Thyroid最新文献

Background: The risk of hypothyroidism after hemithyroidectomy is not well defined in the pediatric population. We sought to determine the incidence of hypothyroidism after hemithyroidectomy in children and the clinical factors associated with this risk. Methods: This is a retrospective cohort study of consecutive pediatric patients (<19 years of age) who underwent hemithyroidectomy in a pediatric thyroid center between 1998 and 2023, with data available on postoperative thyroid function and/or levothyroxine (LT4) treatment. The primary outcome was the composite of persistent hypothyroidism (thyrotropin [TSH] ≥ 5 mIU/L) or LT4 treatment (PersHypo/LT4). Secondary outcomes were persistent hypothyroidism and transient hypothyroidism. Univariable and multivariable survival analysis and logistic regression were used to evaluate associations of these outcomes with clinical characteristics. Results: A total of 136 eligible patients (85% female) underwent hemithyroidectomy at a median (range) age of 15.4 (0.14-19.0) years. The median (interquartile range) postsurgical follow-up was 1.10 (0.15-3.2) years for thyroid function and 1.76 (0.38-4.3) years for LT4 treatment status. PersHypo/LT4 occurred in 27/136 patients (20%), with an estimated risk of 18.1% [CI: 12.1-26.6%] at 1 year and 27.5% [CI: 18.7-39.2%] at 5 years. PersHypo/LT4 occurred within 12 months in 21/27 cases (78%) and after 12 months in 6/27 (22%). PersHypo/LT4 was associated with preoperative TSH (hazard ratio 1.89, [CI: 1.31-2.74], p = 0.001), and preoperative TSH ≥ 2 mIU/L optimally distinguished patients with high (58.8%) versus low (12.8%) 5-year risk of PersHypo/LT4 (receiver operator characteristic AUC 0.73, [CI: 0.60-0.85]). The presence of thyroperoxidase (TPO) antibodies was independently associated with increased risk of PersHypo/LT4 (OR: 7.37, [CI: 1.09-49.9], p = 0.041). Persistent hypothyroidism occurred in 14/128 patients (11%), with an estimated 5-year risk of 12.9% [CI: 7.7-21.1%]. Severe hypothyroidism occurred in 5/136 patients (3.7%), and transient hypothyroidism occurred in 22/136 patients (16%). Conclusions: Persistent hypothyroidism or LT4 treatment occurs in 27.5% of children within 5 years after hemithyroidectomy, usually in the first postoperative year. Preoperative TSH < 2 mIU/L may identify children at low risk, whereas preoperative TSH ≥ 2 mIU/L, particularly in conjunction with TPO antibodies, may identify children at high risk. Transient hypothyroidism also occurs commonly but may not require treatment. These data should inform preoperative counseling and postoperative monitoring around hemithyroidectomy in children.

Background: The prognostic value of unstimulated serum thyroglobulin (Tg) levels for structural recurrence in patients with low- to intermediate-risk differentiated thyroid cancer (DTC) who underwent total thyroidectomy but did not receive radioactive iodine (RAI) therapy remains unclear. This study aimed to determine Tg cutoff values and evaluate the role of dynamic Tg monitoring in risk stratification in these patients. Methods: We retrospectively analyzed 9753 patients with low- to intermediate-risk DTC who underwent total thyroidectomy without RAI at 11 Korean tertiary hospitals. Serum Tg levels were measured under thyrotropin suppression (<2 mIU/L) at 6, 12, and 24 months postoperatively using high-sensitive assays (functional sensitivity, <0.2 ng/mL). Optimal Tg cutoffs were determined by receiver operating characteristic curves and survival analyses. Results: Higher postoperative unstimulated Tg levels consistently predicted structural recurrence, with an optimal cutoff of 0.3 ng/mL (area under the curve: 0.815, 0.772, and 0.816 at 6, 12, and 24 months, respectively). A Tg ≥ 0.2 ng/mL, the Korean Thyroid Association (KTA) guideline cutoff for biochemical remission (excellent response), showed high sensitivity for recurrence. Tg ≥ 5.0 ng/mL at 6 months, a KTA-defined threshold for a biochemical incomplete response, independently predicted an elevated recurrence risk. Kaplan-Meier curves showed stepwise declines in recurrence-free survival with increasing Tg levels. Notably, even Tg < 0.2 or < 0.3 ng/mL were associated with recurrence if levels rose over time. Conclusion: Unstimulated Tg levels are strongly associated with the risk of structural recurrence in patients with DTC who have undergone total thyroidectomy without RAI. The current cutoff values of 0.2 ng/mL and 5.0 ng/mL were clinically relevant, and Tg kinetics over time further improved risk stratification. These findings provide the first large-scale evidence from an East Asian cohort and underscore the importance of early, serial Tg assessment in this growing patient population.

