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.

Influence of iodization programmes on the epidemiology of nodular goitre.

Iodine is essential for the synthesis of thyroid hormones. Iodine deficiency can affect human health in different ways, and is commonly referred to as iodine deficiency disorders (IDD). These range from defective development of the central nervous system during the fetal-neonatal life, to goitre in the adult. Only a few countries were completely iodine sufficient before 1990. Since then, a major effort has been made to introduce salt iodization to ensure sufficient intake of iodine in deficient areas. Iodine prophylaxis has been shown to exert a pivotal role in abating goitre and other iodine-deficiency disorders, and has also been shown to modulate the pattern of thyroid diseases. An increased frequency of thyroid autoimmunity and of hypothyroidism has been observed after introducing iodization programmes. Nevertheless, available evidence clearly confirms that the benefits of correcting iodine deficiency, consisting mainly of reducing nodular goitre and non-autoimmune hyperthyroidism, far outweigh the risks of iodine supplementation.

Epidemiology of nodular goiter in South Georgia and selection of some diagnostic criteria from the view point of prevention.

Mountainous regions of Georgia have been long known as a center of goiter endemia. Study of thyroid gland diseases in this contingent of population represents a key target. The object of the conducted examinations was study of epidemiology of goiter in the South Georgia. According to the results of our study high index of spreading endemic goiter in the population of the South Georgia is conditioned by iodine-deficiency. In addition, the factor providing spreading of thyroid gland pathology in the country is improper feeding. At the same time we aimed to study in these populations such diagnostic indices of various pathologies of thyroid gland as carcinoma - embryonic antigen CEA, which has been less studied. There is scanty information on these markers during thyroid gland pathology and in populations of Georgia it is absent at all. Due to the fact that the mentioned marker makes possible to conduct monitoring of the disease, we consider the study of its infomativity to be important during various forms of nodular goiter. For comparison of the results study of oncomarker REA was conducted in group of healthy individuals and non-nodular goiter. On the base of obtained data it can be supposed that study of oncomarker CEA is informative for diagnosis of various forms of nodular goiter as additional criteria, especially in case of obscure or not conducted morphological diagnosis.

Treatment and prevention of recurrence of multinodular goiter: an evidence-based review of the literature.

BACKGROUND: Reportedly, 10-15% of patients with goiters ultimately require operative intervention, and recurrences of multinodular goiter (MNG) account for up to 12% of all thyroid operations. METHODS: We performed an evidence-based review of articles published in the English language between January 1987 and October 2007 relevant to the subject. RESULTS: Medical treatment with T4 appears to be associated with a greater proportion of patients whose nodules decreased in size by more than 50% (22% vs. 10%; range = 14-39% vs. 0-20%). Recurrence rates of benign nodular goiter after total thyroidectomy were essentially nonexistent (range = 0-0.3%) compared with those after subtotal thyroidectomy (range = 2.5-42%) and more limited resections (range = 8-34%). There was no difference between total and less-than-total thyroidectomy with respect to temporary recurrent laryngeal nerve (RLN) injury (1-10% vs. 0.9-6%, respectively) or permanent RLN palsy (0-1.4%). There was, however, a significantly higher rate of transient hypocalcemia after total thyroidectomy than less extensive operations (9-35% vs. 0-18%, respectively). In relation to redo surgery, permanent hypoparathyroidism appeared to be far more common in the redo group (0-22% vs. 0-4%) Moreover; the redo group had more frequent RLN injury, both temporary (0-22% vs. 0.5-18%) and permanent (0-13% vs. 0-4%). About half the studies examined conclude that postoperative TSH suppression is effective in reducing recurrences, while the other half state that it is not. CONCLUSION: The definitive management and prevention of recurrence of benign nodular goiter is primarily surgical. Total thyroidectomy essentially eliminates the risk of recurrence without an accompanying increased risk of permanent hypoparathyroidism or RLN injury. Therefore, total thyroidectomy should be considered the procedure of choice for benign multinodular goiter whenever possible, especially considering that reoperations for goiter are significantly more morbid than any initial operation.

[Studies on iodine deficiency in adult population of Cracow]. / Badania nad niedoborem jodu wsród doroslych mieszkanców Krakowa.

The aim of the study carried out in 1989-90 and 1998-99 was to define the iodine deficiency state and goiter prevalence in adult population of Cracow. The analysis included data obtained from 230 individuals (143 females and 87 males). The mean age was 36 +/- 15 years. The thyroid size and morphology was determined by ultrasound method using Aloka unit equipped with 7.5 MHz linear transducer. The concentration of iodine in casual morning urine sample was measured using Sandell-Kolthoff's method. The 10- year observation revealed an insignificant decrease in prevalence of goiter from 26.2% to 21.8%. We observed statistically significant (p = 0.001) decrease in the parenchymal goiter prevalence from 22.7% to 11.7 in the same period of time. The significant increase in incidence of nodular goiter was found (6.5% vs 20.8%, p < 0.001). In all groups investigated through 1989-99, there was an increase in medians of ioduria over the 10-year period. The level of urinary iodine excretion was not essential element for risk of nodular goitre. Thus, the results indicate the beneficial effect of iodine prophylaxis which reflects in decrease of prevalence of parenchymal goiter. No clear effect of iodine prophylaxis was noticed regarding rise in nodular goiter incidence.

