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Luca Chiovato and Aldo Pinchera

The search of an explanation for the onset of any disease state is reflected in all cultures, and the idea that psychic distress may predispose to illness is centuries old. Recently, scientific evidence was provided for an interaction between the central nervous and the immune systems (1). Psychological stimuli may set off patterns of neurotransmitters, hormones and cytokines. which act on receptors within the immune system and alter immune function either directly or through induction of other substances (1, 2). As a consequence, during stressful life events, alterations in the neuroendocrine system may functionally affect the immune system. The cause of Graves' disease is unknown, but there is compelling evidence that its pathogenesis is auto-immune. It is therefore possible that stress-related changes in immune function could precipitate the disease in individuals genetically predisposed to thyroid autoimmunity. Despite this theoretical chain of events and an array of early clinical evidence, the

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Domenico Andreani, Guido Menzinger, Aldo Pinchera, Franco Fallucca and Giuseppe Aliberti

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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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Stefania Bargagna, Luca Chiovato, Daniela Dinetti, Lucia Montanelli, Cristina Giachetti, Elisabetta Romolini, Mara Marcheschi and Aldo Pinchera

Abstract

Objective: Neonatal screening for congenital hypothyroidism (CH) prevents the serious neuropsychological features of CH, but the question remains whether intelligence and motor skills of CH children treated early are completely normal.

Design: In this report we describe the rare case of two genetically identical twins, only one of whom was affected by CH due to thyroid agenesis. L-Thyroxine (9 μg/kg body weight/day) therapy was initiated at 27 days of age and was adequate throughout the follow-up.

Methods: Neuropsychological evaluation was performed on the twins in parallel from 3 months to 8 years of age.

Results: The CH twin (NB) did not show major neuromotor impairments but, compared with the unaffected twin (EB), she had a slight delay in postural/motor achievements and in language development that completely disappeared at 8 years of age. On standardised tests of intelligence, NB was indistinguishable from control children but, compared with her twin, she had lower IQ scores in most testing occasions up to 7 years of age (NB = 108 vs EB = 115). School achievements of NB did not significantly differ from those of her classmates but, compared with her twin, she scored worse in writing, mechanical reading, verbal memory, and possibly in arithmetic.

Conclusions: Because the twins were genetically and phenotypically identical, were raised in the same environment, and received a similar education, it is concluded that hypothyroidism in utero and in the first neonatal month was responsible for the lower neuropsychological achievements of the CH twin. While foetal hypothyroidism is at present unavoidable, earlier diagnosis and initiation of treatment in neonates with CH are important and highly recommended.

European Journal of Endocrinology 136 100–104

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Luca Chiovato, Giuseppe Canale, Doretta Maccherini, Valeria Falcone, Furio Pacini and Aldo Pinchera

A patient with suppurative thyroiditis due to infection with Salmonella brandenburg is reported. Localization of the infection occurred to a pre-existing thyroid nodule after Salmonella bacteremia. S. brandenburg was isolated in pure culture from the fluid obtained by needle aspiration of the suppurated thyroid nodule. Surgical drainage followed by subtotal thyroidectomy was required to cure the disease. No evidence of pyriform sinus fistula was found. Suppurative thyroiditis due to Salmonella ubiquitous serotypes is an extremely rare condition, and infection to the thyroid produced by S. brandenburg is reported now for the first time. Indeed, the isolation rate of S. brandenburg from all human sources is low, and this microorganism is an uncommon agent of bacteremia.

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Stefano Mariotti, Enio Martino, Marcello Francesconi, Claudia Ceccarelli, Lucia Grasso, Francesco Lippi, Lidio Baschieri and Aldo Pinchera

Abstract. Hypothyroidism is often observed after radioiodine treatment in Graves' disease, but it is considered a rare complication in single hyperfunctioning thyroid nodule ('hot' nodule). This concept has been recently challenged, but the available data are conflicting. In the present study we therefore assessed the development of permanent hypothyroidism in 126 patients with thyroid hot nodule treated with 131I (180 μCi/g of estimated nodule weight, total dose 5.5–28.9 mCi). Follow-up ranged between 1 to 11 years. Hypothyroidism was observed in 5 (4%) patients, corresponding to a cumulative incidence by life-table analysis of 4.8% ten years after treatment. No relationship was found between the development of hypothyroidism and the size of the nodule or the total amount of administered dose. Fifty-six patients with euthyroid hot nodule at the time of treatment had higher cumulative incidence of hypothyroidism after 10 years (9.7%) than those with toxic adenoma (1.5%) (0.1 > P > 0.05 by logrank test). When the patients were analyzed according to the presence or absence of serum antithyroglobulin and/or antithyroid microsomal autoantibodies, the prevalence of hypothyroidism after 131I treatment was higher (4/25 = 16%) in patients with significant serum antibody titres (≥ 1/400 by pasive haemagglutination), when compared to that observed in subjects with negative antibody tests (1/101 = 1.0%). Life-table analysis showed in antibody positive patients a cumulative incidence of hypothyroidism after 10 years of 18.0% vs 1.4% in antibody negative patients (P <0.001 by log-rank test). In conclusion, the present data provide the first evidence that coexistent thyroid autoimmunity is a significant risk factor for the development of hypothyroidism in patients with hot nodule treated with radioiodine.

