NIFTP-adjusted risk estimation of Bethesda thyroid cytology categories should consider the indication for FNA according to TIRADS.

BACKGROUND: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was firstly described in 2016. Since NIFTP is thought a non-malignant tumor, the Bethesda system for thyroid cytology proposes two estimations of risk of malignancy of the diagnostic categories, one considering NIFTP as cancer and another one considering it as a benign neoplasm. The present study aimed to review NIFTPs in a single center, re-assess them across categories of three Thyroid Imaging Reporting and Data Systems (TIRADSs), and define the indication for biopsy according to the category-specific size cut-offs. METHODS: The study period was from 2017 to 2023. The institutional database was searched for histologically proven NIFTPs with preoperative ultrasound images. NIFTPs were re-assessed according to the American College of Radiology (ACR), European (EU), and Korean (K) TIRADSs. The indication for biopsy was defined according to TIRADS category-specific size threshold. RESULTS: Twenty NIFTPs from 19 patients were included. The median size of the NIFTPs was 23 mm. According to ultrasound, 80-85% of NIFTPs were at low-intermediate risk and 5-15% at high risk without significant difference among the tree TIRADSs (p = 0.91). The indication for FNA, according to three TIRADSs, was found in 52-58% of cases with no significant difference among systems (p = 0.96). CONCLUSION: NIFTPs have heterogeneous presentation according to TIRADSs with very low indication rate for FNA.

Papillary thyroid carcinoma: ≤ 10 mm does not always mean pN0. A multicentric real-world study.

The incidence of papillary thyroid carcinoma (PTC) is increasing and PTC ≤ 10 mm (PTMC) accounts for most new diagnoses. PTMCs are not always low risk, as detection of lymph nodes metastasis (LNM) may occur. The purpose of the study was to analyze the clinical pattern, frequency, and independent risk factors of patients with PTMC and LNM. From January 2022 to June 2023, PTCs managed at CTO Hospital, Rome; Policlinico Vanvitelli, Naples; and Garibaldi Nesima Hospital, Catania were included. PTC management followed the same diagnostic-therapeutic procedures according to the ATA guidelines. Variables such as age, sex, maximum diameter, histologic evidence of LNM (HELNM +), Hashimoto's thyroiditis (HT), multifocality, capsule invasion, and histological subtype were considered. PTCs were divided according to HELNM and size. Two hundred ninety-eight PTCs were included. PTMCs were 136 (45.6%) and LNM occurred in 27.2% of them. In the HELNM + group, analysis of PTMC vs 'MacroPTC' (PTC > 10 mm) did not show any statistical difference. Multivariate regression revealed that young age (OR 0.93; CI 95% 0.90-0.96; p < 0.01) and male sex (male OR 3.44; CI 95% 1.16-10.20; p = 0.03) were the only independent risk factors for HELNM + in PTMC. The risk of LNM in PTMC is not negligible; therefore, a careful evaluation by an expert thyroidologist is mandatory for patients with small thyroid nodule, especially in younger and male patients before excluding surgery. In the future, new tools are needed to detect early PTMC with LNM before surgery.

Analysis of dose-TSH response effect of levothyroxine soft-gel formulation.

