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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

Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusions

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

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

Design

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.

Methods

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).

Results

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).

Conclusions

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

Aim

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.

Methods

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.

Results

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.

Conclusions

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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Mario Rotondi, Roberta Minelli, Flavia Magri, Paola Leporati, Paola Romagnani, Maria Cristina Baroni, Roberto Delsignore, Mario Serio and Luca Chiovato

Objective: Thyroid autoimmunity is a common side effect of interferon-α (IFN-α) treatment for chronic hepatitis C. There are currently no reliable parameters to predict the occurrence of thyroid dysfunctions in patients undergoing IFN-α therapy. CXC chemokine ligand 10 (CXCL10) is a chemokine known to play a role in both thyroid autoimmune disease and hepatitis C virus (HCV) hepatitis.

Design: The aim of this study was to evaluate serum CXCL10 levels in HCV patients treated with IFN-α in relation to the occurrence of thyroid dysfunctions. Serum CXCL10 levels were assayed in 25 HCV patients (proven to be negative for serum thyroid antibodies) before and during IFN-α therapy (2, 4 and 6 months) and in 50 healthy controls. HCV patients were retrospectively selected according to the occurrence of IFN-α-induced thyroid dysfunction and were assigned to two groups. Group I included 15 patients who did not develop thyroid antibody positivity or dysfunction; group II included ten patients who showed the appearance of serum thyroid antibodies, followed by clinically overt thyroid dysfunction.

Results: Patients with HCV, regardless of the development of thyroid dysfunctions, had significantly higher serum CXCL10 than controls (261.6±123.4 vs 80.4±33.6 pg/ml; P<0.00001). Pretreatment mean serum CXCL10 levels were significantly higher in Group I versus Group II (308.6±130.7 vs 191.1±69.4 pg/ml; P<0.05). Groups I and II showed different rates of favourable response to IFN-α treatment (33 and 90% respectively).

Conclusion: Our results suggest that measuring serum CXCL10 before IFN-α treatment may be helpful for identifying those patients with higher risk to develop thyroid dysfunction, and require a careful thyroid surveillance throughout the treatment.

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Mario Rotondi, Barbara Pirali, Sara Lodigiani, Simona Bray, Paola Leporati, Spyridon Chytiris, Simona Balzano, Flavia Magri and Luca Chiovato

Objective

Aggravation of autoimmune diseases due to a rebound reaction to the pregnancy-associated immune changes is common during the post partum (PP) period. Previous studies demonstrated that up to 45% of women developing Graves' disease (GD) in the childbearing age had a PP onset of disease. Thus, the PP period was identified as a major risk factor for GD onset.

Design

The aim of this study was to evaluate the role of the PP period as a risk factor for GD occurrence.

Methods

The reproductive histories of 291 consecutive GD patients (165 patients in the childbearing age and 126 in the non-childbearing age) were retrospectively collected.

Results

The rate of PP onset of GD in all patients with at least one successful pregnancy was 9.8 and 20.0% when only patients in the childbearing age were considered. In the entire cohort of GD women, independent of their age and parity status (i.e., the number of successful pregnancies), the rate of PP onset of GD was 7.2%. The relative frequencies of the rate of PP onset of GD were similar in relation with increasing parity. The rates of false negative (nulliparous) and false positive (parous non-childbearing+childbearing with a non-PP onset of GD) were estimated. The positive predictive value of the PP period for the onset of GD was less than 10%.

Conclusions

The results of the current study would not support a role for the PP period as a major risk factor for de novo occurrence of GD.