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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.

Purpose: Toxic multinodular goiter is a heterogeneous disease associated with hyperthyroidism frequently detected in areas with deficient iodine intake, and functioning and non-functioning nodules, characterized by increased proliferation but opposite functional activity, may coexist in the same gland. To understand the distinct molecular pathology of each entity present in the same gland, the gene expression profile was evaluated by using the Affymetrix technology., Methods: Total RNA was extracted from nodular and healthy tissues of two patients and double-strand cDNA was synthesized. Biotinylated cRNA was obtained and, after chemical fragmentation, was hybridized on U133A and B arrays. Each array was stained and the acquired images were analyzed to obtain the expression levels of the transcripts. Both functioning and non-functioning nodules were compared versus healthy tissue of the corresponding patient., Results: About 16% of genes were modulated in functioning nodules, while in non-functioning nodules only 9% of genes were modulated with respect to the healthy tissue. In functioning nodules of both patients and up-regulation of cyclin D1 and cyclin-dependent kinase inhibitor 1 was observed, suggesting the presence of a possible feedback control of proliferation. Complement components C1s, C7 and C3 were down-regulated in both types of nodules, suggesting a silencing of the innate immune response. Cellular fibronectin precursor was up-regulated in both functioning nodules suggesting a possible increase of endothelial cells. Finally, Frizzled-1 was down-regulated only in functioning nodules, suggesting a role of Wnt signaling pathway in the proliferation and differentiation of these tumors. None of the thyroid-specific gene was deregulated in microarray analysis., Conclusion: In conclusion, the main finding from our data is a similar modulation for both kinds of nodules in genes possibly implicated in thyroid growth., (© 2021. The Author(s).)

Objective: To examine the outcomes of cochlear implantation in children with Pendred Syndrome., Material and Methods: A retrospective case series of nine pediatric patients with Pendred syndrome undergoing cochlear implantation at a tertiary academic medical center from 2003 to 2017., Results: All patients were diagnosed with bilateral mild-to-profound to severe-to-profound sensorineural hearing loss and used hearing aids prior to implantation. Preoperative imaging results revealed that all patients exhibited bilateral enlarged vestibular aqueducts and 8 of 9 had cochlear dysplasia equivalent to Incomplete Partition II. Despite inner ear malformations, all electrodes were successfully implanted with minimal complications and favorable post-operative audiological outcomes., Conclusions: Cochlear implantation is an effective and successful treatment for severe-to-profound hearing loss in children with Pendred syndrome and for whom traditional amplification aids provide limited benefit. With early intervention, cochlear implantation allows speech and cognitive development in Pendred children comparable to that of normal hearing individuals, allowing patients to learn in a mainstream educational setting., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Reliable cut-offs for basal (bCT) and calcium stimulated calcitonin (casCT) are needed for an early and accurate diagnosis of medullary thyroid cancer (MTC)., Patients and Methods: Fifty-four new patients with nodular goiter were enrolled and analysed together with those previously published by our group for a total of 135 cases. bCT and casCT were measured by a highly sensitive method and the results compared with histological findings. In a subgroup of patients, cardiac rhythm was recorded before and during the calcium test., Results: In both females (F) and males (M), there was a significant correlation between tumor size and bCT levels (P < 0.001). The receiver operating characteristic plot analyses showed that, for bCT, the new cut-off points able to separate non-MTC from MTC patients were > 30 (F) and > 34 pg/mL (M), whereas the best casCT thresholds were > 79 (F) and > 466 pg/mL (M). bCT was shown to harbour a high accuracy, though some cases were diagnosed only upon stimulation test. Importantly, combining bCT, below or above the cut-offs, with casCT above the cut-offs, all the MTC cases were correctly identified. A reversible sinus bradycardia was observed in 9% of cases during the test., Conclusions: Refined cut-offs for bCT and casCT in patients with nodular goiter are reported. Sensitive bCT was shown to have a high accuracy, but the combination with casCT data was needed to identify all MTC cases. The reliability and safety of calcium test strongly favour the routine use of CT determination in nodular thyroid disease.

Objective: Acromegaly is characterized by high neoplastic morbidity as a side effect of growth hormone (GH) hypersecretion. Increased incidence of goiter, thyroid carcinoma, and thyroid dysfunction is also reported. The aim of the present study was to find the prevalence of thyroid dysfunction and goiter in patients with acromegaly and determine its relationship to disease activity, disease duration, and the presence of secondary hypothyroidism., Subjects and Methods: In a cross-sectional study of the period 2008-2012 were included 146 patients with acromegaly (56 men, 90 women) of mean age 50.3 ± 12.4 years. Acromegaly disease activity and thyroid function were evaluated in all patients. Thyroid ultrasonography was performed to calculate thyroid volume and detect the presence of nodular goiter., Results: Ninety-one patients were determined to have an active disease, and 55, a controlled disease. The mean thyroid volume in patients without previous thyroid surgery was 37.6 ± 38.8 mL. According to disease activity, thyroid volume was significantly higher in patients with active disease (38.5 ± 45.4 mL vs. 27.2 ± 18.4 mL, p = 0.036). A weak positive correlation was found between thyroid volume and insulin-like growth factor 1 (IGF-1) in the whole group and in females (R = 0.218; p = 0.013, and R = 0.238; p = 0.037, respectively). There was no significant correlation of thyroid volume with disease duration and GH level in the whole group and in both sexes. The patients with secondary hypothyroidism had twofold smaller thyroid volume, relative to the rest of the group. The prevalence of thyroid dysfunction was 39%, with a female to male percentage ratio of 1.73. Goiter was diagnosed in 87% of patients, including diffuse goiter (17.1%) and nodular (69.9%), with no significant difference between patients with active and controlled disease or the presence of secondary hypothyroidism., Conclusions: Thyroid volume in patients with acromegaly depends on disease activity and the presence of secondary hypothyroidism as a complication. The increased prevalence of nodular goiter determines the need of regular ultrasound thyroid evaluation in the follow-up of patients with acromegaly. Arch Endocrinol Metab. 2020;64(3):269-75.

Thyroid hormones have a specific effect on glucose-induced insulin secretion from the pancreas. We aimed to investigate the association between euthyroid hormones and islet beta-cell function in general population and non-treated type 2 diabetes mellitus (T2DM) patients. A total of 5089 euthyroid participants (including 4601 general population and 488 non-treated T2DM patients) were identified from a cross-sectional survey on the prevalence of metabolic diseases and risk factors in East China from February 2014 to June 2016. Anthropometric indices, biochemical parameters, and thyroid hormones were measured. Compared with general population, non-treated T2DM patients exhibited higher total thyroxine (TT4) and free thyroxine (FT4) levels but lower ratio of free triiodothyronine (T3):T4 (P<0.01). HOMA-β had prominently negative correlation with FT4 and positive relationship with free T3:T4 in both groups even after adjusting for age, body mass index (BMI) and smoking. When analyzed by quartiles of FT4 or free T3:T4, there were significantly decreased trend of HOMA-β going with the higher FT4 and lower free T3:T4 in both groups. Linear regression analysis showed that FT4 but not FT3 and free T3:T4 was negatively associated with HOMA-β no matter in general population or T2DM patients, which was independent of age, BMI, smoking, hypertension and lipid profiles. FT4 is independently and negatively associated with islet beta-cell function in euthyroid subjects. Thyroid hormone even in reference range could play an important role in the function of pancreatic islets.

