TSH lowering effects of metformin: a possible mechanism of action.

Preliminary clinical evidence suggests that metformin has TSH lowering effects in patients with T2DM and hypothyroidism or in those with TSH serum levels in the upper normal value. Also, metformin may exert a protective role against thyroid nodules growth in patients without insulin-resistance. The cross-talk between tyrosine kinase receptors and the G protein-coupled receptors (which the TSHR belongs to) has been already shown and IRS1 may represent the hub link between TSHR and IR pathways. By influencing IRS1 phosphorylation pattern, metformin may sensitize TSHR to TSH, thus explaining the findings of clinical studies. However, the existence of this molecular pathway must be confirmed through proper studies and further prospective randomized placebo-controlled studies are needed to confirm this hypothesis.

The effects of iodine blocking on thyroid cancer, hypothyroidism and benign thyroid nodules following nuclear accidents: a systematic review.

A potential radiation protection method to reduce the risk of adverse health outcomes in the case of accidental radioactive iodine release is the administration of potassium iodide (KI). Although KI administration is recommended by WHO's Guidelines for Iodine Prophylaxis following Nuclear Accidents, a systematic review of the scientific evidence for the guidelines is lacking. Therefore, this study aims to systematically review the effects of KI administration in the case of accidental radioactive iodine release on thyroid cancer, hypothyroidism and benign thyroid nodules. We applied standard systematic review methodology for a search of the literature, selection of eligible studies, data extraction, assessment of risk of bias, assessment of heterogeneity, data synthesis, and the assessment of the quality of the evidence. We searched MEDLINE (via PubMed) and EMBASE. We found one cross-sectional study, one analytic cohort study and two case-control studies relating to our question. The number of participants ranged from 886-12 514. Two studies were conducted in children and two other studies in children and adults. It was not possible to conduct a meta-analysis. We identified low to very low-quality evidence that KI administration after a nuclear accident resulted in a reduction of the risk of thyroid cancer in children; however, the KI administration and dose was not well described in the studies. None of the studies investigated the effects of KI administration in the case of a nuclear accident on hypothyroidism and benign thyroid nodules. Low to very low-quality evidence suggests that KI intake following a nuclear accident may reduce the risk of thyroid cancer in children. No conclusions can be drawn about the effectiveness of KI intake with respect to the prevention of hypothyroidism and benign thyroid nodules.

The effect of raw vegetable and fruit intake on thyroid cancer risk among women: a case-control study in South Korea.

Thyroid cancer is the most common cancer among Korean women. However, there are few data on dietary factors related to thyroid cancer risk. The objective of the present study was to evaluate the association between raw vegetables and fruits intake and thyroid cancer in a case-control study. We included 111 histologically confirmed malignant thyroid cancer cases and 115 benign cases. Controls who did not have nodules in thyroid ultrasonography were matched to cases by age (± 2 years). Food and nutrient intakes were estimated using a quantitative FFQ with 121 items. Conditional logistic regression analysis was used to obtain OR and corresponding 95 % CI. The intake of total vegetables was not associated with malignant thyroid cancer, but inversely associated with benign cases. High raw vegetable intake was inversely associated with thyroid cancer risk both in malignant and benign cases (P for trend = 0·01 in both malignant and benign cases). Among fruits, persimmon intake had an inverse association with thyroid cancer risk in both malignant and benign cases (P for trend = 0·06 in malignant cases; P for trend = 0·01 in benign cases) and tangerine intake had an inverse association in malignant cases (P for trend = 0·03). The frequency of consumption of raw vegetables and persimmon also had a consistent inverse association in both malignant and benign cases. These results suggest that high consumption of raw vegetables, persimmons and tangerines may decrease thyroid cancer risk and help prevent early-stage thyroid cancer.

Long-Term Outcomes Following Thermal Ablation of Benign Thyroid Nodules as an Alternative to Surgery: The Importance of Controlling Regrowth.