Background: RASAL1 is a prominent tumor suppressor gene through inactivating RAS, whose functional loss has been widely found to play an important role in thyroid cancer and occurs usually through its genetic and epigenetic inactivation. In this study, we intended to explore aberrant alternative splicing (AS) as an important novel mechanism for the oncogenic inactivation of RASAL1 in thyroid cancer. Methods: We used comprehensive bioinformatic and molecular experimental approaches to identify and characterize aberrant alternative splice variants of RASAL1. This included structural and functional investigation of the potentially oncogenic splice variants of RASAL1, with a focus on exploring the molecular mechanisms and clinical impacts on thyroid cancer. Results: We identified an aberrant alternative splice variant of RASAL1, known as RASAL1-004, that commonly compromised the function of RASAL1 in thyroid cancer. Specifically, we found common skipping of exon 18.1 in RASAL1, leading to the abundant formation of transcript RASAL1-004 in cancer, which was significantly associated with poor survival of patients with thyroid cancer. Mechanistically, Argonaute2 regulates exon 18.1 splicing by binding to the response element in exon 17 containing CCAGCC motif, promoting RASAL1-004 formation. The exon 18.1 skipping caused a conformational change in the RNA structure of RASAL1-004 at the junction of exons 17 and 18, resulting in ribosome stalling, halting RASAL1 translation. This reduced RAS GTPase-activating-like protein 1 (RASAL1 protein) synthesis, consequently leading to the functional loss of RASAL1. Compared with RASAL1-001, the canonical wild-type RASAL1 transcript, the absence of exon 18.1 in RASAL1-004 also conformationally altered the pleckstrin homology domain of RASAL1 protein, which, as we demonstrated, led to the loss of the ability of RASAL1 to localize with cell membrane, thereby impairing its RAS-inactivating function. We further demonstrated that compared with RASAL1-001, RASAL1-004 displayed impaired RAS-signaling pathway-suppressing and cancer cell-suppressing functions. Conclusions: This study identified a novel RASAL1-impairing mechanism, alternative to the classically known genetic and epigenetic mechanisms, for the inactivation of the tumor suppressor gene RASAL1 through aberrant AS to form RASAL1-004 with impaired protein translation. This represents a new oncogenic mechanism in thyroid cancer, with novel cancer biological, prognostic, and therapeutic-targeting implications in thyroid cancer.

Background: Bile acid sequestrants have been reported to reduce serum thyroid hormone levels by binding T4 and T3 excreted into the intestinal lumen, preventing their reabsorption into the systemic circulation and interrupting the enterohepatic circulation of these hormones. This meta-analysis evaluates whether adjunctive bile acid sequestrants accelerate reductions in serum iodothyronine when added to standard hyperthyroidism therapy. Methods: A systematic review and meta-analysis were conducted and registered in PROSPERO (CRD42025643217). MEDLINE, Embase, Web of Science, and Cochrane databases were searched from March 1971 to September 2025 for randomized controlled trials (RCTs) assessing adult non-critically ill patients with hyperthyroidism treated with standard therapy (thionamides and beta-blocker) plus adjunctive bile acid sequestrants (cholestyramine or colestipol) versus standard therapy alone. Primary outcomes included a reduction in serum-free T4 and total T3. The secondary outcome was adverse effect frequency. Results: Initial search yielded 705 results. After removal of duplicates and title/abstract screening, 17 full-text articles were reviewed, and five RCTs met the inclusion criteria, totaling 173 adult patients: 93 (53.75%) received adjunctive therapy, and 80 (46.25%) were controls. Causes for thyrotoxicosis included Graves' disease, toxic adenoma, and multinodular goiter. Doses ranged from cholestyramine 1 g twice a day to 4 g four times a day, and colestipol 20 g daily. At 2 weeks of treatment, bile acid sequestrants showed a non-significant reduction in serum total T3 (mean difference [MD] -0.44 nmol/L, 95% confidence interval [CI]: -1.2 to +0.32) and free T4 level (MD -0.55 ng/dL, CI: -1.15 to +0.04). At 4 weeks, there was a statistically significant reduction in total T3 (MD -1.59 nmol/L, CI: -2.90 to -0.27) and free T4 level (MD -1 ng/dL, CI: -1.74 to -0.25). Conclusions: Adjunctive bile acid sequestrants with standard hyperthyroidism therapy appear to enhance reductions in serum total T3 and free T4 at the mark of four weeks and were well tolerated. However, due to considerable heterogeneity and low quality of evidence, our results should be interpreted with caution. Larger, high-quality RCTs are needed to strengthen the evidence regarding the efficacy of adjunctive bile acid sequestrant therapy.