Objective: Study the nature of structural and functional changes in the thyroid gland in patients with malignant tumors of the mammary glands that have suffered from the Chornobyl accident., Materials and Methods: Examination of 80 patients with malignant tumors of the mammary glands at the age of 27-85 years. In 78 patients were diagnosed with breast cancer with different stages of the spread of the tumor process. The participants in the aftermath of the accident were 12 people, living in radioactive contaminated areas - 68. Mammography was performed with the help of mammographs Senographe 700 T and 800 Tsm. Echo- graphic study of the structure of the mammary gland and the thyroid gland was performed on the ultrasound devices Nemio XG SSA-580. Computed tomography was performed on a multi-detector computed tomography 64 КТ «LightSpeed VCT». MRI was performed on a magnetic resonance imager «Magnetom Vision Plus 1,5 T». For trepan biopsies, special needles were used in combination with a biopsy system gun «Magnum». The functional state of the thyroid gland was studied by studying the level of the thyroid hormone in peripheral venous blood., Results: The results of the ultrasound study on the structural changes in the thyroid gland (TG) and markers that characterize the functional state of the TG in women with breast cancer, show that 60 out of 80 patients who asked for help with various forms of breast cancer and examined in the clinic, revealed the presence of structural changes in the thyroid gland, which is 75 %.Сonclusions. Structural changes in the thyroid gland in patients with breast cancer, who are considered victims of the Chornobyl Nuclear Power Plant accident, were diagnosed in 75 %, of which 71.25 % of patients did not know about the presence of pathological changes in the thyroid gland before the examination in the clinic. In the struc- ture of the identified pathological changes in the thyroid gland, 47.5 % accounted for the nodular goiter, 10 % for small hydrophilic and small fibrous areas, 3.75 % for previously undergone surgery for thyroid removal, 3.75 % for chronic thyroiditis, 7.5 % - CAIT, 2.5 % - cystic changes in the thyroid gland, 3.75 % - nodular goiter and CAIT., (D. A. Basyka, O. O. Lytvynenko, S. G. Bugaicov, G. F. Shakhrai, I. I. Daniluk.)

The aim of this study was to determine the association between thyroid-stimulating hormone (TSH) level and pregnancy outcomes in euthyroid women undergoing in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI). A total of 1185 women were enrolled in the retrospective study, and 12 studies with a total of 6624 women were included in the meta-analysis (including the data of the present retrospective study). Participants in the retrospective study were divided into two groups in terms of their serum TSH levels: TSH ≤2.5 mIU/L group (n=830) and TSH >2.5 mIU/L group (n=355). They were monitored for the status of clinical pregnancy or miscarriage. In the TSH ≤2.5 mIU/L group, 441 (53.1%) women achieved clinical pregnancy, while 48 (5.8%) had early pregnancy loss and 12 (1.4%) had ectopic pregnancy. In the TSH >2.5 mIU/L group, 175 (49.3%) women achieved clinical pregnancy, while 21 (5.9%) had early pregnancy loss and 3 (0.8%) had ectopic pregnancy. No significant differences were observed between the two groups in pregnancy outcomes (P=0.126, P=0.512, P=0.297). The meta-analysis also revealed no significant difference in the clinical pregnancy rate and the miscarriage rate between women with serum TSH ≤2.5 mIU/L and those with serum TSH >2.5 mIU/L. In conclusion, high TSH levels (TSH level >2.5 mIU/L) did not affect clinical pregnancy rate or increase miscarriage rate in euthyroid women undergoing IVF/ICSI.

SLC26A4 gene mutations lead to Pendred syndrome and non-syndromic hearing loss (DFNB4). The mouse model is well used to study the pathology of Pendred syndrome, however, mice with different Slc26a4 mutations exhibit different phenotypes, and these mice have severe deafness and inner ear malformations that are not imitated less severely Human phenotype. In this study, we generated a knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation to mimic the most common mutation found in human. Some L236P mice were observed to have significant vestibular dysfunction including torticollis and circling, the giant otoconia and destruction of the otoconial membrane was observed in L236P mice. Unlike other profoundly deafness in Slc26a4 mouse model, L236P mice present mild to profound hearing loss, consistent with the hearing threshold, inner ear hair cells also lost from slight to significant. Together, these data demonstrate that the L236P mouse phenotype is more similar to the human phenotype and should be used as a tool for further research into the human Pendred syndrome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Publications suggesting that thyroid nodule might be associated with insulin resistance and metabolic syndrome are quite interesting. There is a need for studies assessing the relationship between nodule presence and cardiovascular risk in individuals with non-functioning nodular goiter. The purpose of the present study is to reveal whether or not insulin resistance, nodule presence, and nodule stiffness affect arterial stiffness, which is a reliable and valid cardiovascular risk indicator, in individuals with euthyroid nodular goiter using the pulse wave analysis (PWA)., Materials and Methods: 50 patients with euthyroid nodular goiter and 50 healthy volunteers were included in the study. All participants were examined by B-mode thyroid ultrasound, and the participants in the nodular goiter group were also examined by strain elastography (SE). The strain index of nodules was calculated according to the Rago scoring. Also, fasting plasma glucose (FPG) and insulin levels were measured, and HOMA-IR. Arterial stiffness measurements of the participants were performed using a PWA device which employs a cuff-based oscillometric method from the brachial artery., Results: PWV was found to be significantly higher in the euthyroid nodular goiter group (p < 0.001). PWV was found to be positively correlated with FPG and waist circumference. Fasting plasma glucose was found to be higher in the group with nodular goiter (p = 0.03). However, no difference was found between the groups in terms of HOMA-IR and insulin level. HOMA-IR was not correlated with thyroid volume, nodule volume, and nodule count. Also, HOMA-IR was not correlated with strain index value and PWA data., Conclusion: We found that PWV was significantly higher in patients with euthyroid nodular goiter. This result suggests that these patients may be at risk for cardiovascular disease.

Objective The study's objective was to evaluate the thyroid parameters in obese insulin-resistant patients with euthyroid diffuse or nodular goiter, following Metformin treatment. Patients and methods The study was experimental, open, and prospective. Fifty-three patients aged 18-68 were enrolled for two years. Obese insulin-resistant patients (cut-off Homeostasis-Model-Assessment of Insulin Resistance-HOMA-IR ≥ 2.5) with euthyroid nodular/diffuse goiter were included. Subjects with diabetes, hypo-/hyper-thyroidism, autoimmune thyroiditis, psychiatric disorders, liver or heart failure were excluded. Patients were randomly assigned to one of the following treatment: Metformin 1000 mg/day + Levothyroxine 25 μg/day (M + LT4 group) and only Levothyroxine 25 μg/day (LT4 group). Thyroid and metabolic parameters' evolution was investigated over six months. Results The two groups were comparable at baseline (p ≥ 0.10). TSH, waist/hip ratio (WHR), visceral fat thickness (VFT), insulin, and HOMA-IR decreased significantly more in M + LT4 group compared to LT4 group. TSH decrease correlated with WHR reduction (p = 0.002) only in M + LT4 group. Moreover, the multivariate regression analysis revealed that insulin's and HOMA-IR levels' decrease was an independent factor associated with FT4's increase (p = 0.031, p = 0.033) just in M + LT4 group. No other independent association between the evolution (Δ) of TSH, thyroid volume (TTV), thyroid nodules-maximum diameter (TN-MD), and metabolic parameters was found. In addition, no significant threshold between groups was reached when ΔFT4, ΔTTV, ΔTN-MD were compared (p > 0.07), although their significant improvement was recorded between the baseline and the follow-up moment in each group (p < 0.003). Conclusion Metformin added to obese insulin-resistant patients treated with Levothyroxine for diffuse/nodular goiter determined a significant decrease in TSH and metabolic parameters, compared to those treated with Levothyroxine alone, but no significant difference regarding thyroid morphology after 6 months.

