Paola Leporati

Raised serum TSH levels in patients with morbid obesity: is it enough to diagnose subclinical hypothyroidism?

OBJECTIVE Morbid obesity (body mass index (BMI)> or =40 kg/m(2)) is associated with thyroid function disturbances, with a high rate of subclinical hypothyroidism (SH) being the most consistently reported. We evaluated the circulating thyroid function parameters in morbid obese patients and related the results to the presence of circulating thyroid antibodies (Thyr-Ab). DESIGN AND METHODS Morbid obese patients were consecutively enrolled (n=350). Two control groups were used: control group (CG)1, healthy normo-weight subjects (n=50); CG2, normo-weight patients with SH (n=56) matched for TSH with the obese patients with SH. Serum levels of free triiodothyronine (FT(3)), free thyroxine (FT(4)), TSH, antithyroglobulin antibodies, and antithyroperoxidase antibodies were measured in all patients. RESULTS i) Compared with CG1, obese patients having thyroid function parameters in the normal range and negative Thyr-Ab showed significantly higher serum TSH and lower free thyroid hormones levels, but a similar FT(4)/FT(3) ratio; ii) SH was recorded in 13.7% obese patients; iii) compared with CG2, obese patients with untreated SH had a significantly lower rate of positive Thyr-Ab (32.1 vs 66.1%; P<0.005); iv) no gender prevalence was observed in SH obese patients with negative Thyr-Ab; and v) the comparison of the untreated SH patients (obese and normo-weight) with CG1 demonstrated that in SH obese subjects, unlike normo-weight SH patients, the FT(3) levels were significantly lower. This resulted in a normal FT(4)/FT(3) ratio in SH obese patients. CONCLUSION Thyroid autoimmunity is not a major cause sustaining the high rate of SH in morbid obese patients. In these patients, the diagnosis of SH itself, as assessed by a raised TSH alone, appears questionable.

THYREOTROPIN LEVELS IN DIABETIC PATIENTS ON METFORMIN TREATMENT

OBJECTIVE A retrospective study to evaluate the changes in TSH concentrations in diabetic patients treated or not treated with metformin and/or L-thyroxine (L-T(4)). METHODS Three hundred and ninety three euthyroid diabetic patients were divided into three groups on the basis of metformin and/or L-T(4) treatment: Group (M-/L-), 119 subjects never treated with metformin and L-T(4); Group (M+/L-), 203 subjects who started metformin treatment at recruitment; and Group (M+/L+), 71 patients on L-T(4) who started metformin recruitment. RESULTS 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 1.450.53 to 1.011.12 mU/L (P=0.037); Q2, from 3.600.53 to 1.910.89 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)). CONCLUSIONS These data strengthen the known TSH-lowering effect of metformin in diabetic patients on L-T(4) treatment and shows a significant reduction of TSH also in euthyroid patients with higher baseline TSH levels independently from the presence of AbTPO.

Expression of estrogen and androgen receptors in differentiated thyroid cancer: An additional criterion to assess the patient's risk

Estrogen receptor (ER) and androgen receptor (AR) may be expressed in thyroid tumors, but their prognostic role is controversial. We investigated whether ER and AR expressions could confer a more aggressive phenotype to thyroid tumors. We enrolled 91 patients (13 males and 78 females, mean age 49.3±14.8 years) bearing small (T1 in the 2006 TNM system) differentiated thyroid cancers (DTC). Thirty-eight tumors were incidental histological findings. Using immunohistochemistry, we evaluated ERα, ERβ, and AR expressions in tumors and in its correspondent extra-tumor parenchyma. In tumors, 13 (16.7%) women and one (7.7%) man expressed ERα; 42 (53.8%) women and six (46%) men expressed ERβ; and 16 (20.5%) women and three (23.1%) men expressed AR. In normal thyroid parenchymas, ERβ was expressed in 52 (66.7%) women and nine (69.2%) men, ERα in three (3.8%) women, and AR in 13 (16.7%) women. Compared with normal thyroid parenchyma, tumors gained ERα and lost ERβ expressions. Incidental cancers were more commonly ERα(-) than ERα(+) (47.7 vs 14.3%, P=0.037). Postsurgical serum thyroglobulin was higher in ERα(+) tumors than in the ERα(-) tumors (P=0.04). ERβ(-) tumors showed vascular invasion more frequently than the ERβ(+) tumors (26.2 vs 4.1%, P=0.005). AR(+) tumors showed capsular invasion more frequently than the AR(-) tumors (77.8 vs 46.6%, P=0.014). In conclusion, ERα positivity, ERβ negativity, and AR expressions are associated with a more aggressive phenotype of small T1-DTC. ER and AR expressions may represent an additional criterion in deciding whether to perform radioiodine ablation in these tumors.

