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Purpose In this paper, the members of the Italian Working Group on Minimally-Invasive Treatments of the Thyroid (MITT group) aim to summarize the most relevant information that could be of help to referring physicians and that should be provided to patients when considering the use of MITT for the treatment of benign thyroid nodules. Methods An interdisciplinary board of physicians with specific expertise in the management of thyroid nodules was appointed by the Italian MITT Group. A systematic literature search was performed, and an evidence-based approach was used, including also the knowledge and the practical experience of the panelists to develop the paper. Results The paper provides a list of questions that are frequently asked by patients to operators performing MITT, each with a brief and detailed answer and more relevant literature references to be consulted. Conclusions This paper summarizes the most relevant information to be provided to patients and general practitioners/referring physicians about the use of MITT for the treatment of benign thyroid nodules.

FAM83B has been recently identified as an oncogene, but its role in thyroid cancers (TC) is still unclear. We examined the expression of FAM83B and its possible involvement in cell migration and differentiation, in neoplastic/normal thyroid tissues and in TC human cell lines. FAM83B expression in TC varies according to the tumor histotype, being significantly downregulated in more aggressive and metastatic tissues. FAM83B levels in cell lines recapitulate patients' samples variations, and its total and cytoplasmic levels decrease upon the induction of migration, together with an increase in its nuclear localization. Similar variations were detected in the primary tumor and in the metastatic tissues from a follicular TC. FAM83B knock down experiments confirmed its role in thyroid differentiation and cell migration, as demonstrated by the reduction of markers of thyroid differentiation and the increase of the mesenchymal marker vimentin. Moreover, the silencing of FAM83B significantly increased cells migration abilities, while not affecting the oncogenic RAS/MAPK/PI3K pathways. Our data indicate for the first time a role for FAM83B in TC cell differentiation and migration. Its expression is reduced in dedifferentiated tumors and its nuclear re-localization could favour distant migration, suggesting that FAM83B should be considered a possible diagnostic and prognostic biomarker.

Introduction: Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. Case Presentation: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. Conclusion: Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotypephenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants

Background:Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second-line therapy in patients unresponsive to intravenous steroids. We conducted an open-label prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose.Methods:Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone and eight with newly diagnosed GO, were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long-term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events.Results:Mean baseline CAS was 4.56 ± 0.96 and decreased to 1.25 ± 1.14 at 24 weeks (p= 0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+and CD19+cells at the end of RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome.Conclusions:A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time, and are extremely cost effective, compared with higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid ON.

Background:The overall changes of ocular motility in Graves' orbitopathy (GO) are not easily quantifiable with the methods currently available, especially in clinical studies. The aim of the present study was to calculate parameters that quantify the changes of ocular motility in GO in relation to the Gorman score for diplopia.Methods:We studied 100 GO patients (Group 1) and 100 controls (Group 2). We also included 30 patients treated with intravenous methylprednisolone (iv-MP), assessed at baseline and after 12 and 24 weeks (Group 3), and 66 patients submitted to squint surgery, assessed at baseline and after 12 weeks (Group 4). Ocular ductions were measured in four gaze directions by a perimeter arc and were used to calculate a total motility score (TMS) as the sum of ductions in each direction; a biocular TMS (b-TMS) as the sum of the TMS of two eyes; and an asymmetry ratio (AR) as the sum of the differences of the corresponding ductions between the two fellow eyes divided by the mean difference found in controls. Quality of life was accessed by a specific questionnaire (Graves' orbitopathy quality of life [GO-QoL] questionnaire).Results:TMS and b-TMS were lower, while AR was higher, in Group 1 compared with controls (p< 0.001). In Group 1, TMS and b-TMS were inversely correlated with the Gorman score (p< 0.001) and AR was higher in patients with constant diplopia compared with the others (p< 0.001). In Group 3, TMS and b-TMS increased after treatment in responders to iv-MP (p< 0.001). In Group 4, TMS and b-TMS improved in all patients after surgery (p< 0.01), while AR and GO-QoL score improved only in those without residual constant diplopia (p< 0.001).Conclusion:We describe a quantitative method to assess eye motility dysfunction in any stage of GO to be used as an outcome measure in clinical studies.

