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Context: Nodular goiter in patients from areas of iodine deficiency is due to the growth of follicular and endothelial cells, involving different vascular-related growth factors in its pathogenesis., Objective: The aim of our study was to examine the association of known single polymorphisms of vascular endothelial growth factor-A [VEGF-A], VEGF receptor-2 [VEGFR-2] and hypoxia-inducible factor-1α [HIF-1α] genes or their genetic interactions with the risk of nodular goiter development., Patients and Methods: 116 normal subjects, without any thyroid disease, and 108 subjects with nodular goiter [subjects with goiter and at least one thyroid nodule of > 1 cm of maximum size and in absence of signs of autoimmunity] were selected from a homogeneous population living in a mild iodine deficiency geographic area. Analyses were performed on germline DNA obtained from blood samples and VEGF-A rs3025039, VEGFR-2 rs2071559, and HIF-1αrs11549465 SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction [MDR] methodology was applied to investigate the genetic interaction between SNPs. Hardy-Weinberg equilibrium was performed., Results: None of the studied polymorphisms were individually associated with a higher risk to develop nodular goiter [P > 0.05]. The combination of the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms had the highest accuracy of 0.58 [P = 0.018] and the interaction of some genotypes was significantly associated with the risk of nodular goiter development., Conclusions: Our results support a genetic interaction between the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms as a predictor of the risk to develop nodular goiter in subjects coming from an area with mild iodine deficiency.

Purpose: The evidence regarding association between thyroid disorders and benign and malignant breast diseases is increasing. The studies exploring the relationship between thyroid and breast diseases usually have focused on thyroid autoimmunity and functions in patients with breast pathologies. In this study, we aimed to reveal the frequency of benign breast conditions in patients with nodular thyroid disease (NTD) and Hashimoto's thyroiditis (HT)., Methods: Seventy-one women with NTD, ninety-five women with HT and seventy-two healthy people as a control group were included in the study. Serum thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and thyroid peroxidase autoantibody levels were measured, and thyroid and breast ultrasonography were performed by a single operator in order to determine thyroid and breast pathology., Results: Benign breast diseases were detected in 54.9% of patients with NTD, in 47.4% of those with HT, and 29.2% of control group in the study (p < 0.01 for nodular and Hashimoto groups versus control group). Simple cyst was found to be the most frequent pathology among benign breast diseases; fibrocystic changes, mixed lesions, benign solid mass, ductal ectasia, and complex cyst followed it. No significant relation was found regarding thyroid function and autoimmunity in patients diagnosed with benign breast disease (p > 0.05)., Conclusions: The results of our study support the association between benign breast diseases and thyroid diseases. An important implication of this finding may be demonstration of the necessity of scanning for potential breast pathology in women with nodular or autoimmune thyroid disease in clinical practice.

Purpose: A large goiter can cause a series of compressive symptoms such as dyspnea and dysphagia, and previous case reports have indicated the coexistence of obstructive sleep apnea syndrome (OSAS) in these patients. The aim of this study was to evaluate the impact of thyroidectomy on the control of OSAS in patients with large goiters., Methods: Twenty-four patients with euthyroid goiters larger than 100 ml were consecutively selected. Of these, 17 (70.8%) presented OSAS and formed the research group. The protocol consisted of sleep questionnaires, physical examination, and polysomnography in baseline and after 3 months of surgery., Results: The average age of the patients was 58.3±9.9 years, and there were 5 (29.4%) males and 12 (70.6%) females. The significant findings in the postoperative period included a reduced neck circumference (p=0.041), reduced Epworth sleepiness score (p=0.025), decreased percentage of high-risk OSAS cases according to the Berlin questionnaire (p<0.001), and a tendency for a significant reduction in snoring (p=0.052). However, polysomnographic respiratory parameters showed no significant improvement after surgery., Conclusion: Despite the high prevalence of OSAS in patients with large goiters and the improvement of OSAS symptoms, thyroidectomy showed no significant impact on the polysomnographic parameters.

