European Thyroid Journal最新文献

Graves' orbitopathy (GO) is characterized by orbital inflammatory infiltration, expansion of orbital tissues due to de novo adipogenesis and over-production of hydrophilic glycosaminoglycans, as well as myofibroblastic differentiation resulting in tissue fibrosis. Thyrotropin receptor antibody (TSH-R-Ab) is the major stimulus, which activates thyrotropin receptor (TSH-R)/insulin-like growth factor-1 receptor (IGF-1R) and its downstream signalling in orbital fibroblasts (OF). Clinical evaluation of TSH-R-Ab, the specific biomarker of Graves' disease (GD) and the associated orbitopathy, provides important clinical information concerning diagnosis, disease monitoring and prognosis of GO. TSH-R/IGF-1R crosstalk represents the principal mechanism of activation of OF, the key effector cells in GO. T cells and monocytes/macrophages predominate in the inflammatory infiltrates and B-T cell co-stimulation results in mutual activation. Mast cell-derived products also activate OF. In the presence of various pro-inflammatory molecules, activated OF and lymphocytes perpetuate orbital inflammation and mediate tissue remodelling. Enhanced oxidative stress drives various pathological processes in GO and many antioxidant agents have shown inhibitory effects on OF. Highly differential gene and protein expression exists between GO and normal subjects, as well as between active/severe and inactive/mild GO, providing important insights into the disease mechanisms. The lack of confirmed genetic susceptibility to GO development suggests that epigenetic mechanisms (e.g. DNA methylation and microRNAs) may play a role in regulating gene and protein expression, and hence disease phenotypes. The gut microbiome differs significantly between GO patients and healthy individuals. Modifying gut microbiota in GO animal models improves GO. Emerging evidence indicates that hypercholesterolaemia is associated with increased risk of developing GO, while statin use is a protective factor.

Objective: Iodine deficiency (ID) causes a wide range of health issues, from endemic goiter to more subtle effects resulting from reduced thyroid hormone production. The recommended daily iodine intake for adolescents and adults is 150 μg, which corresponds to a median urinary iodine concentration (UIC) of 100-299 μg/L at the population level. Individuals with anorexia nervosa typically suffer from deficiencies in micronutrients and vitamins, but there is little data on iodine status. This study assessed UIC and associated factors in a cohort of patients with anorexia nervosa.

Methods: This was a prospective monocentric exploratory observational study performed at the Centre Vaudois anorexie boulimie (abC) and the Division interdisciplinaire de santé des adolescents (DISA) of the Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland. The study included 39 patients with anorexia nervosa, aged ≥14 years, recruited between May and August 2022. After obtaining informed consent, anthropometric data were extracted from the electronic medical record and random spot urine samples were collected. The UIC was determined by ion-chromatography mass spectrometry.

Results: Median age (IQR) was 18 (14-62) years and median body mass index (BMI) was 17.72 (14.86-23.54) kg/m2. Median UIC was 67.7 μg/L, and 22/39 individuals had a UIC <100 μg/L. There was a positive correlation between BMI and UIC (P = 0.047).

Conclusion: The findings suggest that patients with anorexia nervosa are at risk of ID, and lower BMI predicts lower UIC. Although these data need to be corroborated in a larger cohort, clinicians caring for patients with anorexia should consider recommending an iodine-containing multivitamin.

