Total vs less than total thyroidectomy for benign multinodular non-toxic goiter: an updated systematic review and meta-analysis.

BACKGROUND: We have performed an updated meta-analysis of randomized controlled trials (RCT) comparing total thyroidectomy (TT) with less than total thyroidectomy (LTT) for benign multinodular non-toxic goiter (BMNG). OBJECTIVES: The objective was to evaluate the effects and outcomes of TT as compared to LTT. METHODS: Eligibility criteria: RCTs comparing TT vs LTT. INFORMATION SOURCES: PubMed, Embase, Cochrane Library and online registers were searched for articles comparing TT with LTT. Risk of bias: Articles were assessed for risk of bias using the Cochrane's revised tool to assess risk of bias in randomized trials (RoB 2 tool). SYNTHESIS OF RESULTS: The main summary measures were risk difference using a random effects model. RESULTS: Five randomized controlled trials were included in the meta-analysis. Recurrence rate was lower for TT compared to LTT. Adverse events like temporary or permanent recurrent laryngeal nerve (RLN) palsy and permanent hypoparathyroidism were similar in both groups except for the rate of temporary hypoparathyroidism which was lower in the LTT group. DISCUSSION: All studies had unclear risk of bias for blinding of the participants and personnel and high risk of bias for certain selective reporting. This meta-analysis did not show any clear benefit or harm of either procedure (TT vs LTT) for goiter recurrence and re-operation rates (for both recurrence and incidental thyroid cancer). However, re-operation for goiter recurrence was significantly higher in the LTT group based on a single RCT. Evidence suggests increased rates of temporary hypoparathyroidism with TT but there was no difference in the rate of RLN palsy and permanent hypoparathyroidism between the two methods. The overall quality of evidence was low to moderate.

Maternal UPD of chromosome 7 in a patient with Silver-Russell syndrome and Pendred syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder featuring severe intrauterine and postnatal growth retardation and dysmorphic features. Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the SLC26A4 gene characterized by sensorineural hearing loss. METHODS: Karyotyping analysis was performed to investigate any chromosomal abnormalities. Whole-genome copy number variation and loss of heterozygosity were analyzed using an Affymetrix CytoScan 750 K Microarray. Variant screening was performed by targeted next-generation sequencing on all known deafness-causing genes. RESULTS: The proband was a patient with SRS caused by maternal uniparental disomy 7. The PDS of the proband was caused by homozygous variant c.919-2A > G of SLC26A4; both mutated alleles were inherited from his mother. CONCLUSION: This is the first report of uniparental disomy 7 leading to SRS and Pendred syndrome. Patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure should undergo molecular testing to reach a clinical diagnosis.

Review of Factors Contributing to Nodular Goiter and Thyroid Carcinoma.

There is an increased incidence of thyroid nodules and cancer. In this article, the reasons for this increase are evaluated and discussed. The factors causing increases in the incidence of nodules are the same as those causing increases in thyroid cancer. There are publications from all over the world regarding the rising incidence of thyroid cancer; it is especially associated with papillary cancer. The literature was reviewed and evaluated with regard to this significant phenomenon. Thyroid-stimulating hormone (TSH) is the main mitotic factor. Any agent that elevates TSH will stimulate nodule formation. Therefore, the incidence of thyroid nodules is high in endemic goiter regions due to iodine deficiency. This paper has described many of the factors causing this higher incidence. Of note, metabolic syndrome and insulin resistance are important factors associated with the increased incidence of nodular goiter and papillary thyroid cancer today. However, these data must be confirmed by other studies in the future.

Thyroid autoimmunity: is really associated with papillary thyroid carcinoma?