Background: Few data exist on the prevalence of female sexual dysfunction (FSD) in thyroid disorders., Aim: We evaluated FSD in women with thyroid diseases and in control age-matched healthy women to investigate the relationship between sexual function and thyroid hormones., Methods: One hundred and four women with thyroid diseases and 53 controls participated in the study. Eighteen with hyperthyroidism (Group 1), 22 hypothyroidism (Group 2), 45 Hashimoto's thyroiditis (Group 3), 19 nodular goiter (Group 4) underwent thyroid function evaluation and sonography. The Female Sexual Function Index (FSFI) assessed sexual function., Results: The prevalence of FSD was 46.1% in thyroid diseases and 20.7% in controls. Only in Group 4, the prevalence (68.4%) was significantly higher than in controls (p<0.005). The mean total FSFI score was 20.1 ± 7.1 in women with thyroid diseases and 25.6 ± 4.7 in the controls (p<0.001). Compared with controls, there was a significant decrease of desire in Group 2; desire, arousal and lubrication in Group 3; desire, arousal, lubrication, orgasm and satisfaction in Group 4. In thyroid diseases the prevalence of FSD was 53% and 42%, while in the controls was 55% and 20%, in menopausal and pre-menopausal groups, respectively. We found a significant inverse correlation between TSH and FSFI (r=-0.7, p=0.01) in Group 4, which showed the lowest FSFI score (17.8 ± 5.7) and the highest body mass index (28.4 ± 7.1 kg/m(2))., Conclusions: Women with thyroid diseases present a higher prevalence of FSD than controls. Although our findings suggest a higher impairment of sexual function in Group 4 and a role for TSH in FSD, further researches are needed.

Background: Italy is characterized by high prevalence of goiter. To date, only limited data about the prevalence of goiter in the Italian adult population are available., Aim: To investigate the prevalence of thyroid ultrasound abnormalities in adults unaware of any thyroid disease and evaluate the rate of differentiated thyroid cancer (DTC) obtained by this intervention., Methods: Ultrasound (US) thyroid scan was performed in adult volunteers recruited by advertisement in Modena, Italy. One hundred and thirty-five women and 66 men (no.= 201), unaware of any thyroid disease (mean age of 46 ± 10.7 yr) underwent their first thyroid US scan., Results: US thyroid abnormalities were found in 101 subjects (50.3%): 91 nodular goiters (45.2%) and 13 US-thyroiditis (6.5%) associated with positive auto-antibodies in 11 of them. Seventeen subjects (18%) with nodules underwent US-fine needle aspiration biopsy with the following cytological class (C) outcome: 14 patients C2 (82%), 1 patient C3 (6%), 2 patients had C4 (12%), the latter received histological confirmation., Conclusions: The prevalence of thyroid abnormalities is very high in subjects unaware of any thyroid disease. DTC was found in 1% of subjects and in 2% of those affected by nodular goiter. Compared to the detection rate of the well-established screening programs for breast (0.45%) and colorectal (0.27%) cancer, the prevalence of DTC seems to be much higher. Thyroid US screening could allow the detection of DTC in asymptomatic subjects and this diagnosis often includes DTC at an advanced stage. Thus, US screening not necessarily results in the over-diagnosis of clinically not relevant thyroid diseases.

Introduction: Goiters cause a series of compressive symptoms, including dyspnea and dysphagia. There have been reports of the coexistence of this syndrome with obstructive sleep apnea (OSA). The objective of this study was to evaluate the prevalence of OSA in a group of patients with goiters., Methods: Twenty-four patients with a mean age of 52.7 ± 12.7 years, including five males (20.8 %) and 19 (79.2 %) females, who were diagnosed with euthyroid goiters with volumes exceeding 100 ml were consecutively selected. The protocol consisted of sleep questionnaires, physical examinations, and baseline polysomnography measurements. Patients were divided into two groups, OSA and NOSA (no OSA), and all findings were compared between the two groups., Results: Of the studied patients, 70.8 % had OSA (p = 0.004). Regarding clinical parameters, age (p = 0.001), Epworth Sleepiness Scale scores (p = 0.039) and complaints of habitual snoring (p < 0.001) had higher values in the OSA group. Regarding physical examination parameters, body mass index (p = 0.012), neck circumference (p = 0.009) and the presence of tracheal compression (p = 0.021) had higher values in the OSA group. The polysomnographic parameters that were significantly different between the two groups were the greater apnea and hypopnea index per hour of sleep (p < 0.001) and the lower minimum oxyhemoglobin saturation in the OSA group (p = 0.011)., Conclusions: There is a high prevalence of OSA in patients with goiters. The main findings that were associated with the presence of OSA are known clinical predictors of OSA and the presence of tracheal compression.

