Thyroid®

Thyroid hormone exerts its function on virtually all tissues in the human body through binding to the thyroid hormone receptor (TR), making it an interesting vehicle for therapeutic intervention in nonthyroid conditions with metabolic consequences, as well as genetic thyroid hormone signaling disorders. Since the 1990s, several thyroid hormone analogs have been developed that have tissue specificity. Given the recent approval of two thyroid hormone analogs, the aim of this review is to give an update on developments in the field since 2020.

Although initial therapeutic use of thyroid hormone analogs for nonthyroid conditions with metabolic consequences focused on cardiovascular disease and dyslipidemia, nowadays the primary focus is on the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Clinical trials with MGL-3196 (resmetirom) showed significant improvement on hepatic steatosis, fibrosis, and lipids, which led to approval by the U.S. Food and Drug Administration in 2024 for the treatment of MASH. Results are currently awaited for prodrug VK2809, exerting organ specificity through prodrug conversion in the liver, ultimately targeting MASH. For the treatment of genetic thyroid hormone signaling disorders (resistance to thyroid hormone β [RTHβ] and monocarboxylate transporter 8 [MCT8] deficiency), different thyroid hormone analogs have been tested. 3,5,3ʹ-triiodothyroacetic acid (Triac), an endogenous thyroid hormone analog, has been prescribed on a compassionate use basis for RTHβ. In MCT8 deficiency, 3,5-diiodothyropropionic acid has been explored in patients, and Sob-AM2, a prodrug of which the active compound accumulates in the brain, has been investigated in preclinical studies. Recently, the European Medicines Agency has granted market authorization for Triac, being the first approved medicine for this rare disease.

Ongoing strategies to enhance organ specificity of thyroid hormone analogs should include not only TR specificity but also other determinants of tissue selectivity, such as tissue-specific transporters or enzymes that activate the prodrug. This, together with the recent approval of two thyroid hormone analogs, may ensure a promising future for the development and application of thyroid hormone analogs.

Careful consideration of the differential diagnosis of discordant thyroid function tests (TFTs) is fundamental to prevent mismanagement, waste of resources, uncover rare thyroid disorders, or other underlying critical conditions in patients referred for the evaluation of this issue. Here, we describe the frequency of underlying diagnoses and focus on cases in which the identification of analytical interferences led to the discovery of lymphoproliferative disorders.

This is a retrospective cross-sectional study including all consecutive patients referred to the Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, for suspected central hyperthyroidism between January 2017 and February 2025. Inclusion criteria were based on laboratory findings of (1) elevated or inappropriately normal thyrotropin (TSH) with high FT4 and/or FT3, (2) elevated TSH with FT4 in the upper reference range, and (3) failure of TSH to normalize despite levothyroxine therapy, along with rising FT4 levels. The differential diagnosis was made by (1) reassessment of discrepant results in the hormone panel by different analytical methods or tandem mass spectrometry; (2) serum serial dilution or polyethylene glycol precipitation; (3) evaluation of rheumatoid factor, serum protein electrophoresis (SPEP), and cryoglobulins; and (4) deep clinical phenotyping and/or confirmatory genetic testing, as appropriate.

Among 144 patients referred for discordant TFTs mimicking central hyperthyroidism, 44% were genuine rare thyroid disorders—32% with resistance to thyroid hormone beta (RTHβ), 7% with TSH-secreting adenomas, and 5% other diagnosis—and 56% had assay interference. In this latter group, interfering clonal paraproteins were detected in 6/81 cases. One patient was ultimately diagnosed with multiple myeloma, another one with type 1 cryoglobulinemia due to indolent marginal zone B non-Hodgkin lymphoma, and the remaining four cases were found to have monoclonal gammopathy of uncertain significance. The clonal paraprotein was an IgM kappa/lambda in five cases and IgG kappa or IgA kappa in one case, respectively.

In patients referred for discordant TFTs, RTHβ is the most prevalent thyroid disorder, but variable assay interferences represent the most frequent condition. In these cases, SPEP and hematological investigations are highly recommended.

