Perchlorates in the treatment of hyperthyroidism and thyrotoxicosis: a comprehensive review.

INTRODUCTION: Perchlorates are ionic inhibitors antagonizing iodine transport into thyrocytes, hampering thyroid hormone synthesis. Nevertheless, perchlorates are not considered as first-line treatment in hyperthyroidism and thyrotoxicosis as compared to other pharmacological and non-pharmacological interventions. AIM: Reassessing the therapeutic role of perchlorates in hyperthyroidism and thyrotoxicosis throughout a systematic review of the Literature. METHODS: Guidelines were searched and examined to summarize current recommendations on the use of perchlorates in the management of hyperthyroidism. Randomized and non-randomized clinical trials were also searched and reviewed to summarize the efficacy/effectiveness and safety of perchlorates in hyperthyroidisms and thyrotoxicosis. RESULTS: The management of specific forms of hyperthyroidism was considered, including Graves' disease (GD) in non-pregnant adults, hyperthyroidisms in pregnancy, iodine media contrast-induced hyperthyroidism, amiodarone-induced hyperthyroidisms, and thyroid storm. Most of the reported studies had remarkable limitations in terms of study design (non-controlled trials, lack of blinding), low number of participants, and the lack of clinically relevant endpoints, such as cardiovascular events, cardiovascular mortality, and teratogenicity. Overall, perchlorates could be considered a second-line treatment after thionamides, radioiodine, and total thyroidectomy in both GD and hyperthyroidisms in pregnancy. The therapeutic potential of perchlorates alone or in combination with other agents could be considered a second-line treatment of iodine-related hyperthyroidisms and thyroid storm. CONCLUSION: Despite the low level of evidence, perchlorates could be considered in such specific forms of thyroid disorders, including iodine-induced hyperthyroidism and thyroid storm.

Choosing the best algorithm among five thyroid nodule ultrasound scores: from performance to cytology sparing-a single-center retrospective study in a large cohort.

OBJECTIVE: Incidental diagnosis of thyroid nodules, and therefore of thyroid cancer, has definitely increased in recent years, but the mortality rate for thyroid malignancies remains very low. Within this landscape of overdiagnosis, several nodule ultrasound scores (NUS) have been proposed to reduce unnecessary diagnostic procedures. Our aim was to verify the suitability of five main NUS. METHODS: This single-center, retrospective, observational study analyzed a total number of 6474 valid cytologies. A full clinical and US description of the thyroid gland and nodules was performed. We retrospectively applied five available NUS: KTIRADS, ATA, AACE/ACE-AME, EUTIRADS, and ACRTIRADS. Thereafter, we calculated the sensitivity, specificity, PPV, and NPV, along with the number of possible fine-needle aspiration (FNA) sparing, according to each NUS algorithm and to clustering risk classes within three macro-groups (low, intermediate, and high risk). RESULTS: In a real-life setting of thyroid nodule management, available NUS scoring systems show good accuracy at ROC analysis (AUC up to 0.647) and higher NPV (up to 96%). The ability in FNA sparing ranges from 10 to 38% and reaches 44.2% of potential FNA economization in the low-risk macro-group. Considering our cohort, ACRTIRADS and AACE/ACE-AME scores provide the best compromise in terms of accuracy and spared cytology. CONCLUSIONS: Despite several limitations, available NUS do appear to assist physicians in clinical practice. In the context of a common disease, such as thyroid nodules, higher accuracy and NPV are desirable NUS features. Further improvements in NUS sensitivity and specificity are attainable future goals to optimize nodule management. KEY POINTS: • Thyroid nodule ultrasound scores do assist clinicians in real practice. • Ultrasound scores reduce unnecessary diagnostic procedures, containing indolent thyroid microcarcinoma overdiagnosis. • The variable malignancy risk of the "indeterminate" category negatively influences score's performance in real-life management of thyroid lesions.

Integrity and Quantity of Total Cell-Free DNA in the Diagnosis of Thyroid Cancer: Correlation with Cytological Classification.

Cell-free DNA (cfDNA) quantity and quality in plasma has been investigated as a non-invasive biomarker in cancer. Previous studies have demonstrated increased cfDNA amount and length in different types of cancer with respect to healthy controls. The present study aims to test the hypothesis that the presence of longer DNA strands circulating in plasma can be considered a biomarker for tumor presence in thyroid cancer. We adopted a quantitative real-time PCR (qPCR) approach based on the quantification of two amplicons of different length (67 and 180 bp respectively) to evaluate the integrity index 180/67. Cell-free DNA quantity and integrity were higher in patients affected by nodular thyroid diseases than in healthy controls. Importantly, cfDNA integrity index was higher in patients with cytological diagnosis of thyroid carcinoma (Thy4/Thy5) than in subjects with benign nodules (Thy2). Therefore, cfDNA integrity index 180/67 is a suitable parameter for monitoring cfDNA fragmentation in thyroid cancer patients and a promising circulating biomarker in the diagnosis of thyroid nodules.