Background: Obesity and insulin resistance predispose individuals to the development of both metabolic syndrome and non-toxic nodular thyroid diseases., Aim: The aim of this observational, cross-sectional study is to evaluate the relationship between metabolic syndrome and multinodular nontoxic goiter in an inpatient population from a geographic area with moderate iodine deficiency., Subjects and Methods: We examined 1422 Caucasian euthyroid inpatients. Thyroid volume was determined by ultrasound of the neck. A fine-needle aspiration biopsy was performed to evaluate single thyroid nodules and dominant nodules ≥15 mm in euthyroid multinodular goiter. The diagnosis of metabolic syndrome was made according to the criteria of the American Heart Association/ National Heart, Lung, and Blood Institute., Results: Of the sample, 277 patients had clinical evidence of multinodular nontoxic goiter, 461 met the criteria for the diagnosis of metabolic syndrome, and 132 were found to have both conditions. After adjusting for age, gender, body mass index, nicotinism, parity, alcohol intake, thyroid function, and metabolic syndrome- related pharmacological treatment, metabolic syndrome was found to be an independent risk factor for the occurrence of multinodular non-toxic goiter. The relationship between metabolic syndrome and multi nodular non-toxic goiter was apparent in both men and women., Conclusions: In this study of euthyroid inpatients, we demonstrate that metabolic syndrome is an independent risk factor for the occurrence of multinodular non-toxic goiter in a geographic area with moderate iodine deficiency. We propose that patients meeting the criteria for metabolic syndrome should be screened for the presence of multinodular non-toxic goiter.

Objective: The association between iodine status and the prevalence of goiter and thyroid nodules has been well established but the extent to which different iodine intake levels influence the incidence of goiter and thyroid nodules is unclear. The aim of the study was to determine the incidence of goiter and thyroid nodules in 3 regions with different iodine intake levels: mildly deficient, more than adequate, and excessive., Design, Patients and Measurements: Of the 3385 unselected subjects enrolled in 1999 in Panshan, Zhangwu, and Huanghua where median urinary iodine excretion (UIE) was 83.5 microg/l, 242.9 microg/l, and 650.9 microg/l, respectively, 2708 (80.0%) participated in the follow-up study in 2004. The examinations of thyroid ultrasonography, thyroid function, thyroid autoantibodies and UIE were performed at baseline and follow-up., Results: The cumulative incidence of diffuse goiter was 7.1%, 4.4%, and 6.9%, respectively, higher in Panshan and Huanghua than in Zhangwu (p=0.013 and p=0.015) and that of nodular goiter was 5.0%, 2.4%, and 0.8%, respectively, declining with increasing iodine intake levels (p<0.001). Mild iodine deficiency, chronic iodine excess as well as positive thyroid autoantibodies were associated with the occurrence of goiter [Logistic regression: odds ratio (OR)=1.83 (95% confidence interval (CI) 1.26-2.65), OR=1.46 (95% CI 1.01-2.11) and OR=1.68 (95% CI 1.14-2.48), respectively]. The cumulative incidence of single nodule was 4.0%, 5.7%, and 5.6%, respectively and that of multiple nodules was 0.4%, 1.2%, and 1.0%, respectively., Conclusions: The relationship between iodine and the risk for the occurrence of diffuse goiter shows a U-shaped curve. Nodular goiters are more prevalent in iodine-deficient areas.