Introduction: Swallowing difficulties, the pathophysiology behind which is incompletely understood, have been reported in 47-83% of goiter patients referred for thyroidectomy. We aimed at examining the influence of thyroid surgery on swallowing symptoms and esophageal motility., Methods: Thirty-three patients with benign nodular goiter undergoing thyroid surgery were included. All completed high-resolution esophageal manometry examinations and the goiter symptom scale score, assessed by the thyroid-specific patient-reported outcome measure. The evaluations were performed before and 6 months after surgery., Results: Before surgery, the goiter symptom score was median 39 points (range 2-61), which improved to median five points (range 1-52) after surgery (p < 0.001). The motility parameters were within the limits of normal swallowing physiology, both before and after surgery. Only the upper esophageal sphincter (UES) pressure increased significantly from 70.6 ± 27.7 to 87.7 ± 43.2 mmHg after surgery (p = 0.04). Using regression analyses, there was no significant correlation between change in goiter symptoms and weight of the removed goiter, motility parameters, or motility disturbances. However, patients undergoing total thyroidectomy experienced a larger reduction in pressure in the area of the UES and former thyroid gland after surgery in comparison with patients undergoing less extensive surgery., Conclusions: Goiter symptoms improved significantly after thyroidectomy, but without correlation to esophageal motility disturbances. This information is essential when interpreting dysphagia in patients with nodular goiter, and when balancing patients' expectations to surgical goiter therapy., Registration Number: NCT03100357 ( www.clinicaltrials.org ).

Pendred syndrome is an autosomal recessive disorder that is classically defined by the combination of sensorineural deafness/hearing impairment, goiter, and an abnormal organification of iodide with or without hypothyroidism. The hallmark of the syndrome is the impaired hearing, which is associated with inner ear malformations such as an enlarged vestibular aqueduct (EVA). The thyroid phenotype is variable and may be modified by the nutritional iodine intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes the multifunctional anion exchanger pendrin. Pendrin has affinity for chloride, iodide, and bicarbonate, among other anions. In the inner ear, pendrin functions as a chloride/bicarbonate exchanger that is essential for maintaining the composition and the potential of the endolymph. In the thyroid, pendrin is expressed at the apical membrane of thyroid cells facing the follicular lumen. Functional studies have demonstrated that pendrin can mediate iodide efflux in heterologous cells. This, together with the thyroid phenotype observed in humans (goiter, impaired iodine organification) suggests that pendrin could be involved in iodide efflux into the lumen, one of the steps required for thyroid hormone synthesis. Iodide efflux can, however, also occur in the absence of pendrin suggesting that other exchangers or channels are involved. It has been suggested that Anoctamin 1 (ANO1/TMEM16A), a calcium-activated anion channel, which is also expressed at the apical membrane of thyrocytes, could participate in mediating apical efflux. In the kidney, pendrin is involved in bicarbonate secretion and chloride reabsorption. While there is no renal phenotype under basal conditions, severe metabolic alkalosis has been reported in Pendred syndrome patients exposed to an increased alkali load. This review provides an overview on the clinical spectrum of Pendred syndrome, the functional data on pendrin with a focus on its potential role in the thyroid, as well as the controversy surrounding the relative physiological roles of pendrin and anoctamin., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: To reduce intraoperative and postoperative complications, using Lugol solution to preoperatively prepare patients with Graves' disease has (1) rapidly reduced the severity of thyrotoxicosis and (2) reduced the vascularity of the thyroid gland. The vascularity reduction normally accompanies reducing the severity of thyrotoxicosis. However, the effects and mechanism of Lugol solution for reducing blood flow have not been well investigated in the patients with euthyroid (normally functioning thyroid) Graves' disease., Methods: Twenty-five patients with euthyroid Graves' disease being preoperatively treated with Lugol solution for 10 days were measured, at baseline and on the operative day, for (1) superior thyroid artery blood flow; (2) systemic angiogenic factor (VEGF); and (3) systemic inflammatory factor [interleukin (IL)-16]., Results: All three parameters were significantly (p < 0.0001) lower after 10 days of Lugol solution treatment. The average reductions were blood flow: 60% (0.294 vs. 0.117 L/min), serum VEGF: 55% (169.8 vs. 76.7 pg/mL), and serum IL-16: 50% (427.2 vs. 214.2; pg/mL)., Conclusion: Lugol solution significantly reduced thyroid arterial blood flow, VEGF, and IL-16, even in patients with euthyroid Graves' disease. We recommend routine preoperative Lugol solution treatment for all patients with Graves' disease.

Background: Thymosin beta 10 (TMSB10) has recently been recognized as being an important player in the metastatic cascade including tumor angiogenesis, invasion, and metastasis. However, a role for this protein in papillary thyroid carcinoma (PTC) has not yet been established., Methods: Real-time polymerase chain reaction was used to examine the expression of TMSB10 messenger RNA in 36 cases of thyroid tissue samples: normal thyroid, PTC without lymph node metastases (LNM) and PTC with LNM (n = 12 cases in each subgroup). For immunohistochemistry, 130 patients with PTC were selected during the period of 2004-2005, 91 with and 39 without LNM. Statistical analysis was applied to evaluate the correlation between TMSB10 expression and LNM of PTC., Results: By real-time polymerase chain reaction analysis, the expression of TMSB10 messenger RNA in normal thyroid tissue, PTC without LNM, and PTC with LNM tissue were significantly different (P < 0.0001). On immunohistochemistry analysis of 130 patients with PTC, in which 91 cases had cervical LNM and 69 cases had central neck LNM, high expression levels for TMSB10 were more common in patients with cervical LNM compared with patients without (81% versus 33%, P < 0.001). Similarly, high expression levels of TMSB10 were more common in patients with central neck LNM compared with those without (87.0% versus 44.3%, P < 0.001)., Conclusions: High expression levels of TMSB10 correlated with LNM in PTC, especially in the central neck region. Patients with PTC with low levels of TMSB10 expression may be unlikely to have central neck LNM and could therefore avoid prophylactic central neck dissection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Anaplastic thyroid carcinoma (ATC) and primary thyroid lymphoma (PTL) are uncommon tumors of the thyroid gland with several overlapping clinical and pathologic features that may render their differentiation difficult in fine-needle aspiration (FNA) cytology. MicroRNA (miRNA) signatures have been recently reported as useful diagnostic tools applied to cytology specimens., Methods: Smears of 23 ATCs, 14 PTLs, and 20 non-neoplastic materials with multinodular goiter (MNG) were retrieved and classified based on their cytologic features and flow cytometric profiles. The ATC-related expression of hsa-miR-26a, hsa-miR-146b, hsa-miR-221, and hsa-miR-222 was quantified using quantitative reverse transcriptase-polymerase chain reaction analysis., Results: All miRNAs were remarkably up-regulated in ATC samples compared with PTL samples (P < .01). Moreover, expression levels of hsa-miR-146b, hsa-miR-221, and hsa-miR-222 were significantly higher in ATCs than in MNG samples (P < .01). Significant down-regulation of hsa-miR-26a was observed in PTLs compared with MNG samples, whereas hsa-miR-146b was overexpressed. Receiver operating characteristic analysis was used to determine the optimal cutoff for distinguishing ATC from PTL. The estimated receiver operating characteristic thresholds displayed a sensitivity level greater than 0.80 in achieving a diagnosis of PTL, allowing the correct identification of 13 of 14 PTL samples (93%)., Conclusions: Histotype-specific miRNA signatures can provide new insight into the molecular mechanisms of thyroid carcinogenesis. The tested 4-miRNA signature is a promising diagnostic tool for differentiating ATC from PTL and non-neoplastic MNG, even in the presence of scant material obtained from minimally invasive procedures., (© 2013 American Cancer Society.)

