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Enio Martino, Furio Pacini, Paolo Vitti and Luigi Bartalena

Percutaneous ethanol injection (PEI) has been proposed for the management of small hepatocellular carcinomas as an alternative modality of treatment devoid of the complications related to surgery in this kind of patient (1–4). Likewise, PEI has been used for liver and peritoneal metastases of abdominal tumors (1), offering the possibility to attack lesions unlikely to be controlled by surgery and/or chemotherapy. The mechanism of action of ethanol appears to be related to cellular dehydration followed by coagulative necrosis and vascular thrombosis and occlusion.

On the other hand, the use of PEI has also been proposed for non-malignant nodular lesions, such as parathyroid adenomas causing either primary (5, 6) or secondary (7) hyperparathyroidism. This modality of treatment appears to be particularly suitable for patients with chronic renal failure in whom the surgical risk of parathyroidectomy is high.

In 1990, Livraghi et al. (8) suggested that autonomous single thyroid nodules can be

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Maria Annateresa Provenzale, Emilio Fiore, Clara Ugolini, Liborio Torregrossa, Riccardo Morganti, Eleonora Molinaro, Paolo Miccoli, Fulvio Basolo and Paolo Vitti

Objective

Papillary thyroid microcarcinomas (microPTC) may be ’incidental’ (Inc-microPTC), occasionally found at histology after surgery for benign disease or ‘non-incidental’ (Non-Inc-microPTC), diagnosed on clinical grounds. It is unclear whether these different microPTC reflect the same disease. The aim of the study was to compare Inc-microPTC and Non-Inc-microPTC for clinical and histological features as well as for serum TSH, a known factor involved in PTC development.

Design

We evaluated histology and serum TSH levels of consecutive patients submitted to thyroidectomy for goiter with compressive symptoms or for cytological diagnosis suspicious/indicative of PTC.

Methods

In total, 665 consecutive patients (259 with a single thyroid nodule, SN and 406 with a multinodular gland, MN) were included in the study. According to histology, patients were classified as: benign nodular goiter (Benign, n=291); Inc-microPTC (n=92); Non-Inc-microPTC (n=67) and PTC≥1cm (macroPTC, n=215).

Results

Inc-microPTC were significantly more frequent in MN than in SN (66/406, 16.2% vs 26/259, 10.0%, P=0.02). Patients with Inc-microPTC compared with Non-Inc-microPTC were older (mean age±s.d. 53.3±13.2 years vs 44.9±14.8 years, P=0.0002), had a smaller tumor size (median 4mm vs 9mm, P<0.0001), a higher frequency of multifocality (70/92, 76.1% vs 35/67, 52.2% P=0.001) and lower levels of TSH (median 0.6mIU/L, IR: 0.4–1.0mIU/L vs value 1. mIU/L, IR: 0.6–1.4mIU/L vs P=0.0001).

Conclusion

Incidental and non-incidental papillary thyroid microcarcinomas appear to be two different entities.

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Brunella Bagattini, Caterina Di Cosmo, Lucia Montanelli, Paolo Piaggi, Mariella Ciampi, Patrizia Agretti, Giuseppina De Marco, Paolo Vitti and Massimo Tonacchera

Background

Levothyroxine (l-T4) is commonly employed to correct hormone deficiency in children with congenital hypothyroidism (CH) and in adult patients with iatrogenic hypothyroidism.

Objective

To compare the daily weight-based dosage of the replacement therapy with l-T4 in athyreotic adult patients affected by CH and adult patients with thyroid nodular or cancer diseases treated by total thyroidectomy.

Design and methods

A total of 36 adult patients (27 females and nine males) aged 18–29 years were studied; 13 patients (age: 21.5±2.1, group CH) had athyreotic CH treated with l-T4 since the first days of life. The remaining 23 patients (age: 24±2.7, group AH) had hypothyroidism after total thyroidectomy (14 patients previously affected by nodular disease and nine by thyroid carcinoma with clinical and biochemical remission). Patient weight, serum free thyroid hormones, TSH, thyroglobulin (Tg), anti-Tg, and anti-thyroperoxidase antibodies were measured. Required l-T4 dosage was evaluated. At the time of the observations, all patients presented free thyroid hormones within the normal range and TSH between 0.8 and 2 μIU/ml.

Results

Patients had undetectable Tg and anti-thyroid antibodies. The daily weight-based dosage of the replacement therapy with l-T4 to reach euthyroidism in patients of group CH was significantly higher than that in those of group AH (2.16±0.36 vs 1.73±0.24 μg/kg, P<0.005). Patients of group CH treated with l-T4 had significantly higher serum TSH levels than patients of group AH (P=0.05) as well as higher FT4 concentrations.