Thermal ablation (TA) procedures, such as radiofrequency ablation and laser ablation, are used for the treatment of benign thyroid nodules. Short-term studies (<2 years) have demonstrated that TA is an effective and safe procedure to improve cosmetic or symptomatic problems. However, studies including a longer follow-up period show that treated thyroid nodules can increase in size after 2 to 3 years. Several studies suggest that this results from regrowth at the undertreated nodule margins. Here, we review current data on regrowth after TA and describe factors related to it and possible approaches to prevent it.

Reduced thyroid volume and nodularity in dyslipidaemic patients on statin treatment.

BACKGROUND: Little information is available concerning the possible antiproliferative effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on the thyroid gland. We have hypothesized that the antiproliferative effects of statins observed in thyroid cell lines in vitro may have a clinical counterpart that could be detected by investigating the prevalence and size of thyroid nodules in patients on long-term treatment with statins. METHODS: We retrospectively evaluated 135 dyslipidaemic patients receiving statin therapy continuously for at least 5 years, and 137 controls. All the subjects were submitted to ultrasound investigation of the thyroid gland, to establish prevalence, number and volume of thyroid nodules. RESULTS: Subjects treated with statins showed markedly lower prevalence of thyroid nodules (36.3%vs. 67.9%, P < 0.001), as well as reduced number and smaller total volume of lesions, as compared to the control group. A logistic regression analysis, taking into account age, sex, risk factors for the development of thyroid nodules and concomitant drug treatment, revealed that treatment with statins remained the only important predictor of the presence of thyroid nodules [odds ratio (OR) 0.312, 95% confidence interval (CI) 0.156-0.625, P < 0.001] besides risk factors. CONCLUSIONS: Our data provide the first circumstantial evidence of an association between HMG-CoA reductase inhibitor treatment and reduced prevalence, number and volume of thyroid nodules. This finding may be explained by an antiproliferative and/or pro-apoptotic effect of long-term statin treatment on thyroid cells, in vivo.

The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives.

OBJECTIVE: Denmark was an area of iodine deficiency, and mandatory iodine fortification of table salt and salt in bread (13 p.p.m. iodine) was initiated in 2000/2001. The Danish investigation on iodine intake and thyroid disease (DanThyr) is the monitoring of the iodine fortification program. DESIGN AND METHODS: DanThyr consists of three main parts: a study of population cohorts initialized before (n=4649) and after (n=3570) iodization of salt, a prospective identification of incident cases of overt hyper- and hypothyroidism in a population of around 550,000 people since 1997, and compilation of data from the national registers on the use of thyroid medication, thyroid surgery, and radioiodine therapy. Studies were carried-out in parallel in subcohorts living in areas with differences in iodine content of ground water. RESULTS: The study showed profound effects of even small differences in iodine intake level on the prevalence of goiter, nodules, and thyroid dysfunction. Mild and moderate iodine deficiency was associated with a decrease in serum TSH with age. Other environmental factors were also important for goiter development (increase in risk, smoking and pregnancy; decrease in risk, oral contraception and alcohol consumption), and the individual risk depended on the genetic background. Environmental factors had only a minor influence on the prevalence of thyroid autoantibodies in the population. There were more cases of overt hypothyroidism in mild than in moderate iodine deficiency caused by a 53% higher incidence of spontaneous (presumably autoimmune) hypothyroidism. On the other hand, there were 49% more cases of overt hyperthyroidism in the area with moderate iodine deficiency. The cautious iodine fortification program, aiming at an average increase in iodine intake of 50 mug/day has been associated with a 50% increase in incidence of hyperthyroidism in the area with the most severe iodine deficiency. The incidence is expected to decrease in the future, but there may be more cases of Graves' hyperthyroidism in young people. CONCLUSION: A number of environmental factors influence the epidemiology of thyroid disorders, and even relatively small abnormalities and differences in the level of iodine intake of a population have profound effects on the occurrence of thyroid abnormalities. Monitoring and adjustment of iodine intake in the population is an important part of preventive medicine.

Postoperative suppressive therapy for thyroid adenomas.

