Constitutional Mutation of PIK3CA: A Variant of Cowden Syndrome?

We present a family in which four individuals have been identified with the same likely pathogenic genetic alteration in the PIK3CA gene at the germinal level; specifically, c.1145G>A p.(Arg382Lys) missense type. The index case patient was diagnosed with multinodular goiter and breast cancer at 61 years old. Among the other three carrier relatives: one has been diagnosed with serous cystadenoma of the ovary and a thyroid nodule with no radiological suspicion of malignancy; the other two present multinodular goiter. Additionally, a sister of three of the carriers suffered from an ovarian teratoma, follicular thyroid carcinoma on multinodular goiter, and high-grade serous ovarian carcinoma. No direct mutation study was performed on her as she had died due to ovarian carcinoma. This finding suggests that the PIK3CA gene should be considered in Cowden-like families when no other gene mutations have been found. Furthermore, this report contributes to characterization of the clinical phenotype caused by mutations in PIK3CA, which may be shared with other hereditary breast and ovarian cancer syndromes.

Posthemithyroidectomy hypothyroidism. Prevalence and predictive markers. Comparison between patients with euthyroid and hyperthyroid nodular goitre.

BACKGROUND AND OBJECTIVE: Posthemithyroidectomy hypothyroidism (PHH) is a relatively common complication (22%-30%) for which we have no published information from our country. The objective of the study is to determine the prevalence of PHH and evaluate its predictive markers by comparing patients who had euthyroidism with those who had hyperthyroidism before hemithyroidectomy. PATIENTS AND METHOD: Retrospective observational cross-sectional study on 106 patients, 88 euthyroid before hemithyroidectomy and 18 hyperthyroid. RESULTS: Prevalence of PHH in euthyroid patients 42% (89.2% subclinical hypothyroidism; 10.8% manifest hypothyroidism) and in hyperthyroid patients 50% (77.8% subclinical hypothyroidism; 22.2% manifest hypothyroidism). Predictive markers in euthyroid patients: preoperative thyrotropin ≥ 2.2 mIU/L (OR: 4.278, 95% CI: 1.689-10.833; sensitivity: 54.1%, 95% CI: 38%-70.1%; specificity: 78.4%, 95% CI: 67.1%-89.7%), age ≥50 years (OR: 3.509, 95% CI: 1.438-8.563; sensitivity: 64.9%, 95% CI: 49.5%-80.3%; specificity: 64.7%, 95% CI: 51.6%-77.8%) and percentage of remainder lobe ≤ 19.6% (OR: 1.024, 95%: 1.002-1.046; sensitivity: 70.2%, 95% CI: 55.5%-84.9%; specificity: 48.6%, 95% CI: 34.9%-62.3%). Predictive marker in hyperthyroid patients: weight >70 kg (OR: 28, 95% CI: 2.067-379.247; sensitivity: 88.9%, 95% CI: 68.4%-100%; specificity: 88.9%, 95% CI: 68.4%-100%). CONCLUSIONS: This is the first study in our country that demonstrates a prevalence of PHH above the average in euthyroid patients, which is slightly higher and more intense in hyperthyroid patients, and that recognizes the classic predictive markers in euthyroid patients but highlights a novel predictive marker marker in hyperthyroid patients, useful to assess a different risk of PHH when indicating hemithyroidectomy and to establish closer control of postoperative hormonal evolution.

Assessing the impact of short-term Lugol's solution on toxic nodular thyroid disease: a pre-post-intervention study.

Purpose: Preoperative iodine therapy in toxic nodular goiter (TNG) is discouraged as iodine may cause aggravation of hyperthyroidism. We aimed to examine if a short course of iodine treatment is safe to administer in TNG. Methods: Patients with TNG (n=20) and subclinical to mild hyperthyroidism (free (f)T4 <30 pmol/L) without complicating illnesses were included in this pre-post-intervention study at Karolinska University Hospital. All participants received Lugol's solution 5%, three oral drops thrice daily for 10 days. Heart rate, TSH, fT4, fT3 concentrations were collected before (day 0) and after treatment (day 10). Thyroid hormone concentrations were also measured at two time points during treatment to discover aggravations of hyperthyroidism. ThyPRO39se, a quality-of-life questionnaire, was filled out day 0 and day 10. Differences in heart rate, thyroid hormone concentrations, and quality-of-life before and after treatment were compared. Adverse reactions were reported. Results: The median age was 63.5 years. Female to male ratio 19:1. FT4 and fT3 concentrations decreased (both p<0.001), and TSH concentration increased (p<0.001) after 10 days of treatment. There was no difference in heart rate. No aggravations of thyrotoxicosis were noticed in any of the participants. ThyPRO39se scores improved on three scales, including hyperthyroid symptoms, while the remaining scale scores were unchanged. Mild and transient symptoms related to or possibly related to treatment were observed in six participants. Conclusion: A short course of Lugol's solution improved thyroid hormone concentrations, reduced patient-reported hyperthyroid symptoms and was safe in TNG. Lugol's solution might be an option for preoperative treatment in TNG. Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT04856488.

