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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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Mario Rotondi, Andrea Carbone, Francesca Coperchini, Rodolfo Fonte, and Luca Chiovato

IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel’s thyroiditis, Hashimoto’s thyroiditis and its fibrotic variant, Graves’ disease and Graves’ orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.

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Mario Rotondi, Luca de Martinis, Francesca Coperchini, Patrizia Pignatti, Barbara Pirali, Stefania Ghilotti, Rodolfo Fonte, Flavia Magri, and Luca Chiovato


Despite high sensitivity of current assays for autoantibodies to thyroperoxidase (TPO) and to thyroglobulin (Tg), some hypothyroid patients still present with negative tests for circulating anti-thyroid Abs. These patients usually referred to as having seronegative autoimmune thyroiditis (seronegative CAT) have not been characterized, and definite proof that their clinical phenotype is similar to that of patients with classic chronic autoimmune thyroiditis (CAT) is lacking.


To compare the clinical phenotype of seronegative CAT (SN-CAT) and CAT as diagnosed according to a raised serum level of TSH with negative and positive tests for anti-thyroid Abs respectively.


A case–control retrospective study enrolling 55 patients with SN-CAT and 110 patients with CAT was performed. Serum free triiodothyronine (FT3), free thyroxine (FT4), TSH, Tg Abs, and TPO Abs were measured in all patients.


Patients with SN-CAT displayed significantly lower mean levels of TSH (6.6±3.4 vs 10.2±9.8 μU/ml; P=0.009), higher mean FT4 levels (1.1±0.2 vs 0.9±0.2 ng/dl; P=0.0002), and similar FT3 levels when compared with CAT patients. Mean thyroid volume was significantly greater in patients with CAT when compared with SN-CAT patients (11.2±6.5 vs 8.1±3.7 ml; P=0.001). Logistic regression demonstrated that FT4 (0.123 (0.019–0.775); (P=0.026)) and thyroid volume (1.243 (1.108–1.394); (P=0.0002)) were significantly and independently related to the diagnosis (CAT/SN-CAT). Patients with SN-CAT had a similar prevalence of thyroid nodules and female gender but a lower prevalence of overt hypothyroidism (5.4 vs 20.9%; P=0.012) as opposed to patients with CAT.


These results suggest an autoimmune etiology of SN-CAT, which, however, seems to have a milder clinical course when compared with CAT.

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


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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Mario Rotondi, Valentina Capelli, Francesca Coperchini, Sara Pinto, Laura Croce, Massimo Tonacchera, and Luca Chiovato


Graves’ disease (GD) patients in remission after a full course of methimazole (MMI) therapy are at risk for a relapse of hyperthyroidism during the post-partum (PP) period, but whether this relapse may display any peculiarity is still unknown. Aim of this study was to compare GD patients undergoing a relapse of hyperthyroidism either in the PP period or not.


We retrospectively evaluated forty-three GD female patients in their childbearing age who experienced a relapse of hyperthyroidism. Eighteen of them relapsed in the PP period (i.e. within 12 months after delivery, PP group); the remaining 25 relapsed elsewhere during life (NPP group).


Age at relapse, thyroid volume, thyroid function tests, TRAb titers, smoking habit, presence and degree of orbitopathy and duration of methimazole (MMI) treatment did not differ in the two groups. However, the remission rate was much greater (79%) in the PP as compared with the NPP (32%) group (P = 0.002). A significant reduction in TRAb levels occurred at 12-month MMI treatment in the PP (F = 9.016; P = 0.001), but not in the NPP group (F = 2.433; NS). At 12 months, the PP group had significantly lower mean TRAb levels (0.6 ± 1.1 U/L and 4.5 ± 4.7 U/L in the PP and the NPP group, respectively; P = 0.029).


Relapsing Graves’ hyperthyroidism in the PP period is more prone to undergo a remission after a second course of MMI treatment. In these patients, a conservative therapeutic approach is more appropriate.

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Flavia Magri, Michelangelo Buonocore, Antonio Oliviero, Mario Rotondi, Anna Gatti, Silvia Accornero, Antonella Camera, and Luca Chiovato


To evaluate, by using skin biopsy technique, the intraepidermal nerve fiber (IENF) density in a group of untreated patients with hypothyroidism, either overt (OH) or subclinical (SH), who did not complain of neurologic symptoms.


We evaluated 18 neurologically asymptomatic patients newly diagnosed with OH or SH. Fifteen healthy, age-matched, controls were also studied. A nerve conduction study was performed. Skin biopsy was carried out from the skin of upper thigh and distal leg. Nerve fiber density was measured using an immunofluorescence technique. The density of innervation was calculated by counting only fibers crossing the basement membrane.


Electroneurographic parameters were similar in patients and controls. When compared with healthy controls, patients with OH or SH showed a significantly lower IENF density. As assessed by the proximal/distal fiber density ratio, the hypothyroid neuropathy was length dependent. When individually considered, an abnormally reduced IENF was observed in 60% of patients with OH at the distal leg and in 20% at the proximal site. In patients with SH, an abnormal IENF density was found at the distal leg in 25% of cases and at the proximal thigh in 12.5% of cases.


Our study provides the first direct demonstration of reduced IENF density in patients with OH or SH. In all patients, the IENF density reduction was length dependent. These findings suggest that a considerable number of untreated hypothyroid patients may have preclinical asymptomatic small-fiber sensory neuropathy.

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Ferruccio Santini, Paolo Marzullo, Mario Rotondi, Giovanni Ceccarini, Loredana Pagano, Serena Ippolito, Luca Chiovato, and Bernadette Biondi

Obesity and thyroid diseases are common disorders in the general population and they frequently occur in single individuals. Alongside a chance association, a direct relationship between ‘thyroid and obesity’ has been hypothesized. Thyroid hormone is an important determinant of energy expenditure and contributes to appetite regulation, while hormones and cytokines from the adipose tissue act on the CNS to inform on the quantity of energy stores. A continuous interaction between the thyroid hormone and regulatory mechanisms localized in adipose tissue and brain is important for human body weight control and maintenance of optimal energy balance. Whether obesity has a pathogenic role in thyroid disease remains largely a matter of investigation. This review highlights the complexity in the identification of thyroid hormone deficiency in obese patients. Regardless of the importance of treating subclinical and overt hypothyroidism, at present there is no evidence to recommend pharmacological correction of the isolated hyperthyrotropinemia often encountered in obese patients. While thyroid hormones are not indicated as anti-obesity drugs, preclinical studies suggest that thyromimetic drugs, by targeting selected receptors, might be useful in the treatment of obesity and dyslipidemia.

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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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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