Thyroid adenoma is a common disease. If partial thyroidectomy is performed, postoperative suppression therapy is often given to avoid nodule development in the remaining thyroid. It is unclear whether this treatment is warranted. Patients who underwent a partial thyroidectomy with a histologic diagnosis of follicular thyroid adenoma from January 1985 until February 1998 were studied retrospectively. Patients were analyzed on the basis of postoperative therapy, new thyroid nodule growth, and costs. Seventy-six patients were identified with a recurrence rate of 4 per cent (3/76). Sixty-one per cent (46/76) were treated with postoperative thyroid suppression therapy, and no difference in new nodule development was noted with at least 6 months of follow-up (P = 0.274). No patients required reoperation. A large cost saving was shown for patients who were not treated with levothyroxine. We conclude that postoperative thyroid suppression may not be routinely indicated. A prospective, randomized study would be necessary to answer this question conclusively.

[Comments on the prevention of recurrence with thyroid hormone therapy]. / Commentaires sur la prévention des récidives par l'hormone thyroïdienne.

Hemithyroidectomy is the basic operation for isolate thyroid nodules or unilateral multinodular goiters. However, surgeons must check the absence of contralateral nodules by palpation, in order to avoid residual nodules that are not readily amenable to hormone therapy. In a review of 1456 goiters operated between 1968 and 1983, the authors identify only the multinodular nature as a significant risk factor of recurrence. In view of the prevention of residual nodules, they note only 2.5% recurrence. Although some studies demonstrate an increase in the TSH level after hemithyroidectomy, these results do not allow recommending systematic postoperative hormone therapy. This seems to be justified only in a population at risks, namely patients with multinodular goiter, increased postoperative TSH levels, thyroiditis or a family history.

[Is thyroid hormone useful in the prevention of nodular recurrence after hemithyroidectomy?]. / L'hormone thyroïdienne est-elle utile pour prévenir les récidives nodulaires après hémithyroïdectomie?

The frequency of recurrence of thyroid nodule following hemithyroidectomy is variably assessed according to the individual authors. Few studies put a figure to ultrasonographic recurrence, clinical recurrence only being taken into account: its percentage ranges from 10 to 20%, increasing with the time lapse after thyroidectomy. Attempts to prevent recurrence are based on an approach of the physiopathology of thyroid nodules. Clinical and epidemiological studies of patients with goiters suggest that TSH may play a role in the generation of goiters, as has been confirmed by experimental work. However, several other local autocrine or paracrine growth factors may also be involved in the generation of goiters, including IGF I and IGF II (Insulin Growth Factors), FGF (Fibroblast Growth Factor), EGF (Epidermal Growth Factor), TGFB (Transforming Growth Factor beta). On the basis of the possible role of TSH in goiter generation, some teams have advocated a postoperative course of thyroid hormones aimed at limiting thyreostimulin production. These studies, most of them retrospective studies, do not allow drawing a meaningful conclusion because their methods are open to criticism and the results observed are disparate. On a whole, although thyroid hormone therapy is often used after hemithyroidectomy, the physiopathological bases of its prescription are disputable, and the results obtained in terms of recurrence of nodules are not conclusive enough. It is therefore desirable to set up randomized studies.

Prevalence of goiter and thyroid nodules before and after implementation of the universal salt iodization program in mainland China from 1985 to 2014: a systematic review and meta-analysis.

OBJECTIVES: We comprehensively estimated the prevalence of goiter and thyroid nodules (TNs) before and after the implementation of the Universal Salt Iodization (USI) program in mainland China and provided information for creating effective health policies. METHODS: PubMed, Google Scholar, CNKI, Chinese Wanfang and Chongqing VIP databases were searched for relevant studies from Jan 1985 to Feb 2014. Data from eligible citations were extracted by two independent reviewers. All analyses were performed with Stata 11.0 and SPSS 17.0. RESULTS: Eligible articles (N = 31; 4 in English and 27 in Chinese) included 52 studies (15 about goiter rates made before 1996 and 14 afterwards, and 23 about TNs). Our meta-analysis suggests a pooled prevalence for goiter before and after 1996 and for TNs of 22.8% (95% CI: 15.3%, 30.3%), 12.6% (95% CI: 9.4%, 15.8%) and 22.7% (95% CI: 18.3%, 27.0%), respectively. Egger's test of three independent categories revealed no evidence of publication bias (p = 0.101, 0.148 and 0.113, respectively). CONCLUSIONS: The prevalence of goiter was reduced by almost half after 1996 in mainland China, so the USI program was considered beneficial. However, subgroup analysis suggests that both insufficient and excess iodine may be associated with goiter. The prevalence of goiter and TNs increased significantly after 2002, suggesting a risk of excessive iodine intake. Thus, salt iodization standardizations should be set according to local conditions.