Thyroid tuberculosis mimicking multinodular goiter: a case report.

BACKGROUND: Mycobacterium tuberculosis is the second most common infectious cause of death in adults worldwide. The ability of this organism to efficiently establish latent infection has enabled it to spread to nearly one-third of individuals worldwide. Approximately 8 million new cases of active tuberculosis disease occur each year, leading to about 1.7 million deaths. The disease incidence is magnified by the concurrent epidemic of human immunodeficiency virus infection. A total of 1.3 million people died from tuberculosis in 2022. In 2022, an estimated 10.6 million people fell ill with tuberculosis worldwide, including 5.8 million men, 3.5 million women, and 1.3 million children. We report a case of thyroid tuberculosis presenting as multinodular goiter. Neck ultrasound was done and revealed abscess collection on the background of multinodular colloid goiter. The diagnosis of thyroid tuberculosis was confirmed by a positive GeneXpert of the pus sample and the presence of extensive caseous necrosis on cytopathology examination. Furthermore, anterior neck swelling may provide a diagnostic challenge by clinically mimicking multinodular goiter or thyroid neoplasms. Owing to its rarity and its tendency to pose a clinical diagnostic challenge, we decided to report it. CASE PRESENTATION: A 60-year-old retired female Ethiopian high-school teacher presented to University of Gondar Hospital, Gondar, Ethiopia with firm, nontender multinodular anterior neck swelling measuring at largest 2 × 3 cm that moves with swallowing. GeneXpert of the pus sample and cytopathology examination confirmed the diagnosis of thyroid tuberculosis, and the patient was started on 2 rifampicin-ethambutol-isoniazid-pyrazinamide/4 rifampicin-isoniazid 3 tablets by mouth/day, which is defined as the preferred first-line anti-tuberculosis regimen in Ethiopia, and pyridoxine 50 mg by mouth per day for 6 months. Since then, she has been followed with regular liver function tests. The patient has shown a smooth course with no significant adverse effects encountered. Currently, the patient has completed her anti-tuberculosis treatment and is doing well. CONCLUSION: In the clinical evaluation of a patient with anterior neck swelling, tuberculosis must be considered as a differential diagnosis in subjects from endemic areas for early diagnostic workup and management.

The Effect of Conventional Open Thyroidectomy on Clinical Results and Respiratory Function Tests in Multinodular Goitre.

AIM: The primary aim of our study was to measure the effect of conventional open thyroidectomy performed for patients with multinodular goiter (MNG) on pulmonary volumes measured with respiratory function tests independent from surgical indications. A secondary aim was to determine whether there was a significant improvement in the complaints due to obstructive symptoms after MNG surgeries. METHODS: This study was conducted between October 2020 and June 2022. Patients who were hospitalized to undergo surgery for giant multinodular goiter were prospectively included in the study. Patients were questioned about complaints of pressure, hoarseness, dyspnea, sleep apnea, snoring, and dysphagia before the surgery and during the follow-up 6 months after surgery. In addition, pulmonary function tests were performed preoperatively, 48 hours after surgery and 6 months after surgery. Forced expiratory volume in 0.5 seconds forced expiratory volume in 1 second and forced vital capacity values in pulmonary function test (PFT) measurements were recorded. RESULTS: A total of 55 patients, 42 females and 13 males, mean age 49.54 ± 13.6 years, were included in the study. Although there was a significant decrease in clinical symptoms caused by the thyroid volume within 6 months in patients who were operated for giant MNG there was no significant change in pulmonary function tests. There was a positive correlation between the thyroid volume and nodule weight in patients with MNG. CONCLUSIONS: Our results suggest that it is not necessary to follow up with patients without obstructive findings in preoperative pulmonary function tests with pulmonary function tests in the postoperative period.