Background: Hypothyroidism is treated with daily levothyroxine (LT4). In recent years, soft gel caps of LT4 (LT4-C) have been commercialized, and their performance has been optimized. Since guidelines recommend dose LT4 according to the tablet preparation efficacy, the present study was undertaken to obtain data about the daily requirement, normalized per body weight, of LT4-C. Methods: Patients undergoing LT4-C after total thyroidectomy and radioiodine treatment for differentiated thyroid carcinoma were selected. There was no specific indication of suppression of TSH (i.e., <0.5 or <0.1 mIU/L). Patients were required to maintain a stable LT4 dose during the study period. Patients with interfering factors were excluded from this study. Results: Thirty patients were enrolled (18 females and 12 males; median age, 50 years; median body weight, 71 kg; median LT4-C dose, 1.71 µg/kg/day). The analysis of patient age did not reveal any differences. The LT4-C dose correlated with free-T4 p = 0.03), but not with TSH (p = 0.42) and free-T3 (p = 0.13). TSH was <1.0 mIU/L in 90% of the cases. The LT4-C dose-TSH response effect was analysed by probit regression model: the probability to achieve TSH <1.0 mIU/l was 99% with a dose of 1.84 (95%CI 1.57-2.12) µg/kg/day, 75% with a dose of 1.38 µg/kg/day (95%CI 1.17-1.59), and 50% with a dose of 1.20 (95%CI 0.96-1.43). At ROC curve analysis, the most accurate cut-off of LT4-C dose to achieve TSH <1.0 mIU/l was 1.53 ug/kg/day with 70% sensitivity and 100% specificity. Conclusions: Athyreotic patients can be initially treated with an LT4-C dose lower than previously stated. Therefore, further prospective studies are warranted.

Determinants of circulating calcitonin value: analysis of thyroid features, demographic data, anthropometric characteristics, comorbidities, medications, and smoking habits in a population with histological full exclusion of medullary thyroid carcinoma.

Objective: Calcitonin (Ctn) measurement is crucial for the early diagnosis of medullary thyroid carcinoma (MTC). However, Ctn levels can be skewed/elevated due to other reasons, and the Ctn upper reference value remains controversial. In this field, studies have heterogeneous settings, published data are controversial, and no evidence has been achieved. The study's aim was to evaluate all previously investigated Ctn determinants in a population with histological exclusion of MTC. Methods: The institutional records from 2010 to 2022 were reviewed to select patients with thyroid nodules who had undergone total thyroidectomy with histological exclusion of MTC and who had tested for Ctn just before surgery. Thyroid features, demographic and anthropometric data, comorbidities, medications, and lifestyle information were collected. Univariate and multivariate analyses were performed. Results: A total of 127 cases were included. The median age for thyroidectomy was 51 years. Median Ctn was 1.04 pg/mL (interquartile range (IQR) 1.04-2.77), with two cases having values above 10 pg/mL. In univariate analysis, Ctn was correlated with gender (p < 0.001), body weight (p = 0.016), height (p = 0.031), body surface area (p = 0.016), thyroid size (p = 0.03), thyroglobulin (p < 0.001), and chronic kidney disease (p < 0.001). After multivariate analysis, the model with the highest accuracy included gender, chronic kidney disease, and thyroid-stimulating hormone (TSH) with an adjusted R-squared of 0.4. Conclusions: This study demonstrates, in a population histologically proven as MTC-free, that the Ctn value is mainly influenced by gender, anthropometric/thyroid features, and chronic kidney disease, with the further impact of TSH.

Incidence of subclinical and overt hypothyroidism in children treated with [131I]mIBG: a systematic review and meta-analysis.

INTRODUCTION: Treatment with [131I]mIBG is commonly used in pediatric metastatic neuroblastoma (NB); however, unbound [131I]I might be taken up by the thyroid, causing hypothyroidism. To prevent this occurrence, thyroid blockade with iodine salts is commonly used; despite this precaution, thyroid dysfunction still occurs. This review and meta-analysis aim to clarify the mean frequency of hypothyroidism in children with NB treated with [131I]mIBG and to investigate the possible causes. EVIDENCE ACQUISITION: The literature was searched for English-language scientific manuscripts describing the incidence of TSH elevation and overt hypothyroidism in children with NB treated with [131I]mIBG. Preclinical studies, small-case series, and reviews were excluded. A proportion meta-analysis was conducted to test the influence of potentially relevant factors (type and duration of thyroid blockade, year of the study, sample size) on the incidence of TSH elevation/overt hypothyroidism. EVIDENCE SYNTHESIS: Eleven studies were included. The pooled percentage of TSH elevation was 0.41 (95% CI: 0.27-0.55); the duration of the thyroid blockade (P=0.004) was inversely correlated with the incidence of TSH elevation. Moreover, a TSH increase was more common in patients treated with potassium iodide (KI) alone than in those managed with a multi-drug thyroid blockade (P<0.001). The pooled percentage of children requiring hormone replacement therapy was 0.33 (95% CI: 0.16-0.49). As in the case of TSH elevation, a longer duration of the thyroid blockade (P=0.006) and a multi-pronged approach (P<0.001) were associated with a lower incidence of overt hypothyroidism. CONCLUSIONS: Hypothyroidism appears to occur frequently in children treated with [131I]mIBG, which should be monitored closely after the radionuclide treatment to start hormone replacement therapy as soon as needed. The duration, as well as the type of thyroid blockade, seem to influence the incidence of hypothyroidism; however, more data from prospective evaluations are needed.