Objective: To present a case of dysphagia secondary to a progressively increasing nontoxic multinodular goiter caused by sarcoidosis., Methods: We summarize the clinical presentation and pertinent pathology in a patient with sarcoidosis involving the thyroid gland. A review of literature regarding this topic is also presented., Results: A 54-year-old man was noted to have asymptomatic nontoxic thyromegaly. Biopsy of right thyroid nodule was benign while the biopsy from the isthmus nodule was nondiagnostic. He presented with acute onset of dysphagia two months later and the work-up for gastrointestinal causes was negative. Chest imaging showed left-sided lymphadenopathy, and biopsy of a lymph node showed sarcoidosis. Two years after the initial presentation a repeat biopsy of the isthmus nodule was again reported as nondiagnostic. Because he had persistent dysphagia, he underwent total thyroidectomy with resolution of dysphagia. Histopathological examination of the thyroid revealed non necrotizing granulomas consistent with sarcoidosis., Conclusion: This case brings to light this uncommon etiology of a nontoxic multinodular goiter. Involvement of the thyroid gland by sarcoidosis is very rare. It has been reported in 4.2 to 4.6% of patients with sarcoidosis. In patients with pulmonary or extrapulmonary sarcoidosis and associated thyromegaly, possible involvement of the thyroid by this process should be considered.

Objective: In the last 6 years, several studies reported a positive association between thyrotropin (TSH) and papillary cancer risk. The rationale is based on stimulatory action exerted by TSH on thyroid cell proliferation and/or progression of a pre-existing papillary carcinoma. To validate this hypothesis, we performed a meta-analysis comparing the incidence of thyroid cancer in 2 groups of patients who underwent surgery for toxic or nontoxic nodular goiter., Methods: Using data from 2,150 patients with toxic multinodular goiter (TMNG) and 873 patients with toxic adenoma (TA), the overall incidence of thyroid cancer (and 95% confidence interval [CIs]) was estimated to be 5.9% (3.9 to 8.3) for patients with TMNG and 4.8% (2.5 to 7.9) for patients with TA. Four studies were included in the meta-analysis with a total of 1,964 subjects undergoing thyroidectomy for allegedly benign thyroid disease (520 patients with TMNG or TA and 1,444 for multinodular goiter [MNG] or uninodular goiter [UNG])., Results: We did not find any significant differences in the risk of incidental thyroid cancer (ITC) in patients with TMNG versus MNG (odds ratio [OR]: 0.91, 95% CI: 0.47 to 1.77, I²: 62.6%), TA versus uninodular goiter (UNG) (OR: 0.46, 95% CI: 0.12 to 1.79, I²: 12%), and TMNG or TA versus MNG or UNG (pooled analysis) (OR: 0.86, 95% CI: 0.46 to 1.60, I²: 51.5%)., Conclusions: The results of this meta-analysis did not confirm an association between low TSH values and lower thyroid cancer rate, at least in patients with nodular disease.

Objective: To detect genetic cause of two Chinese siblings (patient 1 and 2) with Pendred syndrome., Design: Patients and their parents underwent clinical and genetic evaluations. To identify genetic mutations, sequencing of SLC26A4 was carried out., Study Sample: Two siblings and their parents., Results: Clinical evaluations showed that patient 1 suffered from bilateral postlingual progressive sensorineural hearing loss with enlarged vestibular aqueduct and slight diffuse multinodular goiter with euthyroid, and patient 2 suffered from bilateral prelingual progressive sensorineural hearing loss with enlarged vestibular aqueduct and no goiter with euthyroid. Furthermore, the sequence analysis of SLC26A4 indicated that either of the two siblings presented a compound heterozygote for the c.919A>G mutation in the splice site of intron 7 and for the c.1548insC mutation in exon 14. Their mother was a heterozygous carrier of the splice site mutation in intron 7, and their father was a heterozygous carrier of the insertion mutation in exon 14., Conclusions: Mutation analysis identified a compound heterozygous mutation (c.919A>G/c.1548insC) in SLC26A4 in two Chinese siblings with Pendred syndrome. Also, c.1548insC was first reported in the Chinese population. Although the two siblings from the same family carried the same genotype, they presented different phenotypes.

Aim: This study has been performed on a Turkish population with multinodular goiter (MNG) to investigate the thyroid-stimulating hormone receptor (TSHR) gene D727E and P52T polymorphisms., Methods: DNA samples were isolated from 300 patients with MNG and 142 controls. Polymerase chain reaction-restriction fragment length polymorphism and agarose gel electrophoresis were used., Results: The D727E polymorphism G-allele frequency and the CG and GG genotypes were significantly higher in patients with MNG. However, there was no significant difference in the P52T polymorphism between patients and control subjects., Conclusions: As a conclusion, the D727E polymorphism G allele may be related to MNG development in the studied population.

Autonomously functioning thyroid nodules (AFTN) are known to receive an increased blood influx necessary to sustain their high rate of growth and hormone production. Here, we investigated the expression of hematic and lymphatic vases in a series of 20 AFTN compared with the contralateral non-tumor tissues of the same patients, and the transcript levels of proteins involved in the control of vascular proliferation, including the vascular endothelial growth factor (VEGF) and platelet-derived growth factors (PDGF) and their receptors and the endothelial nitric oxide synthase (eNOS). In parallel, the expression of the differentiation markers sodium/iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (Tg), and TSH receptor (TSHR) was also investigated. The data were further analyzed comparing subgroups of tumors with or without mutations in the TSHR gene. Analysis by means of CD31 and D2-40 immunostaining showed in AFTN an increased number of hematic, but not lymphatic, vessels in parallel with an enhanced proliferation rate shown by increased Ki67 staining. Quantitative RT-PCR analysis revealed an increase of VEGF, VEGFR1 and 2, PDGF-A, PDGF-B, and eNOS expression in tumor versus normal tissues. Also, higher transcript levels of NIS, TPO, and Tg were detected. Comparison of the two subgroups of samples revealed only few differences in the expression of the genes examined. In conclusion, these data demonstrate an increased expression of angiogenesis-related factors associated with an enhanced proliferation of hematic, but not lymphatic, vessels in AFTNs. In this context, the presence of TSHR mutations may only slightly influence the expression of pro-angiogenic growth factors.

Objective: The objective of the study was to evaluate the long-term outcome of recombinant human TSH (rhTSH)-augmented radioiodine ((131)I) therapy for benign multinodular nontoxic goiter., Patients and Methods: Between 2002 and 2005, 86 patients with a multinodular nontoxic goiter were treated with (131)I in two randomized, double-blind, placebo-controlled trials. (131)I-therapy was preceded by 0.3 mg rhTSH (n = 42) or placebo (n = 44). In 2009, 80 patients completed a follow-up (FU) visit, including determination of thyroid volume, thyroid function, and patient satisfaction by a visual analog scale., Results: In both groups, thyroid volume was further reduced from 1 yr to final FU (71 months). The mean goiter volume reductions obtained at 1 yr and final FU [59.2 ± 2.4% (sem) and 69.7 ± 3.1%, respectively] in the rhTSH group were significantly greater than those obtained in the (131)I-alone group (43.2 ± 3.7 and 56.2 ± 3.6%, respectively, P = 0.001 and P = 0.006), corresponding to a gain of 24% at final FU. At last FU the mean reduction in compression visual analog scale score was significantly greater in patients receiving rhTSH (P = 0.049). Additional therapy (thyroid surgery or (131)I) was required more often in the placebo group (nine of 44) compared with the rhTSH group (two of 42) (P = 0.05). The prevalence of hypothyroidism at 1 yr [9 and 43% in the placebo and rhTSH groups, respectively (P < 0.0001)] increased to 16 and 52%, respectively, at final FU (P = 0.001)., Conclusion: Enhanced goiter volume reduction with rhTSH-augmented (131)I therapy improves the long-term reduction in goiter-related symptoms and reduces the need for additional therapy compared with plain (131)I therapy. Overall patient satisfaction is benefited, despite a higher rate of permanent hypothyroidism.