Variability in Inner Ear Morphology Among a Family With Pendred Syndrome Due to a SLC26A4 Gene Variant.

OBJECTIVES: Pendred syndrome, an autosomal recessive disorder, is often associated with pathogenic variants of the SLC26A4 gene that encodes the pendrin protein. Given its autosomal recessive inheritance, tracing the family history and screening siblings become crucial once a diagnosis of Pendred syndrome is confirmed. This case report aims to underscore the variability in inner ear morphology within a family diagnosed with Pendred syndrome, all carrying the same SLC26A4 gene mutation. METHODS: A chart review and a review of the literature. RESULTS: We present a family of 4, all of whom possess sensorineural hearing loss due to the same homozygous SLC26A4 variant c.919-2A>G. Intriguingly, clinical manifestations, especially inner ear deformities, displayed variability among family members. Notably, 1 family member exhibited a normal cochleovestibular structure morphology, which was rarely reported in the literature. CONCLUSIONS: This report highlights the significance of genetic testing and familial consultation when a proband exhibits typical Pendred syndrome symptoms. It also underscores that the inner ear morphology can exhibit variability among family members, even with the same homozygous SLC26A4 variant.

Incomplete partition type II in its various manifestations: isolated, in association with EVA, syndromic, and beyond; a multicentre international study.

PURPOSE: Incomplete partition type II (IP-II) is characterized by specific histological features and radiological appearance. It may occur in isolation or in association with an enlarged vestibular aqueduct (EVA). Among those with IP-II and EVA, a subset has a diagnosis of Pendred syndrome. This study aimed to explore the prevalence of isolated IP-II, IP-II with EVA, and cases with a genetic or syndromic basis in our cohort. METHODS: From a large, multicentre database of dysplastic cochleae (446 patients, 892 temporal bones), those with imaging features of IP-II were examined in detail, including whether there was a genetic or syndromic association. RESULTS: A total of 78 patients with IP-II were identified. Among these, 55 patients had bilateral IP-II and EVA (only 12 with typical Mondini triad), 8 with bilateral IP-II and normal VA, 2 with bilateral IP-II and unilateral EVA, and 13 with unilateral IP-II (9 with unilateral EVA). Among the group with bilateral IP-II and bilateral EVA in whom genetic analysis was available, 14 out of 29 (48%) had SLC26A4 mutations and a diagnosis of Pendred syndrome, 1 had a FOXI1 mutation, and a few other genetic abnormalities; none had KCNJ10 pathogenic variants. CONCLUSION: Bilateral IP-II-bilateral EVA may be seen in the context of Pendred syndrome (SLC26A4 or FOXI1 mutations) but, in the majority of our cohort, no genetic abnormalities were found, suggesting the possibility of unknown genetic associations. IP-II in isolation (without EVA) is favored to be genetic when bilateral, although the cause is often unknown.

Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities.

Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.

Establishing and Monitoring an Effective Management of Benign Nontoxic Multinodular Goitre in Kuwait "Utilizing Two Different Dose Levels of Recombinant Human TSH in Combination with Radioactive Iodine".