Background: International guidelines now recommend adopting individualized approaches which consider patient preferences when deciding the extent of surgical resection for low-risk differentiated thyroid carcinoma (LRDTC). Information-sharing must be methodical to help patients make informed decisions without feeling overwhelmed by information. Understanding the factors influencing decision-making is therefore essential. Methods: Semi-structured interviews were conducted between May 2023 and June 2024 at two large tertiary referral centers in England, United Kingdom. Consecutive sampling via the multidisciplinary team meetings was used to identify patients newly diagnosed with LRDTC measuring 1-4 cm without adverse features, choosing between hemithyroidectomy and total thyroidectomy, or, if diagnosed following hemithyroidectomy, active surveillance and total thyroidectomy. Clinicians directly involved in their care were approached and recruited, with six consultant thyroid surgeons (five male, one female), and two thyroid cancer nurse specialists (both female), agreeing to participate. All had experience managing over 10 LRDTC patients annually. Transcripts were analyzed using the framework method of thematic analysis. Results: Twenty-four patients were identified, and 19 agreed to participate (13 female, 6 male). Information-sharing was often perceived as a didactic process, leaving patients overwhelmed with complex clinical details. Both groups emphasized tailoring information to meet patients' needs and delivering it in bite-sized portions to enhance comprehension. Key factors influencing individual decisions included a desire among most patients to minimize the number of, and extent of, surgical procedures, the need to preserve the thyroid gland and avoid hormone supplementation, and the patient's ability to accept the cancer recurrence risk. Although autonomy was paramount for patients, providers' recommendations still significantly impacted the final decision. Some clinicians expressed concern that multiple treatment options might confuse patients, instead entrusting decision-making to the multidisciplinary team meetings. Conclusions: This study identified essential information needs for LRDTC treatment decision-making, which can help inform the development of decision-support tools. Multidisciplinary team discussions may need to evolve to allow greater flexibility and support individualized decision-making.

Background: Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of less than six months. So far, no therapies offering a survival benefit are established. Thus, new therapeutic approaches are urgently needed. In general, genetic alterations leading to ATC increase PI3K and MAPK/ERK signaling and include mutations in receptor tyrosine kinases and tumor suppressor genes. They often occur together with the loss of p53, the most prevalent mutation in human ATC. Among such alterations are mutations and rearrangements of the anaplastic lymphoma kinase (ALK) gene. Methods: To study ATC and potential treatment options, we generated a mouse model with inducible thyrocyte-specific expression of constitutively active mutant ALK^F1174L and homozygous deletion of Trp53 due to a Cre recombinase under control of the thyroglobulin promoter (thyroglobulin [Tg]-Cre^ERT2+/0;lox-stop-lox (LSL)-ALK^F1174L/+;Trp53^LoxP/LoxP mice, here referred to as Trp53^KO/ALK^F1174L mice). Moreover, we established several primary thyroid cancer cell lines harboring ALK^F1174L and Trp53^KO and investigated the effects of ALK inhibition in vitro and in vivo. Results: Median survival of Trp53^KO/ALK^F1174L mice was severely reduced, and the mice showed massively enlarged thyroids. Histopathology confirmed the development of locally invasive and metastatic ATC. Treatment of primary Trp53^KO/ALK^F1174L ATC cells with the ALK inhibitor TAE-684 decreased AKT and ERK phosphorylation and induced a dose-dependent cytotoxicity. Trp53^KO/ALK^F1174L mice treated with TAE-684 showed significantly extended median survival compared with the solvent group (66 days vs. 18 days, p < 0.0001). Conclusions: Our data demonstrate that the combination of ALK^F1174L mutation with Trp53 loss leads to the development of ATC. This study provides the first functional data supporting the use of ALK inhibitors in patients with ALK-driven ATC. Our novel ATC mouse model and the derived cell lines offer valuable tools to explore the molecular characteristics of ATC, especially signaling pathway activation and tumor microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers.

Background: We assessed the effectiveness of administering subcutaneous levothyroxine in a medically complex patient, a 51-year-old male who previously underwent total thyroidectomy for papillary thyroid carcinoma. His thyrotropin (TSH) worsened to >100 mIU/L, caused by encapsulating sclerosing peritonitis that led to thyroxine malabsorption and enteral loss of protein-bound thyroxine. Several routes of levothyroxine were evaluated prior to subcutaneous levothyroxine. Methods: Subcutaneous levothyroxine was initiated at a low dose of 100 mcg thrice a week. A pharmacokinetic absorption study was performed to assess the bioavailability of subcutaneous levothyroxine against oral levothyroxine. Results: A 103% increase in free thyroxine at 6 hours post-subcutaneous levothyroxine 100 mcg confirmed effective absorption. Area-under-curve analysis showed that the relative bioavailability of subcutaneous levothyroxine was 8.75 times of oral levothyroxine for our patient. Hence, subcutaneous levothyroxine was initiated, with TSH normalizing 20 days later. Conclusions: Subcutaneous levothyroxine may be an alternative in patients with oral malabsorption.