Objective: Due to the fact that SLC26A4 has been suggested as the second cause of hearing loss (HL) in Iran as well as many other countries, obtaining more comprehensive information about SLC26A4 mutations can facilitate more efficient genetic services to the patients with hereditary hearing loss. This investigation aims to detect genetic cause of two Iranian families with hearing loss., Methods: In the present study, genetic linkage analysis via 4 short tandem repeat markers linked to SLC26A4 was performed for two consanguineous families originating from Hormozgan and Chaharmahal va Bakhtiari provinces of Iran, co-segregating autosomal recessive hearing loss and showed no GJB2 mutations in our preliminary investigation. For identification of mutations, DNA sequencing of SLC26A4 including all the 21 exons, exon-intron boundaries and the promoter was carried out., Results: The results showed linkage to this gene in both families. After sequencing, two novel SLC26A4 mutations (c.65-66insT in exon 2 and c.2106delG in exon 19) were revealed in the two studied families., Conclusion: Results of this study stress the necessity of considering the analysis of SLC26A4 in molecular diagnosis of deafness especially when phenotypes such as goiter or enlarged vestibular aqueduct are present., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Interleukine-16 (IL-16) and RANTES (regulated upon activation, normal T cell expressed and secreted) are 2 cytokines with the function of T helper cell recruitment, which might play a key role in pathogenesis of autoimmune thyroid diseases (AITD). This study was aimed to evaluate the IL-16 and RANTES in patients with AITD. Serum IL-16 and RANTES levels were measured in patients with Graves' disease (GD; n=45), Hashimoto's thyroiditis (HT; n=68), nontoxic multinodular goiter (NTMNG; n=20), and healthy individuals (n=61). The results showed that serum IL-16 and RANTES levels were elevated both in HT and higher in untreated GD patients when compared to NTMNG patients and the healthy individuals, which were decreased after MMI therapy in untreated GD patients. However, in HT patients, serum IL-16 and RANTES levels were comparable among the conditions of hyperthyroid and euthyroid received by l-thyroxine therapy and untreated hypothyroid. Furthermore, serum IL-16 levels were correlated with FT3, FT4, TRAb in GD, but not in HT patients. The data did not show any correlation between RANTES levels and clinical factors. In conclusion, IL-16 and RANTES might be involved in the pathogenesis of GD and HT, and serum IL-16 levels in GD maybe a potential marker of disease activity and severity., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To systematically evaluate auditory perceptual voice characteristics in people with thyroid disease prior to undergoing thyroid surgery., Patients and Methods: This study examined the auditory perceptual voice characteristics of 96 individuals with thyroid disease. Participants were categorised by type of thyroid disease (i.e. multinodular goitre, thyroid cancer, thyroid nodule, toxicity or parathyroidism) and by status of compression (i.e. compression versus no compression). Auditory perceptual voice ratings were made on samples of connected speech by using the Perceptual Voice Profile., Results: A high prevalence of participants had deviant auditory perceptual voice features; however, the majority of these abnormalities were slight to mild in severity and only 8% of participants had a clinically significant auditory perceptual abnormality. There was no significant difference in features between diagnostic categories, and only high pitch was rated as more significantly deviant in patients without compression versus those with compression., Conclusions: This study supports the need for auditory-perceptual ratings to be included as part of pre-operative multidimensional assessment of voice in patients with thyroid disease., (Copyright © 2012 S. Karger AG, Basel.)

Objective: Autonomously functioning thyroid nodules (AFTNs) associated with Hashimoto's thyroiditis (HT) are rarely reported. This study evaluates the magnitude of such association, elaborating the clinical and biochemical characteristics of HT and AFTN., Materials and Methods: We reviewed the records of our patients with thyroid nodules, including serum TSH, free T4 and T3, Tg-Ab, TPO-Ab, ultrasonography, Tc-99m Sodium Pertechnetate scintigraphy (performed in overt or subclinical hyperthyroid patients). HT patients with coexisting AFTN(s) (group A) were compared with patients with AFTNs alone (group B, n=267)., Results: 80 patients (65 women and 15 men; F:M ratio 4.3:1; age 57±15 years) had AFTN(s) and coexisting HT. Except 9 patients who were under methimazole, all had suppressed (<0.01 mU/L) or low (<0.4 mU/L) TSH; 17/71 (24%) had increased FT4 and/or FT3. Subclinical hyperthyroidism prevailed over frank hyperthyroidism in group A (76 vs. 24%), but not in group B (56 vs. 44%) ( P=0.005). Group A patients had lower serum FT3 (∼0.6 pmol/L or 9%) and FT4 (∼0.9 pmol/L or 4%) as compared to group B. The maximum diameter of the AFTN(s) was 8% smaller in group A as compared with group B, thus matching the said difference in FT3. A positive correlation between nodule size and age was found only in group B ( P=0.015)., Conclusion: Even if difference in the size of nodules between groups A and B does not reach statistical significance, the chronic intrathyroid lymphocytic infiltration of HT may decrease the tendency of the AFTNs to grow and diminish their degree of functioning., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Data on the antioxidant levels enzyme in patients with hyperthyroidism are limited and conflicting. Therefore, the objective of this study was to evaluate the oxidative status using an automated method in patients with hyperthyroidism. Thirty-six subjects with hyperthyroidism and 30 healthy controls were enrolled in this study. Serum oxidative status was determined via measurement of total antioxidant capacity (TAC) and total oxidant status (TOS) and calculation of oxidative stress index (OSI). Serum TAC levels were significantly lower in patients with hyperthyroidism than controls (P=0.002), while serum TOS levels and OSI values were significantly higher (P=0.008, 0.004; respectively). Serum TAC levels were correlated with TSH levels (rho=0.223, P=0.032), FT3 levels (rho=-0.434, P=0.002) and FT4 levels (rho=-0.363, P=0.003) in patients. Further, TOS levels and OSI values were correlated with TSH levels (rho=-0.245, P=0.037; rho=-0.312, P=0.011, respectively), FT3 levels (rho=0.293, P=0.017, rho=0.505, P=0.002, respectively), and FT4 levels (rho=0.302, P=0.006, rho=0.321, P=0.008, respectively) in patients. Duration of disease was significantly correlated with OSI values in patients (rho=0.420, P=0.011), while no correlation with serum TAC levels and TOS levels (P>0.05). Oxidants are increased and antioxidants are decreased in patients with hyperthyroidism; as a result, the oxidative-antioxidative balance is shifted to the oxidative side. Increased oxidative stress may play a role in the pathogenesis of hyperthyroidism. It is believed that supplementation of antioxidant vitamins such as vitamins C and E may be helpful for these patients.

Background: Mutations in the SLC26A4 gene, coding for the anion transporter pendrin, are responsible for Pendred syndrome, characterized by congenital sensorineural deafness and dyshormonogenic goiter. The physiological role of pendrin in the thyroid is still unclear and the lack of a thyroid phenotype in some patients with SLC26A4 mutations and in Slc26a4 (-/-) mice indicate the existence of environmental or individual modifiers able to compensate for pendrin inactivation in the thyroid. Since pendrin can transport iodide in vitro, variations in iodide supply have been claimed to account for the thyroid phenotype associated with pendrin defects., Aim: The Slc26a4 (-/-) mouse model was used to test the hypothesis that iodide supply may influence the penetrance and expressivity of SLC26A4 mutations., Materials and Methods: Slc26a4 (-/-) and (+/+) mice were fed up to 6 months on a standard or low iodine diet and were evaluated for thyroid structural abnormalities or biochemical hypothyroidism., Results: A 27-fold iodide restriction induced similar modifications in thyroid histology, but no differences in thyroid size, T4 or TSH levels were observed between between Slc26a4 (-/-) and (+/+) mice, either in standard conditions and during iodine restriction., Conclusions: Iodide restriction is not able to induce a thyroid phenotype in Slc26a4 (-/-) mice. These experimental data, together with those coming from a review of familial Pendred cases leaving in regions either with low or sufficient iodide supply, support the idea that the expression of thyroid phenotype in Pendred syndrome is more powerfully influenced by individual factors than by dietary iodide.