INTRODUCTION: rhTSH-assisted radioiodine therapy of multinodular goiter is not fully known and only a few studies, with a limited number of patients have evaluated the effect of rhTSH assisted radioiodine therapy beyond 1 year. Though there is an effective and safe management of benign non-toxic MNG available, it is not applicable to all patient categories in Kuwait covering the impact of the past environmental events (Gulf War) and the genetic relation. The proposed project aims to address those points raised, that is exclusive to the Kuwait population. MATERIALS AND METHODS: In this cohort study, 2 groups of patients, group one (G1) and group two (G2) patients (N=50, ≥18 years old) went undergo evaluated according to a proposed criteria followed by FNA to exclude cancer, toxicity and those who have refused surgery. All patients had a CT scan, TSH, T3, T4 and CBC and complete biomedical tests at a 6-months interval during the treatment period and the follow up. The Volumetric application of GE 670 SPECT/CT (i.e. Xeleris) and in-house developed MATLAB used for quantitative measurement. All patients had a 131-I uptake at baseline and 24 intervals post intramuscular a single dose of 0.3mg or 0.1mg (group 1, group 2) of rhTSH. RESULTS: There was no significant difference in TSH levels at 24-month follow-up between the two groups (p=0.327), whereas there was a statistically significant difference at the baseline and at the 6-months interval between the 2 groups for T4. Post treatment follow up at the 24-hour time point, Group 1 displayed significantly higher uptake than Group 2 (G1:41.74 ± 6.27 vs. G2:34.80 ± 3.84, p < 0.001). The change in I131 uptake from baseline to 24 hours was significantly greater in Group 1compared to Group 2 (p < 0.001). The ROC analysis (AUC) post treatment indicated an excellent discriminatory power for AUC (0.960) and (p < 0.001). There was a much better correlation posttreatment between BMI and thyroid volume for group 1 (R2=0.661) than for group 2 (R2=0.008). Our results suggest 42.1% thyroid volume reduction for group 1 and 20% for group 2. CONCLUSION: The study underscores the potential benefits of the higher rhTSH dose (0.3mg) in managing multinodular non-toxic goiter for the Kuwaiti population and the region considering the impact of dietary, and experience to the drastic environmental exposure.

Thyroid Malignancy in Patients Who Underwent Thyroidectomy for Multinodular Goiter and Solitary Thyroid Nodule.

PURPOSE: Worldwide, incidence of thyroid malignancy is increasing. The purpose of this study was to evaluate the pattern and magnitude of nodule types. METHODS: A cross-sectional retrospective study was performed at Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia, among patients who underwent thyroidectomy from May 2018 to June 2022. Data were extracted using a structured format. Descriptive statistics were performed using SPSS version 26 software. Results were presented in terms of percentages and frequencies. RESULTS: During a 4-year period, 1,476 patients had thyroidectomies and histopathologic information of 212 malignant cases was studied. Within multinodular goiter (MNG), thyroid cancer accounted for 69.8% (n = 148) of patients, whereas in solitary nodules, it accounted for 30.2%. From the total, 160 participants (75.5%) were female, and the female:male ratio was 3.1 (mean, 41.72; ± standard deviation [SD], 16.44) years, and age range of 12-88 years versus men, who have a mean of 44.71 (±SD, 14.91) years and an age range of 21-78 years. The mean age of male cases with solitary nodule and MNG was 40.6 and 46.5 years, respectively. The most frequent cancer in both types of nodules, accounting for 59% of patients, was papillary carcinoma, which was found in 64% of solitary nodules and 57.4% of multinodular nodules. Overall, 14.1% of tumors had multiple centers (17.4% in multinodular nodules and 6.9% in solitary nodules). In 7.1% of patients, microcarcinoma (<1 cm) was found, with papillary carcinoma accounting for 91.7% of the total. CONCLUSION: Compared with men, women with cancer typically manifested at a younger age. Males with malignancy in solitary nodules had a lower mean age than those with MNGs. The most frequent and significant cause of multicentric presentation is papillary carcinoma.

The BRAF V600E Mutation and Clinicopathological Changes Among Patients With Hashimoto Thyroiditis, Papillary Thyroid Carcinoma With Hashimoto Thyroiditis, and Nodular Goiter.

The study aimed to investigate the BRAF V600E mutation and clinicopathological changes among patients with Hashimoto thyroiditis (HT), papillary thyroid carcinoma (PTC) with Hashimoto thyroiditis (HT), or nodular goiter (NG). A total of 87 patients with the BRAF V600E mutation who were diagnosed with HT (including with hyperplasia dysplasia), PTC with HT, and PTC with NG were enrolled. Clinical data, concentrations of antithyroglobulin antibodies (TGAb) and thyroid microsomal antibodies (TMAb) in the serum thyroid-function levels, and the result presence of the BRAF V600E mutation were retrospectively analyzed. There were significant differences in the BRAF V600E mutation rates between the HT and PTC with HT groups ( P <0.05) and the HT and PTC with NG groups ( P <0.05), whereas no significant difference was found between the PTC with HT and PTC with NG groups. There was no difference in incidences of PTC between HT with elevated TGAb and TMAb group and those with baseline levels. The incidence of multifocal PTC was higher in the PTC with HT group; however, the difference was not significant. Our findings documented that BRAF mutation distinguished between the benign HT and the malignant PTC groups. The serum levels of TGAb and TMAb autoantibodies did not directly correlate with PTC in the background of HT. HT and NG may similarly contribute to the pathogenesis of PTC.