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Enio Martino, Alessandro Pacchiarotti, Fabrizio Aghini-Lombardi, Lucia Grasso, Giovanni Bambini, Lidio Baschieri and Aldo Pinchera

Abstract. The serum free thyroxine concentration was measured by direct radioimmunoassay in 38 untreated T3-thyrotoxic patients with elevated serum total and free triiodothyronine, normal serum thyroxine and free thyroxine index, no TSH response to TRH, and with clinical evidence of hyperthyroidism. An elevation of circulating free thyroxine values was observed in 58% of the patients, whereas total serum thyroxine concentration was within the normal range. It is suggested, therefore, that T3-thyrotoxicosis should be reserved for patients with elevated serum total T3 and free T3 concentrations and normal serum total T4 and free T4 concentrations. Serum thyroxine-binding globulin concentrations were significantly lower (P < 0.025) in patients with an elevated serum free thyroxine (18.7 ± 3.6 μg/ml: mean ± sd) as compared with those in patients with a normal free thyroxine concentration (23.4 ± 2.6 μg/ml). In addition, no daily fluctuations in total and free thyroxine concentration were observed in 6 patients over a 4–8 day period.

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Furio Pacini, Stefano Mariotti, Nunzio Formica, Rossella Elisei, Stefano Anelli, Enrico Capotorti and Aldo Pinchera

Abstract. In the present investigation we studied serum anti-thyroglobulin and anti-thyroid microsomal autoantibodies, measured by hemagglutination technique, in 600 patients with thyroid cancer seen by us from 1975 to 1985 (mean follow-up 46 months). Positive thyroglobulin antibodies and/or microsomal antibodies were found in 138 (23%) patients (23.9% with papillary, 25% with follicular, 16.1% with anaplastic, and 4.1% with medullary thyroid carcinomas). The incidence of positive tests was similar in each decade of life (ranging between 21.9% and 27.9%), whereas in a normal sex-matched population with no evidence of thyroid disease, the frequency of positive tests was very low in young people and increased to 23% in people older than 60. In 64 patients with no evidence of residual or metastasic thyroid tissue after surgery and radioiodine, initially positive antibody titres became negative in 54.6%, decreased in 32.8%, did not change in 3.1%, and increased in 9.3%. On the contrary, antibody titres of patients with persistent disease became undetectable in 8.3%, decreased in 16.6%, remained unchanged in 25%, and increased in 50%. The clinical course of differentiated thyroid cancer was unaffected by the presence of thyroid antibodies and no difference was found in the death rate between antibody-positive and antibody-negative patients (11.5% and 13.6%, respectively). In conclusion, our data indicate that: 1) autoimmune phenomena are not an infrequent finding in thyroid cancer; 2) as in non-malignant thyroid diseases, positive-antibody tests are more frequently observed in females than in males; 3) at variance with normal controls, no age-dependent increase in serum anti-thyroid antibodies was found in thyroid cancer; 4) the presence of metastatic thyroid tissue seems to be necessary to perpetuate the autoantibody synthesis, and 5) anti-thyroid autoantibodies are not a protective or worsening factor in the tumour outcome.

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Luca Chiovato, Daniela Larizza, Giovanna Bendinelli, Massimo Tonacchera, Michele Marinò, Claudia Mammoli, Renata Lorini, Francesca Severi and Aldo Pinchera

Chiovato L, Larizza D, Bendinelli G, Tonacchera M, Marinò M, Mammoli C, Lorini R, Severi F, Pinchera A. Autoimmune hypothyroidism and hyperthyroidism in patients with Turner's syndrome. Eur J Endocrinol 1996;134:568–75. ISSN 0804–4643

A high prevalence of autoimmune thyroid disease (AITD) has been described in Turner's syndrome (TS) but the extent of this association is controversial for the prevalence of thyroid autoantibody and the clinical impact of thyroid dysfunction. In this study we searched for thyroid disease and thyroid autoantibodies in patients with TS. Seventy-five unselected TS patients (age range 3–30 years) were studied. Sera were tested for thyroid hormones, thyrotropin (TSH), thyroglobulin (TG-ab) and thyroperoxidase (TPO-ab) antibodies. The TSH-receptor antibodies with thyroid-stimulating (TS-ab) or TSH-blocking activity (TSHB-ab) were measured in the IgG fraction using a bioassay. Ten out of 75 (13.3%) TS patients had AITD: eight had autoimmune thyroiditis (AT) (six with subclinical and two with overt hypothyroidism and one with euthyroidism) and one had Graves' disease. The prevalence of AITD increased significantly (p < 0.05) from the first (15%) to the third (30%) decade of life. The prevalence of TPO-ab and/or TG-ab (20%) was higher (p < 0.05) in TS than in age-matched female controls and increased from the first (15%) to the third (30%) decade of life. Clinical AITD was diagnosed in 46% of TS patients with TPO-ab and/or TG-ab. Thyroid-stimulating antibody was detected in the hyperthyroid patient, and TSHB-ab was found in one of eight patients with hypothyroid AT. It was concluded that: TS patients are at higher than average risk of developing AITD not only in adolescence and adult age but also in childhood; hypothyroidism, mainly subclinical, is the most frequent thyroid dysfunction; elevated TPO-ab and/or TG-ab alone do not imply thyroid dysfunction; TS-ab or TSHB-ab are always associated with thyroid dysfunction although most cases of autoimmune hypothyroidism are not due to the latter antibody.

Luca Chiovato, Istituto di Endocrinologia, Università di Pisa, Viale del Tirreno, 64, 56018 Tirrenia, Pisa, Italy

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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.