Conclusions

To correct hypothyroidism, patients of group CH required a daily l-T4 dose/kg higher than group AH patients, despite higher levels of TSH. The different requirement of replacement therapy between adult patients with congenital and those with surgical athyroidism could be explained by a lack of thyroid hormones since fetal life in CH, which could determine a different set point of the hypothalamus–pituitary–thyroid axis.

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Patrizia Agretti, Giuseppina De Marco, Melissa De Servi, Claudio Marcocci, Paolo Vitti, Aldo Pinchera and Massimo Tonacchera

Objective: Thyroid-associated ophthalmopathy (TAO) is a chronic autoimmune disorder characterized by an increased volume of adipose/connective tissue in the human orbit.

Design: The aim of this study was to investigate the thyrotropin receptor (TSHr) expression in orbital fibroblasts from TAO patients undergoing adipocytic differentiation.

Methods: Retro-ocular tissue and skin were obtained from five patients undergoing orbital decompression surgery for TAO and placed in culture. Proliferating fibroblasts were subjected to adipocytic differentiation for 10 days. Total RNA was isolated from fibroblasts and was reverse transcribed. TSHr mRNA levels were determined by real-time PCR. cAMP was determined by radioimmunoassay (RIA) after fibroblast incubation with the substances to test.

Results: Orbital differentiated fibroblasts became rounded and acquired lipid droplets. The amount of TSHr mRNA in these fibroblasts was higher than fibroblasts not subjected to adipocytic differentiation. Immunocytochemical analysis showed TSHr protein in differentiated orbital fibroblasts. Differentiated orbital fibroblasts stimulated with bovine (b) TSH showed a cAMP production greater than that in paired undifferentiated cultures. A specific thyroid-inhibiting antibody (TBAb) inhibited cAMP production after bTSH challenge, and a thyroid-stimulating antibody (TSAb) stimulated cAMP production in differentiated fibroblasts.

Conclusions: We suggest that orbital fibroblasts subjected to adipocytic differentiation increase TSHr expression that responds specifically to bTSH and TSAb stimulation, and to TBAb inhibition.

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Paolo Vitti, Teresa Rago, Francesco Mancusi, Stefania Pallini, Massimo Tonacchera, Ferruccio Santini, Luca Chiovato, Claudio Marcocci and Aldo Pinchera

An abnormal thyroid echographic pattern characterized by a diffuse low echogenicity has been described in Hashimoto's thyroiditis and Graves' disease. The aim of the present work was to study the relationship between thyroid hypoechogenicity and the outcome of treatment for hyperthyroidism with antithyroid drugs in patients with Graves' disease. The study group included 105 patients who underwent a course of methimazole treatment. Thyroid ultrasonography was carried out at diagnosis, and autoantibodies to thyrotropin receptor (TR-ab) were measured at the end of treatment. During the follow-up after methimazole treatment, 87/105 (83%) patients had relapse of hyperthyroidism and 18/105 (17%) were in remission. Recurrence of hyperthyroidism occurred in 71/76 (93%) patients with thyroid hypoechogenicity and in 16/29 (55%) of those with normal thyroid echogenicity (ϰ2= 19.0; p<0.0001). Positive TR-ab values at the end of methimazole treatment were found in 59/76 (78%) patients with thyroid hypoechogenicity and in 12/29 (41%) patients with normal thyroid echogenicity (ϰ2 = 10.9; p< 0.0001). Sixty-five/87 (74%) patients with relapse of hyperthyroidism and 6/18(3 3%) of those who remained euthyroid were TR-ab-positive at the end of methimazole treatment (ϰ2 = 9.8; p< 0.002). The finding of thyroid hypoechogenicity at diagnosis had higher specificity (0.81) and sensitivity (0.72) with respect to TR-ab positivity at the end of methimazole treatment (0.74 and 0.66 respectively) for the prediction of relapse of hyperthyroidism. Therefore, the evaluation of thyroid echographic pattern can be considered a useful prognostic tool in patients with Graves' disease.

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Eleonora Sisti, Barbara Coco, Francesca Menconi, Marenza Leo, Roberto Rocchi, Francesco Latrofa, Maria Antonietta Profilo, Barbara Mazzi, Eleonora Albano, Paolo Vitti, Claudio Marcocci, Maurizia Brunetto and Michele Marinò

Objective

Intravenous glucocorticoid (i.v.GC) pulse therapy for Graves' ophthalmopathy (GO) can be associated with acute liver damage (ALD), which was roughly estimated to occur in ∼1% of patients, with an overall mortality of 0.4%. The aim of this study was to evaluate the frequency of ALD after the introduction of a series of exclusion criteria and preventive measures.

Design

Retrospective evaluation of all consecutive patients candidate to i.v.GC over a period of 5 years.