Impact of pregnancy on prognosis of differentiated thyroid cancer: clinical and molecular features.

OBJECTIVE: Differentiated thyroid cancer (DTC) commonly occurs in women of child-bearing age and represents the second most frequent tumor diagnosed during pregnancy only behind breast cancer. It is possible that associated physiological changes could favor tumor development and growth. However, few data are available about the outcome of DTC related to pregnancy, leading to conflicting results. METHODS: Among the study population, 340 patients with DTC <45 years old were retrospectively studied. Patients were divided into three groups according to the time of tumor diagnosis in respect of pregnancy. Group 1, diagnosis of DTC at least 2 years after delivery; group 2, diagnosis during pregnancy or within the second year after delivery; and group 3, nulliparous patients at the time of diagnosis. We evaluated clinical outcome and immunohistochemical expression of estrogen receptor α (ERα), ERß, progesterone receptor, and aromatase. We also analyzed the gene expression of NIS (SLC5A5) and the prevalence of BRAF(V600E) mutations. RESULTS: Persistence/recurrence of disease was significantly higher in group 2 patients than control groups (P=0.023). No significant differences were observed in other clinical parameters. Furthermore, no differences among the groups were recorded about ER pattern, NIS expression, and BRAF mutations. CONCLUSIONS: Persistence/recurrence of DTC is significantly higher in pregnant patients, suggesting that pregnancy could really exert a negative prognostic role in patients with DTC. The underlying mechanisms are not yet clarified and further studies are required. Our results suggest that a more careful follow-up is needed when diagnosis of DTC occurs during pregnancy or shortly after.

Associations of noniodized salt and thyroid nodule among the Chinese population: a large cross-sectional study.

BACKGROUND: The controversy that iodized salt may increase the risk of thyroid disorders has arisen in China during the past several years. OBJECTIVE: This study aimed to explore whether iodized salt increased the risk of thyroid nodule among a Chinese population. DESIGN: A cross-sectional study was conducted in Hangzhou, China, in 2010. Iodized salt intake, urinary iodine concentration (UIC), and thyroid nodule (by ultrasonography) were measured in 9412 adults. The associations of iodized salt with thyroid nodule were evaluated by using multiple mixed logistic regression models. RESULTS: The prevalence of thyroid nodule among men and women was 24.1% and 34.7%, respectively. Adults consuming noniodized salt had an increased risk of thyroid nodule (OR: 1.36; 95% CI: 1.01, 1.83). Similarly, compared with moderate salt appetite, mild salt appetite was associated with an increased risk of thyroid nodule among all adults (OR: 1.19; 95% CI: 1.03, 1.37) and among women (OR: 1.23; 95% CI: 1.03, 1.46). Furthermore, those who consumed neither iodized salt nor milk had a higher risk of thyroid nodule (OR: 1.72; 95% CI: 1.21, 2.43) than did those who consumed both iodized salt and milk. In addition, an increased risk of thyroid nodule (OR: 1.25; 95% CI: 1.07, 1.45) was observed among both pooled samples and women with low UIC. CONCLUSIONS: These findings indicate that low iodine intake may increase the risk of thyroid nodule in a Chinese population, particularly in women. Hence, the Universal Salt Iodization program may be indispensable for a coastal Chinese population such as that living in Hangzhou. This trial was registered at clinicaltrials.gov as NCT01838629.

Interstitial laser photocoagulation (ILP) of benign cystic thyroid nodules--a prospective randomized trial.