Use of a dosimetry-based RAI protocol for treatment of benign hyperthyroidism optimises response while minimising exposure to ionising radiation.

BACKGROUND: The optimal treatment strategy for radioiodine (RAI) treatment protocols for benign hyperthyroidism remains elusive. Although individualised activities are recommended in European Law, many centres continue to provide fixed activities. Our institution implemented a dosimetry protocol in 2016 following years of fixed dosing which facilitates the calculation of individualised activities based on thyroid volume and radioiodine uptake. METHODS: This was a retrospective study comparing success rates using a dosimetry protocol targeting an absorbed dose of 150 Gy for Graves' disease (GD) and 125 Gy for Toxic Multinodular Goiter (TMNG) with fixed dosing (200MBq for GD and 400MBq for TMNG) among 204 patients with hyperthyroidism. Success was defined as a non-hyperthyroid state at 1 year for both disease states. Results were analysed for disease specific or patient specific modulators of response. RESULTS: This study included 204 patients; 74% (n = 151) received fixed activities and 26% (n = 53) of activities administered were calculated using dosimetry. A dosimetry-based protocol was successful in 80.5% of patients with GD and 100% of patients with TMNG. Differences in success rates and median activity administered between the fixed (204Mbq) and dosimetry (246MBq) cohort were not statistically significant (p = .64) however 44% of patients with GD and 70% of patients with TMNG received lower activities following treatment with dosimetry as opposed to fixed activities. Use of dosimetry resulted in successful treatment and reduced RAI exposure for 36% of patients with GD, 70% of patients with TMNG, and 44% of patients overall. CONCLUSION: This retrospective clinical study demonstrated that treatment with a dosimetry-based protocol for TMNG and GD achieved comparable success rates to fixed protocols while reducing RAI exposure for over a third of patients with GD and most patients with TMNG. This study also highlighted that RAI can successfully treat hyperthyroidism for some patients with activities lower than commonplace in clinical practise. No patient or disease specific modulators of treatment response were established in this study; however, the data supports a future prospective trial which further scrutinises the individual patient factors governing treatment response to RAI.

Uncommon diagnosis of multinodular goiter - isolated extrapulmonary manifestation of sarcoidosis in thyroid gland (scientific case reports).

AIM: By means of the scientific description of two uncommon cases who underwent. surgical resection of multinodous goiter and following histopathological investigation revealing isolated extrapulmonary manifestation of sarcoidosis, this uncommon diagnosis including symptomatology, clinical findings, diagnostic and therapeutic management is to be illustrated. CASE DESCRIPTIONS: Diagnostics: Scintigraphy of the thyroid gland with a left-thyroid cold node; ultrasound-guided puncture (cytological investigation, non-suspicious). THERAPY: Elective thyroidectomy with no macroscopic anomalies und no abnormal aspects with regard to surgical tactic and technique. Histopathological investigation: Complete resection specimen of the thyroid gland with granulomatous inflammation consistent with sarcoidosis. CLINICAL COURSE: Uneventful with no further manifestations of sarcoidosis in the following diagnostics. DIAGNOSTICS: Ultrasound, inhomogeneous node (37×30×35 mm) of the right thyroideal gland with echo-poor parts and peripheral vascularization; scintigraphy showing marginally compensated unifocal autonomy of the thyroid gland (laboratory parameters, increased serum level of thyroglobulin [632 ng/mL]). THERAPY: Planned right hemithyroidectomy with confirmed nodous structure of thyroid parenchyma, without suspicious lymph nodes. Histopathological investigation: 33-mm follicular, nodular, encapsulated structure of thyroid parenchyma (diagnosed as follicular adenoma); 2nd opinion: low-grade differentiated carcinoma of thyroid gland with angioinfiltrating growth and granulomatous inflammation of sarcoidosis type. Procedural intent: After tumor-board consultation, completing thyroidectomy was performed within a 5-weeks interval (pT2 pN0[0/1] V1 L0 G3 R0) with subsequent ablating radio'active iodine therapy; 18 F-FDG-PET-CT (several atypical infiltrates within the right upper lobe of the lung) and bronchoscopy with no detection of further manifestation of sarcoidosis. CONCLUSION: Sarcoidosis is considered a rare granulomatous multi-locular, systemic disease of not completely known etiopathogenesis with substantial heterogeneity. In most cases, it is associated with the lung, but which can become manifest in various organs. Frequently, extrapulmonary manifestations are usually detected as histological findings by coincidence, which require further investigation to find out additional manifestations as well as to exclude florid infection or other granulomatous processes (clarifying competently differential diagnosis). Therapy is only indicated in symptomatic organ manifestations, taking into account the high rate of spontaneous healing and possible side effects.