Synchronous occurrence of medullary and papillary carcinoma of the thyroid in a patient with cutaneous melanoma: determination of BRAFV600E in peripheral blood and tissues. Report of a case and review of the literature.

The purpose of this study is to describe a case of concurrent medullary and papillary thyroid carcinoma (MTC and PTC) and cutaneous melanoma and to analyze BRAF(V600E) mutation in plasma and tissues. We report the clinical history and the laboratory, imaging, and histopathological findings of a 47-year-old man affected by multinodular goiter. BRAF(V600E)-mutated DNA was quantified in plasma samples and in cancer sections by quantitative real-time polymerase chain reaction (qPCR). At ultrasound examination, the dominant right nodule of the thyroid was weakly hyperechoic and hypervascularized, while the left one was hypoechoic without internal vascularization. Regional lymphadenomegalia was not detected. Basal plasma calcitonin was elevated, and the patient underwent total thyroidectomy and resection of central cervical lymph nodes. Histopathological examination identified two distinct foci of MTC and PTC and micrometastasis of well-differentiated carcinoma in one of the six resected lymph nodes. RET proto-oncogene germline mutations were not detected. Cutaneous melanoma of the thorax was subsequently diagnosed. BRAF(V600E) tissue DNA was detected in PTC and melanoma but not in MTC. The cell-free plasma percentage of BRAF(V600E) DNA was detected in pre-thyroidectomy peripheral blood and was drastically reduced after cancer treatments. This study confirms the occurrence of synchronous MTC and PTC and is the first evidence of the co-existence of melanoma and distinct thyroid cancers of different origin. BRAF(V600E) allele was detected in PTC and melanoma but not in MTC tissues. BRAF(V600E) molecular quantification in pre- and post-treatment blood supports our previous data, suggesting its possible role in diagnosis and follow-up of BRAF-positive tumors.

Interferon-α, -ß and -γ induce CXCL11 secretion in human thyrocytes: modulation by peroxisome proliferator-activated receptor γ agonists.

It has been previously shown IFN-α, -ß, -γ and TNF-α (synergically with IFNs) dose-dependently induce the release of CXCL9 and CXCL10 chemokines by thyroid follicular cells, suggesting that this process may be related, at least in part, to the appearance of thyroid dysfunction during IFNs therapy. No study has evaluated the effect of IFN-α and -ß on CXCL11 chemokine production in thyrocytes. The aims of this study were: (a) to test the effect of IFN-α, -ß and -γ on the secretion of the Th1 chemokine CXCL11, in primary cultures of human thyroid follicular cells; (b) to assess the effect of PPAR-γ activation on CXCL11 secretion. In primary cultures of human thyroid follicular cells, CXCL11 was undetectable in the supernatant. IFN-γ, -α and -ß dose dependently induced CXCL11 release. TNF-α alone had no effect. The combination of each of the IFNs with TNF-α had a significant synergistic effect on CXCL11 secretion. Treatment of primary cultures of human thyroid follicular cells with rosiglitazone dose dependently inhibited the IFNs stimulated CXCL11 release. Compared with IFN-α and -ß, IFN-γ was the most potent stimulus of CXCL11 secretion. In conclusion, we first show that IFN-α, -ß and -γ and TNF-α (synergically with IFNs) dose-dependently induce the release of CXCL11 by primary cultures of human thyroid follicular cells, suggesting that this process may be related to the appearance of thyroid dysfunction during IFNs therapy. Furthermore, PPAR-γ activation partially inhibits this process.

A high-resolution melting protocol for rapid and accurate differential diagnosis of thyroid nodules.