Differentiated thyroid carcinoma (DTC) in pediatric patients has specific clinical, pathological, and molecular characteristics, making its management different from that of adults. Our study aimed to evaluate the outcome and factors associated with persistent disease in a large cohort of pediatric patients.

We performed a multicenter retrospective cohort study, including patients aged ≤18 years, diagnosed with a DTC, since January 2000. Both biochemical (BIR) and structural (SIR) incomplete responses were evaluated.

We included 538 patients, 401/538 (74.5%) females, with a median age of 15 years (interquartile range [IQR] 13–17 years). Papillary thyroid cancer was the most prevalent histotype and 277/530 (52.3%) had lymph node metastases at diagnosis. Vascular invasion and gross extrathyroidal extension (ETE) were reported in 133/326 (40.8%) and 91/533 (17.1%) of patients, respectively. T4 tumors represented 5% of the entire cohort. Radioactive iodine treatment (RAIT) was administered to 493/533 (92.5%) patients, and among them 138/493 (28%) received more than one RAIT cycle. After a median follow-up of 85 months (IQR 42–126 months), 414/538 patients (77%) had no evidence of disease and 124/538 patients (23.0%) a disease persistence: BIR in 68/538 patients (12.6%) and SIR in 56/538 patients (10.4%). In a multivariable analysis, the features significantly associated with persistent disease (BIR or SIR) were gross ETE (odds ratio [OR] 2.81, confidence interval [CI] 1.49–5.32, p = 0.0015) and lymph node uptake at whole-body scan (WBS) after the first RAIT (OR 3.31, CI 1.77–6.19, p = 0.0002). Multivariable analysis showed that the features significantly associated with SIR were T4 tumor (OR 4.3, CI 1.38–13.44, p = 0.01) and lymph node uptake at WBS after the first RAIT (OR 3.39, CI 1.5–7.67, p = 0.003).

Our study of a very large series of pediatric DTC with long follow-up provides valuable insights into the clinical and pathological features associated with disease persistence. We identified T4 tumor, lymph node uptake on WBS, and gross ETE as independent factors associated with persistent disease. These findings emphasize the importance of careful risk stratification in pediatric DTC, allowing for more individualized treatment approaches.

Thyroid nodules are common in the general population, and most are benign. Thyroidectomy remains the most common treatment for symptomatic benign thyroid nodular disease. The objective of this study is to determine if a novel, cell-specific, nonthermal modality called nanosecond pulsed field ablation (nsPFA) can provide a safe and effective treatment for symptomatic thyroid nodules.

In this clinical feasibility trial (NCT06117085), an nsPFA percutaneous electrode was used to ablate benign thyroid nodules under ultrasound guidance. In Cohort 1 (5 patients), ablations were created during a thyroidectomy procedure (treat-and-resect), so that initial ablation zone characterization could be assessed histologically. In Cohort 2 (20 patients), up to 4 isolated ablations were created in the in situ thyroid for dose-ranging and to allow for estimation of ablation zone volume. In Cohort 3 (5 patients), the entire nodule was ablated with therapeutic intent using multiple, overlapping ablations for resolution of symptoms.

For Cohort 1, the mean ablation zone measured 1.7 cm long by 0.7 cm wide post-ablation. For Cohort 2, the mean ablation zone was estimated to be 2.7 cc in volume at 90 days post-ablation (based on nodule size reduction from baseline). Transient dysphonia (<24 hours) was seen in two patients treated at the highest ablation setting (93 mJ/mm²). For Cohort 3, treated nodules had a mean volume reduction of 48.2% as early as 2 weeks, and 71.1% at 1 month and 85.8% at 1 year. Patients could typically resume normal activities on the same day. There was no transient dysphonia in this group. Noticeable volume reduction and relief of symptoms were seen as early as 2 weeks post-treatment. No fibrosis or scars were seen on follow-up ultrasounds. No serious adverse events were reported for any cohorts.

This first-in-human study supports the initial safety/efficacy profile of the nsPFA electrode system in treating benign thyroid nodules. The minimally invasive and nonthermal nature of nsPFA energy has the potential to reduce risk of major complications in treatment of benign thyroid nodules as compared with thyroidectomy or thermal ablation and to improve healing through rapid reduction ofablated areas and lack of postprocedural scarring.