CONTEXT: Recurrence rate, after aspiration, in cystic thyroid nodules is very high. Interstitial laser photocoagulation (ILP) is a minimally invasive procedure that reduces the need for surgery in patients with a benign solid thyroid nodule. OBJECTIVE: The aim of the study was to evaluate the efficacy of ILP on remission rates in recurrent, predominantly cystic thyroid nodules. DESIGN AND METHODS: Forty-four consecutive outpatients with a symptomatic, recurrent, and cytologically benign cystic (cyst volume ≥ 2 mL) thyroid nodule were randomized to a single aspiration with (n = 22) or without (n = 22) subsequent ILP and followed up after 1, 3, and 6 months. RESULTS: Successful outcome (cyst volume ≤ 1 mL) was obtained in 15 of 22 (68%) patients in the ILP group, compared to 4 of 22 (18%) in the aspiration group (P = .002). In the ILP group, the solid part of the nodule was reduced from a median of 1.8 to 1.0 mL (P = .02). In the aspiration-alone group, neither the cyst volume nor the solid nodule volume was significantly reduced. The reduction in median visual analog score (0-10 cm) for pressure symptoms was significantly higher in the ILP group (from 3.0 to 0.0 cm) than in the aspiration-alone group (from 4.0 to 3.5 cm) (P = .006, between groups). No major side effects occurred, and thyroid function was unaffected throughout. CONCLUSIONS: US-guided aspiration and subsequent ILP of benign recurrent predominantly cystic thyroid nodules is safe. It significantly reduces recurrence rate, the volume of the solid nodule component, and pressure symptoms. ILP constitutes an important alternative to surgery in such patients.

Subacute thyroiditis manifesting as a thyroid mass, vocal cord paralysis, and hypercalcemia.

OBJECTIVE: To report a case of subacute thyroiditis manifesting as a thyroid mass, vocal cord paralysis, and hypercalcemia. METHODS: We describe the clinical, laboratory, and radiologic findings in a patient with an unusual clinical course of subacute thyroiditis. RESULTS: A 65-year-old woman presented with a hoarse voice and an enlarging tender mass in the right side of the neck. On admission, thyroid function was consistent with thyrotoxicosis from subacute thyroiditis. Laboratory studies showed a corrected serum calcium concentration of 11.4 mg/dL, intact parathyroid hormone of 125 pg/mL, 25-hydroxyvitamin D of 12 ng/mL, and creatinine of 1.8 mg/dL. Computed tomography of the neck without use of a contrast agent showed a heterogeneous mass in the right side of the neck in conjunction with deviation of the trachea from right to left but without invasion of the trachea. Thyroid ultrasonography disclosed a heterogeneous mass in the right thyroid lobe measuring 4.7 cm by 5.5 cm by 4.5 cm. Flexible laryngoscopy revealed right vocal cord paralysis. Treatment with a course of prednisone yielded normalization of the serum calcium level, improvement in her voice, and a decrease in size of the thyroid mass. Four months after initial presentation of the patient, thyroid hormone levels became normal, she was clinically euthyroid, and she had a full recovery of her voice. Her serum calcium concentration was normal (9.8 mg/dL) in association with a near-normal parathyroid hormone level of 90 pg/mL. The 25-hydroxyvitamin D and creatinine values were also normal. Repeated thyroid ultrasonography showed a smaller right thyroid lobe with a dominant nodule measuring 2.0 cm by 1.3 cm by 1.4 cm in the right upper pole. CONCLUSION: This case illustrates that subacute thyroiditis can have the unusual initial manifestations of a thyroid mass, vocal cord paralysis, and hypercalcemia. In similar patients, a trial of corticosteroid therapy may be warranted in an effort to improve clinical symptoms and thus avoid unnecessary surgical treatment.

Recurrent differentiated thyroid cancer.

