Thyroid®

Mild thyroid eye disease (TED) is the most common form of TED, yet it is the least studied. Uncertainties about the natural history and prevention, and underfunding for clinical research, are an obstacle to improving the management of this important group of patients.

The available evidence suggests that the prevalence of mild TED can reach up to two-thirds of all cases, depending on the expertise of the assessor and the criteria used for diagnosis. Prevalent symptoms and signs of mild TED predominantly arise from lid changes, soft tissue involvement and ocular surface disease, but disease presentation is heterogeneous and in some patients proptosis and eye motility changes may be underrated with the current classification. Little is known about the impact of the various manifestations of mild disease on patients’ risk of progression and quality of life (QoL). Although in most patients with mild TED the disease remits spontaneously, some patients progress, and a significant proportion evolve to persistent, inactive TED. Current therapeutic options for these patients are based on scarce, low-to-moderate quality and sometimes conflicting evidence, resulting in significant differences in the management of mild TED in different countries and by different specialists. Among the most recommended therapeutic interventions, selenium supplementation was mainly studied in selenium-insufficient populations with active mild TED and it lacks efficacy in longstanding, inactive disease. The use of immunosuppressive drugs and targeted therapies for mild TED are commonly reported by surveys of medical professionals in a clinical setting, but the indication and efficacy of these agents in mild TED remain unclear.

Mild TED has a significant psychosocial and functional burden that should be reconsidered and addressed by local, systemic or surgical treatments in an individualized manner. Given the overall effect on QoL and the socioeconomic impact, it is of immediate importance to highlight the knowledge gaps and the need for research in mild TED.

Depression is a large and expanding worldwide unmet clinical need that has proven difficult to treat. Thyroid hormone has been used clinically for decades as an augmentation therapy to first-line antidepressants, although the mechanism of action (MOA) behind the beneficial effect of thyroid hormone augmentation is not clear. Here we present a narrative review of the literature to provide an understanding of the known pathophysiology that occurs in depression and the different actions that thyroid hormone promotes in the brain to develop new insight into the mechanism behind the antidepressant activity of thyroid hormone.

We believe this review of published literature illustrates the complex picture of depression pathophysiology and provides new insight into the MOA of thyroid hormones used as augmentation therapy to antidepressants. Impaired monoaminergic neurotransmission is an established pathophysiological hallmark of depression. However, there are other pathways that are impacted, including inflammatory and endocrine responses. Brain bioenergetics is affected, with depressed patients having lower brain ATP levels than healthy subjects. In addition, and perhaps related, depression patients display a loss in brain volume, particularly in the mood control regions of the brain. This is brought about by a dampening in neuroplasticity, the process by which new dendrites and synapses are formed. Here the connection to thyroid hormone augmentation becomes intriguing because thyroid hormone is known to play a role in stimulating neuroplasticity. At the target gene level, brain-derived neurotrophic factor, an initiator and biomarker of neuroplastic changes, is positively regulated by thyroid hormone, as are some of the immediate-early genes implicated in driving neuroplasticity. Thyroid hormone induces neuroplasticity and brain remodeling in a mouse model of behavior associated with increased decision-making and exploration, as well as mouse models of traumatic brain injury and stroke.

We propose that thyroid hormone augmentation of antidepressant therapy works by stimulating the processes of neuroplasticity in the regions of the brain that are affected by depression, restoring synaptic connections lost from depression. Since neuroplasticity is an energy-demanding process, the cellular increase in brain bioenergetics stimulated by thyroid hormone action likely drives the initiation and maintenance of plasticity.

Suboptimal treatment of hypothyroidism with levothyroxine (LT4) is common and associated with adverse cardiovascular outcomes. Patients treated with LT4 doses >100 µg may be at increased risk of under- and overtreatment and therefore may benefit from more frequent thyroid stimulating hormone (TSH) surveillance. Our study aim was to determine the association between LT4 dose and the occurrence of suboptimal treatment within 6 months of a normal TSH value.

A total of 4449 LT4-treated adults were included in a 6-month longitudinal study. All included patients were required to have at least 2 TSH collections over the study period at least 30 days apart. Patients were grouped according to LT4 dose (≤50, 51–100, 101–150, and >150 µg), which served as the primary exposure. Outcomes included the occurrence of TSH values outside an age-adjusted normal range and a wide range (0.1–10.0 mIU/L). Model covariates included sociodemographics, index TSH value, and a range of codiagnoses and comedications that were prevalent in the population and/or known to impact LT4 treatment. Longitudinal data were analyzed using both repeated measures (generalized estimating equations) and time-to-event (Cox proportional hazards models) methodologies. Kaplan–Meier curves were plotted to examine the incidence of out-of-range TSH values stratified by LT4 dose class.