Calcitonin (CT), a well-established tumor marker for medullary thyroid carcinoma (MTC), is limited by a high rate of false positives in the diagnostic phase. Potential new markers for MTC are procalcitonin (PCT) and progastrin-releasing peptide (proGRP). Where literature has proven noninferiority for PCT, evidence is lacking for proGRP. Therefore, the present study prospectively evaluated the clinical performance of proGRP and PCT in a multicohort study of patients with MTC compared with other thyroid diseases.

Adult patients undergoing thyroid surgery for thyroid nodular disease diagnosed in a tertiary center from the Netherlands (discovery cohort) between 2013 and 2025 were prospectively included. Serum samples were collected preoperatively. Diagnostic performance of CT, PCT, proGRP, and carcinoembryonic antigen was calculated separately. A two-step approach, combining different markers, was investigated. Analyses were repeated in a validation cohort from Switzerland.

The discovery and validation cohorts consisted of 335 and 61 patients, respectively. Patients had benign disease (n = 166), other thyroid carcinomas (non-MTC, n = 186), or MTC (n = 44). Median proGRP and PCT levels were significantly higher in MTC compared with benign disease and non-MTC. ProGRP had a low sensitivity (69.2% [CI 48.2–85.7]), while PCT performed similarly to CT (100.0% [CI 89.1–100.0] and 100.0% [CI 88.8–100.0], respectively). The combination of CT and PCT, both in the individual cohorts and when combining the two cohorts, showed the best diagnostic performance with a sensitivity of 100% [CI 91.8–100.0] and negative predictive value of 100% [CI 98.9–100.0] and specificity and positive predictive value of 99.7% [CI 98.4–100.0] and 97.7% [CI 88.0–99.9], respectively.

ProGRP alone or with CT does not have additional value as a diagnostic marker for MTC. A two-step approach combining the use of CT and PCT measurement, in the CT concentration range between 10 and 100 pg/mL, is a promising method to diagnose MTC in patients with thyroid nodules with high diagnostic accuracy.

Thyroid cancer survivors may experience significant health-related quality-of-life (HRQoL) detriments. Currently available HRQoL survey tools, used in isolation, can be insensitive to change over time and may incompletely assess thyroid cancer-specific symptoms and fear of cancer recurrence. This study aimed to measure the trajectory of HRQoL changes in thyroid cancer survivors using repeated measures, comparing commonly used surveys, over the first 12–18 months following diagnosis.

A prospective longitudinal cohort study recruited all patients with newly diagnosed thyroid cancer (excluding low-risk papillary thyroid microcarcinoma and anaplastic thyroid cancer) from a mixed metropolitan and regional health district (public and private). Patients were invited to complete Short Form-12 (SF-12), EORTC-QLQ-C30, Thyroid Cancer Quality of Life (ThyCaQoL) Survey, City of Hope–Thyroid Version, and Assessment of Survivor Concerns surveys postoperatively, and at 3, 6, and 12 months. Responses were assessed for changes over time, and multivariable analysis was used to identify variables associated with outcomes at follow-up.

Between January 2021 and June 2023, 111 patients completed surveys at a minimum of one time point (response rate 59%). Most were female (72%), mean age 55 years, 56% metropolitan, 56% privately insured, 55% American Thyroid Association low-risk differentiated thyroid cancer. Treatment included surgery (total thyroidectomy 49%, two-stage thyroidectomy 24%, lobectomy 25%, active surveillance 2%); 58% received radioactive iodine ablation. At the completion of the study, 82% were euthyroid and 92% disease-free. At all time points, SF-12 physical and mental component scores (PCS and MCS), remained below normative population values (>12 months; mean PCS = 39.4, mean MCS = 46.7, normative = 50). MCS showed more consistent improvement over the first year following thyroid cancer diagnosis (global p = 0.03). ThyCaQoL surveys identified improvement in voice and scar symptoms (p < 0.01 each), but distress regarding neuromuscular (p < 0.01), sensory symptoms (p = 0.01), and weight gain (p = 0.04) worsened over the course of the study. Fear of cancer recurrence was common and persisted over time.