Repeated Laser Thermal Ablation of a Large Functioning Thyroid Nodule Restores Euthyroidism and Ameliorates Constrictive Symptoms

A 57-yr-old man was referred for tachycardia, weight loss, throat constraint, and worsening dyspnea. The serum levels of TSH were below 0.05 U/ml, with elevated free T4 (21.2 pg/ml) and normal free T3 (4.1 pg/ml). Ultrasound scan showed a right dominant thyroid nodule (volume, 55 ml) with both periand intranodular intense vascularization pattern. Tracheal deviation and narrowing were shown by magnetic resonance imaging (MRI) (Fig. 1, A and B). The patient refused surgery and/or I ablative therapy, and his compliance to medical treatment was poor. Thus, a minimally invasive interventional procedure was chosen (1). Laser thermal ablation (LTA) constitutes an alternative strategy for the ablation of both hyperfunctioning and nonfunctioning thyroid nodules (1–4). The patient underwent four LTA sessions, each 45 d apart. The ablation procedure was performed under ultrasound guidance by using a 400m bare fiber and a continuous wave diode laser operating at 980 nm. Energy was delivered with an output power of 7 W for a mean total amount of 3000 Joule at each session. Six months later, thyroid hormones and TSH were within the normal range and remained so throughout a 30-month follow-up. MRI performed 10 months later showed an impressive decrease of nodule size (posttreatment volume, 5.0 ml) with significant amelioration of tracheal deviation and narrowing (Fig. 1, C and D). The patient reported an improvement of dyspnea and was satisfied with the cosmetic result. Although side effects have been described (5), LTA can be performed in selected cases on an outpatient basis and may also be effective for functioning large thyroid nodules. Acknowledgments

A hypoechoic pattern of the thyroid at ultrasound does not indicate autoimmune thyroid diseases in patients with morbid obesity

OBJECTIVE Thyroid ultrasound (US) scan is a valuable tool for diagnosing thyroid diseases. In autoimmune thyroid disease (AITD), an hypoechoic pattern of the thyroid at US is related to circulating thyroid antibodies (Abs). The aim of this study was to evaluate the diagnostic accuracy of thyroid US for the detection of AITD in patients with morbid obesity. DESIGN Thyroid US scans showing an hypoechoic pattern of the thyroid were collected from 105 morbid obese patients (body mass index (BMI) >40 kg/m(2)) and 105 non-obese patients (BMI<or=30 kg/m(2)). RESULTS A thyroid hypoechoic pattern at US was consistent with clinical/biochemical features of AITD in 90/105 (85.7%) non-obese patients and in 22/105 (20.9%) morbid-obese patients (P<0.0001). By performing a complete thyroid work-up, including clinical examination, thyroid morphology, serum hormones, and auto-Ab measurements, the discrepancy between the US pattern and the results of the thyroid Ab tests was justified in 6/15 non-obese patients, and only in 1/83 morbid obese patients. Thus, an unexplained hypoechoic pattern of the thyroid at US, defined as negative tests for thyroid Ab and absence of justifying thyroid disturbances, was found in 2/105 (1.9%) non-obese patients and in 68/105 (64.8%) morbid obese patients (P<0.0001). CONCLUSIONS Our results suggest that i) morbid obesity may affect thyroid morphology, and ii) an hypoechoic pattern of the thyroid at US, a well-established parameter for diagnosing AITD, has a poor diagnostic accuracy when patients with morbid obesity are taken into account.

Prevalence of parathyroid cysts by neck ultrasound scan in unselected patients

Background: Parathyroid cysts (PC) are a rare entity, representing only 0.5–1% of all parathyroid lesions and <1% of neck masses. Since its first description, in the second half of the 19th century, fewer than 300 cases have been reported. By reviewing the literature, it appears that the data available arose from surgical series, and the precise incidence of PC as detected by ultrasound (US) has not been described. The aim of this study was to review 5 yr of routine neck US, mainly performed for thyroid diseases, in order to estimate the prevalence of PC in a large series of patients. Methods: We reviewed our database of neck US investigations performed from 2003 to 2007: all data regarding patient’s clinical history, US images, and fine needle aspiration cytology were retrospectively collected. Results: Among 6621 patients submitted to neck US investigation, a PC (mean diameter 36.4±14.2 mm; range 25–61 mm) was diagnosed in 5 cases. Serum PTH levels were high in all the patients (221±140.7 pg/ml; range 111–456 pg/ml), whereas serum calcium levels only in 3 subjects (10.8±1.4 mg/dl; range 9.2–12.9 mg/ml). Conclusion: This is the first study evaluating the prevalence of PC in a large series of unselected patients by US. Our results demonstrate a much lower incidence (0.075%) of incidentally detected PC than previously reported.

Interferon-γ and tumor necrosis factor-α sustain secretion of specific CXC chemokines in human thyrocytes: a first step toward a differentiation between autoimmune and tumor-related inflammation?