Subcutaneous implantation of nodular goiter after transoral endoscopic thyroidectomy vestibular approach: A case study and review of literature.

BACKGROUND: Extrathyroid implantation or dissemination of thyroid tissue secondary to a thyroid procedure is rare. Most of these belonged to thyroid carcinoma with metastatic potential and uncommon for benign pathologies. METHODS: We report the case of a 31-year-old female who was identified to have multiple subcutaneous implantation of thyroid tissue 5 years after transoral endoscopic thyroidectomy vestibular approach. A comprehensive literature search on implantation of thyroid tissue secondary to thyroid procedures was performed. RESULTS: Accidental tearing of the capsule during previous surgery may lead to the subcutaneous implantation. Through literature review, a total 29 articles with 47 patients were identified. 33.3% were benign lesions, and implantation was mostly secondary to fine needle aspiration biopsy (46.5%). CONCLUSIONS: Subcutaneous or port site implantation after endoscopic thyroid surgery may occur in benign thyroid pathologies and therefore, oncologic principles must be strictly followed during surgery regardless of its histopathological nature.

NKX2-1 gene is targeted by H19 lncRNA and is found to be overexpressed in benign nodular goiter tissues.

OBJECTIVE: Nodular goiter may increase the risk of thyroid cancer, but the genetic factors contributing to nodular goiter are not well understood. There is an overexpression of H19 lncRNA in goiter tissue and its target remains unknown. In this study, we attempted to identify a new target for H19 in the context of goiter development. METHODS: Using interaction energy calculations, the interaction between NKX2-1 mRNA and H19 lncRNA was examined. Putative microRNAs were found at the H19 lncRNA target site with the highest affinity for NKX2-1. RNAseq data was analyzed to determine the tissue specificity of gene expression. Samples were taken from 18 goiter and 18 normal tissues during thyroidectomy. The expression of NKX2-1 was determined by RT-qPCR using specific primers. RESULTS: The interaction between NKX2-1 and H19 was characterized by six local base-pairing connections, with a maximum energy of -20.56 kcal/moL. Specifically, the sequence that displayed the highest affinity for binding with H19 overlapped with the binding site of has-miR-1827 to NKX2-1. It was found that NKX2-1 is exclusively co-expressed with H19 in normal thyroid tissue. As compared to adjacent normal tissues, nodular goiter tissues have a significant overexpression of NKX2-1 (relative expression = 1.195, p =  0.038). CONCLUSION: NKX2-1 has been identified as the putative target of H19 lncRNA, which is overexpressed in nodular goiter tissues significantly.

Prevalence of DICER1 variants in large multinodular goiter: thyroid function, clinical and imaging characteristics.

Objective: Mutations in DICER1 are found in differentiated thyroid carcinoma (DTC) and in multinodular goiter (MNG) at a younger age with other tumors, which characterizes DICER1 syndrome. DICER1 is one driver to DTC; however, it is also found in benign nodules. We speculated that patients with mutations in DICER1 may present long-lasting MNG. Our aim was to investigate the frequency of DICER1 variants in patients with MNG. Subjects and methods: Patients who submitted to total thyroidectomy due to large MNG with symptoms were evaluated. DICER1 hotspots were sequenced from thyroid nodule samples. To confirm somatic mutation, DNA from peripheral blood was also analyzed. Results: Among 715 patients, 154 were evaluated with 56.2 ± 12.3 years old (28-79) and the thyroid volume was 115.7 ± 108 mL (16.2-730). We found 11% with six DICER1 variations in a homo or heterozygous state. Only rs12018992 was a somatic DICER1 variant. All remaining variants were synonymous and likely benign, according to the ClinVar database. The rs12018992 was previously described in an adolescent with DTC, measuring 13 mm. There were no significant differences according to gender, familial history of goiter, age, thyroid volume, TSH and TI-RADS classification between DICER1 carriers. Free T4 were lower in patients with DICER1 polymorphisms (13.77 ± 1.8 vs. 15.44 ± 2.4 pmol/L, p = 0.008), regardless of TSH levels. Conclusion: We conclude that germline DICER1 variants can be found in 11% of large goiters but no second-hit somatic mutation was found. DICER1 is one driver to thyroid lesion and a second-hit event seems unnecessary in the MNG development.