A large majority of thyroid nodules are benign, and only 5% have malignant features on cytological examination. Unfortunately, fine-needle aspiration is inconclusive in approximately 30% of all thyroid biopsies, because the cytological features are indeterminate (suspicious for malignancy but not completely diagnostic or nondiagnostic). Wide panels of somatic mutations have been identified in thyroid cancers, and detection of genetic alterations in fine-needle aspirate has been demonstrated to improve diagnostic accuracy. Nevertheless, the relatively high number of genetic targets to be investigated, in comparison with the low percentage of malignant samples, makes the usual diagnostic protocol both time-consuming and expensive. We developed a reliable and sensitive protocol based on high-resolution melting analysis for the rapid screening of mutations of KRAS, HRAS, NRAS, and BRAF oncogenes in thyroid fine-needle aspirations. The entire procedure can be completed in approximately 48 hours, with a dramatic reduction in costs. The proposed protocol was applied to the analysis of 260 consecutive fine-needle aspiration biopsy (FNAB) samples. In 35 of 252 samples, 36 sequence variants were detected for BRAF (17 samples), NRAS (6 samples), HRAS (3 samples), KRAS codon 12 (9 samples), and KRAS codon 61 (1 sample).

ß (CCL2) and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves' ophthalmopathy.

No data are present in the literature about the effect of cytokines on the prototype ß chemokine (C-C motif) ligand 2 (CCL2) or of peroxisome proliferator-activated receptor α (PPARα (PPARA)) activation on CCL2 and CXCL10 chemokines secretion in fibroblasts or preadipocytes in Graves' ophthalmopathy (GO). We have tested the effect of interferon γ (IFNγ (IFNG)) and tumor necrosis factor α (TNFα) on CCL2, and for comparison on the prototype α chemokine (C-X-C motif) ligand 10 (CXCL10), and the possible modulatory role of PPARα activation on secretion of these chemokines in normal and GO fibroblasts or preadipocytes in primary cell cultures. This study shows that IFNγ alone, or in combination with TNFα, stimulates the secretion of CCL2 in primary orbital fibroblasts or preadipocytes from patients with GO at levels similar to those observed in controls. IFNγ and TNFα also stimulated CXCL10 chemokine secretion as expected. The presence of PPARα and PPARγ (PPARG) in primary fibroblasts or preadipocytes of patients with GO has been confirmed. PPARα activators were able to inhibit the secretion of CXCL10 and CCL2, while PPARγ activators were confirmed to be able to inhibit CXCL10 but had no effect on CCL2. PPARα activators were stronger inhibitors of chemokine secretions than PPARγ agonists. In conclusion, CCL2 and CXCL10 are modulated by IFNγ and TNFα in GO. PPARα activators inhibit the secretion of the main prototype α (CXCL10) and ß (CCL2) chemokines in GO fibroblasts or preadipocytes, suggesting that PPARα may be involved in the modulation of the immune response in GO.

Peroxisome proliferator-activated receptor-α agonists modulate CXCL9 and CXCL11 chemokines in Graves' ophthalmopathy fibroblasts and preadipocytes.

Peroxisome proliferator-activated receptors (PPAR)α have been shown to exert immunomodulatory effects in autoimmune disorders; no study evaluated the effect of PPARα activation in Graves' ophthalmopathy (GO). We show the presence of PPARα, δ and γ in GO fibroblasts and preadipocytes. PPARα activators have a potent inhibitory action on the secretion of CXCL9 and CXCL11 chemokines (induced by IFNγ and TNFα) in fibroblasts and preadipocytes. The potency of the used PPARα agonists was maximum on the secretion of CXCL11 (67% inhibition by fenofibrate) in fibroblasts. The relative potency of the compounds in GO fibroblasts was different with each chemokine. PPARα agonists were stronger inhibitors of CXCL9 and CXCL11 (in GO fibroblasts and preadipocytes) than PPARγ activators. This study first shows that PPARα activators inhibit CXCL9 and CXCL11 chemokines in normal and GO fibroblasts and preadipocytes, suggesting that PPARα may be involved in the modulation of the immune response in GO.

Peroxisome proliferator-activated receptor α agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease.

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR)α activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPARα and PPARγ activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN)γ and tumor necrosis factor (TNF)α. IFNγ stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNFα alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFNγ and TNFα had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPARα activators inhibited the secretion of both chemokines (stimulated with IFNγ and TNFα) at a level higher (for CXCL10, about 60-72%) than PPARγ agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFNγ and TNFα in GD and normal thyrocytes. Furthermore we first show that PPARα activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

The presence of autoimmune thyroiditis in mixed cryoglobulinemia patients is associated with high levels of circulating interleukin-6, but not of tumor necrosis factor-alpha.