An optimal supply of iodine--150-200 microg/day--has not yet been secured in all regions and in all phases of life. The appreciable diminishment in thyroid gland mass in children and adolescents is, however, indicative of an improvement in this situation. In elderly persons, however, prophylactic measures do not result in struma or nodule regression. Nodules are found in some 40% of women and 28% of men older than 45. Medical treatment of nodular goiter is aimed at achieving a reduction in size or preservation of the status quo. Depending on the size of the goiter, iodine-deficiency goiter is treated with iodine or a combination of iodine and levothyroxine. In view of the pathogenesis and the marginal alimentary lack that still persists, there are no adequate arguments for L-thyroxine monotherapy of uncomplicated iodine-deficiency goiter.

Investigations within the framework of the thyroid gland initiative "Papillon" turned up an unexpectedly high level of pathogenic findings. Determination of TSH and sonography are considered the pillars of the diagnostic evaluation of the thyroid gland. Useful further investigations aimed at excluding functional disorders are, for example, the determination of FT3 and FT4 or a search for autoantibodies. To investigate suspicious nodules and to exclude malignant processes, additional scintigraphy and, were indicated, fine-needle puncture can be applied. Depending on the individual situation of the patient, the therapeutic option of choice is surgical operation or treatment with iodine-31 therapy. Medical treatment of nodular goiter is currently still controversial.

Iodine deficiency is widely known to be the main cause of nodular goiter (NG). In iodine deficient areas subclinical and overt hyperthyroidism is the major cause of morbidity and it is mainly due to toxic NG rather than Graves' disease. Toxic NG, including toxic multinodular goiter and toxic thyroid adenoma is usually encountered in subjects with long-standing NG, in whom thyrotoxicosis is usually preceded by a long phase of euthyroidism and then subclinical hyperthyroidsm (abnormally low TSH with normal circulating thyroid hormones). Epidemiological studies indicate that, compared to Graves' disease, the incidence and prevalence of non-autoimmune hyperthyroidism due to toxic adenoma and toxic multinodular goiter differ in different regions of the world, being much more frequent in areas of iodine deficiency. Recently, mutations of the TSH receptor (TSHr) gene causing permanent activation of the thyroid follicular cell adenylate-cyclase, have been shown to be the most probable cause of the hyperfunction and growth of toxic adenoma. In this review we will focus our attention on the role of external factors (i.e. iodine deficiency) with respect to individual factors (i.e. genetic mutations) in the pathogenesis of toxic NG.

Despite the observation that parity may increase the risk of thyroid carcinoma, very few studies have investigated the possible repercussion of parity on thyroid benign pathology. Recently, parity has been identified as one of the factors contributing to a larger thyroid size in healthy females. The aim of this work was to investigate a possible role for parity on the prevalence of multinodular goiter in iodine deficient areas. For this purpose, the reproductive histories of 2 cohorts of women, normal (Group I, 235 cases) and non-toxic multinodular goiter (NTMNG) affected (Group II, 274 cases) were compared. All subjects were euthyroid and had no previous history of thyroid function abnormalities. The number of full-term previous pregnancies (2.55+/-0.11 vs 1.77+/-0.10) and age (47.7+/-0.76 vs 42.3+/-0.83 yr) were found significantly higher (p<0.001) in multinodular goiter (MNG) patients than controls. Parity and age were found to be directly correlated (p<0.001), nevertheless the partial correlation coefficients demonstrated an independent and statistically significant difference for both variables between normal and NTMNG. Therefore, the independent effects of parity and age were further investigated. The effect of age on NTMNG prevalence seems to be weaker, in fact significant differences (p<0.001) for age between patients and controls were detected only when the effect of parity was absent (nulliparous), while with increasing gestations the effect of age disappeared. Our results indicate that age plays a minor role compared to parity which can therefore be considered as a stronger risk factor. In conclusion, the present study shows that, at least in iodine deficient regions, non-toxic multinodular goiter women show a statistically significant higher parity rate than healthy controls. Age may play a certain role but only when additional stronger risk factors are absent.