Background: The treatment paradigm for thyroid eye disease (TED) in the United States has shifted from corticosteroids toward targeted therapies such as teprotumumab. However, it remains unknown whether teprotumumab decreases the need for subsequent treatments for TED compared with intravenous methylprednisolone (IVMP). This study compares the long-term need for additional medical or surgical interventions in TED patients treated with teprotumumab versus IVMP. Methods: A retrospective cohort study identified TED patients treated with IVMP or teprotumumab utilizing the TriNetX Analytics platform. Patients with comorbidities requiring high-dose steroids, prior TED therapy within 6 months, or concurrent TED treatments were excluded. Propensity score matching (PSM) adjusted for baseline demographic and TED-related risk factor differences. Patients were followed for 6, 12, and 18 months after a 6-month washout period. The primary outcome was the incidence of additional TED-related interventions. Secondary outcomes included post-treatment care trajectories, treatment burden, and complexity, assessed through longitudinal pathway analysis. Results: The IVMP cohort included 308 patients, and the teprotumumab cohort included 417; after PSM, each contained 263 patients. No significant differences were found in the incidence of additional TED-related interventions between cohorts. A similar percentage required additional medical therapies (41% vs. 37%, p = 0.423), while fewer in the IVMP cohort underwent additional surgical interventions (3.8% vs. 8.8%, p = 0.019, 4.8% vs. 10.0%, p = 0.040) at 12 and 18 months. Among those needing additional TED interventions, the IVMP cohort exhibited a higher treatment burden and more complex treatment trajectories, requiring a greater average number of treatments (2.34 vs. 1.34 per patient; 32.8% vs. 5.5% requiring ≥3 additional treatments). Conclusions: TED patients treated with IVMP or teprotumumab had similar overall rates of additional interventions. However, IVMP was associated with greater treatment complexity, requiring more varied medical therapies. Teprotumumab-treated patients typically required fewer additional medical therapies and underwent more surgical interventions as a second-line step, suggesting that teprotumumab may simplify the treatment pathway. These data have important implications for patient education and future assessment of the cost-effectiveness of TED therapies.

Background: There is evidence of quality of life (QoL) impairment and weight gain in treated hyperthyroidism. It is not known whether treatment-related weight gain is associated with QoL impairment in this patient group of this cohort. Our primary aim was to examine whether percentage weight gain (PWG) after treatment of hyperthyroidism was associated with QoL impairment. Methods: We enrolled patients with treated hyperthyroidism 6 months to 8 years after diagnosis. We obtained anthropometric measurements from a prospectively completed database. With a cross-sectional study design, we assessed QoL using the thyroid-specific patient-reported outcome (ThyPRO) tool. We pre-specified three dependent variables in ThyPRO: "cosmetic complaints," a composite of "tiredness and overall QoL" and "depressivity and anxiety" domains. We included age, sex, thyrotropin categories, comorbidities, and disease duration as covariates. We applied a generalized linear model (GLM) for the analysis. Results: We included 108 patients, including 68 (63%) females, with a mean (standard deviation [SD]) age 50 (14.5) years. The median weight at diagnosis was 65.5 (interquartile range [IQR]: 58.7, 75.5) kg and BMI was 23.9 (21.9, 27.1) kg/m², and at final evaluation, weight was 72.7 (64.1, 83.8) kg (p < 0.001) and BMI was 26.5 (23.9, 30.8) kg/m² (p < 0.001). The mean (SD) weight gain observed was 7.2 (6.2) kg over a mean (SD) disease duration of 41 (22.5) months. Median PWG was 8.8% (4.3%, 17%). There was a significantly reduced QoL in all comparable domains against general population normative data. PWG was associated with "cosmetic complaints" (odds ratio = 1.11, p = 0.008 via logistic regression; b = 0.47, p = 0.022, q (adjusted p) = 0.033 via GLM) and "tiredness and overall QoL" (b = 0.62, p = 0.011, q = 0.017), but not with the "anxiety and depressivity" domains (b = -0.005, p = 0.661). Conclusions: Our study suggests that weight gain after treatment of hyperthyroidism is associated with a large adverse effect on QoL, with reduced scores on appearance, combined "tiredness and overall QoL" domains of the ThyPRO questionnaire. Management of weight change upon treatment of hyperthyroidism merits further clinical attention and research.