The incidence of thyroid cancer has been greatly increasing. Several studies aimed to investigate biomarkers for prediction of thyroid cancer. Some of these studies have suggested that thyroid autoantibodies (TAb) could be used as predictors of thyroid cancer risk, but the correlation between TAb and PTC is still a matter of debate. The aim of this study is to evaluate thyroid autoimmunity and TAbs in patients with PTC and benign multinodular goiter (MNG) to investigate if TAbs and autoimmune thyroid disease (ATD) could predict thyroid malignancy. A total of 577 patients with thyroid papillary carcinoma (PTC) and 293 patients with benign MNG disease were enrolled postoperatively. Demographic features, thyroglobulin (TgAb) and thyroid peroxidase antibodies (TPOAb) and histologic outcome of the patients were evaluated. The prevalence of ATD and TgAb or TPOAb measurements was not statistically different in PTC and MNG groups. However, tumors were significantly smaller and tumor capsule invasion was seen less frequently in patients with PTC and ATD than without ATD. Patients without ATD had more advanced stage (TNM stage III/IV) tumors than with ATD. Only one of the 11 patients with distant organ metastasis had ATD. The present study demonstrated that the prevalence of ATD diagnosed even with histology or TAb positivity was not different in patients with PTC and MNG. However, having ATD might be associated with a better prognosis in PTC patients.

Etiopathology, clinical features, and treatment of diffuse and multinodular nontoxic goiters.

Goiter, an enlargement of the thyroid gland, is a common problem in clinical practice associated with iodine deficiency, increase in serum thyroid-stimulating hormone (TSH) level, natural goitrogens, smoking, and lack of selenium and iron. Evidence suggests that heredity also has an important role in the etiology of goiter. The current classification divides goiter into diffuse and nodular, which may be further subdivided into toxic (associated with symptoms of hyperthyroidism, suppressed TSH or both), or nontoxic (associated with a normal TSH level). Nodular thyroid disease with the presence of single or multiple nodules requires evaluation due to the risk of malignancy, toxicity, and local compressive symptoms. Measurement of TSH, accurate imaging with high-resolution ultrasonography or computed tomography, and fine-needle aspiration biopsy are the appropriate methods for evaluation and management of goiter. This review discusses the clinical presentation, diagnostic evaluation, and treatment considerations of nontoxic diffuse and nodular goiters.

An analysis of the relative risk for goitre in euthyroid patients with type 2 diabetes.

AIM: To assess the relative risk for goitre in a cohort of euthyroid patients with type 2 diabetes with special reference to the use of metformin and insulin therapy. PATIENTS AND METHODS: Eight hundred euthyroid patients with type 2 diabetes (433 women, mean age 65·8 ± 12·5 years) and 671 euthyroid subjects without diabetes were retrospectively evaluated. There were 250 patients on metformin and 455 patients on insulin treatment. RESULTS: The gender-, age-, body mass index- and thyrotropin (TSH)-adjusted relative risk for goitre occurring among diabetic patients relative to controls was 3·01 (1·61-5·64) (P < 0·01). This odds ratio was significant in females, patients with and without metformin therapy, patients without insulin therapy and without micro- and macrovascular complications of diabetes. However, male pateints, patients on insulin therapy or with micro- or macroangiopathy did not exhibit an increase in the risk of goitre. Patients on metformin therapy showed a significant increase in the risk of goitre only in the absence of insulin therapy. Multi-adjusted logistic regression analysis showed that goitre was significantly related to gender, TSH and haemoglobin A1c levels. Metformin and insulin therapy were nonsignificant variables in this model. CONCLUSION: This is the first survey analysing the relationship between the presence of palpable goitre and clinical parameters in a large cohort of patients with type 2 diabetes. Our data suggest a significant relationship between goitre and glycaemic control, but do not support the presence of independent and significant relationships between goitre and metformin or insulin treatment in euthyroid patients with type 2 diabetes.

Thyroid and menopause.