Toxic nodular goiter (TNG) is the most frequent cause of thyrotoxicosis in the elderly, specially in iodine deficient areas. Epidemiological studies have shown that in iodine deficient areas (Jutland) the incidence of hyperthyroidism is significantly higher with respect to areas with normal iodine intake (Iceland) and it is due to TNG. A careful epidemiological study recently carried out in Pescopagano, in southern Italy, an area characterized by a mild to moderate iodine deficiency, indicates that, in its natural history, nodular goiter contributes to the development of functional autonomy and eventually hyperthyroidism. Somatic activating mutations of the TSH receptor are involved in the pathogenesis of TNG. It is supposed that the prolonged iodine deficiency associated with chronic TSH stimulation increases the replication of follicular thyroid cells, and favor the appearance and expression of mutations of the TSH receptor gene. The clinical signs are usually more subtle than those observed in Graves' disease: a long phase of subclinical hyperthyroidism (normal circulating thyroid hormones and undetectable TSH levels) can precede the appearance of the symptoms. Cardiac symptoms are most frequent, (arrhythmia and atrial fibrillation). Thyroid scintigraphy in toxic multinodular goiter shows an uneven distribution of the radionuclide with multiple hyperfunctioning nodules and cold nodules. Thyroid US shows goiter with inhomogeneous solid nodules often with ill-defined borders. The treatment with antithyroid drug does not allow a permanent remission of hyperthyroidism, but its use is indicated to achieve euthyroidism before the definitive treatment. The definitive treatment is radioiodine or thyroidectomy.

Primary hyperparathyroidism (HPT) and thyroid disease are both relatively common diseases, which can coexist in the same patient. However, mere coincidence does not seem to be a satisfactory explanation for this association. Some factors like prior exposure to radiation may play a role in the association. The aim of this study was to determine the frequency of thyroid disease associated with HPT in 54 consecutive patients who underwent parathyroidectomy in our center from January 1990 to December 1997. Twenty-eight (52%) patients had thyroid disease associated to HPT. The patients had a mean age of 61+/-13 yr; they were predominantly postmenopausal women. Thyroid disease was detected preoperatively in 20 (71%) patients and during the surgical procedure in 8 (29%). Two patients had previous radiation exposure; one of them with papillary carcinoma of the thyroid. Two patients had hypothyroidism. UItrasonography was performed in the majority of patients in their preoperative evaluation. A multinodular goiter was seen to be the most frequent finding (76%). In addition to parathyroidectomy, 23 (82%) patients were also thyroidectomized. In conclusion, patients with HPT showed a high prevalence of thyroid disease, especially in postmenopausal women. Unsuspected thyroid lesions were found with sufficient frequency to warrant careful preoperative and intraoperative evaluation of both glands, in order to obviate reoperation. In experienced hands, combined surgery can be safely performed. Cervical ultrasonography is useful in the preoperative detection of nodular thyroid disease in these patients.

We evaluated the prevalence of antithyroid peroxidase antibodies (anti-TP0 Ab) in 402 patients with thyroid disease and 30 healthy controls by a commercial radioimmunoassay (RIA) and compared the results with the passive hemagglutination (HA) method. The patients in the study had autoimmune thyroid disorders (AITD) such as Graves' disease and Hashimoto's disease or had nonautoimmune thyroid diseases (NAITD) such as thyroid cancer, congenital goiter, endemic goiter, and nodular goiter. Subjects were recruited from a population with a mild iodine deficiency (Sao Paulo, Brazil). The effect of specific therapy (for either thyrotoxicosis or chronic thyroiditis) on the circulating anti-TPO levels was also investigated. Positive anti-TPO Ab was detected in 89.9% of the patients with AITD as compared with a prevalence of positive tests of only 4.8% in patients with NAITD. Positive microsomal antibody (M Ab) was found in 68.4% of the patients with AITD and in 6.4% of the patients with NAITD. A positive and significant correlation was obtained between M Ab and anti-TPO Ab. A positive anti-TPO test with negative anti-M was found in 14.1% of the patients with AITD but in only 4.3% of the patients with NAITD and normal controls. These results suggest that anti-TPO Ab by RIA is more sensitive and specific than M Ab by HA. In patients with AITD, anti-TPO Ab levels usually decreased after treatment, suggesting that this parameter could be used in the follow-up of these thyroid disorders.