Abstract: Apalutamide, a selective androgen receptor antagonist, is a new treatment for prostate cancer. Among the side effects observed during apalutamide treatment, an increased risk of hypothyroidism has been reported, particularly in patients previously treated with levothyroxine compared with untreated patients. Apalutamide is thought to stimulate hepatic UDP-glucuronosyltransferase activity, resulting in increased clearance and stimulation of the thyroxine enterohepatic cycle. A 65-year-old man on 150 μg/day levothyroxine treatment after total thyroidectomy for Graves' disease was euthyroid. Treatment with apalutamide (240 mg/day) was started for metastatic prostate neoplasia. After 1 month, the TSH level was 47.9 μIU/mL, and the dose of levothyroxine was gradually increased. In the presence of refractory hypothyroidism (TSH 38 μIU/mL) despite 275 μg/day of levothyroxine (3.25 μg/kg/d), a levothyroxine absorption test was performed: the basal concentration of total T4 was 5.8 μg/dL; after oral absorption of 1,000 μg of levothyroxine, total T4 concentration increased, peaking at 8.1 μg/dL after 2 h. The percentage absorption of levothyroxine was 27.1% (normal: >60%). After 14 h, total T4 concentration fell to 5.7 μg/dL before rising again to 8.5 μg/dL at 20 h. In the absence of further levothyroxine intake, the second peak of total T4 concentration may be related to stimulation of UDP-glucuronosyltransferase activity, with increased T4 solubility in the bile, released into the small intestine, and finally absorbed, with increased T4 concentration at 20 h in the patient, attesting to the stimulated T4 enterohepatic cycle during apalutamide treatment. Overall, the result of this clinical study suggests that apalutamide reduces the digestive absorption of levothyroxine, in addition to stimulating the activity of hepatic UDP-glucuronosyltransferase, explaining the higher prevalence of hypothyroidism during apalutamide treatment in patients previously treated with levothyroxine.

Objective: To investigate the prevalence of endogenous normal thyroid function 3 years after hemithyroidectomy for low-risk differentiated thyroid cancer if a postoperative thyroid-stimulating hormone increase up to 4 mIU/L is accepted.

Method: A retrospective review of a total of 162 Eastern Danish patients was conducted. Patients were initially followed up without levothyroxine treatment after hemithyroidectomy for differentiated thyroid cancer if thyroid-stimulating hormone was below 4 mIU/L, in accordance with the Danish treatment guideline. Patients' hospital charts were reviewed, and data on the initiation of levothyroxine treatment, pre- and postoperative thyroid-stimulating hormone, recurrence, and remnant lobe nodularity were collected.

Results: A total of 143/162 (88%) did not take levothyroxine before hemithyroidectomy, with a median (interquartile range) age of 53 (43-65) years; 80% were women. During follow-up, the prevalence of endogenous normal thyroid function gradually decreased to 80, 69, and 66% after 1, 2, and 3 years. Concomitantly, hypothyroidism developed with thyroid-stimulating hormone >4.0 mIU/L in 20, 31, and 34% of patients, who were replaced with levothyroxine. In patients not on levothyroxine, TSH was significantly increased within the normal range 1, 2, and 3 years after hemithyroidectomy for DTC (P < 0.0001). 4/143 (3%) had completion thyroidectomies due to growth of preexisting nodules; no patient had a recurrence.

Conclusion: One-third of differentiated thyroid cancer patients require levothyroxine treatment 3 years after hemithyroidectomy if postoperative thyroid-stimulating hormone levels up to 4 mIU/L are accepted. Avoidance of levothyroxine treatment happens at the expense of a significant increase in thyroid-stimulating hormone levels.

Background: Accurate assessment of thyroid status is essential for maternal and fetal management during pregnancy. This study measured human chorionic gonadotropin (HCG), albumin, and thyroxine-binding globulin (TBG) levels during pregnancy to clarify how their fluctuations affect thyroid hormone measurements by two immunoassays - chemiluminescent immunoassay (CLIA) and electrochemiluminescence immunoassay (ECLIA).

Method: Free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin (TSH) levels were measured in 897 serum samples obtained from 604 pregnant women by two immunoassays. In 176 cases selected from each trimester, thyroid hormone concentrations were also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following ultrafiltration. Associations between thyroid function and relevant determinants were evaluated using multivariable regression analysis.