Head-to-head comparison of American, European, and Asian TIRADSs in thyroid nodule assessment: systematic review and meta-analysis.

Context: Ultrasound-based risk stratification systems (Thyroid Imaging Reporting and Data Systems (TIRADSs)) of thyroid nodules (TNs) have been implemented in clinical practice worldwide based on their high performance. However, it remains unexplored whether different TIRADSs perform uniformly across a range of TNs in routine practice. This issue is highly relevant today, given the ongoing international effort to establish a unified TIRADS (i.e. I-TIRADS), supported by the leading societies specializing in TNs. The study aimed to conduct a direct comparison among ACR-, EU-, and K-TIRADS in the distribution of TNs: (1) across the TIRADS categories, and (2) based on their estimated cancer risk. Methods: A search was conducted on PubMed and Embase until June 2023. Original studies that sequentially assessed TNs using TIRADSs, regardless of FNAC indication, were selected. General study characteristics and data on the distribution of TNs across TIRADSs were extracted. Results: Seven studies, reporting a total of 41,332 TNs, were included in the analysis. The prevalence of ACR-TIRADS 1-2 was significantly higher than that of EU-TIRADS 2 and K-TIRADS 2, with no significant difference observed among intermediate- and high-risk categories of TIRADSs. According to malignancy risk estimation, K-TIRADS often classified TNs as having more severe risk, ACR-TIRADS as having moderate risk, and EU-TIRADS classified TNs as having lower risk. Conclusion: ACR-, EU-, and K-TIRADS assess TNs similarly across their categories, with slight differences in low-risk classifications. Despite this, focusing on cancer risk estimation, the three TIRADSs assess TNs differently. These findings should be considered as a prerequisite for developing the I-TIRADS.

Inflammatory Profile Assessment in a Highly Selected Athyreotic Population Undergoing Controlled and Standardized Hypothyroidism.

Background: Hypothyroidism (hT) presents heterogeneous symptoms and findings. Evidence on this topic comes mainly from heterogeneous populations in terms of disease duration, residual thyroid function, and comorbidities. Therefore, it would be useful to assess systemic inflammation in a homogeneous hT population. The aim of this study was to investigate inflammation in a population that underwent standardized controlled hT. Methods: We recruited thyroidectomized patients diagnosed with thyroid cancer who were otherwise fit and healthy, showing hypothyroidism before I131 treatment using a standard protocol of LT4 withdrawal. The blood inflammatory indexes (BIIXs) (i.e., NLR, PLR, MLR, SII, SIRI, and AISI) were calculated using the blood tests collected just before I131 administration. Patients were divided according to sex, BMI, and thyroglobulin. The relationships between the BIIXs, age, and thyroid hormones were also investigated. Results: We included 143 patients. The median age of the sample was 43 years. The BIIX median values showed significant differences based on sex, BMI, and thyroglobulin levels (p < 0.05). No significant correlations were found between the BIIXs and age, TSH, FT4, and FT3. Conclusions: This study shows the BIIX median values of a population which underwent standardized hT. It suggests a role for some BIIXs in the evaluation of hypothyroidism in obese people and as hypothetical prognostic markers for thyroid cancer.