Thyroid dysfunction is common in the general population especially in women. All thyroid diseases are in fact more common in women than in men and may interfere with the reproductive system. Thyroid function and the gonadal axes are related throughout the woman's fertile period. The relationship between the two glands is mutual. In particular, thyroid hormones affect the reproductive function both directly and indirectly through several actions. Studies on the relationship between menopause and thyroid function are few and do not allow to clarify whether menopause has an effect on the thyroid regardless of aging. With aging, the main changes regarding thyroid physiology and function are: a reduction of thyroid iodine uptake, free thyroxine and free triiodothyronine synthesis and catabolism of free thyroxine while reverse triiodothyronine increases; the level of thyroid stimulating hormone remains normal with sometimes a tendency to higher limits. These changes are present in both sexes without distinction between males and females. The complexity of the relationships can be summarized in three aspects: thyroid status does not influence significantly the climacteric syndrome; menopause may modify the clinical expression of some thyroid diseases, particularly the autoimmune ones; thyroid function is not directly involved in the pathogenesis of the complications of menopause. However, coronary atherosclerosis and osteoporosis may be aggravated in the presence of hyperthyroidism or hypothyroidism. The effects of postmenopausal estrogen replacement on thyroxine requirements in women with hypothyroidism should be considered.

Thyrotoxicosis.

Thyrotoxicosis is a common disorder, especially in women. The most frequent cause is Graves' disease (autoimmune hyperthyroidism). Other important causes include toxic nodular hyperthyroidism, due to the presence of one or more autonomously functioning thyroid nodules, and thyroiditis caused by inflammation, which results in release of stored hormones. Antithyroid drugs are the usual initial treatment (thionamides such as carbimazole or its active metabolite methimazole are the drugs of choice). A prolonged course leads to remission of Graves' hyperthyroidism in about a third of cases. Because of the low remission rate in Graves' disease and the inability to cure toxic nodular hyperthyroidism with antithyroid drugs alone, radioiodine is increasingly used as first line therapy, and is the preferred choice for relapsed Graves' hyperthyroidism. Total thyroidectomy is an option in selected cases. Future efforts are likely to concentrate on novel and safe ways to modulate the underlying disease process rather than stopping excess thyroid hormone production.

Overview of thyroid physiology: an essential for understanding familial euthyroid multinodular goiter.

Nontoxic goiter is a diffuse or nodular enlargement of the thyroid gland that does not result from an inflammatory or neoplastic process and is not associated with abnormal thyroid function. Familial forms of goiter in areas not known to feature iodine deficiency are much less common. However, not all individuals in the same iodine deficiency region develop goiter and iodine supplementation does not prevent goiter development in all treated individuals. The etiology of euthyroid goiter is still incompletely understood. It is assumed that the development of goiter depends on various interactions between genetic and environmental factors. We present an overview on the thyroid physiology, which is important for a better understanding of Familial Euthyroid Multinodular Goiter.

Does a small difference in iodine status among children in two regions of Belgium translate into a different prevalence of thyroid nodular diseases in adults?

PURPOSE: To explore whether there are regional differences in iodine status and in prevalence of thyroid diseases in the two main regions of Belgium. METHODS: A national survey of iodine status among children was performed in 1998. The raw data of this survey were reanalyzed to explore regional differences. The total number of thyroidectomies, carried out for multinodular goiter or solitary nodules, was obtained from the Minimal Clinical Summary hospital discharge database. Percentage of people with thyroid diseases going to the general practitioner or the specialist was assessed by means of data about the number of adults using anti-thyroid medications. Food consumption patterns were explored using national food consumption data. RESULTS: In Flanders, median urinary iodine concentration (UIC) was higher than in Wallonia, 84 µg/L (n = 1,316) and 78 µg/L (n = 1,268), respectively (p < 0.001). There were no differences in goiter prevalence and thyroid volume between the regions among children. Data from the food consumption survey showed a significant higher consumption of seafood in Flanders compared to Wallonia. Further, it was observed that the number of thyroidectomies, carried out for MNG or solitary nodules, and the use of anti-thyroid medication were significantly higher in Wallonia than in Flanders. CONCLUSION: Iodine status in children was found slightly different in both regions of the country. This finding is in agreement with a higher incidence of thyroidectomies and more extensive use of anti-thyroid medications in the adult population in the region with the lowest iodine excretion.

