Ultrasound (US) is the most accurate tool for the assessment of thyroid nodules (TNs). Despite the subcapsular position of TNs may represent a game changer for clinical practice in selecting cases for biopsy or surgery, this parameter is not included in US-based risk stratification systems. The present study evaluated the agreement of endocrinologists using US in clinical practice with the experts’ results employed as reference standard. A sub-series of TNs for which the agreement between US expert endocrinologists and radiologists was perfect was assumed as reference. Participants of the 2025 Thyroid Update of Associazione Medici Endocrinologi (AME) were asked to assess TNs in a 3-choice answer: subcapsular, non-subcapsular, or uncertain. The agreement was determined according to majority consensus (i.e., ratings > 50

Ultrasound (US)-guided thermal ablation (TA) is widely used as a minimally invasive alternative to surgery for symptomatic benign thyroid nodules. Although less invasive, complications occur in up to 4

INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICIs) play a central role in advanced cancer treatment, but they are associated with immune-related adverse events (irAEs) that include two cases of hypercalcemia induced by the programmed death-1 (PD-1) inhibitor, pembrolizumab. We report a unique case of a colon cancer patient treated with pembrolizumab who acutely developed life-threatening hypercalcemia. CASE PRESENTATION:This case presents a seventy-five-year-old woman suffering from colon adenocarcinoma with liver metastasis undergoing pembrolizumab therapy. Shortly after its second administration, she developed severe hypercalcemia (21 mg/dL) with acute kidney failure. Serum intact parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrP), 25-OH vitamin D, and 1,25-OH vitamin D were suppressed while computerized tomography (CT) imaging ruled out relevant osteolytic or granulomatous lesions. Treatment included hydration, infusion of zoledronic acid, and high-dose glucocorticoids. The patient's serum calcium levels normalized, and her condition improved. Primary hyperparathyroidism, ectopic PTHrP secretion, and ectopic 25(OH) D-1-hydroxylase expression were ruled out by clinical and laboratory data. Notably, experimental models of PD-1/PD-L1 inhibition have demonstrated increased bone resorption. Although the absence of specific bone turnover markers and a recent 18FDG-PET/CT scan partly limits the understanding of the pathophysiological mechanism, immune-mediated osteoclast activation represents a potential pathophysiological mechanism of acute reversible hypercalcemia. CONCLUSION:The present case is unique due to its early onset, absence of calcitriol and PTHrP elevation, and rapid response to corticosteroids. Serum calcium should be assessed both before each ICI’s dose administration and throughout treatment in case of symptoms suspicious for hypercalcemia to prevent the onset and progression of this rare but critical irAE.

Background:Recent surveys have highlighted substantial variability in the management of hypothyroidism that is associated with physician demographic and geo-economic characteristics. This study aimed to assess preferences for thyroid hormone therapy among medical thyroid specialists in Korea. Methods:An online survey was conducted using the Treatment of Hypothyroidism in Europe by Specialists: An International Survey (THESIS) questionnaire. Participants were medical thyroid specialists who were members of the Korean Thyroid Association (KTA). Results:Among the 349 regular members of the KTA who were physicians, 53 (15.2%) completed the survey. All respondents reported prescribing levothyroxine (LT4) as the initial treatment of choice for hypothyroidism. For patients with biochemical euthyroidism, 64.2% of respondents indicated that treatment was unnecessary; however, several conditions were cited as potential indications for thyroid hormone use (multiple responses were allowed), including female infertility with elevated thyroid antibody levels (30.2%), enlarging simple goiter (17.0%), and severe hypercholesterolemia as adjunctive therapy (9.4%). Although 24.5% of respondents reported avoiding LT4+liothyronine (LT3) therapy because of low-quality evidence, 62.3% indicated that they would consider it for symptomatic patients receiving LT4 monotherapy with normal thyroid-stimulating hormone levels. Conclusion:Korean thyroid specialists generally adhere to current clinical guidelines, favoring LT4 as the standard treatment for hypothyroidism. However, there is considerable willingness to use LT4+LT3 combination therapy and to prescribe thyroid hormones for certain non-thyroid conditions. Ongoing educational efforts are needed to improve understanding that many persistent symptoms despite biochemical euthyroidism are influenced by psychosocial factors and to facilitate consistent implementation of evidencebased, guideline-aligned clinical practice.