The incidence of at least one out-of-range TSH value approached 25% across the entire population and exceeded 45% in the LT4 > 150 µg group. In the repeated measures analysis, a dose-dependent relationship between LT4 dose and the occurrence of TSH outside the age-adjusted range (OR: 1.98, 3.39, and 5.65 for LT4 doses of 51–100, 101–150, and >150 µg, respectively, p-values <0.001). Results were similar when the outcome was defined as a TSH outside 0.1–10.0 mIU/L. In the time-to-event analysis, the hazard ratios were 1.58, 2.73, and 3.08, respectively (p-values <0.001).

We identified a dose-dependent relationship between LT4 dose and suboptimal treatment over a 6-month study period. It may be beneficial for medically complex patients taking high doses of LT4 to increase TSH surveillance, in particular for those with a history of suboptimal treatment.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by progressive cyst development and renal dysfunction. While thyroid hormones (THs) are known to regulate key pathways in various kidney diseases, their role in ADPKD pathobiology and therapeutic potential remains unexplored. Here, we aimed to elucidate the role of THs in ADPKD and evaluate whether their pharmacological modulation could serve as a therapeutic strategy.

Patient-derived renal epithelial cells were used to engineer 3D polycystic tubules and to test the anti-cystogenic effects of THs and their analogs. The therapeutic efficacy of thyroxine (T4) in reducing cyst formation and delaying disease progression was assessed in vivo using PCK rats, an animal model of ADPKD. Lastly, serum THs levels were measured in 90 ADPKD patients enrolled in the REORIENTED clinical study and correlated with estimated glomerular filtration rate to explore their clinical relevance (Clinical Trial Gov NCT 05646420).

Mechanistically, thyroxine inhibits cyst growth by modulating proliferative, metabolic and ferroptotic pathways through αvβ3 integrin binding. In PCK rats, an animal model of ADPKD, T4 administration decreased kidney weight and significantly reduced macrocystic area (%, Vehicle 9.255 ± 2.654 vs. T4 1.945 ± 0.850, p < 0.05). Clinical data from ADPKD patients showed that altered TH serum levels correlate with disease severity: in the overall population of the study reverse triiodothyronine (rT3, a T3′s metabolite) levels inversely correlate with renal function (R² = 0.159, r = −0.397, p < 0.001), while free triiodothyronine (fT3) levels show a positive correlation (R² = 0.110, r = 0.332, p < 0.01).

This study reveals that THs contribute to ADPKD progression and identifies them as potential prognostic and therapeutic agents. By modulating multiple pathogenic pathways, THs may offer a novel, multi-targeted approach to reduce cyst growth and preserve renal function. These findings further support the development of personalized, hormone-based treatments and more refined stratification in the clinical management of ADPKD.

The standard of care for hypothyroidism treatment worldwide is daily oral levothyroxine (LT4) sodium. Limitations associated with daily oral administration highlight the need for alternative formulations to address challenges in maintaining euthyroidism. XP-8121 (LT4 sodium for subcutaneous [SC] administration) is a ready-to-use, liquid formulation of LT4 intended for once-weekly administration, offering an alternative hormone replacement approach by bypassing the gastrointestinal tract. This study assessed the safety, tolerability, and target dose conversion factor from oral LT4 to XP-8121 SC in adult participants.

This Phase 2, multicenter, nonrandomized, open-label, single-arm, self-controlled study (NCT05823012) evaluated XP-8121 SC in 46 adults with hypothyroidism receiving a consistent dose of oral LT4 for at least 3 months prior to screening, with documented normal thyrotropin (TSH) levels at least 3 months prior to screening and normal free thyroxine (fT4) at screening. The weekly XP-8121 SC dose was initiated at 50% of the target dose and titrated every 2 weeks for up to 8 weeks based on individual response using fT4 trough concentrations. Following titration, participants continued the established dose during a 4-week maintenance period.