OBJECTIVE: To discuss the risk of recurrence in patients with differentiated thyroid cancer and emphasize the importance of risk-group stratification. METHODS: Common risk factors associated with recurrent thyroid cancer are outlined, and appropriate management strategies are reviewed. RESULTS: The overall prognosis in patients with differentiated thyroid cancer is excellent. Factors associated with recurrent thyroid cancer include extrathyroidal extension of the primary tumor, bulky nodal metastatic lesions, macroscopic local invasion, and aggressive histologic subtypes. The locoregional recurrence and mortality are higher in patients with high-risk thyroid cancers. Patients initially presenting with locally aggressive and advanced thyroid cancer have a higher incidence of recurrent disease in the thyroid bed or nodal metastasis. These patients also have a high incidence of distant metastatic lesions. Locally recurrent thyroid cancer may be seen in more than 25% of patients with aggressive differentiated thyroid cancer. Recurrent disease in the thyroid bed can be a difficult problem to manage because of the proximity of the tumor to the recurrent laryngeal nerve, visceral structures in the central compartment, and occasional involvement of the trachea or larynx. External beam radiation therapy after surgical treatment may be important for better local control in the thyroid bed region, especially in patients with poorly differentiated histologic features. The role of additional radioiodine therapy remains undefined at this stage. CONCLUSION: Management of patients with recurrent thyroid cancer necessitates a true multidisciplinary approach. These patients require close follow-up, with cross-sectional imaging and positron emission tomographic scanning in selected individuals.

Optimization of iodine intake in Belgium.

Mild iodine deficiency (MID) is a long-standing problem in Belgium and was recognized only recently as public health issue by the Ministry of Health (MOH). The main MID-related health problems in Belgium are a high prevalence of thyroid nodules and multinodular goiter. The economic cost of thyroid nodular disease only in Belgium was estimated at about €40 millions per year. The Belgian health authorities adopted a selective strategy to optimize iodine intake through the fortification of bread with iodized salt. A progressive, step-by-step increase of the iodine content of salt was chosen in order to minimize the incidence of hyperthyroidism. MOH monitors this strategy by assessing periodically the urinary iodine concentration in school-aged children and pregnant women, as well as by a yearly follow-up of TSH concentrations in all Belgian newborns. Although the implementation of this strategy was an important step, the main drawback of the current situation is the absence of a legal framework to support the strategy. The utilization of iodized salt in bread on a voluntary basis was endorsed by the bakery industry and MOH. However a legal framework is required to assure the effectiveness and continuity of the program and to avoid a higher than optimal iodine intake in the population.

Influence of long-term statin use in type 2 diabetic patients on thyroid nodularity in iodine-sufficient area.

Statins have marked beneficial effects on lipid profile, but also have pleiotropic actions. A previous study in an iodine-deficient area suggested that statin use is associated with reduced thyroid volume and nodularity. We performed this study to investigate how long-term statin use in type 2 diabetic patients affects thyroid nodularity in iodine-sufficient area.We recruited euthyroid type 2 diabetic patients, receiving statin therapy continuously for at least 5 years (statin group) and, age and sex matched statin-naive type 2 diabetic patients (control group). Subjects with past history of cancer, thyroid disease or treatment with lithium or amiodarone; family history of thyroid cancer; palpable goiter or thyroid nodule, and/or positive thyroperoxidase antibody were excluded. The prevalence, number, and volume of thyroid nodules, size of thyroid were evaluated in all subjects by high resolution ultrasound.Prevalence of non-palpable thyroid nodules of statin group (n=70) and control group (n=98) were 51 and 53%, respectively. There was no difference of prevalence, number, and volume of non-palpable thyroid nodules and size of thyroid between statin and control group. But, the patients aged between 60 and 65 years from statin group showed lower prevalence of non-palpable thyroid nodules than the patients with same age interval from control group (4 out of 12 patients, 33%, statin group; 19 out of 27 patients, 70%, control group; P=0.04).Long-term statin use in elderly type 2 diabetic patients was associated with lesser prevalence of thyroid nodules in an iodine-sufficient area. Our data might support a possible antiproliferative effect of statins on thyroid in old type 2 diabetic patients. But, the effect was not as strong as that in an iodine-deficient area and further studies with enough numbers of subjects and revised design will be needed.