Karyopathological traits of thyrocytes and exposure to radioiodines in Belarusian children and adolescents following the accident at the Chernobyl nuclear power plant.

The Belarus-American (BelAm) thyroid study cohort consists of persons who were 0-18 years of age at the time of exposure to radioactive iodine fallout from the 1986 Chernobyl nuclear power plant accident and who have undergone serial thyroid screenings with referral for fine-needle aspiration biopsy (FNAB) using standardized criteria. We investigated thyrocyte nuclear abnormalities in cytological samples from FNABs in 75 BelAm subjects with single and multiple thyroid nodules and 47 nodular goiter patients from Leningrad, Russia, unexposed to Chernobyl fallout. Nuclear abnormalities examined included internuclear chromosome bridges and derivative nuclei with broken bridges (i.e., "tailed" nuclei), which are formed from dicentric and ring chromosomes and thus may be cellular markers of radiation exposure. Among subjects with single-nodular goiter, thyrocytes with bridges were present in 86.8% of the exposed BelAm cohort compared with 27.0% of unexposed controls. The average frequency of thyrocytes with bridges and with tailed nuclei was also significantly higher in the BelAm subjects than in controls. Among subjects with multinodular goiters, thyrocytes with bridges were present in 75.7% of exposed BelAm patients compared with 16.7% of unexposed controls; thyrocytes with tailed nuclei were observed in all of the BelAm subjects but in only 40% of controls, and the mean frequencies of bridges and tailed nuclei were significantly higher in the exposed group. Unusually, long bridges were detected in 29% of BelAm patients with single-nodular goiters and 35% of those with multinodular goiters, while no such abnormalities were observed among patients from the Leningrad region. In the exposed subjects from BelAm, we also found positive correlations between their estimated dose of Iodine-131 from Chernobyl fallout and the frequency of tailed nuclei (p = 0.008) and bridges (p = 0.09). Further study is needed to confirm that these phenomena represent consequences of radiation exposure in the human organism.

Intrathyroid parathyroid carcinoma with intrathyroidal metastasis to the contralateral lobe: source of diagnostic and treatment pitfalls.

Intrathyroidal parathyroid carcinoma is extremely rare clinical entity with potentially multiple diagnostic pitfalls. We report a case of 40-year-old man presented with classical manifestations of primary hyperparathyroidism, severe hypercalcemia and profoundly increased serum parathyroid hormone level. Neck ultrasonography demonstrated multinodular goiter with predominant 34 mm nodule in left thyroid lobe. Additional 16 mm nodule was found beneath the left lobe. Routine percutaneous fine-needle aspiration of predominant nodule indicated follicular thyroid carcinoma, while left inferior nodule was confirmed to be of parathyroid origin. The patient underwent surgery, during which frozen sections identified medullary thyroid carcinoma with metastasis to upper mediastinal lymph node. Permanent sections of the predominant left lobe nodule revealed intrathyroidal parathyroid carcinoma surrounded with multiple microscopic metastases. Left inferior nodule was metastatic lymph node. Additional 10 mm intrathyroidal metastasis of primary parathyroid carcinoma was found within right thyroid lobe. This case indicates that fine-needle-aspiration and intraoperative biopsy are of limited value in diagnosing parathyroid carcinoma, especially if localized intrathyroidally. Oncological en-block resection is treatment of choice, implying ipsilateral lobectomy in case of thyroid invasion. This firstly described case of intrathyroidal parathyroid carcinoma causing intrathyroidal dissemination may influence future treatment strategies.

Effect of smoking intensity on thyroid volume, thyroid nodularity and thyroid function: the Melen study.

