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.
Mario Rotondi, Andrea Carbone, Francesca Coperchini, Rodolfo Fonte and Luca Chiovato
Alessandro Antonelli, Mario Rotondi, Poupak Fallahi, Paola Romagnani, Silvia Martina Ferrari, Aldo Paolicchi, Ele Ferrannini and Mario Serio
Objective: To measure serum levels of CXCL10 and CCL2 prototype chemokines of the two major subclass (CXC and CC) in patients with newly diagnosed chronic autoimmune thyroiditis (AT), and relate the findings to the clinical phenotype.
Design and methods: Serum CXCL10 and CCL2 were assayed in 70 consecutive patients with newly diagnosed chronic AT, in sex- and age-matched healthy volunteers (n = 37) and in 20 patients with non-toxic multinodular goiter, extracted from a random sample of the general population from the same geographic area.
Results: CXCL10 serum levels were significantly higher in patients with thyroiditis than in controls or multinodular goiter patients, while comparable CCL2 levels were found between groups. CXCL10 levels were significantly increased in hypothyroid patients and in those with an hypoechoic pattern (P = 0.0004 and P = 0.0001, respectively) while serum CCL2 levels were significantly increased in patients older than 50 years and in those with hypothyroidism (P = 0.0001 and P = 0.03, respectively). No correlation between CXCL10 and CCL2 serum levels could be demonstrated. CXCL10 and CCL2 were studied separately in relation to clinical features of AT patients. Two separate multiple linear regression models for CXCL10 and CCL2 were performed, including age, thyroid volume, thyroid stimulating hormone (TSH), FT4, anti-thyroid peroxidase (AbTPO), hypoechoic pattern, and the presence of hypervascularity, demonstrating that ln of serum CXCL10 levels was associated with TSH independently of other possible confounders levels [regression coefficient (R.C.) 0.143 confidence interval (C.I.) (0.042–0.245); P = 0.0059], while serum CCL2 were significantly associated only with age [R.C. 5.412 C.I. (3.838–6.986); P < 0.0001].
Conclusion: Our results, obtained in a large cohort of newly diagnosed AT patients demonstrate increased CXCL10 especially in hypothyroid patients with a more aggressive disorder, and normal CCL2 serum levels in AT.
Alessandro Antonelli, Poupak Fallahi, Mario Rotondi, Silvia Martina Ferrari, Paola Romagnani, Mariano Grosso, Ele Ferrannini and Mario Serio
Objective: Serum CXCL10 (an interferon-γ-inducible chemokine) levels (sCXCL10) are increased in several autoimmune conditions, including Graves’ disease (GD) and autoimmune thyroiditis (AT). Longitudinal assessment of sCXCL10 in autoimmune hypo- or hyperthyroidism has not yet been performed.
Design and methods: We longitudinally assayed sCXCL10 in the following groups:
- thirty-three GD and 11 toxic nodular goiter (TNG) patients when hyperthyroid (Hyper) and when reaching euthyroidism (Eu) with methimazole therapy (MMI)
- sixty-six AT (33 hypothyroid (Hypo) and 33 Eu) patients, basally and after reaching EU (for Hypo) with levothyroxine (L-T4) therapy
- twenty-two patients with thyroid cancer (CA) under L-T4-suppressive treatment, of whom 11 were re-evaluated after L-T4 withdrawal for diagnostic WBS, and 11 after recombinant TSH (rhTSH) administration
- thirty-three healthy controls.
Results: At initial evaluation, Hyper GD and AT (Hypo significantly higher than Eu) showed significantly higher mean sCXCL10 than all other groups. MMI treatment led to a significant decrease in sCXCL10 only in GD (not in TNG), while restoration of Eu, in Hypo AT, by L-T4 was not accompanied by significant sCXCL10 change. CA showed sCXCL10 comparable to controls, and both Hypo after L-T4 withdrawal and rhTSH injection had no effect on sCXCL10.
Conclusions: Treatment of Hyper leads to a significant decrease in sCXCL10 only in GD, and this probably depends upon the MMI immunomodulatory effect. L-T4 correction of Hypo is not accompanied by significant modification of sCXCL10 in AT. Increased sCXCL10 is not associated with Hyper or Hypo per se, but is specifically sustained by the autoimmune inflammatory event occurring in both GD and AT.
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.
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.
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.
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.
Mario Rotondi, Barbara Pirali, Sara Lodigiani, Simona Bray, Paola Leporati, Spyridon Chytiris, Simona Balzano, Flavia Magri and Luca Chiovato
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.
The aim of this study was to evaluate the role of the PP period as a risk factor for GD occurrence.
The reproductive histories of 291 consecutive GD patients (165 patients in the childbearing age and 126 in the non-childbearing age) were retrospectively collected.
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%.
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.
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.
Carlo Cappelli, Mario Rotondi, Ilenia Pirola, Barbara Agosti, Annamaria Formenti, Emanuela Zarra, Umberto Valentini, Paola Leporati, Luca Chiovato and Maurizio Castellano
A retrospective study to evaluate the changes in TSH concentrations in diabetic patients treated or not treated with metformin and/or l-thyroxine (l-T4).
Three hundred and ninety three euthyroid diabetic patients were divided into three groups on the basis of metformin and/or l-T4 treatment: Group (M−/L−), 119 subjects never treated with metformin and l-T4; Group (M+/L−), 203 subjects who started metformin treatment at recruitment; and Group (M+/L+), 71 patients on l-T4 who started metformin recruitment.
The effect of metformin on serum TSH concentrations was analyzed in relation to the basal value of TSH (below 2.5 mIU/l (Q1) or between 2.51 and 4.5 mIU/l (Q2)). In patients of group M+/L+, TSH significantly decreased independently from the basal level (Q1, from 1.45±0.53 to 1.01±1.12 mU/l (P=0.037); Q2, from 3.60±0.53 to 1.91±0.89 mU/l (P<0.0001)). In M+/L− group, the decrease in TSH was significant only in those patients with a basal high-normal serum TSH (Q2: from 3.24±0.51 to 2.27±1.28 mU/l (P=0.004)); in M−/L− patients, no significant changes in TSH levels were observed.
In patients of group M+/L− showing high-normal basal TSH levels, a significant decrease in TSH was observed independently from the presence or absence of thyroid peroxidase antibodies (AbTPO; Q2 AbTPO +: from 3.38±0.48 to 1.87±1.08 mU/l (P<0.001); Q2 AbTPO −: from 3.21±0.52 to 2.34±1.31 mU/l (P<0.001)).
These data strengthen the known TSH-lowering effect of metformin in diabetic patients on l-T4 treatment and shows a significant reduction of TSH also in euthyroid patients with higher baseline TSH levels independently from the presence of AbTPO.