Of the 46 participants enrolled, 39 completed the study. The majority were female (37; 80.4%) and identified as White (44; 95.7%). The final dose conversion factor point estimate ranged from 4.02 (90% confidence interval [CI]: 3.79–4.27) to 4.24 (90% CI: 4.06–4.42), supporting a conversion factor of approximately four times the daily oral LT4 dose when transitioning to XP-8121 SC. Although participants were initially underdosed during titration, TSH normalization was observed in 79.5% and fT4 normalization in 100% among those who completed the study on a consistent dose (unchanged for 6 weeks) at the end of maintenance. Overall, 78 treatment-emergent adverse events (TEAEs) were reported in 30 participants (65.2%) who received at least one dose of XP-8121 SC; fatigue (21.7%) and injection-site pain (10.9%) were the most common TEAEs. A majority of participants who completed the study reported higher satisfaction, convenience, and perceived effectiveness with once-weekly XP-8121 SC and expressed preference over daily oral LT4.

Once-weekly XP-8121 SC was generally well-tolerated in all treated participants and supported a dose conversion factor of four times the daily oral LT4 dose.

Thyroid dysfunction has been associated with adverse postoperative outcomes, but little is known about its effects on patients undergoing coronary artery bypass grafting (CABG). Here, our goals were (1) to evaluate the incidence of CABG in patients with hypothyroidism receiving thyroid hormone replacement therapy, and (2) to assess short-term and long-term outcomes in patients with hypothyroidism undergoing CABG compared with controls without thyroid disease, and (3) to determine whether abnormal preoperative thyroid-stimulating hormone (TSH) levels modify postoperative surgical risk in this patient population.

Retrospective longitudinal study using the TriNetX Global Collaborative Network database. The incidence of CABG was evaluated in about 1.23 million patients with hypothyroidism during a 20-year observation period (median of 4.4 ± 5.9). Post-CABG outcomes, including mortality, cardiovascular events, and postsurgical complications, were evaluated in 6557 patients with hypothyroidism over 10 years after 1:1 propensity score-matching.

Over 20 years, patients with a diagnosis of hypothyroidism had a higher incidence of CABG compared with controls (0.27% vs. 0.22%; hazard ratio [HR] 1.08; confidence interval [CI]: 1.03–1.14). Among patients who underwent CABG, the diagnosis of hypothyroidism was associated with mild increased risk of short-term postsurgical infections (HR:1.10, CI:1.01–1.20), CABG-specific complications (HR: 1.24, CI: 1.08–1.42), and critical care utilization (HR:1.14, CI:1.07–1.21). During long-term follow-up, these patients were at increased risk of incident heart failure (HR:1.15, CI:1.04–1.28), stroke (HR:1.18, CI:1.01–1.39), and major adverse cardiovascular events (MACE) (HR:1.15, CI:1.01–1.29). Sensitivity analysis, including only patients with hypothyroidism diagnosis, showed that abnormal preoperative TSH levels, particularly those with elevated TSH, had a higher risk of short-term mortality and long-term embolic events.

Hypothyroidism is associated with a higher incidence of coronary disease requiring CABG and increased risks of postoperative complications, heart failure, stroke, and MACE. These findings support the potential value of preoperative thyroid function assessment and optimization to mitigate postoperative complications and improve surgical outcomes in this high-risk group.

Serum thyroglobulin (Tg) is a key tumor marker in papillary thyroid carcinoma (PTC), but its reliability may be compromised by the presence of antithyroglobulin antibodies (TgAb). Utilizing the assay-specific limit of quantification (LOQ) may enhance the detection of TgAb-related interference compared with the traditional reference limit. This study evaluated postoperative TgAb levels based on LOQ as a surrogate marker for tumor monitoring in PTC.

A total of 1039 patients with PTC (≥1 cm) who had undetectable unstimulated serum Tg (<0.2 ng/mL) 6–12 months after total thyroidectomy with radioactive iodine (RAI) ablation therapy (2009–2012) were retrospectively analyzed. Simultaneously measured TgAb levels were classified using both the reference limit (60.0 U/mL) and LOQ (43.4 U/mL) into three groups undetectable (<43.4 U/mL), borderline (43.4–60.0 U/mL), and elevated (>60.0 U/mL).

The median age was 48.2 years, and 188 (18.1%) were male. The median tumor size was 1.5 cm, and lymph node metastases were present in 705 patients (67.8%). During a median follow-up of 12.0 years, recurrence occurred in 4.8%. Based on initial TgAb level, patients were classified as undetectable (65.6%), borderline (23.5%), and elevated (10.9%), with corresponding 10-year progression-free survival rates of 97.9%, 94.6%, and 88.5%, respectively (p < 0.001). Multivariable analysis revealed a significantly higher recurrence risk in the borderline group compared with the undetectable group (adjusted hazard ratio, 2.01; confidence interval, 1.03–3.96; p = 0.043). In the borderline group, TgAb became undetectable in 75.0% of patients over 6.3 years, whereas those who remained borderline exhibited a higher recurrence rate of 12.9% (p = 0.01).