AIM: The purpose of our study was to determine the association between smoking habit, goiter, thyroid functions and ultrasonographic nodularity in moderately iodine deficient area. METHODS: The MELEN study is a prospectively designed survey on the prevalence of thyroid diseases in Turkish adults. A total of 2298 subjects with a mean age of 50 (age range 18 to 92) were interviewed. Smoking habits were registered from questionnaires and subsequent interviews with a physician. Thyroid ultrasonography was performed and interpreted by the same experienced physician, using the same equipment. After an overnight fast, blood samples were collected from all the study subjects for the determination of serum free thyroxine, thyroid stimulating hormone (TSH) were measured. RESULTS: Mean thyroid volumes of current smokers were significantly lower than either former or never smokers (P=0.014). There were no difference according to smoking habits on goiter and established multinodularity in current smokers (P<0.05). Heavy smokers (>20 pack/year) had higher thyroid volumes, higher goiter and multinodular goiter (MNG) prevalence than moderate smokers (P<0.001). Thyrotoxicosis (TSH<0.35) cases were more frequent among heavy smokers than moderate smokers (14.1% versus 8.2%, P<0.001; respectively). Heavy smoking independently predicted goiter (odds ratio: 1.459 [95% confidence interval: 1.029 and 2.068]; P=0.034). CONCLUSION: Heavy smoking was associated with increased prevalence of thyroid multinodularity and goiter in respect to moderate smoking. No association was found between smoking habit and thyroid dysfunction.

Multinodular goiter as the initial presentation of systemic sarcoidosis: limitation of fine-needle biopsy.

Sarcoidosis is a chronic systemic disease characterized by noncaseating granulomas. Thyroid involvement is rare, with a prevalence of 1-4% in large series of autopsied patients with systemic sarcoid. We report a case of a 65-year-old woman with a nontoxic multinodular goiter, dyspnea in the supine position, and rightward tracheal deviation as the initial presentation of systemic sarcoidosis. Fine-needle biopsy of the thyroid mass was consistent with benign adenomatoid goiter. A total thyroidectomy was performed because of compression symptoms. Histopathology revealed numerous diffuse noncaseating granulomata typical of thyroid sarcoidosis. Subsequent chest computed tomography showed extensive bulky mediastinal and hilar adenopathy and multiple small pulmonary nodules consistent with sarcoidosis. Transbronchial fine-needle biopsy also revealed noncaseating granulomas. The patient's supine dyspnea resolved quickly after total thyroidectomy. This case report illustrates that in patients with known sarcoidosis, careful thyroid examination is essential and supine dyspnea may be directly related to tracheal compression by a multinodular goiter rather than pulmonary sarcoidosis.

The association between multinodular goiter and thyroid cancer.

In many parts of the world, especially those of current or former iodine deficiency, multinodular goiter is still an endemic disease. In this brief review several clinically relevant issues in the complex association between nodular goiter and differentiated thyroid cancer will be highlighted. There are some intriguing links between the etiologies of multinodular goiter and that of thyroid cancer. This could also influence the incidence of thyroid cancer in multinodular goiter. However, multinodular goiter causes extra difficulties in the diagnosis of differentiated thyroid cancer; these same difficulties also cause additional issues in thyroid cancer treatment in multinodular goiter patients. Last but not least it will be discussed whether there is a possibility to impede the development of thyroid cancer in multinodular goiter.

Detection of enterovirus RNA in postoperative thyroid tissue specimens.