Methods

The study includes 376 GO patients candidate to i.v.GC. Several liver tests were performed before, during, and after i.v.GC. To prevent ALD morbidity and mortality, the following measures were applied: i) exclusion of patients with active viral hepatitis and/or severe liver steatosis; ii) reduction in the GC dose, frequency, and number of pulses; and iii) administration of oral GC after i.v.GC, and also during i.v.GC in patients positive for nonorgan-specific autoantibodies (to prevent autoimmune hepatitis due to immune rebound). ALD was defined as an increase in alanine aminotransferase ≥300 U/l.

Results

A total of 353 patients were given i.v.GC and 23 were excluded for various conditions. ALD was detected in 4/376 patients candidate to i.v.GC, resulting in a morbidity of 1.06%. One patient recovered spontaneously and three after additional treatment with oral GC, given to re-establish immune suppression in the suspect of an autoimmune hepatitis.

Conclusions

ALD related to i.v.GC is a relatively rare adverse event. Provided an accurate selection of patients and a series of preventive measures are applied, i.v.GC is a safe treatment for the liver.

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Patrizia Agretti, Eleonora Ferrarini, Teresa Rago, Antonio Candelieri, Giuseppina De Marco, Antonio Dimida, Filippo Niccolai, Angelo Molinaro, Giancarlo Di Coscio, Aldo Pinchera, Paolo Vitti and Massimo Tonacchera

Objective

MicroRNAs (miRNAs) are small endogenous noncoding RNAs that pair with target messengers regulating gene expression. Changes in miRNA levels occur in thyroid cancer. Fine-needle aspiration (FNA) with cytological evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytological diagnosis remains undetermined for 20% of nodules.

Design

In this study, we evaluated the expression of seven miRNAs in benign nodules, papillary thyroid carcinomas (PTCs), and undetermined nodules at FNA.

Methods

The prospective study included 141 samples obtained by FNA of thyroid nodules from 138 patients. miRNA expression was evaluated by quantitative RT-PCR and statistical analysis of data was performed. Genetic analysis of codon 600 of BRAF gene was also performed.

Results

Using data mining techniques, we obtained a criterion to classify a nodule as benign or malignant on the basis of miRNA expression. The decision model based on the expression of miR-146b, miR-155, and miR-221 was valid for 86/88 nodules with determined cytology (97.73%), and adopting cross-validation techniques we obtained a reliability of 78.41%. The prediction was valid for 31/53 undetermined nodules with 16 false-positive and six false-negative predictions. The mutated form V600E of BRAF gene was demonstrated in 19/43 PTCs and in 1/53 undetermined nodules.

Conclusions

The expression profiles of three miRNAs allowed us to distinguish benign from PTC starting from FNA. When the assay was applied to discriminate thyroid nodules with undetermined cytology, a low sensitivity and specificity despite the low number of false-negative predictions was obtained, limiting the practical interest of the method.

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Ferruccio Santini, Giulia Galli, Margherita Maffei, Paola Fierabracci, Caterina Pelosini, Alessandro Marsili, Monica Giannetti, Maria Grazia Castagna, Serenella Checchi, Eleonora Molinaro, Paolo Piaggi, Furio Pacini, Rossella Elisei, Paolo Vitti and Aldo Pinchera

TSH-receptor (TSHR) has been found in a variety of cell types, including preadipocytes and adipocytes. In vitro, TSH-mediated preadipocyte and adipocyte responses include proliferation, differentiation, survival, and lipolysis.

Objective

To measure the response of serum leptin to exogenous administration of recombinant human TSH (rhTSH) in vivo.

Patients

One hundred patients with differentiated thyroid cancer already treated by total thyroidectomy and 131I remnant ablation were enrolled. Mean (±s.e.m.) body mass index (BMI) was 26.9±0.6 kg/m2.

Methods

Patients received a standard dose of rhTSH for measurement of thyroglobulin in the follow-up of their disease. Blood samples were taken for the assay of TSH and leptin before the first administration of rhTSH (time 0), and 24 h (time 1), 48 h (time 2), 72 h (time 3), and 96 h (time 4) after the first administration of rhTSH.

Results

Significant mean serum leptin increments, with respect to basal value, were 16, 13, 18, and 11% at times 1, 2, 3, and 4 respectively. Significant positive correlations of leptin–area under the curve with respect to basal leptin levels (r=0.43; P<0.0001) and BMI (r=0.32; P<0.005) were observed.

Conclusions

Acute rhTSH administration in hypothyroid subjects under l-thyroxine therapy produces a rise in serum leptin. This increase is proportional to the adipose mass suggesting that a functioning TSHR is expressed on the surface of adipocytes. The role that TSHR activation in adipocytes might play in physiological and pathological conditions remains a matter of investigation.