Pendred syndrome is an autosomal recessive disorder defined by sensorineural deafness, goiter and a partial defect in the organification of iodide. It is caused by biallelic mutations in the SLC26A4 gene, which encodes pendrin, a multifunctional anion exchanger. At the level of the inner ear, pendrin is important for the creation of a normal endolymph composition and the maintenance of the endocochlear potential. In the thyroid, pendrin is expressed at the apical membrane of thyroid follicular cells and it appears to be involved in mediating iodide efflux into the lumen and/or maintenance of the follicular pH. Goiter development and hypothyroidism vary among affected individuals and seem to be partially dependent on nutritional iodide intake. In the kidney, pendrin functions as a chloride/bicarbonate exchanger. Elucidation of the molecular basis of Pendred syndrome and the function of pendrin has provided unexpected novel insights into the pathophysiology of the inner ear, thyroid hormone synthesis, and chloride/bicarbonate exchange in the kidney., (Copyright © 2011. Published by Elsevier Masson SAS.)

Objective: To determine the incidence of hypothyroidism following radioactive iodine (RAI) treatment for hyperthyroidism and to study the relationship between pretreatment RAI uptake and treatment dose and the subsequent development of hypothyroidism., Methods: Retrospective chart review of patients treated with RAI for hyperthyroidism between 1995 and 2000. 180 charts were reviewed; 41 met the inclusion criteria. Data were collected regarding the cause of hyperthyroidism, initial RAI uptake, initial dose of RAI, number of RAI treatments, and post treatment thyroid status., Results: Patients in toxic nodular goiter group had significantly lower 24-hour RAI-123 uptake as compared to those with Graves' disease. However patients with Graves' disease received significantly lower RAI dose in comparison to those with toxic nodular goiters. Cure rates following RAI administration were similar in both groups. 70% of patients with Graves' disease developed post-ablative hypothyroidism as compared to 42% in toxic nodular goiter group (p = 0.086). There was no relationship between the dose of RAI or pretreatment RAI uptake and the likelihood of developing hypothyroidism., Conclusion: We found that, within our study population, post-ablative hypothyroidism tended to be more prevalent in patients with Graves' disease as compared to those with toxic nodular goiter. However cure rates following RAI administration were similar in both groups. We also found that neither the magnitude of the administered RAI dose nor the pre-treatment RAI uptake predicted the development of subsequent hypothyroidism.

Background: Specific criteria are used to diagnose thyroid neoplasms; however, the distinction between certain neoplasms, such as follicular adenoma and carcinoma, could be difficult. Thus, additional diagnostic features that can assist in this distinction would have great clinical usefulness., Aims: To evaluate the role of the proliferative marker Ki-67 in nonneoplastic and neoplastic lesions of the thyroid, with a special emphasis on the distinction between follicular adenoma and follicular carcinoma., Settings and Design: A retrospective study from a tertiary care center., Materials and Methods: One hundred cases of thyroid lesions, including 50 nonneoplastic and 50 neoplastic lesions, were retrieved from the archives of the Department of Pathology, Pt. BD Sharma PGIMS, Rohtak, Ki-67 immunostaining was performed by peroxidase-antiperoxidase method and compared with mitotic counts., Results: Ki-67 labeling index (LI) showed a progressive rise from multinodular goiter to benign to malignant neoplasms. A statistically significant difference was observed in Ki-67 counts between multinodular goiter vs papillary carcinoma (P < 0.05) and follicular adenoma vs follicular carcinoma (P < 0.05). The correlation between mitotic counts and Ki-67 LI was found to be significant., Conclusions: In the present study, Ki-67 was found to be useful in differentiating between follicular adenoma and follicular carcinoma, but since the sample size of our study was small, larger studies are needed to confirm this observation as well as to assign a cutoff value for differentiating benign from malignant tumors.

Background: The aim of this study was to measure maximum P wave duration (Pmax) and P wave dispersion (PWD), which can be indicators for the risk of paroxysmal atrial fibrillation when increased, and to reveal their relationship with thyroid hormone levels in patients with endogenous and exogenous subclinical hyperthyroidism., Methods: Seventy-one patients with sublinical thyrotoxicosis (34 endogenous, 37 exogenous) and 69 healthy individuals were enrolled in the study. Pmax and minimum P wave duration (Pmin) on electrocardiogram recordings were measured and PWD was calculated as Pmax-Pmin., Results: Pmax (p<0.001) and PWD (p<0.001) values were significantly higher in patients with endogenous subclinical hyperthyroidism compared with the control group. Pmax (p<0.001) and PWD (p<0.001) values were significantly higher in patients with exogenous subclinical thyrotoxicosis compared with the control group. Pmax (p=0.710) and PWD (p=0.127) were not significantly different in patients with endogenous subclinical hyperthyroidism compared with exogenous subclinical hyperthyroid patients. Pmax and PWD negatively associated with TSH in endogenous and exogenous subclinical hyperthyroidism., Conclusion: In the present study, we observed that Pmax and PWD were longer in patients with endogenous and exogenous subclinical hyperthyroidism. Lack of a difference in Pmax and PWD between patients with endogenous and exogenous subclinical hyperthyroidism seems to support the idea that hormone levels rather than the etiology of thyrotoxicosis affect the heart.

The fundamental role of the thyroid gland is to ensure the biosynthesis of thyroid hormones whose primary role during embryonic development and the maintenance of homeostasis after birth is well known. The challenge here is double, as the hormone synthesis depends on both potentially toxic biochemical processes, as long as they are not fully contained, and the availability of a trace element, iodine, whose uptake may be extremely variable depending on the geographical location and the physiological status of individuals. The squaring of the circle has been resolved by the thyroid gland during its phylogenetic maturation by setting up angiofollicular units, morphological entities whose the perfect functional coherence between the different compartments within them (epithelial, endothelial and interstitial) results from a high level three-dimensional assemblage. This morphological and functional integration warrants adequate supplies of thyroid hormones whose mobilization must be triggered at any time when necessary. This functional requirement finds its expression in the morphological heterogeneity that ultimately culminates in the formation of nodules. Each angiofollicular unit is an individualized entity with its own genotypic and phenotypic asset that runs on the extrinsic control of TSH and a host of autocrine and paracrine factors. But subtle intrinsic mechanisms of self-regulation, operating out of any outside influences, constantly adjust the availability of players involved in the hormonal synthesis (iodine, thyroglobulin) within a biochemical entity (the thyroxisome) that is perfectly suited for this synthesis taking place without prejudice to the thyrocyte. The hormonal synthesis generates oxygen-derived substances as oxidative load or stress, though perfectly controlled in healthy thyrocytes. Any injury related to the nature, the amount, or where in the cell oxygen-derived substances are produced, may lead to morphological and functional breakdowns responsible for various disease processes, including those of autoimmune or even neoplastic nature.

Various abnormalities of coagulation-fibrinolytic system have been reported in patients with thyroid dysfunction. Several studies indicate that coagulation and fibrinolytic system is disturbed in the patients with hyperthyroidism. The levels of plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and tissue factor pathway inhibitor (TFPI) have been very rarely investigated in patients with hyperthyroidism. Therefore, the main purpose of this study was to evaluate the profile of coagulation and fibrinolytic parameters including TAFI and TFPI in patients with hyperthyroidism. We also investigated the relationships between serum thyroid hormones and hemostatic parameters in these patients. Thirty patients with untreated hyperthyroidism and 25 age- and sex-matched healthy controls were included in the study. Factor V (FV), protein C, protein S, TFPI, and TAFI were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with the control subjects, TAFI Ag levels were increased significantly in patients with hyperthyroidism [mean ± SD (ranges)] [177.03 ± 20.37 (131-206%) versus 145.9 ± 23.0 (89-169%)] (P < 0.001), whereas FV [89.8 ± 21.02 (49-124%) versus 116.1 ± 31.4 (56.4-200%)], protein C [72.8 ± 46.22 (2-149%) versus 144.0 ± 26.3 (74-158%)] and protein S [60.06 ± 42.82 (9-156%) versus 151 ± 33 (76-231%)] activities and TFPI Ag levels [69.56 ± 17.63 (39-140 ng/ml) versus 87.5 ± 15.9 (64-121 ng/ml)] were decreased significantly (P < 0.001 for all of them). We did not find a significant difference between Graves' disease and toxic nodular goiter for hemostatic parameters. In patients with Graves' disease, serum-free T₃ levels were inversely correlated with TFPI Ag levels (r: -0.57, P < 0.05). In conclusion, we found some important differences in the hemostatic parameters between the patients with hyperthyroidism and healthy controls. Increased TAFI and decreased FV, protein C, protein S, and TFPI in these patients represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system may contribute to the excess mortality due to cardiovascular disease seen in patients with hyperthyroidism.