Results: Throughout pregnancy, 64 samples (7.13%) measured by CLIA and 241 samples (26.87%) measured by ECLIA had TSH concentrations less than 0.01 mIU/L. The upper limits of thyroid hormone concentrations were observed between 8 and 15 weeks of gestation. In late pregnancy, the lower limits of thyroid hormone concentrations determined by the immunoassays fell below the lower limits of the nonpregnant reference intervals. Thyroid hormone concentrations measured by immunoassay correlated significantly with LC-MS/MS concentrations. In multivariable regression analysis, only HCG was significantly associated with immunoassay measurements of thyroid hormones. Under conditions of TBG ≥31 μg/mL, women with albumin <3.8 g/dL had lower thyroid hormone concentrations than those with ≥3.8 g/dL.

Conclusion: Gestational thyroid hormone concentrations appear to be influenced by HCG levels. As with LC-MS/MS use, immunoassay measurements may vary with albumin and TBG concentrations. These findings underscore the need to consider such fluctuations when interpreting thyroid function tests in pregnant women.

Objective: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine thyroid tumor, with only 30 new patients annually in the Netherlands. PET imaging provides information on distant metastases, after which tyrosine kinase inhibitors (TKIs) may be initiated. The rarity of the disease impedes large controlled trials, and therefore the challenge of selecting the best TKI and PET tracer for individual patients persists. To explore whether an in vitro model could be developed to guide the selection of appropriate PET tracers or TKI therapies in the future, we aimed to establish an MTC organoid model for the first time.

Methods: Dispersed cells from MTC biopsies were suspended in Matrigel, allowing organoid formation. The self-renewal potential was tested by dissociation and re-plating cells and determining organoid-forming efficiency. MTC-specific gene and protein expression were characterized by qPCR and immunofluorescent staining. Moreover, MTC-organoids (MTOs) were exposed to TKIs and PET tracers in proof-of-principle experiments.

Results: Ten MTC biopsies were processed and successfully cultured as MTOs. MTC-derived cells showed self-renewal potency for several passages, indicating the presence of putative stem cells. Gene and protein expression of MTC-specific markers in tissue and MTOs, and function measurements showed the production of calcitonin and CEA. Interpretation of the preliminary experiments with TKIs and PET tracers was limited by sample size but demonstrates their future potential.

Conclusion: We were able to culture MTC organoids that resemble the original tissue in gene expression, protein expression, and functionality. However, international, multi-center studies are required to meet the standards for future clinical applications.

Objective: At present, total thyroidectomy and central neck dissection are the surgical approaches recommended for the initial treatment of medullary thyroid cancer (MTC) independently of the size, number of tumor foci, age of patients, and other demographic and clinico-pathological parameters. The aims of the present study were to assess the prevalence of multifocality in hereditary (hMTC) and sporadic (sMTC) patients and to correlate the presence of multifocality with clinico-pathological parameters to provide a proof of concept that lobectomy can be safely performed in selected cases.

Methods: We analyzed the epidemiological, pathological, and clinical data of 389 MTC (311 sMTC and 78 hMTC) diagnosed in our center from 2005 to 2018.

Results: Multifocality was found in 89/389 cases (22.9%), (45/311 (14.5%) sMTC and 44/78 (56.4%) hMTC). Bilaterality was detected in 27/311 (8.7%) of all sMTC, particularly in 27/45 (60%) of multifocal ones, and in 44/78 of hMTC (56.4%). Multifocality was correlated with a more aggressive phenotype in both sMTC and hMTC, and the multivariate analysis showed that it was statistically and independently associated with tumoral extrathyroidal extension and N1 status in sMTC and with N1 status and persistent disease in hMTC. However, none of the presurgical factors could predict the presence of both multifocality and bilaterality.

Conclusions: Our study demonstrated that the rarity of multifocality and, in particular, of bilaterality, in sMTC represents the proof of concept for considering a more conservative surgical approach in selected sMTC cases. This approach cannot be considered in hMTC due to the high prevalence of multifocal and bilateral cases.

Background: Globally prevalent, thyroid diseases are linked to environmental factors such as air pollution. This study examines the link between particulate matter (PM)1 exposure and thyroid disease rates in China.