A year after diagnosis, thyroid cancer survivors have persisting HRQoL deficits with some symptoms worsening over time. As part of follow-up care, clinicians should specifically inquire about persistent symptoms that could affect HRQoL. Supportive care interventions for those with persistent HRQoL deficits are required.

Statin use is associated with a reduced risk of Graves’ orbitopathy (GO). However, whether the timing of initiating statin treatment after the diagnosis of Graves’ disease (GD) affects the association between statin and GO risk remains unclear. This study aims to evaluate the risk of GO based on varying intervals of statin initiation following GD diagnosis.

This nationwide, population-based retrospective cohort study used data of all beneficiaries aged >40 years diagnosed with GD from Taiwan’s National Health Insurance Research Database (2009–2019). We excluded patients with incomplete data, follow-up <6 months, with a diagnosis of GO, or on medication for hyperlipidemia before GD diagnosis. We performed 1:4 matching based on age, sex, and the duration between GD diagnosis and the index day for statin users and nonusers. GO patients were further classified as having mild or moderate-to-severe GO according to the type of treatment received.

A total of 47,424 patients were categorized into Group A (<1 year, 4649 statin users; 18,584 nonusers), Group B (1–2 years, 3060 statin users; 12,349 nonusers), and Group C (2–3 years, 1752 statin users; 7030 nonusers) by the duration between GD diagnosis and the index date. Cox regression showed that statin users in Group A had a significantly lower risk of total GO (adjusted hazard ratio [HR]: 0.66, confidence interval [CI]: 0.47–0.94, p = 0.023) and moderate-to-severe GO (adjusted HR: 0.39, CI: 0.19–0.80, p = 0.010), but not mild GO (adjusted HR: 0.84, CI: 0.56–1.25, p = 0.385) than nonusers. However, no significant associations were found in Groups B and C. The risk of GO was not statistically different among users of various types or intensities of statins in any group.

Initiating statin treatment within one year after being diagnosed with GD was associated with 34% and 61% reduction in total and moderate-to-severe GO risk, respectively. For patients whose treatment was initiated more than one year after GD was diagnosed, statin use was not related to the risk of total, mild, and moderate-to-severe GO. These findings suggest that the timing of statin initiation may influence the risk of GO, which warrants further confirmation through prospective studies.

The roles of different thyrotropin (TSH) receptor (TSHR) antibodies in Graves’ disease (GD) and thyroid eye disease (TED) remain unclear, and animal models have been used to try and clarify. While several models have been developed using different TSHR antigens, they have failed to robustly replicate the complexities of human disease, regardless of mouse strain, immunization method, or TSHR antigen used, and often overlook the complete TSHR reactome. In this study, we evaluated a mouse model of GD, focusing on TSHR antibodies with different bioactivities.

Female Balb/c mice were immunized intramuscularly with an adenovirus expressing residues 1–289 of the human TSHR (Ad-TSHR 289) or control vector (Ad-Lacz) with 10 injections at 3-week intervals. Thyroid function was assessed by total thyroxine (T4) and TSH levels. The presence of TSHR binding antibodies as well as stimulating TSHR antibodies (TSAb) and TSH-blocking TSHR antibodies (TBAb) was evaluated using flow cytometry and a transcriptional-based luciferase cell bioassay. We also conducted thyroid ultrasound and histology, micro-magnetic resonance imaging (micro-MRI) for orbital changes, and histological analysis of orbital tissue after 30 weeks of immunization to assess immunopathological changes.

Out of a total of 16 mice, 9 became hyperthyroid—characterized by decreased TSH levels, increased T4 levels, and diffuse enlargement of the thyroid glands. All mice developed TSHR antibodies when assessed by flow cytometry. 8/9 of the hyperthyroid mice had TSAb but mostly at low levels, while 7 showed only TBAb but without hypothyroidism. Only 2 mice had detectable linear antibodies. Five hyperthyroid mice showed eye signs, including conjunctival redness and eyelid thickening. Micro-MRI and histology revealed mild retrobulbar adipose and muscle enlargement with macrophage infiltration.