TgAb levels above the LOQ were associated with a higher recurrence risk in patients with PTC with undetectable Tg after RAI treatment. Classification of TgAb positivity based on the LOQ may improve prognostic assessment compared with evaluation using conventional reference limits. Further studies are needed to validate our findings and refine TgAb thresholds.

There is uncertainty regarding whether thyroid-stimulating hormone (TSH) suppression therapy in postmenopausal women with differentiated thyroid cancer (DTC) is associated with menopause-specific health concerns. This study aimed to determine whether prolonged TSH suppression confers an additional burden on postmenopausal health by comprehensively evaluating cardiovascular health (CVH), quality of life (QoL), muscle mass, and bone health using menopause-specific assessment tools.

A cross-sectional study was conducted involving three groups of postmenopausal women 107 patients with DTC receiving TSH suppression therapy following total thyroidectomy for ≥3 years, 80 women receiving levothyroxine (LT4) replacement for primary hypothyroidism, and 97 euthyroid controls. Women with cognitive impairment, a history of osteoporosis, or cardiovascular disease were excluded. CVH was assessed using Life’s Essential 8 (LE8) score, carotid intima-media thickness (cIMT), and electrocardiography. QoL was assessed using the Utian QoL (UQoL) Scale, cognition by the Mini-Mental State Examination, body composition by bioelectrical impedance analysis, and bone density by dual-energy X-ray absorptiometry.

Women with DTC demonstrated significantly lower LE8 scores, lower UQoL scores, higher cIMT values, higher prevalence of osteoporosis, and reduced muscle mass than those in the other two groups (p < 0.001, p < 0.001, p < 0.001, p = 0.003, and p = 0.017, respectively). Multivariable regression analysis revealed that cumulative LT4 dose was independently associated with lower LE8 and UQoL scores (β = −0.354, p < 0.001; and β = −0.396, p < 0.001, respectively), while higher serum TSH levels were positively associated with both LE8 and UQoL scores (β = 0.271, p = 0.002; and β = 0.487, p < 0.001, respectively).

Prolonged TSH suppression may adversely affect postmenopausal health, particularly in low-risk, disease-free women with DTC. The primary clinical implication of these findings is the need to avoid unnecessary long-term TSH suppression. Menopause-specific assessment tools may have a complementary role in selected patients in whom TSH suppression remains clinically indicated.

Antiangiogenic and targeted therapies represent the most effective systemic options for advanced thyroid cancers. In this setting, toxicity management is essential to ensure treatment adherence. Among hematological toxicities, erythrocytosis has been rarely investigated, and its clinical pattern and management remain unclear.

We conducted a retrospective cohort study including patients with any advanced thyroid cancer histology treated with antiangiogenic or targeted therapies between 2012 and 2023 at two Italian referral centers. Therapies included RET inhibitors (RETi: selpercatinib, pralsetinib), cabozantinib, the BRAF/MEK inhibitor combination dabrafenib + trametinib, lenvatinib, sorafenib, and vandetanib. Erythrocytosis, defined according to 2022 World Health Organization criteria, was assessed through serial hemoglobin and hematocrit measurements up to 36 months from treatment start. Associations with clinical variables, event-free survival (EFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and acute vascular events were assessed using Fisher’s exact and regression models, as appropriate.

Among 173 screened patients, 135 were included in the final analysis (median follow-up 68.5 months). Erythrocytosis occurred in 24 patients (17.8%), with 16/24 (66.6%) experiencing recurrent events (total: 50). Median time to onset was 1.28 months (Q1–Q3: 0.76–5.14). RETi showed the highest incidence (46.7%), followed by vandetanib (20.7%). Among 14/24 tested patients, no JAK2 V617F or exon 12 alterations were detected. Management involved temporary treatment interruption in 60.0% (30/50) of events, with 53.3% (16/30) resuming at a reduced dose; in selected cases (4/9, 44.4%), hematology-guided phlebotomy was performed without drug discontinuation. Erythrocytosis was not associated with EFS, OS, or ORR, but was associated with higher DCR (p = 0.031). Incidence of acute vascular events was comparable among patients with (8.3%) and without (14.4%) erythrocytosis.