CONTEXT Chemokines are chemotactic cytokines responsible for the attraction and recruitment of different cell types during leukocyte infiltration, the histopathological hallmark of autoimmunity. Previous data demonstrate that thyrocytes secrete CXC chemokines, particularly CXCL8 and CXCL10. However, the physiopathological significance of such secretion and the effects of a combination of proinflammatory stimuli in terms of preferential CXCL8 and CXCL10 release remain unclear. OBJECTIVE The aim of this study was to investigate whether the secretion of chemokines by human thyrocytes is a generalized inflammatory response or whether it is dependent upon specific proinflammatory stimuli. METHODS CXCL8 and CXCL10 were measured in supernatants of human thyrocytes in primary cultures basally and after 24 h stimulation with interferon-γ (IFNγ) (1000 U/ml) and TNFα (10 ng/ml), alone or in combination. RESULTS CXCL8 but not CXCL10 was detected in basal conditions. The two chemokines showed differences in their response to proinflammatory cytokines. Indeed, significant secretion of CXCL10 was induced by IFNγ (P < 0.01) and not TNFα, whereas CXCL8 was secreted in response to TNFα (P < 0.01) being inhibited by IFNγ (P < 0.01). The combination of TNFα plus IFNγ synergistically increased the IFNγ-induced CXCL10 secretion (P < 0.01) and reversed the TNFα-induced CXCL8 secretion (P < 0.01). CONCLUSIONS These results confirm that human thyrocytes secrete CXC chemokines and demonstrate that the secretion of CXCL8 and CXCL10 is sustained by specific proinflammatory cytokines or their combination, which ultimately determines the nature of the infiltrating lymphocytes in human thyroid diseases. These results indirectly support a major role for CXCL10 in thyroid autoimmunity whereas CXCL8 might be involved in tumor-related inflammation.

Expanding the therapeutic spectrum of metformin: From diabetes to cancer

IntroductionMetformin, an oral hypoglycemic agent, was introduced in the clinical practice for the treatment of type 2 diabetes mellitus more than a half-century ago. Over the years, several studies demonstrated that diabetic patients treated with metformin have a lower incidence of cancer, raising the hypothesis that the spectrum of clinical applications of the drug could be expanded also to cancer therapy. Following these initial findings, a large number of studies were performed aimed at elucidating the effects of metformin on different types of tumor, at explaining its direct and indirect anti-cancer mechanisms and at identifying the molecular pathways targeted by the drug. Several clinical trials were also performed aimed at evaluating the potential anti-cancer effect of metformin among diabetic and non-diabetic patients affected by different types of cancer. While the results of several clinical studies are encouraging, a considerable number of other investigations do not support a role of metformin as an anti-cancer agent, and highlight variables possibly accounting for discrepancies.AimWe hereby review the results of in vitro and in vivo studies addressing the issue of the anti-cancer effects of metformin.ConclusionsIf in vitro data appear solid, the results provided by in vivo studies are somehow controversial. In this view, larger studies are needed to fully elucidate the role of metformin on cancer development and progression, as well as the specific clinical settings in which metformin could become an anti-cancer drug.

Severe disability in patients with relapsing-remitting multiple sclerosis is associated with profound changes in the regulation of leptin secretion.

Objectives: Experimental evidences indicate that leptin is involved in the neuroinflammatory process sustaining multiple sclerosis (MS). However, the relationship between leptin and body fat, as assessed by body mass index (BMI), in MS was not previously evaluated. It was the aim of this study to compare serum leptin levels between patients with MS and healthy controls and to evaluate the possible relationship between circulating leptin levels and disease severity. Patients and Methods: Eighty-four MS patients and 57 sex-matched healthy volunteers were enrolled. Serum leptin levels were measured in all patients and controls. MS patients were stratified in 3 groups according to their degree of disability as assessed by the Expanded Disability Status Scale (EDSS). Patients were classified as having low (33 patients with an EDSS score <1.5), intermediate (28 patients with an EDSS score from 2 to 3) and high disability (23 patients with an EDSS score ≥3.5). Results: No significant differences in serum leptin levels and BMI were observed between patients and controls. In patients with MS, serum leptin levels were significantly correlated with BMI in those patients with low (R2 = 0.363; p < 0.001) and intermediate disability (R2 = 0.408; p < 0.001), but not in patients with a higher disability score (R2 = 0.064; p = 0.256). Conclusion: BMI, the major determinant of leptin level in physiological conditions, has a minor role in determining the serum levels of leptin in MS patients with a high EDSS score. Future longitudinal studies will be required in order to provide further insights into the regulation of leptin secretion in patients with MS.

Serum CXCL10 levels and occurrence of thyroid dysfunction in patients treated with interferon-α therapy for hepatitis C virus-related hepatitis

OBJECTIVE Thyroid autoimmunity is a common side effect of interferon-alpha (IFN-alpha) treatment for chronic hepatitis C. There are currently no reliable parameters to predict the occurrence of thyroid dysfunctions in patients undergoing IFN-alpha 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-alpha 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-alpha therapy (2, 4 and 6 months) and in 50 healthy controls. HCV patients were retrospectively selected according to the occurrence of IFN-alpha-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-alpha treatment (33 and 90% respectively). CONCLUSION Our results suggest that measuring serum CXCL10 before IFN-alpha treatment may be helpful for identifying those patients with higher risk to develop thyroid dysfunction, and require a careful thyroid surveillance throughout the treatment.