Background: Subclinical hyperthyroidism (sHT) affects cardiovascular (CV) morphology and function; whether such changes can impact on sport eligibility is unclear., Aim: This exploratory study evaluated the CV system and sport eligibility in athletes with levothyroxine-induced sHT, in the setting of mandatory pre-participation screening., Subjects and Methods: A full, non-invasive CV screening (history and physical examination, 12-lead ECG, echocardiography, 24-hour Holter ECG, exercise stress test) was performed in two groups of untrained female athletes affected by non-toxic multinodular goiter. One group was taking levothyroxine at mildly suppressive doses (TG) whereas the other was untreated (UG). There was also a group of healthy controls (HC)., Results: In TG the following characteristics were observed: a) a higher resting heart rate (HR; p<0.01 and p<0.05, vs HC and UG respectively), b) a thicker left ventricular posterior wall (p<0.05 vs HC, and p<0.05 vs HC and UG, respectively), c) a higher mean HR during the 24-hour Holter ECG (p<0.01 and p<0.05, vs HC and UG respectively), and d) a lower achieved maximum work load (p<0.05, vs HC). No differences in the prevalence of cardiac arrhythmias among groups were observed. Sport eligibility was granted to all except one subject in the TG., Conclusions: Although some alterations were found in athletes with levothyroxine-induced mild sHT, these are probably of limited clinical relevance and they did not contraindicate sport participation in the majority of cases. Future research to address both health risks and the need for specific evaluations (e.g. free thyroxine, TSH, echocardiography) during the preparticipation screening of athletes with sHT is warranted.

Vascular supply is an obvious requirement for all organs. In addition to oxygen and nutrients, blood flow also transports essential trace elements. Iodine, which is a key element in thyroid hormone synthesis, is one of them. An inverse relationship exists between the expansion of the thyroid microvasculature and the local availability of iodine. This microvascular trace element-dependent regulation is unique and contributes to keep steady the iodide delivery to the thyroid. Signals involved in this regulation, such as VEGF-A, originate from thyrocytes as early TSH-independent responses to iodide scarcity. The question raised in this paper is how thyrocytes, facing an acute drop in intracellular stores of iodine, generate angiogenic signals acting on adjacent capillaries. Using in vitro models of rat and human thyroid cells, we show for the first time that the deficit in iodine is related to the release of VEGF-A via a reactive oxygen species/hypoxia-inducible factor-1-dependent pathway.

Background: Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs., Methods: Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA., Results: All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p < 0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed., Conclusions: RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs, controlling compressive symptoms, and treating thyroid hyperfunction. When performed in experienced medical centers, RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs. It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective.

Background: Hypothyroidism is a risk factor for atherosclerotic cardiovascular disease. This study investigated the effects of L-thyroxine replacement therapy on lipid profile and endothelial function after thyroidectomy in patients with overt transient non-autoimmune hypothyroidism., Methods: Twenty-two patients with non-toxic multinodular goitre treated by total or near-total thyroidectomy and 22 healthy individuals matched for age, sex and body mass index were studied. Lipid profile and endothelial function were determined in each patient at the euthyroid phase before thyroidectomy (stage 1), the hypothyroid phase 3 weeks after surgery (stage 2), and the euthyroid phase 3 months (stage 3) and 6 months (stage 4) after the start of thyroxine treatment., Results: The lipid profile and endothelial function deteriorated between stage 1 and stages 2 and 3. Findings at stage 4 were similar to those at stage 1. There was a positive correlation between serum thyroid-stimulating hormone (TSH) and total cholesterol (r(s) = 0.588, P < 0.001), and a negative correlation between serum TSH and flow-mediated arterial dilatation (r(s) = 0.506, P < 0.001). Total cholesterol and TSH were independent determinants of endothelial function., Conclusion: A 3-week hypothyroid period after thyroidectomy led to a more atherogenic lipid profile and impaired endothelial function that persisted for at least 3 months., (Copyright (c) 2007 British Journal of Surgery Society Ltd.)

CXC chemokine ligand 10 (CXCL10) plays a pivotal role in the self-perpetuation of the inflammatory processes in patients with autoimmune thyroid disease. Treatment with methimazole (MMI) reduces serum CXCL10 in patients with Graves' disease. In isolated human thyrocytes, tumor necrosis factor (TNF)alpha demonstrates a potent synergistic effect on interferon (IFN)gamma-induced CXCL10 secretion. We investigated the mechanism underlying the synergism between IFNgamma and TNFalpha and the effect of MMI on CXCL10 secretion in human thyrocytes. A peroxisome proliferator-activated receptor gamma agonist, rosiglitazone (RGZ), a known inhibitor of T helper 1 (Th1)-mediated responses, was also studied for comparison. Experiments were carried out in human thyrocytes isolated from internodular parenchyma of thyroid tissues derived from patients who had undergone surgery for multinodular goiter. ELISA was used to measure CXCL10 levels in culture supernatant. Flow cytometry was used to assess IFNgamma membrane receptor expression. Specific mRNA analysis was performed by Taqman real-time PCR. Immunofluorescence was performed to detect nuclear translocation of nuclear factor-kappaB (NF-kappaB). In human thyrocytes, the synergistic effect of TNFalpha with IFNgamma on CXCL10 secretion is due to the upregulation of IFNgamma receptor expression. MMI decreased cytokine-induced CXCL10 secretion by reducing TNFalpha-induced upregulation of the IFNgamma receptor. RGZ decreased the cytokine-induced CXCL10 secretion by impairing NF-kappaB translocation, without affecting IFNgamma receptor. MMI and RGZ targeted thyrocytes with the same pharmacological potency, likely acting throughout different mechanisms. Targeting T helper 1-mediated autoimmune thyroid disease with drugs that impair different intracellular pathways could be a novel pharmacological tool.

Aims: To evaluate preoperative and postoperative conjunctival surface changes in multinodular goiter (MNG) patients and to compare their results with healthy control subjects., Methods: Twenty MNG patients who had undergone near total thyroidectomy were evaluated pre- and postoperatively at the end of the 3rd month and the 1st year by performing tear function tests and conjunctival impression cytologic analysis. These results were compared with the results of 15 healthy volunteers., Results: When preoperative and postoperative tear function parameters were compared, the mean Schirmer test value and BUT value were decreased, the mean Rose Bengal staining score was increased during the postoperative period. These differences were statistically significant at the end of the 1st year (p < 0.001). The average goblet cell density of the MNG patients decreased significantly during the postoperative period when compared with the preoperative values (p < 0.001). All these findings of the MNG cases were significantly different from the results of the control group both before and after the operation., Conclusion: Tear function tests and the impression cytology findings of the MNG cases were statistically different from the results of the control group during the pre- and postoperative period. We recommend postoperative follow-up of these patients for ocular surface changes., (Copyright (c) 2007 S. Karger AG, Basel.)