Background:Data on the role of hypothyroidism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are conflicting, although selective Thyroid Hormone Receptor (THR)-β agonists have been identified as potential therapy in patients with non-alcoholic steatohepatitis (NASH). Therefore, we investigated the association between hypothyroidism and NAFLD histological features potentially associated with progressive liver disease. Methods:Between 2014 and 2016, consecutive patients with histologically proven NAFLD and frozen serum available for thyroid function tests assessment were included. NAFLD was staged according to the NAFLD Activity Score (NAS), and fibrosis according to Kleiner. NASH was defined as NAS ≥4, significant fibrosis as F2-F4 and significant steatosis as S2-S3. Thyroid function tests (TFT; TSH, FT3, FT4, rT3), TPO-Ab and Tg-Ab were also assessed. Results:Fifty-two patients were analyzed: median age 54 years, 58% females, LSM 7.8 kPa, 27% diabetics, 14% hypothyroid. At histology, NASH was present in 21 (40%), F2-F4 in 28 (54%) and S2-S3 in 30 (58%) patients. Rates of hypothyroidism were similar independently of the presence of NASH (p = 0.11), significant fibrosis (p = 0.21) or steatosis (p = 0.75). However, hypothyroid patients displayed a higher NAS (p = 0.02) and NASH (p = 0.06) prevalence. At multivariate analysis, TFT were not independently associated with histology. Conclusion:Hypothyroidism was highly prevalent in NAFLD patients, and was associated with increased NAFLD activity, but not with fibrosis and steatosis severity. Thus, thyroid dysfunction might play a direct and/or indirect in the pathogenesis of NAFLD and NASH.

Background: The concomitant presence of papillary thyroid cancer (PTC) and medullary TC (MTC) is rare. In this multicentric study, we documented the epidemiological characteristics, disease conditions and clinical outcome of patients with simultaneous MTC/PTC. Methods: We collected data of patients with concomitant MTC/PTC at 14 Italian referral centers. Results: In total, 183 patients were enrolled. Diagnosis was mostly based on cytological examination (n = 58, 32%). At diagnosis, in the majority of cases, both PTC (n = 142, 78%) and MTC (n = 100, 54%) were at stage I. However, more cases of stage II–IV were reported with MTC (stage IV: n = 27, 15%) compared with PTC (n = 9, 5%). Information on survival was available for 165 patients: 109 patients (66%) were disease-free for both PTC and MTC at the last follow-up. Six patients died from MTC. Median time to progression was 123 months (95% confidence interval (CI): 89.3–156.7 months). Overall, 45% of patients were disease-free after &gt, 10 years from diagnosis (125 months), this figure was 72.5% for PTC and 51.1% for MTC. Conclusions: When MTC and PTC are concurrent, the priority should be given to the management of MTC since this entity appears associated with the most severe impact on prognosis.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism., Author Summary Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.

One of the steps in thyroid hormone biosynthesis is the generation of hydrogen peroxide by dual oxidases (DUOX). Only one study reported mutations in DUOX2 gene in congenital hypothyroidism (CH) associated with total iodide organification defect (TIOD) in homozygosity or with partial iodide organification defect (PIOD) in heterozygous patients. We report genetic and phenotypic characterization of a family affected with isolated CH. The proband was positive at neonatal TSH screening. High serum TSH with low FT4 confirmed the diagnosis. At 4 years, TSH was high after L-T(4) withdrawal and (123)I scintigraphy with perchlorate discharge test revealed a PIOD. His brother was negative at TSH screening, but perinatal iodine overload was documented by urinary test. Serum TSH was elevated at postnatal day 11 and progressively increased together with a decline in urinary iodine. Reevaluation at 4 years confirmed a persistent hyperthyrotropinemia associated with PIOD. Both siblings resulted compound heterozygotes for two novel DUOX2 variants, a nonsense mutation (c.2524C>T, p.Arg842X) and a missense substitution (c.1126C>T, p.Arg376Trp), undetected in 140 control alleles. The parents had normal thyroid function and were heterozygous carriers of mutant alleles. In conclusion, we report two novel sequence variants in DUOX2 gene that are associated with persistent mild hypothyroidism and PIOD in two siblings. Different neonatal iodine supply apparently acted as disease modifier, justifying the discrepant results at TSH screening in the two siblings with same DUOX2 genotype and suggesting that mild dyshormonogenic defects may remain undisclosed in areas characterized by elevated iodine intake