Valentina Capelli

Shear wave elastography in the diagnosis of thyroid nodules: feasibility in the case of coexistent chronic autoimmune Hashimoto’s thyroiditis

Objective  ShearWave™ Elastography (SWE) is real‐time, quantitative and user‐independent technique, recently introduced in the diagnostic work‐up of thyroid nodules. Hashimoto’s thyroiditis (HT), characterized by variable degrees of lymphocytic infiltration and fibrosis, might affect shear wave propagation. The aim of this study was to assess the feasibility of SWE in cytologically benign thyroid nodules within both Hashimoto’s and nonautoimmune thyroid glands. The effect of autoimmunity on the gland stiffness was also evaluated.

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.

Comparison of Elastographic Strain Index and Thyroid Fine-Needle Aspiration Cytology in 631 Thyroid Nodules

CONTEXT Ultrasound (US) elastography (USE) was recently been reported as a sensitive, noninvasive tool for identifying thyroid cancer. However, the accuracy of this technique is hampered by the intra- and interoperator variability, some US features of the nodule, and the coexistence of autoimmune thyroid disease (ATD). OBJECTIVES The purpose of this article was to assess the accuracy of USE findings in the differential diagnosis of thyroid nodules compared with other US features to evaluate its feasibility in the presence of ATDs and identify the strain index (SI) cutoff with the highest diagnostic performance. DESIGN We evaluated 528 consecutive patients for a total of 661 thyroid nodules. All nodules underwent fine-needle aspiration cytology (FNAC) and USE evaluation. The SI was calculated as a ratio of the nodule strain divided by the strain of the softest part of the surrounding normal tissue. RESULTS The median SI value was significantly higher in THY4 and THY5 than in THY2 nodules in ATD-positive, ATD-negative, and ATD-unknown patients. The cutoff of SI for malignancy was estimated to be 2.905 by receiver operating characteristic curve analysis in a screening set (379 FNAC results), and then tested in a replication set (252 FNAC results). In all cases, a SI value of ≥ 2.905 conferred to the nodule a significantly greater probability of being malignant. This SI cutoff had the greatest area under the curve, sensitivity, and negative predictive value, compared with the conventional US features of malignancy. CONCLUSION The elastographic SI has a high sensitivity, specificity, and negative predictive value for the diagnosis of thyroid malignancy both in the presence and in the absence of ATD. If our data on USE are also confirmed in THY3 nodules, FNAC could be avoided in a number of thyroid nodules with certain features.

Impaired Outcome of Controlled Ovarian Hyperstimulation in Women with Thyroid Autoimmune Disease

BACKGROUND Controlled ovarian hyperstimulation (COH) is a crucial step of assisted reproductive technology (ART). Thyroid dysfunction and autoimmune thyroid disease (ATD) may negatively affect the outcome of ART, but the underlying mechanisms are still poorly understood. Our aim was to evaluate the respective role of ATD and thyroid function, as assessed by serum thyrotropin (TSH), on the early outcome of COH. METHODS In total, 262 (202 ATD-negative and 60 ATD-positive) euthyroid subfertile women underwent ART. Before COH, serum follicle-stimulating hormone (FSH), luteinizing hormone, and estradiol (E2) were measured at cycle day 3, and progesterone at cycle day 21. At oocyte pickup and at embryo transfer, we evaluated the performance of recombinant FSH (r-FSH), as assessed by serum E2 concentration/total administered r-FSH units (E2/r-FSH) ratio and by oocyte quality. RESULTS At both oocyte pickup and embryo transfer, the performance of r-FSH was significantly poorer in ATD-positive than in ATD-negative women. In the ATD-positive group, women with a TSH <2.5 mIU/L displayed a higher serum E2 concentration at oocyte pickup, a higher E2/r-FSH ratio, and a greater number of mature metaphase II oocytes than women with a TSH >2.5 mIU/L. When ATD-positive women were divided into quartiles according to their serum TSH level, both the ovarian response to r-FSH and the number of mature metaphase II oocytes significantly increased from the lowest to the highest quartiles of serum TSH concentration. CONCLUSIONS ATD has a negative effect on the early outcome of COH, but this negative influence may be avoided with adequate levothyroxine therapy aimed at keeping TSH <2.5 mU/L. Thyroid antibodies and serum TSH should be checked in any woman undergoing ART.