Methods: We analyzed data from 73,900 adults across 31 Chinese provinces, using a high-resolution spatial-temporal extremity tree model to estimate PM1 and PM2.5 levels, and thyroid function tests to assess disease prevalence. Multivariate-adjusted ORs evaluated PM1's link to thyroid disease. This cross-sectional study is adept at identifying associations but cannot establish causality due to its single-time data collection limitation.

Results: Higher PM1 level exposure was significantly linked to an increased prevalence of thyroid diseases, including overt hypothyroidism, autoimmune thyroiditis (AIT), and TgAb positivity. A linear dose-response relationship was observed between PM1 concentration and both AIT and TgAb positivity. The study also revealed a significant association between PM1 exposure and autoimmune overt hypothyroidism, suggesting that thyroid dysfunction may be primarily mediated through autoimmune mechanisms. In addition, iodine status significantly influenced PM1's effects, with lower levels enhancing susceptibility to thyroid issues. Furthermore, every 1% increase in the PM1/PM2.5 ratio was related to the prevalence of overt hypothyroidism (OR = 1.03; 95% CI: 1.03-1.04) and subclinical hypothyroidism (OR = 1.03; 95% CI: 1.03-1.04).

Conclusions: PM1 exposure is associated with thyroid diseases, particularly AIT and TgAb positivity, with iodine status playing a modifying role. PM1 may be a key factor in PM2.5-related thyroid disease risk. Further prospective cohort studies are warranted to validate these findings.

Objective: To evaluate differences in the presentation, diagnostic/therapeutic approaches, and outcome of differentiated thyroid cancer (DTC) in an Italian and a Dutch referral centre.

Methods: We retrospectively included 919 patients (586 Italian, 333 Dutch), and compared the two cohorts as a whole and according to ATA risk classes. Dynamic risk stratification (DRS) and Kaplan-Meier curves were used to compare progression-free survival (PFS) and disease-specific survival (DSS).

Results: Several differences (P < 0.001) were found in clinicopathological features and in diagnostic/therapeutic modalities. The Dutch cohort had a higher age at diagnosis, a higher number of patients presenting with metastatic disease, and patients with stage III/IV. Most Italian patients showed a low/intermediate ATA risk, while high-risk patients represented half of the Dutch cohort. The Dutch cohort received a more intensive first treatment and more additional treatments during follow-up (i.e. surgery, radiotherapy, and systemic treatments). DRS analysis showed comparable excellent and biochemical incomplete responses, while the Dutch cohort had a lower rate of indeterminate and a higher rate of structural incomplete responses (P < 0.001). The Dutch cohort had a significantly worse 5-year PFS, and TC-related mortality was 10 and 1% for the Dutch and Italian cohorts, respectively, in line with the higher rate of advanced disease at presentation, with DSS still excellent for both.

Conclusion: Data reported in the present comparison between two European countries highlight a different prevalence, presentation, and outcome of DTC, likely due to variabilities in healthcare systems, iodine nutritional status, and diagnostic and treatment approaches.

Primary congenital hypothyroidism (CH) is the most common endocrinopathy of developmental age. In recent years, several studies from different countries have reported a significant increase in CH incidence detected by newborn screening programs, primarily 'mild' forms of CH with gland in situ (GIS). However, more than one-third of affected children with GIS present transient CH and recover endogenous thyroid function in early childhood, permitting the cessation of levothyroxine treatment by the end of the third year of life. Therefore, in CH patients with GIS, a clinical and biochemical reassessment is needed to determine whether the hypothyroidism is transient or permanent and to search for the underlying causes of the thyroid defect. Despite the presence of consensus guidelines for the management of CH in pediatric age, the screening strategy and management of the disease, especially at re-evaluation, differ significantly between centers and present some points of discussion. The following review summarizes the main pathophysiological mechanisms of transient and permanent forms of CH, also underlining the importance of new genetic tools in order to guarantee each patient the best diagnostic and therapeutic approach.