Objective: Several thyroid hormone formulations are available for treatment of hypothyroidism. This study aimed at evaluating the use of these treatment options by Israeli endocrinologists in various clinical scenarios. Methods: Israeli Endocrine Society members were invited to participate in a web-based questionnaire, Treatment of Hypothyroidism in Europe by Specialists: An International Survey. Results: 99.2% of respondents used LT4 tablets as first line therapy for hypothyroidism. Thyroid hormone replacement options considered by respondents included LT4 tablets (100%), soft-gel capsules (4.0%), liquid solution (15.4%), combined LT4 + LT3 (2.4%) and LT3 tablets (17.8%). In cases of impaired absorption or persistent symptoms, most would continue LT4 tablets (86.1% and 95.1%, respectively), of whom 39.0% noted that only tablets are available in Israel. In patients with normal serum TSH and persistent symptoms, 95.1% would continue LT4 tablets, 57.5% would consider the addition of LT3 whereas 24.4% stated that LT4/LT3 combination should never be used. In euthyroid patients, LT4 therapy was considered in infertile women with high levels of thyroid antibodies (33.6%) and for simple goiter growing over time (11.4%). Conclusions: In Israel, LT4 tablets are the treatment of choice for hypothyroidism in most clinical scenarios, including in patients with impaired absorption or with persistent symptoms, for whom a combination therapy with LT4 + LT3 is considered by half of respondents. Other LT4 formulations are not widely available in Israel, thus are infrequently considered compared to other European countries. These data suggest that international guidelines regarding the use of various thyroid hormone formulations in specific clinical scenarios are warranted.

Levothyroxine (LT4) is the established treatment for hypothyroidism but some controversies, such as whether combining it with liothyronine (LT3) for hypothyroid patients and whether prescribing it to euthyroid patients, exist on its use. This survey was conducted to investigate current trends about thyroid hormone use in hypothyroid and euthyroid patients in Japan. Members of the Japan Thyroid Association (JTA) were invited to participate in an online questionnaire based on the THESIS (Treatment of Hypothyroidism in Europe by Specialists: An International Survey) survey. Anonymous responses from 207 of 874 (23.7%) JTA-certified thyroid specialists were analyzed. LT4 was the first line treatment for hypothyroidism by all respondents. 18.8% and 28.0% would also use LT3 and LT3 + LT4 combination, respectively. LT3 + LT4 combination was preferred for patients on LT4 with residual symptoms or low serum T3 levels. Psychological factors and comorbidities were considered as the main contributors to residual symptoms. Respondents would prescribe thyroid hormones in euthyroid subjects for female infertility with positive anti-thyroid antibodies (46.9%), for Hashimoto's disease with a huge goiter (29.0%), and for pregnant or infertile women with TSH between 2.5-4 mU/L irrespective of anti-thyroid antibody status (43.0 and 76.8%, and 46.9 and 77.3%, respectively). In conclusion, Japanese thyroid specialists chose LT4 as first line treatment for hypothyroidism in accordance with current guidelines. The use of LT3 + LT4 combination is less frequent in Japan than in other countries, whereas the use of thyroid hormones for non-hypothyroid indications is similarly high worldwide, which is not necessarily in accord with pertinent society guidelines.

OBJECTIVE:The practice of treating hypothyroid and euthyroid patients with thyroid hormones varies between countries, as observed in the recent surveys of European thyroid experts, THESIS. As part of the THESIS initiative, we investigated Canadian endocrinologists' perspectives on this topic, focusing on combination therapy with either liothyronine (LT3) plus levothyroxine (LT4) or desiccated thyroid extract (DTE). DESIGN:Members of the Canadian Society of Endocrinology and Metabolism (CSEM) were invited to participate in an anonymous online survey. RESULTS:Out of 348 eligible CSEM members, 68 (19.5%) respondents were included in the analysis. All respondents used LT4 as the first-line treatment for hypothyroid patients. Many respondents (64.7%) would consider LT4 + LT3 for patients on LT4 with persistent symptoms, whereas fewer would consider DTE (16.2%). Most respondents attributed persistent symptoms in LT4-treated patients to psychosocial factors, comorbidities, or unrealistic expectations. Approximately half of the respondents stated that thyroid hormone therapy is never indicated for euthyroid patients. The remaining respondents considered thyroid hormones for euthyroid women with infertility and high thyroid antibody levels (36.8%), depression (13.2%), and growing goiter (7.4%). CONCLUSIONS:Following current guidelines, LT4 tablet is the preferred treatment for hypothyroidism. Most respondents would consider triiodothyronine-containing therapy for patients with persistent symptoms, preferring LT4 + LT3 over DTE. The number of endocrinologists considering combination therapy for hypothyroid patients in Canada was higher than in Europe. Finally, at variance with current guidelines, a fraction of the respondents would consider thyroid hormones in patients with non-thyroidal conditions.