Autoimmune Thyroid Diseases in Patients Treated with Alemtuzumab for Multiple Sclerosis: An Example of Selective Anti-TSH-Receptor Immune Response

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for the treatment of active relapsing-remitting multiple sclerosis (MS). Alemtuzumab induces a rapid and prolonged depletion of lymphocytes from the circulation, which results in a profound immuno-suppression status followed by an immune reconstitution phase. Secondary to reconstitution autoimmune diseases represent the most common side effect of Alemtuzumab treatment. Among them, Graves’ disease (GD) is the most frequent one with an estimated prevalence ranging from 16.7 to 41.0% of MS patients receiving Alemtuzumab. Thyrotropin (TSH) receptor (R)-reactive B cells are typically observed in GD and eventually present this autoantigen to T-cells, which, in turn, secrete several pro-inflammatory cytokines and chemokines. Given that reconstitution autoimmunity is more frequently characterized by autoantibody-mediated diseases rather than by destructive Th1-mediated disorders, it is not surprising that GD is the most commonly reported side effect of Alemtuzumab treatment in patients with MS. On the other hand, immune reconstitution GD was not observed in a large series of patients with rheumatoid arthritis treated with Alemtuzumab. This negative finding supports the view that patients with MS are intrinsically more at risk for developing Alemtuzumab-related thyroid dysfunctions and in particular of GD. From a clinical point of view, Alemtuzumab-induced GD is characterized by a surprisingly high rate of remission, both spontaneous and after antithyroid drugs, as well as by a spontaneous shift to hypothyroidism, which is supposed to result from a change from stimulating to blocking TSH-receptor antibodies. These immune and clinical peculiarities support the concept that antithyroid drugs should be the first-line treatment in Alemtuzumab-induced Graves’ hyperthyroidism.

Migration flows affect women’s dietary iodine intake and jeopardize their iodine sufficiency: a pilot study

In Latin American countries iodine deficiency was recognized as a public health problem since the early years of the twentieth Century. Due to effective salt iodization programs, since 2004 the successful elimination of iodine deficiency by iodized salt was reported in Latin America [1]. On the contrary, Italy is still classified as a mild iodine deficiency country [2]. Several studies provide evidence that migration impacts the individual’s life, being a strong determinant of health [3–5]. Migrants live in a new environment, which significantly differs from the one of origin [4–7]. Thus, Latin American immigrants migrating to Italy might experience a lower iodine intake due to both different food habits and different amounts of iodine content in foods. The aim of this pilot study was to investigate the iodine intake of native Latin American women migrating to Italy.

MAXIMAL STIFFNESS EVALUATION BY REAL-TIME ULTRASOUND ELASTOGRAPHY, AN IMPROVED TOOL FOR THE DIFFERENTIAL DIAGNOSIS OF THYROID NODULES

OBJECTIVE The aim of the study was to evaluate the diagnostic performance of a new ultrasound elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI) and to investigate their diagnostic performance according to nodule size. METHODS The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation, and fine-needle aspiration cytology (FNAC). Thyroid nodules were further stratified into 4 subgroups (G) according to their size (G1, <1 cm; G2, 1-2 cm; G3, >3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI. RESULTS The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity, 0.66 and 0.90, respectively; % Index sensitivity and specificity, 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (odds ratio [OR], 18.68; 95% confidence interval [CI], 6.06 to 63.49; P<.0001 versus OR, 26.15; 95% CI, 8.01 to 102.87; P<.0001, respectively) and in the G1 and G2 subgroups. CONCLUSION The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to explore both by conventional US and FNAC.

Improvement of intra-epidermal nerve fibre density in hypothyroidism after L -thyroxine therapy