Effect of thyroid hormone replacement therapy on mortality rate in patients undergoing total or hemithyroidectomy for benign multinodular goitre.

BACKGROUND: Thyroid surgery for benign non-toxic nodular goitre is a common endocrine surgical procedure. It is not known whether thyroid hormone replacement therapy following surgery for benign thyroid disease influences mortality or morbidity rates. METHODS: A retrospective observational study was conducted using national registries in Sweden. Overall mortality and morbidity rates were compared for patients with or without thyroid hormone replacement therapy in patients operated on with hemithyroidectomy or total thyroidectomy for a diagnosis of benign non-toxic nodular goitre. RESULTS: Between 1 July 2006 and 31 December 2017, 5573 patients were included, 1644 (29.5%) patients were operated on with total thyroidectomy and 3929 patients with hemithyroidectomy. In the hemithyroidectomy group, 1369 (34.8%) patients were prescribed thyroid hormone replacement therapy in the follow-up. The patients who underwent hemithyroidectomy and did not use thyroid hormone replacement therapy in the follow-up had a standard mortality ratio of 1.31 (95% confidence interval, 1.09-1.54). The mortality ratio was not increased in patients who underwent total thyroidectomy or hemithyroidectomy and used thyroid hormone replacement therapy. The risk of death analysed by multivariable Cox regression for patients operated on with hemithyroidectomy without later thyroid hormone replacement therapy, adjusted for age and sex, showed an increased hazard ratio of 1.65 (1.19-2.30) compared with hemithyroidectomy with hormone replacement therapy. CONCLUSION: Patients subjected to hemithyroidectomy without later hormone replacement therapy had a 30% higher risk of death compared with the normal Swedish population and a 65% increased risk of death compared with patients undergoing hemithyroidectomy with postoperative hormone replacement therapy.

Hyperthyroidism.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12-18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

Risk of papillary thyroid carcinoma and nodular goiter associated with exposure to semi-volatile organic compounds: A multi-pollutant assessment based on machine learning algorithms.

BACKGROUND: Exposure to semi-volatile organic compounds (SVOCs) may link to thyroid nodule risk, but studies of mixed-SVOCs exposure effects are lacking. Traditional analytical methods are inadequate for dealing with mixed exposures, while machine learning (ML) seems to be a good way to fill the gaps in the field of environmental epidemiology research. OBJECTIVES: Different ML algorithms were used to explore the relationship between mixed-SVOCs exposure and thyroid nodule. METHODS: A 1:1:1 age- and gender-matched case-control study was conducted in which 96 serum SVOCs were measured in 50 papillary thyroid carcinoma (PTC), 50 nodular goiters (NG), and 50 controls. Different ML techniques such as Random Forest, AdaBoost were selected based on their predictive power, and variables were selected based on their weights in the models. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the mixed effects of the SVOCs exposure on thyroid nodule. RESULTS: Forty-three of 96 SVOCs with detection rate >80 % were included in the analysis. ML algorithms showed a consistent selection of SVOCs associated with thyroid nodule. Fluazifop-butyl and fenpropathrin are positively associated with PTC and NG in single compound models (all P < 0.05). WQS model shows that exposure to mixed-SVOCs was associated with an increased risk of PTC and NG, with the mixture dominated by fenpropathrin, followed by fluazifop-butyl and propham. In the BKMR model, mixtures showed a significant positive association with thyroid nodule risk at high exposure levels, and fluazifop-butyl showed positive effects associated with PTC and NG. CONCLUSION: This study confirms the feasibility of ML methods for variable selection in high-dimensional complex data and showed that mixed exposure to SVOCs was associated with increased risk of PTC and NG. The observed association was primarily driven by fluazifop-butyl and fenpropathrin. The findings warranted further investigation.