CONTEXT: Autoimmune thyroiditis is a very common disease. A genetic predisposition and environmental factors such as viruses are thought to contribute to the development of autoimmune thyroiditis. Enteroviruses, which are involved in other autoimmune diseases, are attractive candidates. OBJECTIVE: To investigate the presence of enteroviral genome sequences in postoperative thyroid tissues with lymphocytic infiltration, a common histological feature of thyroiditis. SUBJECTS AND METHODS: Postoperative thyroid specimens collected prospectively from 86 patients were blindly frozen at -80 degrees C. The presence of EV genome sequences in the samples was blindly investigated by real-time RT-PCR. Clinical data, histological findings and levels of anti-TPO antibodies were collected. RESULTS: EV-RNA detection was positive (up to 36 cycles) or weakly positive (37-39 cycles) in 22 out of 86 patients (25%). EV-RNA (positive or weakly positive signal) was detected in 5 out of 27 (18.5%) thyroid specimens with lymphocytic infiltration, and in 17 out of 59 (29%) thyroid specimens without lymphocytic infiltration (P = 0.4). No correlation was observed between EV-RNA detection in thyroid and the presence of anti-TPOAb. EV-RNA was detected in 3 out of 11 patients histologically diagnosed as thyroiditis (27.3%) and in 18 out of 74 patients (24.3%) with thyroid tumours (multinodular goitre, adenoma and carcinoma) (P = 0.5) and in one patient with a normal thyroid. CONCLUSION: EV-RNA can be detected in thyroid tissue from patients with various thyroid diseases, but there is no relationship between the presence of EV-RNA and thyroiditis. Further studies are needed to clarify the role of EV in thyroid diseases.

What constitutes adequate surgical therapy for benign nodular goiter?

BACKGROUND: It is our hypothesis that the extent of thyroid resection for benign nodular thyroid disease (NTD) should be based on the extent of disease. METHODS: Patients operated on for benign NTD from 1990 through 2007 were divided into 3 groups: those who underwent lobectomy for unilateral NTD (Group 1); near-total or total thyroidectomy for bilateral NTD (Group 2); and reoperation for NTD initially treated at other institutions (Group 3). The incidence of recurrence was determined for Groups 1 and 2 and the timing of diagnosis was compared to Group 3. Potential risk factors for recurrent disease were examined. RESULTS: Five hundred forty-five patients were operated on for benign NTD. Contralateral disease was excluded in Group 1 patients using ultrasound (47.7%) and/or intraoperative palpation (100%). Five (1.9%) of 260 patients in Group 1 and 1 (0.4%) of 248 patients in Group 2 developed recurrent NTD after 7 +/- 4 (median = 8) and 4 y compared to a mean 19 +/- 11 (median = 20) y for the 37 patients in Group 3 following 1 to 3 previous thyroidectomies. Recurrent disease was diagnosed by physical exam in 24 (55.8%) and imaging in 19 (44.2%) patients. Thyroid hormone was required for postsurgical hypothyroidism in 70 (26.9%) patients in Group 1. CONCLUSION: Thyroid lobectomy is optimal therapy when benign NTD is limited to 1 lobe, as evidenced by a 2% recurrence rate and maintenance of euthyroidism in 73% of patients. When NTD is bilateral, total thyroidectomy is indicated to eliminate recurrence, underscoring the importance of routine preoperative ultrasound.

Metformin reduces risk of benign nodular goiter in patients with type 2 diabetes mellitus.

Background Whether metformin might affect the risk of benign nodular goiter in patients with type 2 diabetes mellitus has not been investigated. Methods Patients with new-onset type 2 diabetes mellitus during 1999-2005 were enrolled from Taiwan's National Health Insurance database. Analyses were conducted in a propensity score matched-pairs of 20,048 ever users and 20,048 never users of metformin. The patients were followed until December 31, 2011, for the incidence of benign nodular goiter. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the propensity score. Results Among the never users and ever users of metformin, 392 and 221 cases were diagnosed of benign nodular goiter during follow-up, with incidence of 457.88 and 242.45 per 100,000 person-years, respectively. The overall hazard ratio for ever versus never users was 0.527 (95% confidence interval: 0.447-0.621). When cumulative duration of metformin therapy was divided into tertiles, the hazard ratios for the first (<25.3 months), second (25.3-57.3 months) and third (>57.3 months) tertiles were 0.815 (0.643-1.034), 0.648 (0.517-0.812) and 0.255 (0.187-0.348), respectively. Sensitivity analyses estimating the overall hazard ratios for patients enrolled in each specific year from 1999 to 2005 consistently showed a lower risk of benign nodular goiter among users of metformin. Conclusion Metformin use is associated with a lower risk of benign nodular goiter in patients with type 2 diabetes mellitus.