Erythrocytosis represents an underrecognized, early, recurrent, and indolent adverse event of antiangiogenic and targeted therapies, particularly RETi, in advanced thyroid cancer. Its biological mechanisms and optimal management strategies warrant further investigation.

Thyrotropin (TSH) and insulin-like growth factor 1 (IGF-1) signals have been shown to be additive in their action on thyroid cells and fibroblasts, and this coordination emphasizes the role of TSH receptor (TSHR) and IGF-1 receptor (IGF-1R) signaling exerted by stimulating TSHR antibodies in patients with thyroid eye disease (TED). Here, we have reanalyzed the influence of TSHR autoantibodies on TSHR and IGF-1R expression in a fibroblast model.

We developed a new method to assess TSHR expression using a hinge-region monoclonal antibody (MC-1) that does not interfere with TSH or TSHR antibodies. Using molecular dynamic simulations, we first assessed access to the binding sites for TSH and TSHR antibodies within the leucine-rich repeat region of the TSHR ectodomain in the presence of MC-1 binding. 3T3-L1 fibroblasts and human orbital fibroblasts were treated with increasing doses of TSH or the stimulating TSHR antibody M22. TSHR and IGF-1R expressions were measured by flow cytometry and real-time quantitative polymerase chain reaction (RT-qPCR), with 3T3-L1 cell differentiation confirmed by Oil Red O staining. To explore mechanisms of TSH- and M22-induced receptor upregulation, we assessed the effects of inhibiting protein synthesis and endocytosis.

TSH ligand induced a dose-dependent increase in detectable expression of the TSHR as measured using MC-1 binding. Furthermore, parallel assessment of IGF-1R expression showed a similar dose-dependent increase in expression induced by TSH. Studies with stimulating TSHR antibody (M22) also demonstrated a similar increase in TSHR and IGF-1R expression peaking at 48 hours. These data could not be explained by transcriptional changes as measured by RT-qPCR. In addition, analysis of the effect of protein synthesis inhibition failed to reduce TSHR and IGF-1R induction. However, inhibition of endocytosis markedly reduced enhancement of TSHR and IGF-1R expression.

These data strengthen the role of TSHR antibodies in TED by showing that they enhance TSHR and IGF-1R expression in fibroblasts, helping to explain their additive retroorbital signaling. This enhancement is largely driven by receptor recycling, which can be blocked by inhibiting endocytosis and may be therapeutically targeted. The dual increase in both receptors also supports prior evidence of TSHR/IGF-1R complex formation.

Constitutively active mutations (CAMs) in the thyrotropin receptor (TSHR) are the major cause of nonautoimmune hyperthyroidism. TSHR is a key regulator of thyroid hormone synthesis, which is essential for skeletal formation, bone turnover, and craniofacial development. In addition to its role in thyroid hormone regulation, thyrotropin and its receptor have been proposed to independently influence bone formation and resorption. However, the specific effects of constitutively active TSHR mutations on cranial and skeletal development have not been investigated in mouse models.

Cranial morphometry, micro-computed tomography, and three-point bending tests were performed in established TSHR knock-in mouse models carrying patient-derived TSHR D633H or M453T CAMs. Homozygous TSHR D633H mice exhibit mild, transient hyperthyroidism at 2 months of age, more pronounced in females, whereas homozygous TSHR M453T mice develop a more severe, iodine-dependent hyperthyroid phenotype.

Both TSHR CAM lines showed altered craniofacial morphology, particularly in nasal bone dimensions, resulting in a shorter snout compared with wild-type (WT) controls. The incidence of malocclusion was significantly increased in both homozygous and heterozygous mice, regardless of sex. TSHR D633H mice displayed no significant changes in femoral or tibial bone structure or biomechanical properties. In contrast, TSHR M453T mice exhibited hyperthyroidism-dependent alterations in trabecular bone mineral density (BMD) and architecture, while cortical bone was unaffected. Body and tail lengths were unchanged in TSHR D633H mice. M453T homozygous mice had reduced tail length at weaning in an iodine-dependent manner, which normalized with age.

This in vivo study demonstrates that TSHR CAM-induced hyperthyroidism alters craniofacial morphology and increases the incidence of malocclusion in mice. Structural changes and altered BMD in M453T mice were dependent on the severity of hyperthyroidism. These findings highlight the role of TSHR signaling and thyroid status in craniofacial and skeletal development, warranting further mechanistic investigation.