Preoperative neck ultrasound combined with pathological data can significantly impact the outcome of medullary thyroid carcinoma.

The diagnosis of medullary thyroid carcinoma (MTC) is challenging since the accuracy of ultrasound (US) and fine-needle aspiration cytology are suboptimal. As a result, MTC has a generally poor prognosis. The aim of this study was to analyze whether perioperative data can modify the risk of relapse in these patients. The institutional database of Turin Mauriziano Hospital was searched to extract records of MTCs diagnosed between 2000 and 2021. Kaplan-Meier curves and Cox and logistic regression analyses were performed, and the hazard ratio (HR) was calculated. Seventy-three MTC patients (median age 58 yr) were found. Disease-free survival was significantly different according to staging (HR: 9.12; p = 0.037), capsular status (HR: 5.49; p = 0.02), and neck US (HR: 9.19; p = 0.04). In the logistic regression analysis, CEA level (ß: -0.01; p = 0.043), histological multifocality (OR: 7.4; p = 0.034), and metastatic lymph nodes at histology (ß: -0.13; p = 0.006) were significantly associated with structural recurrence. Two logistic multivariate models best explained the variance in recurrence: 1) neck US presentation plus histological multifocality (AIC: 27; r2: 0.37; x2: 12.4; p = 0.002) and 2) number of neck metastases plus capsular invasion (AIC: 26; r2: 0.40; x2: 13.7; p = 0.001). Pathological data are associated with MTC prognosis. Preoperative neck US can significantly help to predict MTC outcome.

Effect of gluten-free diet on autoimmune thyroiditis progression in patients with no symptoms or histology of celiac disease: a meta-analysis.

Background: Hashimoto's thyroiditis (HT) is the most common autoimmune disease. HT may be associated with nonthyroidal autoimmune diseases, including celiac disease (CD) or other gluten-related conditions (GRC). In the last years, interest about gluten-free diet (GFD) has increased for its supposed extraintestinal anti-inflammatory effect; thus, many patients with HT initiate GFD on their own. Objectives: The aim of this meta-analysis is to examine all available data in literature about the effect of a GFD on TgAb, TPOAb, TSH, FT4, and FT3 levels in patients with HT and no symptoms or histology of CD. Methods: The study was conducted according to MOOSE (Meta-analysis Of Observational Studies in Epidemiology). The search was performed on databases PubMed and Scopus. The last search was performed on 7 February 2023. Quality assessment was performed. Meta-analyses were performed using the random-effect model. Hedges' g was used to measure the effect size (ES). Statistical analyses were performed using StataSE 17. Results: The online search retrieved 409 articles, and 4 studies with a total of 87 patients were finally included for quantitative analysis. The risk of bias was generally low. The mean period of GFD was almost 6 months. The meta-analyses showed reduction in antibody levels with ES: -0.39 for TgAb (95% CI: -0.81 to +0.02; p = 0.06; I² = 46.98%) and -0.40 for TPOAb (95% CI: -0.82 to +0.03; p = 0.07; I² = 47.58%). TSH showed a reduction with ES: -0.35 (95% CI: -0.64 to -0.05; p = 0.02; I² = 0%) and FT4 showed an increase with ES: +0.35% (95% CI: 0.06 to 0.64; p = 0.02; I² = 0%). FT3 did not display variations (ES: 0.05; 95% CI: -0.38 to +0.48; p = 0.82; I² = 51%). The heterogeneity of TgAb, TPOAb, and FT3 data was solved performing sub-analyses between patients with or without GRC (TgAb p = 0.02; TPOAb p = 0.02; FT3 p = 0.04) and only for FT3, performing a sub-analysis between patients taking and not taking LT4 (p = 0.03). Conclusion: This is the first meta-analysis investigating the effect of GFD on HT. Our results seem to indicate a positive effect of the gluten deprivation on thyroid function and its inflammation, particularly in patients with HT and GRC. However, current lines of evidence are not yet sufficient to recommend this dietary approach to all patients with a diagnosis of HT.