Background: The purpose was to evaluate the thyroid function after subtotal thyroidectomy., Methods: One hundred and nineteen patients operated on for multinodular benign goiter were included in this prospective study. Results of the surgical treatment were evaluated 6 months after operation by thyroid-stimulating hormone (TSH) assay and cervical echography., Results: Thyroid-stimulating hormone levels correlated inversely (r=-0.78) with the thyroid remnant volumes. Forty-seven patients presented with a hypoechoic aspect of the remnant. Isoechoic and hypoechoic remnant volumes were similar; however, 46 of the 47 patients with a hypoechoic remnant (97.9%) had TSH levels higher than 5 mU/l vs. 39 of the 72 patients (54.2%) with an isoechoic aspect. No predictive factor for the occurrence of this hypoechoic feature was found., Conclusions: After sub-total thyroidectomy for benign multinodular goiter, the volume of the remnant is not the only determinant of the occurrence of postoperative hypothyroidism. The appearance of a hypoechoic aspect of the remnant is also a strong predictive factor for such an outcome. In this case the occurrence of hypothyroidism is quite constant whatever the volume of the thyroid remnant. Since this evolution toward a hypoechoic aspect of the remnant is unpredictable, our results are an additional argument in favor of total thyroidectomy for benign multinodular goiter.

Background: Recombinant human (rh) TSH, in doses from 0.01 to 0.9 mg, has been used to augment the effect of radioiodine ((131)I) therapy in patients with a benign nontoxic nodular goiter. Transient thyroid enlargement and thyrotoxicosis may be seen following (131)I therapy., Aim: The aim of the study was to investigate whether rhTSH per se causes goiter enlargement, until now an issue evaluated only in healthy nongoitrous subjects., Methods: In random order, 10 patients with nontoxic nodular goiter [mean 39.8 +/- 20.5 (sd) ml] received either 0.3 mg rhTSH or isotonic saline in a double-blinded crossover design. Thyroid volume (by ultrasound) and function were closely monitored during the following 28 d., Results: Saline injection did not affect thyroid function or size. After rhTSH, median serum TSH increased from baseline 0.97 mU/liter (range 0.39-1.56) to 37.0 mU/liter (range 18.5-55.0) at 24 h (P < 0.01), with a subsequent decline to subnormal levels at d 7. Mean free T(4) and free T(3) increased significantly from baseline to a maximum at 48 h. Twenty-four hours after rhTSH, the mean goiter volume was significantly increased by 9.8 +/- 2.3% (sem) (P = 0.01) and after 48 h by 24.0 +/- 5.1% (P = 0.002). The goiter enlargement had reverted at d 7. Nine patients had symptoms of hyperthyroidism and/or cervical compression after rhTSH, as opposed to one during placebo treatment (P < 0.02)., Conclusions: A transient average goiter enlargement of up to 24% is seen after 0.3 mg rhTSH. This may lead to a significant cervical compression when used for augmentation of (131)I therapy in patients with goiter. The use of lower doses of rhTSH needs to be explored.

Thyroid nodules are common. It would very helpful if genetic markers that can diagnose malignancy from fine needle aspiration samples were available. Few such markers has been thus identified and none are specific. Large panels of potential markers can be screened by microarray technology. Studies done to date have concentrated on single tumor types and thus provide no help in identifying tumor subtype specific markers. To that end we have studied gene profiles of 5 types of benign and malignant thyroid nodular tissue (multinodular goiter, follicular adenoma, papillary and follicular carcinomas). We have identified 195 genes whose differential expression clustered into clinically relevant groups. Twenty-eight genes were selected for further confirmation using real time quantitative polymerase chain reaction. Despite the differences in the microarray panels used, we confirmed the differential regulation of 12 genes previously reported in thyroid cancer, although we found the expression of several genes to be regulated in other histological tumor subtypes than originally described. We found, PCSK2, TRIB1, RAP1 GA1 to be specifically overexpressed in follicular cancer and S100A4 and GK2 in papillary carcinoma. SERP1, RNASE 2 and STATA5 were suppressed in papillary thyroid cancer. We have thus identified new potential markers specific to malignant thyroid tumors. It is apparent that a range of nodular thyroid tissue using large tumor sample numbers is necessary to establish robust markers for malignancy and to categorize tumors on the basis of small tumor samples.

Objective: To examine the natural history of a subnormal serum thyroid-stimulating hormone (TSH) concentration with normal concentrations of both serum free thyroxine (FT4) and free triiodothyronine (FT3) (subclinical hyperthyroidism). PATIENTS, DESIGN, AND MEASUREMENTS: A retrospective analysis was undertaken and yielded 16 ambulatory patients who had presented with subclinical hyperthyroidism and were longitudinally followed with measurements of serum TSH and both FT4 and FT3 for a cumulative follow-up of 11 to 36 months. Seven of the patients had subclinical Graves' hyperthyroidism as judged from the presence of thyroid-stimulating immunoglobulins (TSI) in serum, and 9 had multinodular goiter confirmed with ultrasound and no TSI., Results: In the 7 patients with TSI, serum TSH reverted to normal in 5 patients, with disappearance or decrease of TSI in 4, within 3 to 19 months. In 1 patient, subnormal serum TSH accompanied by both normal FT4 and FT3 has persisted for 15 months, and in a second patient serum TSH reverted to normal within 9 months, but at follow-up 27 months later overt hyperthyroidism had emerged. In the 9 patients with multinodular goiter, subnormal serum TSH accompanied by both normal FT4 and FT3 persisted during cumulative follow-up that ranged from 11 to 36 months., Conclusions: This study suggests that the natural history of subclinical hyperthyroidism is variable, resolving or occasionally evolving in subclinical Graves' disease and persisting unchanged in multinodular goiter.

The purpose of this review is to summarize current knowledge of the etiology of euthyroid and toxic multinodular goiter (MNG) with respect to the epidemiology, clinical characteristics, and molecular pathology. In reconstructing the line of events from early thyroid hyperplasia to MNG we will argue the predominant neoplastic character of nodular structures, the nature of known somatic mutations, and the importance of mutagenesis. Furthermore, we outline direct and indirect consequences of these somatic mutations for thyroid pathophysiology and summarize information concerning a possible genetic background of euthyroid goiter. Finally, we discuss uncertainties and open questions in differential diagnosis and therapy of euthyroid and toxic MNG.

Although cardiovascular manifestations in thyroid disorders are frequently encountered in clinical practice, atrioventricular (AV) conduction disorders, especially in hyperthyroidism, are rare. There are some proposed mechanisms for AV blocks in hyperthyroidism but the exact mechanism is still unknown. The authors report 2 cases with thyroid function disorders and complete AV block, and the electrophysiologic characteristics of these 2 patients, and they review and speculate on similar reported cases.

Feline hyperthyroidism is a common, spontaneous disease in older cats that is similar clinically and histopathologically to human toxic multinodular goiter (TNG). In this study, the functional response of feline normal thyroid (NT) and hyperthyroid (HT) cells grown in monolayer culture to thyrotropin (TSH) was determined. Basal levels of DNA synthesis were similar in NT and HT cells. TSH stimulated concentration-dependent DNA synthesis in NT and HT cells, with maximal stimulation seen at 1 and 10 mU/mL TSH in NT and HT cells, respectively. HT cells had higher basal levels of thyroglobulin (Tg) expression. TSH stimulated Tg expression in NT and HT cells in a concentration-dependent fashion, with maximal activity at 0.5 and 5 mU/mL TSH, respectively. These results demonstrate that NT and HT cells in monolayer culture exhibit growth and functional responses to TSH. HT cells have higher basal Tg expression than NT cells and require higher TSH concentrations to stimulate DNA synthesis and Tg expression, two measures of thyroid cell activation. These data support the idea that feline hyperthyroidism is caused by cell abnormalities, resulting in dysregulated growth and hormone synthesis, and emphasize its importance as an animal model for TNG.