Hyperthyroidism occurred in 56% (9/16) of mice, despite all developing TSHR antibodies. The detected TSAbs were of low-level despite their high levels by flow cytometry, suggesting that the simultaneous presence of TBAbs may explain the weak stimulating activity. In the mice with TBAbs, there was no hypothyroidism, suggesting they were not highly effective due to simultaneous TSAb activity and may indeed have prevented hyperthyroidism. These findings highlight the importance of considering the full TSHR antibody reactome in GD mouse models, as it ultimately determines thyroid outcomes.

Primary thyroid lymphoma (PTL) is a rare malignancy, comprising less than 5% of all thyroid cancers and about 2.5% of lymphomas. Historically, treatment with surgery and radiation yielded poor outcomes. The advent of combined chemotherapy and radiation has improved survival, but long-term trends and prognostic factors remain underexplored. This study aimed to characterize the clinical and demographic features of PTL, evaluate changes in survival over time, and identify factors independently associated with survival.

A retrospective cohort study was conducted using Surveillance, Epidemiology, and End Results data from PTL patients aged ≥20 years, diagnosed between 1975 and 2021. Variables analyzed included age, sex, race/ethnicity, lymphoma subtype, stage, and treatment modality. Survival outcomes were estimated using Kaplan–Meier curves, and Cox proportional hazards models were used to identify factors associated with survival. Treatment was categorized as chemotherapy plus radiation (with or without surgery), chemotherapy alone, radiation alone, or no treatment.

A total of 2465 patients were included; 76% (n = 1,874) were diagnosed from 2001 to 2021. Median age at diagnosis was 67 years (interquartile range [IQR]: 56–77); 69.9% (n = 1723) were female, and 88.8% (n = 2189) were White. The most common subtype was diffuse large B-cell lymphoma (62.5%, n = 1540). Median follow-up was 83 months (IQR: 24–156). Median overall survival (OS) was 150 months, with 1-, 5-, and 10-year OS rates of 84.9%, 72.9%, and 57.7%, respectively. Disease-specific survival (DSS) rates at the same time points were 89.1%, 83.7%, and 80.5%. Survival significantly improved for patients diagnosed after 2000 (p < 0.001). Variables associated with poorer DSS survival included age ≥70 years (hazard ratio [HR] = 5.77; confidence interval [CI] 2.71–12.32, p < 0.001), regional metastatic disease (HR = 1.45; CI 1.04–2.02; p = 0.03) and distant metastatic disease (HR = 1.53; CI 1.17–1.99; p = 0.002). The highest 10-year DSS (86.6%) was seen in those receiving combined chemotherapy and radiation, outperforming chemotherapy alone (77.2%), radiation alone (77.0%), and no treatment (68.2%).

PTL survival has significantly improved in recent decades, which may reflect both advances in treatment, particularly the combined use of chemotherapy and radiation, and shifts in disease presentation, including earlier diagnosis and changes in stage distribution.

Traumatic brain injury (TBI) disrupts blood supply, damages neurons and glial cells, and reduces local activation of the prohormone thyroxine (T4) to the active form, triiodothyronine. We treated mice with T4 post-TBI to evaluate the role of thyroid hormone in neural cell protection and injury recovery after TBI, especially the effects on neuroglial cells.

A T4 dose was given 1 hour after controlled cortical injury, and in some groups, an additional T4 dose was given 5 days post-TBI. We analyzed the reactive astrocytes and activated microglia in the ipsilateral cortex. We assessed cortical gliogenesis, with or without T4 treatment, in live animals using 5-ethynyl 2′-deoxyuridine-labeling. Finally, learning and spatial memory retention were tested using the Morris water maze (MWM).

T4 treatment 1-hour post-TBI significantly reduced the number of reactive astrocytes and activated microglia in the ipsilateral cortical area. An additional dose of T4 on day 5 post-TBI further reduced the number and size of reactive astrocytes. T4 treatment induced gliogenesis 2.6-fold greater than with saline treatment. T4 treatment induced neuron-glia antigen 2-expressing glial cell proliferation but not astrocytes. Mice treated with T4 post-TBI had improved MWM performance, better escape latency, and better spatial memory compared with saline-treated mice.

Our data indicate that T4 treatment shortly after TBI significantly reduced acute astroglial cell activation and improved recovery of neurons and brain function.