Overweight and obesity represent common chronic metabolic disorders in the general population, and observed trends describe a substantial growth in the prevalence of weight excess also among individuals with type 1 diabetes (T1D), the so-called 'lean phenotype' of diabetes. The sharp rise of weight excess and obesity-related cardio-nephron-metabolic burdens observed in T2D is expected to produce similar consequences in T1D, leading to the urgent need to endorse therapeutic protocols as in most parts of the World no adjunctive treatments are approved for T1D, making weight excess management challenging in these individuals. The notable results shown by newer glucagon-like peptide 1 receptor agonists (GLP-1RAs) and emerging dual agonists, especially while managing cardio-metabolic burdens, in T2D have encouraged fervent anecdotal and non-anecdotal research also in T1D, indicating that non-insulin injective agents can be effective and safe. With this expert opinion paper, the members of four of the most representative Committees of the Italian Association of Clinical Endocrinologists provide the scientific community with a state-of-the-art report on the use of GLP-1RAs and other incretin-based injective therapy to treat body weight excess in T1D individuals and new insights on the topic with reliable methodology and clinical expertise.

BackgroundManaging patients with fatigue is a clinical challenge. Because fatigue is often reported in hypothyroidism, thyroid hormone (TH) therapy may sometimes be incorrectly considered for biochemically euthyroid individuals. This study aimed to evaluate the prevalence and determinants of this practice in different European countries.MethodsWe analyzed aggregate data from the THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) online survey. We analyzed responses from 5,695 members of 28 national endocrine/thyroid societies’ specialists to the statement: “Thyroid hormones may be indicated in biochemically euthyroid patients with unexplained fatigue”.ResultsOverall, 7.5% (426/5695) of respondents indicated that TH therapy might be considered for euthyroid patients with unexplained fatigue. The proportion of positive responses varied widely across different countries (between 1.1% in Switzerland and 29.3% in Serbia; p=2 ×10-16) and regions (between 4.7% in Western Europe and 8.7% in Western Asia or 8.8% in Eastern Europe; p=0.004). TH were more frequently prescribed for unexplained fatigue by male respondents (Odds Ratio, OR 1.45, 95% CI 1.18-1.78) and physicians practicing in private practice (OR 1.27, 95% CI 1.02-1.58), and less frequently by endocrinologists (OR 0.62, 95% CI 0.46-0.83).ConclusionA small, yet not negligible percentage of European thyroid-focused physicians consider using TH for euthyroid patients with unexplained fatigue, with significant variations based on geographic, demographic, and practice-related factors. Using levothyroxine and/or liothyronine in such cases lacks evidence and may partially contribute to the concerning overuse of TH therapy.

Thyroid hormone (TH) prescribing practices, particularly on hypothyroid and euthyroid patients, were compared between Japan Thyroid Association (JTA)-certified thyroid specialists and non-certified members. A nationwide questionnaire survey (Treatment of Hypothyroidism in Europe by Specialists: An International Survey) was conducted among all 2,938 JTA members, including 874 certified specialists and 2,064 non-certified members, to assess self-reported TH prescription choices in various clinical scenarios. Responses from certified specialists and non-certified members were statistically compared. A total of 207 certified specialists (23.7%) and 129 non-certified members (6.3%) responded and completed the questionnaire. Although all certified specialists and non-certified members selected levothyroxine (LT4) as first-line therapy for hypothyroidism, certified specialists more often used liothyronine (LT3) plus LT4 combination therapy than non-certified members (28% vs. 12%, p < 0.001), particularly for LT4-treated patients with persistent hypothyroid-like symptoms (9% vs. 2%, p = 0.02). For euthyroid individuals, 71% of certified specialists and 60% of non-certified members considered TH treatment (p = 0.043). Non-certified members who see >100 hypothyroid patients per year were more inclined to use combination therapy for hypothyroid patients and TH for euthyroid patients than those of ≤100 patients (p < 0.049 and 0.001, respectively). In conclusion, JTA-certified thyroid specialists and non-certified members exhibit distinct TH prescribing patterns. Certified specialists are more open to combination therapy and treating selected euthyroid patients, whereas non-certified members favor guideline-based LT4 monotherapy. These differences underscore the impact of specialization on clinical practice and suggest a need for updated guidelines and targeted education to rationalize thyroid care.