Hypothyroidism may induce a wide range of neurological complaints, frequently described in the past, but nowadays rarely reported because of earlier diagnosis and treatment. By investigating a series of neurologically asymptomatic, untreated patients with hypothyroidism, either overt (OH) or subclinical (SH), we found in 11% of them an asymptomatic polyneuropathy, as assessed by conventional neurophysiological studies. In the same group of patients, using a skin biopsy technique, we observed a significant reduction in intra-epidermal nerve fibre (IENF) density with a prevalence of 60% and 25 % in OH and SH, respectively. In all patients, the reduction in IENF density was length dependent, that is, more evident in the distal region of the leg. Skin biopsy, a safe and validated technique to assess IENF density, is more sensitive than clinical examination or quantitative sensory testing for detecting neurological abnormalities. The standardized method to determine the innervation is based on the quantification of linear IENF density, although recently the morphometry of dermal nerves has been proposed to improve the diagnostic yield of skin biopsy. Here, we describe the changes in skin IENF density, as assessed by skin biopsy, in six hypothyroid patients of the original study group who were rendered euthyroid after a 1-year course of L-thyroxine (LT4) replacement therapy. Six patients diagnosed with overt (n = 3) or subclinical (n = 3) hypothyroidism (mean age, 51 ± 4·8 SD years) had a second skin biopsy performed 1 year after starting LT4 treatment, that is, after a stable period of euthyroidism of at least 9 months. Overt hypothyroidism was defined as raised serum levels of TSH associated with free thyroxine (FT4) values below the normal range, while subclinical hypothyroidism included patients with high serum levels of TSH (>4 mIU/l) and FT4 concentrations in the normal range. In all patients, hypothyroidism was caused by chronic autoimmune thyroiditis. The duration of hypothyroidism calculated as the time elapsed from the biochemical diagnosis or from the surgical or radiometabolic procedure not followed by hormonal substitution, ranged from 6 to 36 months (median 12 months). As previously described, using a 3-mm punch tool, biopsies were carried out from the skin of the upper thigh (20 cm below the iliac spine) and of the distal leg (10 cm proximal to lateral malleolus). Nerve fibres were identified by indirect immunofluorescence. The primary antibody, directed against the nonspecific neuronal marker PGP 9.5 (Biogenesis, Poole, UK; 1:1000), was detected using a second antibody conjugated to the cyanine dye fluorophore Cy3 (Jackson Immuno Research, West Grove, PA, USA). Using a fluorescence microscope (magnification 409, Axioskop 40 FL; Zeiss, Gottingen, Germany), IENF density was evaluated by counting only fibres crossing the basement membrane. The serum concentrations of FT4 (normal range, 10·2– 24·4 pM) and TSH (third-generation TSH assay; normal range, 0·4–4 mIU/l) were measured using immunochemiluminescent assays by an automated analyser (Immulite 2000; DPC Cirrus, Los Angeles, CA, USA) employing commercial kits (Diagnostic Products Corporation, Los Angeles, CA, USA). All patients gave their written informed consent according to the local Ethics Committee, and the guidelines of the Declaration of Helsinki after full explanation of the purpose and nature of all procedures used. Data were expressed as mean ± SD. Between-group comparisons were performed by Student’s t-test for unpaired data. All hypothyroid patients were rendered euthyroid by a 1-year course of LT4 treatment. Figure 1 shows the results of skin biopsies performed before hypothyroidism was treated and after 1 year of LT4 replacement therapy. IENF density improved in all patients irrespective of the severity of initial thyroid failure. The increase in IENF density was statistically significant at the distal leg, which was the more severely affected district before treatment. To our knowledge, this is the first demonstration that the impairment of IENF density observed in neurologically asymptomatic hypothyroid patients is reversible after LT4 treatment. The only previous description of a reversible IENF density impairment after LT4 treatment is the case report of a patient with subclinical hypothyroidism complaining from neuropathic pain. Hypothyroidism, particularly when subclinical, is a common disorder with a prevalence of 4–10% in the general adult population. While LT4 replacement therapy is mandatory in overt hypothyroidism, the question of whether subclinical hypothyroidism should always be treated is still debated. Although some experts recommend treatment in patients with subclinical hypothyroidism, even when the TSH increase is mild, others believe that a routine treatment with LT4 is not necessary in the absence of specific or potentially reversible symptoms. The results of this preliminary study show that a small fibre sensory neuropathy is present in both overt and subclinical hypothyroidism and suggest that this is reversible after LT4

Poverty and immigration as a barrier to iodine intake and maternal adherence to iodine supplementation

PurposeIodine deficiency still remains a significant health issue worldwide. Pregnant and lactating women are at risk for iodine deficiency when living in mild iodine-deficient areas such as Italy. This study aims at evaluating the consumption of iodized salt, iodine-rich-foods and maternal micronutrient supplements in a group of women with limited access to the Italian National Health System.MethodsA cross-sectional survey was conducted among immigrant and Italian women living in poverty and referring to 40 Non-Governmental Organization throughout Italy for their health needs. 3483 women answered the ad hoc questionnaire between January 2017 and February 2018.ResultsThe consumption of iodized salt was very low, and even lower among immigrant women. Determinants of iodized salt consumption were the period spent in Italy for immigrant women and living in a family-type setting, parity and, particularly, the degree of education for Italian ones. 17.5% of immigrant women and 8.6% of the Italian ones reported a diagnosis of thyroid disease. 521 women, 75.4% of whom were immigrants, were pregnant or breast-feeding. The majority (57.3%) had no specific maternal supplementation.ConclusionsBoth Italian and immigrating women with a low income or without access to the public health system have a poor adherence both to the salt iodization policy and to folic acid and iodine supplements in preconception and pregnancy. They also referred a low-frequency intake of iodine-rich-foods. The identification of barriers to health care access could be useful to promote specific health interventions in this target population.