTCs. These data have important therapeutic implications for future novel therapies targeting thyroid cancer gene fusions.

A recent pediatric study has further shed understanding on the role of molecular drivers in our younger patients with differentiated thyroid cancers (DTCs), as summarized in a commentary by Franco et al.¹⁸ A cohort of children with PTC (n = 106; age range, 4.3–19.8 years; 79% females) were compared with 125 adult PTC controls, from whom oncogenic drivers were found in 75% of the pediatric DTC patients.¹⁹ Fusion oncogenes were more likely to be present in younger children (<10 years) than older children, associated with advanced stage DTC, and associated with increased risks of recurrent/persistent PTC. The study also reported the outcomes of two girls with progressive ¹³¹I-refractory lung metastases harboring TPR-NTRK1 and CCDC6-RET fusion oncogenes; their tumors decreased in size and ¹²⁵I radioiodine uptake was restored following treatment with fusion-targeted therapies (larotrectinib, selpercatinib). Overall, these findings outline oncogenic fusions as the main genetic drivers in pediatric DTCs, for whom those with radioiodine-refractory fusion-oncogene PTCs may benefit from targeted therapies.

Another study of DTC in adults provides further insight on the clinical significance of histologic features that are traditionally regarded aggressive. Robenshtok and colleagues performed a systematic review and meta-analysis, queried up to December 2020, of autopsy studies among individuals without a known history of thyroid cancer.²⁰ From 29 included studies (n = 8750 individuals, median age 61 years), undiagnosed DTC containing ≥1 high-risk feature was present in 8.5% of the sample (highest prevalence in Japan, lowest in the United States), with multifocality as the most common aggressive histologic feature (28.5% of the sample). These incidental findings provide a framework to potentially reconsider the clinical implications of what are currently regarded as high-risk features observed in some patients with DTC.

Finally, there were two systematic reviews and meta-analyses recently conducted to inform the coming update to the ATA's guidelines for the diagnosis and management of DTC. The first was on the use of active surveillance in low-risk PTCs by Chou et al.²¹ From 18 included studies (n = 5970 patients) comparing active surveillance to immediate thyroid surgery in established protocols (three studies from Japan enrolled PTCs ≤1 cm, one from Korea enrolled PTCs ≤1.2 cm, and one from Brazil enrolled PTCs <2 cm), overall rates of tumor growth, mortality, and distant metastases were low and similar over a mean follow-up of 2–7 years (longest 25 years). In another group of 88,654 patients pooled from four cohort studies of thyroid surgery versus no thyroid surgery (i.e., not enrolled in a formal thyroid cancer active surveillance protocol, with very little data available regarding the reasons for thyroid surgery), findings were overall heterogeneous and not generalizable to the use of active surveillance in patients with low-risk DTCs.

The second systematic review and meta-analysis, published by Chou and colleagues, examined the role of serum Tg levels in patients with DTC who had undergone either a thyroid lobectomy, a total thyroidectomy without a plan to administer radioactive iodine, or a total thyroidectomy before postoperative radioiodine ablation (this last group thus likely representing a higher risk population).²² From 37 included studies (n = 8930), serum Tg levels were variable and inaccurate after thyroid lobectomy (n = 561) and generally low/stable after total thyroidectomy in those with no plans for radioiodine ablation (n = 751). It was only in the latter group (total thyroidectomy whose Tg was measured before planned radioiodine) that a minimal cutpoint of 1.0–2.5 ng/mL was the most useful; Tg levels above this threshold would most likely identify patients with low-risk persistent/metastatic DTC who had not undergone ablation.

As we look toward the future of newer therapies for thyroid nodules and thyroid cancer, a consensus statement on ablative techniques endorsed by multiple professional societies was recently published by Orloff et al.²³ This international expert panel (comprising surgeons, radiologists, and endocrinologists) conducted a systematic literature search of ethanol, microwave, laser, radiofrequency, and high-intensity focused ultrasound ablation for benign and malignant thyroid nodules. Based on 690 studies, the panel issued 18 best practice statements, which included the use of ablative techniques as a suitable first-line therapy of benign thyroid nodules associated with compressive symptoms, for micro-PTCs, and for recurrent PTCs. The techniques were less efficacious for autonomous thyroid nodules but still a safe therapeutic option, and retreatment may be needed. The authors concluded that advanced training and demonstrated proficiency were essential for these emerging therapeutic options.

I hope that this clinical thyroid year in review has been interesting, informative, and perhaps even thought-provoking in exploring how we approach the research and clinical questions related to iodine nutrition, thyroid and pregnancy, hypothyroidism, hyperthyroidism, thyroid eye disease, thyroid autoimmunity, thyroid cancer, and thyroid nodules.

Footnotes

Author Disclosure Statement

Editor-in-Chief, Clinical Thyroidology; Writing Committee, American Thyroid Association/European Thyroid Association Thyroid Eye Disease Consensus Statement; Writing Committee, Update to the American Thyroid Association 2015 DTC Guidelines; Co-Chair, Update to the American Thyroid Association 2017 Thyroid and Pregnancy Guidelines.

Funding Information

No funding was received for this article.

To review other articles in the “Year in Thyroidology” series please go into these links:

https://orcid.org/0000-0001-8935-9332

https://doi.org/10.1089/thy.2022.0633

https://doi.org/10.1089/ve.2022.0045

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22.

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24.

Shah

, Maraka

Hypothyroid patients describe what brain fog feels like. Clin Thyroidol, 2022; 34:106–108.

25.

McAninch

EA.

Switching generic-to-generic levothyroxine does not change serum TSH. Clin Thyroidol, 2022; 34:295–297.

26.

McAninch

EA.

Phase 1 clinical trial of poly-sinc-liothyronine demonstrates slow-release serum T3 kinetics. Clin Thyroidol, 2022; 34:9–12.

27.

Maraka

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28.

Udyavar

, Morris-Wiseman

. Preexisting thyroid autoimmunity is associated with increased thyroid cancer risk. Clin Thyroidol, 2022; 34:250–252.

29.

Klubo-Gwiezdzinska

Childhood exposure to excess ionizing radiation is associated with dose-dependent fusions as molecular drivers of papillary thyroid cancer. Clin Thyroidol, 2022; 34:161–164.

30.

Francis

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31.

Balcerek

, McLeod

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32.

Biondi

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33.

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Year in Thyroidology: Clinical Science (2021–2022)