OBJECTIVES: To our knowledge, no study has evaluated serum levels of interleukin-6 (IL-6), together with tumour necrosis factor-alpha (TNF-α), in a large series of patients with 'mixed cryoglobulinemia and HCV chronic infection' (MC+HCV) in relation to the presence of autoimmune thyroiditis (AT). The aims of the study were to evaluate serum levels of IL-6 in MC+HCV patients and to correlate this parameter with the presence of AT and with circulating levels of TNF-α. METHODS: Serum IL-6 and TNF-α were assayed in 41 MC+HCV patients, in 41 MC+HCV patients with autoimmune thyroiditis (MC+AT), in 41 sex- and age-matched controls, and 20 AT patients. RESULTS: MC+HCV patients showed significantly (p<0.01; Mann-Whitney U-test) higher IL-6 (median 8.1ng/l, range 0.7-651) serum levels than controls (median 0.6ng/l, range 0.5-41), or AT (median 2.8ng/l, range 0.5-67). MC+AT showed significantly (p<0.01; Mann-Whitney U-test) higher mean IL-6 (median 15.8ng/l, range 0.5-781) than controls, AT and MC+HCV. Serum TNF-α levels were significantly higher in MC+HCV (median 9.9ng/l, range 1.5-283) or MC+AT (median 11.2ng/l, range 1.6-412) than in controls (median 1.0ng/l, range 0.6-6.4), or AT (median 1.7ng/l, range 0.6-11.8) (p<0.01, for each comparison). CONCLUSIONS: Our study demonstrates significantly higher serum levels of IL-6 and TNF-α in patients with MC+HCV and MC+AT compared to healthy controls. Furthermore, the study first shows a significant increase in circulating IL-6 observed in MC+AT patients with respect to MC+HCV. Future studies in larger patients' series will be needed to evaluate the relevance of serum IL-6 and TNF-α determination as clinico-prognostic markers of MC+HCV patients and its usefulness in the therapeutic approach to these patients.

Interleukin-1ß, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis.

The aim of this study was to evaluate serum levels of interleukin-1ß (IL-1ß), chemokine (C-X-C motif) ligand 10 (CXCL10), and interferon-gamma (IFN-γ) in a series of patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC + HCV) in the presence or absence of autoimmune thyroiditis (AT) and to relate them to the clinical phenotype of these patients. Serum IL-1ß, IFN-γ, and CXCL10 were assayed in 30 patients with MC + HCV without AT, in 30 patients with MC + HCV and AT, and in 30 sex- and age-matched controls. Cryoglobulinemic patients showed significantly higher mean IL-1ß and CXCL10 levels than controls (P < 0.01). Moreover, CXCL10 was significantly increased in patients with AT patients with respect to those without AT (P < 0.01). Serum IFN-γ levels were not significantly higher in MC + HCV patients than in controls. In conclusion, our study demonstrates significantly high serum levels of IL-1ß in patients with MC + HCV with and without AT compared with healthy controls. Further, significantly high serum levels of CXCL10 in patients with MC + HCV compared with healthy controls were confirmed, overall in the presence of AT. Moreover, a pathophysiological association between high circulating levels of IL-1ß and CXCL10 has been suggested. A possible therapeutic role of the anti-IL-1 receptor antagonist (Anakirna) in MC remains to be evaluated.

CXCL9 and CXCL11 chemokines modulation by peroxisome proliferator-activated receptor-alpha agonists secretion in Graves' and normal thyrocytes.

CONTEXT: Peroxisome proliferator-activated receptor (PPAR)-α has been shown to exert immunomodulatory effects in autoimmune disorders. However, until now, no data were present in the literature about the effect of PPARα activation on CXCL9 and CXCL11 chemokines in general or on secretion of these chemokines in thyroid cells. OBJECTIVE AND DESIGN: The presence of PPARα and PPARγ has been evaluated by real-time-PCR in Graves' disease (GD) and control cells in primary culture. Furthermore, we have tested the role of PPARα and PPARγ activation on CXCL9 and CXCL11 secretion in GD and control cells after stimulation of these chemokines secretion with IFNγ and TNFα. RESULTS: This study shows the presence of PPARα and PPARγ in GD and control cells. A potent dose-dependent inhibition by PPARα-agonists was observed on the cytokines-stimulated secretion of CXCL9 and CXCL11 in GD and control cells. The potency of the PPARα agonists used was maximum on the secretion of CXCL9, reaching about 90% of inhibition by fenofibrate and 85% by ciprofibrate. The relative potency of the compounds was different with each chemokine; for example, gemfibrozil exerted a 55% inhibition on CXCL11, whereas it had a weaker activity on CXCL9 (40% inhibition). PPARα agonists were stronger (ANOVA, P<0.001) inhibitors of CXCL9 and CXCL11 secretion in thyrocytes than PPARγ agonists. CONCLUSIONS: Our study shows the presence of PPARα in GD and control thyrocytes. PPARα activators are potent inhibitors of the secretion of CXCL9 and CXCL11, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.