Introduction: Primary hyperparathyroidism (PHPT) is a common endocrine disorder, primarily caused by single adenomas or multiglandular disease. This study evaluates the economic impact of different PHPT treatment approaches from both the Italian National Health Service and societal perspectives. Methods: A micro-costing approach was used to estimate the costs of surgical and non-surgical treatments. Data were gathered through a survey among panel members responsible for the Italian PHPT treatment guidelines, ensuring alignment with national clinical practice. The survey examined various cost components, including diagnostic tests, pre-hospitalization assessments, surgery duration, drug use, healthcare professionals involved, disposable materials, and follow-up care requirements. Results: The total cost for PHPT diagnosis and comorbidity assessment is € 887.96. Parathyroidectomy (PTX) costs € 4,588.00. Non-surgical alternatives, including pharmacological treatment (€ 953.34 annually) and active surveillance (€ 197.42 annually), result in cumulative 30-year costs of € 28,590 and € 5,910, respectively. Since PTX is typically performed at age 55, pharmacological treatment over 30 years incurs an additional € 22,876 per patient compared to surgery. Conclusions: Despite its higher upfront cost, PTX demonstrated long-term cost efficiency due to the relatively low rates of follow-up complications and the absence of recurring annual costs associated with conservative strategies.

Background: Ultrasound (US) examination is the pivotal test to assess the risk of cancer and the indication for fine needle aspiration cytology (FNAC) in thyroid nodules (TNs). The subcapsular location of a TN may strengthen the indication for FNAC as, in TN resulting malignant at cytology may favor surgery rather than active surveillance. However, the definition of a subcapsular TN remains unclear. This study aimed to evaluate the interobserver agreement (IOA) among thyroid US experts in classifying TNs as subcapsular or not. Methods: Twelve raters received an electronic link to a file containing static US images and were asked to assess 60 TNs for subcapsular location, blinded to all other TN characteristics. The overall IOA was calculated, and the TN US features were subsequently analyzed to evaluate their potential influence on interobserver variability. The raters had high or very high thyroid US experience. Two experienced operators preliminarily selected the case series and analyzed the findings. All cases were derived from patients undergoing surgery and histological diagnosis. The IOA was calculated according to Fleiss' kappa, ranging from 0.0 (no agreement) to 1.0 (perfect agreement). Results: The overall IOA was fair (κ = 0.34), with a slightly better result in the subgroup of raters with higher experience (κ = 0.39). A higher IOA value (κ = 0.38) was observed in TNs of medium size. Following multiple sub-analyses, the highest κ value (0.46) was observed in the subgroup of TNs that were categorized as EU-TIRADS 5 and were smaller than 2 cm. Conclusions: The overall IOA among US experts when assessing TNs as subcapsular was unsatisfactory. A clear and standardized definition of subcapsular position is needed to improve clinical decision-making. Future guidelines should address this issue to ensure consistent assessment and management of subcapsular TNs.

Benign thyroid nodules are common in adults, with incidental detection rates reaching 50–60

PurposeTreatment-resistant depression (TRD) is most commonly defined as depression that has not responded to two different pharmacological agents used for an adequate period of time. We explored the views of European specialists via survey, regarding the use of thyroid hormone (TH) in euthyroid patients with TRD as part of ‘Treatment of Hypothyroidism in Europe by Specialists: An International Survey’ (THESIS).MethodsThe question “Thyroid hormones may be indicated in biochemically euthyroid patients with treatment resistant depression” was posed to specialists from 28 countries.Results5695 valid responses were received following 17,232 invitations (33.0% response rate; 65% female, 90% endocrinologists). 348 (6.1%) stated that TH may be indicated in biochemically euthyroid patients with TRD. This view was more common in males (p<0.01), respondents who saw ≥100 patients with hypothyroidism per year (p<0.01), respondents who worked in private practice (p=0.05) and respondents who were not members of international specialist associations (p=0.05). Geographical variation existed with respondents in Eastern Europe significantly more likely to use TH in TRD (p<0.01). Linear regression showed a statistically significant reduction in the use of TH for TRD with increasing gross national income (F-statistic=7.35, CI -0.15 - -0.02, p=0.01). TH in TRD was recommended in psychiatry guidelines but not endocrinology guidelines.ConclusionWhile there is limited evidence for their use, over 6% of respondents stated that TH may be indicated in TRD. Due to the risk of iatrogenic thyrotoxicosis and increased morbidity the use of TH should be addressed in relevant endocrinology guidelines and consensus should be reached between specialties.