Prevalence and significance of indeterminate calcitonin values in patients with thyroid nodules: A systematic review and meta-analysis.

BACKGROUND: Although calcitonin (Ctn) measurement is recognized as the most accurate diagnostic test for medullary thyroid carcinoma (MTC), its routine execution is not universally accepted for several reasons, including the lack of recommendations for managing indeterminate Ctn values (ICV); such as 10-to-100 pg/mL. This study aimed to gather data on 1) the frequency of ICV among patients undergoing Ctn test and 2) the MTC rate among patients with ICV. METHODS: This review was conducted according to the Meta-analyses Of Observational Studies in Epidemiology guidelines. PubMed and Cochrane databases were searched, with no language restrictions. The final search was completed on January 2023. Then, quality assessment and proportion meta-analyses were performed. RESULTS: The online search retrieved 233 articles and 15 were included for quantitative analysis. The risk of bias was low. The number of patients undergone Ctn testing was 29,533. The pooled percentage of those with ICV was 1.7% (95% confidence interval [CI]:1.2-2.3). The pooled proportion of MTC incidence among patients with ICV was 9.6% (95% CI:5-14.1). Heterogeneity was explained by the covariates of Ctn assay sensitivity and the resection rate. The subgroup with Ctn 10-20 pg/mL showed a significantly lower MTC rate than the subgroup with Ctn 20-100 pg/mL. CONCLUSIONS: The percentage of ICV among patients with thyroid nodules who underwent Ctn testing is negligible. The rate of MTC in patients with ICV cannot be overlooked. Among the ICV intervals, the risk of MTC increases significantly when Ctn is above 20 pg/mL.

Levothyroxine therapy, calculated deiodinases activity and basal metabolic rate in obese or nonobese patients after total thyroidectomy for differentiated thyroid cancer, results of a retrospective observational study.

INTRODUCTION: Therapy for hypothyroid obese patients is still under definition since the thyrotropin-stimulating hormone (TSH) level is a less reliable marker of euthyroidism than nonobese patients. Indeed, TSH levels positively correlate with body mass index (BMI), and this increase may be a compensatory mechanism aimed at increasing energy expenditure in obese people. In contrast, the correlation of BMI with thyroid hormone levels is not completely clear, and conflicting results have been obtained by several studies. The L-T4 replacement dose is more variable in obese hypothyroid patients than in nonobese patients, and a recent study indicated that the L-T4 replacement dose is related to lean body mass in obese thyroidectomized patients. We aimed to study the correlations of L-T4-administered dose, thyroid hormone levels and TSH secretion with basal metabolic rate (BMR) and total calculated deiodinase activity (GD) in obese and nonobese athyreotic patients. We also looked for individualized L-T4 replacement dose set points to be used in clinical practice. METHODS: We studied retrospectively 160 athyreotic patients, 120 nonobese and 40 obese. GD was calculated by SPINA Thyr 4.2, the responsiveness of the hypothalamic/pituitary thyrotrope by Jostel's thyrotropin (TSH) index and BMR by the Mifflin-St. Jeor formula, the interplay of GD and BMR with L-T4, thyroid hormones and TSH index (TSHI) was also evaluated. RESULTS: In our study, the L-T4 dose was an independent predictor of GD, and approximately 30% of athyreotic patients under L-T4 therapy had a reduced GD; FT4 levels were higher and negatively modulated by BMR in obese athyreotic patients respect to nonobese, in these patients a T4 to T3 shunt, in terms of TSHI suppression is observed suggesting a defective hypothalamic pituitary T4 to T3 conversion and a resistance to L-T4 replacement therapy. CONCLUSIONS: L-t4 dose is the most important predictor of GD, BMR modulates T4 levels in obese athyreotic patients that are resistant to L-T4 replacement therapy.

Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management.

Obesity is strongly associated with chronic low-grade inflammation. Obese patients have an increased risk to develop thyroid autoimmunity and to became hypothyroid, suggesting a pathogenetic link between obesity, inflammation and autoimmunity. Moreover, type 2 diabetes and dyslipidemia, also characterized by low-grade inflammation, were recently associated with more aggressive forms of Graves' ophthalmopathy. The association between obesity and autoimmune thyroid disorders may also go in the opposite direction, as treating autoimmune hyper and hypothyroidism can lead to weight gain. In addition, restoration of euthyroidism by L-T4 replacement therapy is more challenging in obese athyreotic patients, as it is difficult to maintain thyrotropin stimulation hormone (TSH) values within the normal range. Intriguingly, pro-inflammatory cytokines decrease in obese patients after bariatric surgery along with TSH levels. Moreover, the risk of thyroid cancer is increased in patients with thyroid autoimmune disorders, and is also related to the degree of obesity and inflammation. Molecular studies have shown a relationship between the low-grade inflammation of obesity and the activity of intracellular multiprotein complexes typical of immune cells (inflammasomes). We will now highlight some clinical implications of inflammasome activation in the relationship between obesity and thyroid disease.

Early detection of suspicious lymph nodes in differentiated thyroid cancer.

BACKGROUND: Early identification of cervical lymph node (LN) metastases cervical lymph node metastases (CLNM) is crucial in the management of differentiated thyroid cancer differentiated thyroid cancer (DTC) as it influences the indication and the extent of surgery with an impact on the recurrence risk and overall survival. The present review focused on novel sensitive and specific diagnostic techniques, by searching through online databases like MEDLINE and Scopus up to February 2022. AREAS COVERED: The techniques identified included contrast-enhanced ultrasound (CEUS), dosage of fragment 21-1 of cytokeratin 19 (CYFRA 21-1) in lymph node fine needle aspiration washout, sentinel LN biopsy (SNB), and artificial intelligence (AI) - deep learning applied to ultrasonography and computed tomography. These methods displayed widely varying sensitivity and specificity results, ranging from approximately 60-100%. This variability is mainly due to the operator's experience because of the great complexity of execution of these new techniques, which require a long-learning curve. EXPERT OPINION: Despite the appearance of many candidate methods to improve the detection of metastatic lymph nodes, none seem to be clearly superior to the tools currently used in clinical practice and FNA-Tg measurement remains the more accurate tool to detect neck recurrences and CLNM from DTC.

Recent insights into the pathogenesis of autoimmune hypophysitis.

INTRODUCTION: Hypophysitis is an inflammation of the pituitary gland and a rare case of hypopituitarism. Despite the expanding spectrum of histological variants and causative agents, its pathogenesis is far to be fully understood. The present review is focused on recent evidence concerning the pathogenesis of autoimmune hypophysitis by searching through online databases like MEDLINE and Scopus up to May 2021. AREAS COVERED: Hypophysitis frequently develops in the context of a strong autoimmune background, including a wide spectrum of subtypes ranging from the commonest form of lymphocytic hypophysitis to the newly described and less common IgG4-, anti-PIT-1, and ICI-induced forms. A peculiar combination of genetic predisposition, pituitary damage and immunological setting represents the pathogenetic basis of autoimmune hypophysitis, which is characterized by diffuse infiltration of the gland by lymphocytes and variable degrees of fibrosis followed by pituitary cell destruction. Anti-pituitary antibodies (APA) have been described in sera from patients suffering from autoimmune hypophysitis, though their pathophysiological significance remains largely unknown and their diagnostic value limited. EXPERT OPINION: In recent years hypophysitis has gained interest due to the increased number of new diagnoses and the recognition of novel subtypes. Further studies could lead to improvements in biochemical/immunological diagnosis and targeted treatments.