[Molecular aetiology of nodular goitre -- consequences for therapy?]. / Die Knotenstruma. Die molekulare Entstehung -- Konsequenzen für die Therapie?

Up to 15 % of the adult German population display an enlarged thyroid gland and up to 30 % present thyroid nodules. Iodine deficiency is the most important factor in the etiology of nodular goiter. Insulin-like growth factor-I is overexpressed in thyroids in severely iodine deficient areas. There is evidence that iodolactones are mediators of thyroid hormone autoregulation. However familial and twin studies demonstrated a genetic component in the etiology of nodular goiter. Linkage analysis identified two chromosomal regions (MNG-1, Xp 22) in multinodular goiter. Other possible candidate genes or markers such as TG, TPO, NIS, PDS and TSH-R were not identified. Nodular goiter certainly comprises a number of genotypes. TSH receptor mutations result in activation of the cAMP cascade. Cells with a constitutively activated cAMP cascade have an increased growth advantage due to their TSH independent cAMP stimulation. Alimentary iodine supply should be the first choice in primary prevention of nodular thyroid disease in iodine deficient areas, because prevalence of nodular goiter is negative correlated with individual iodine status in epidemiological surveys. Surgical removal of nodular goiters should include nearly the hold thyroid tissue to avoid recurrent goiter.

[Repeated surgeries on the thyroid gland in nodular euthyroid goiter]. / Povtornye operatsii na shchitovidnoi zheleze pri uzlovom éutireoidnom zobe.

Medical histories of 214 patients hospitalized with diagnosis "recurrent nodular goiter" were studied retrospectively. Complex clinical, laboratory and instrumental examination was carried out in all the patients. Comparative analysis demonstrated that in the structure of recurrent goiter nodular colloid form dominated (84.1%), only in 42.1% cases repeated surgeries were indicated. Other patients (15.9%) were the ones underwent surgery for other thyroid diseases (hypertrophied form of autoimmune thyroiditis, follicular adenoma, thyroid cysts, thyroid cancer). Inadequate surgery and prophylactic therapy with iodine drugs were the main causes of recurrent goiter. Adequate iodine prophylaxis (potassium iodide 100-200 mg per day), complex examination of patients, correct indications for primary surgery and adequate surgical volume, valuable postoperative therapy (iodine drug, LT-4 if it is necessary) permit to reduce the risk of recurrent nodular (multiple-nodular, diffuse-nodular) goiter. Ways of researches for improvement of diagnosis, prophylaxis and treatment results of "recurrence nodular goiter" are projected.

[Diagnosis, treatment and prophylaxis of postoperative recurrent nodular goiter]. / Diagnostika, lechenie i profilaktika posleoperatsionnogo retsidivnogo uzlovogo zoba.

Results of surgical treatment of 81 patients with recurrent goiter and 79 patients with benign nodular forms of goiter are analyzed. Based on clinical data, results of ultrasonic and histological examinations, it was determined that recurrence of goiter does not depend on volume of surgery. It is seen in patients with subclinical forms of postoperative hypothyreosis and in half of cases with lymphoid infiltration of I - IV degree. Dispensary observation and timely prescription of suppressive therapy, if it is necessary, permit to reduce number of goiter recurrences from 8.2 to 2.5%.

[Optimal recurrence prevention of iodine deficiency related goiter after thyroid gland operation. A prospective clinical study]. / Optimale Rezidivprophylaxe der Jodmangelstruma nach Schilddrüsenoperation. Eine prospektive klinische Studie.

In summary the data of our study show: (1) Sonographically determined thyroid volume of patients with euthyroidism after surgery is found to be significantly lower with a combination therapy (iodide 150 microgram +Levothyroxine 75 microgram) compared to patients with iodide monotherapy (200 microgram). (2) Thyroid volume of patients with hypothyroidism after surgery is found to be significantly lower during a combination therapy (150 microgram iodide + 75 microgram L-thyroxine) compared to patients with a Levothyroxine monotherapy. (3) Patients with hypothyroidism and Levothyroxine monotherapy, however present with a significant increase of thyroid volume after surgery. (4) Urinary iodide excretion in the treatment groups with iodide or combination therapy increases significantly during therapy, however, patients with Levothyroxine monotherapy do not show changes. (5) Thyroid function is well stabilized in all treatment groups with adequate controls and adjustment of Levothyoxine dosage. There data clearly demonstrate that the combination therapy with Levothyoxine and iodide significantly improves prophylaxis of goiter recurrence.

Gain of function TSH receptor mutations and iodine deficiency: implications in iodine prophylaxis.

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.

Iodized salt improves the effectiveness of L-thyroxine therapy after surgery for nontoxic goitre: a prospective and randomized study.

OBJECTIVE: To investigate whether the addition of iodized salt to daily diet in thyroidectomized patients for nontoxic goitre could influence the effectiveness of nonsuppressive L-thyroxine (L-T4) therapy on thyroid remnant size, during 12 months' follow-up after thyroid surgery. DESIGN AND PATIENTS: A consecutive series of selected 139 patients (26 males, 113 females; median age 45 years, range 30-69 years) living in a moderate iodine-deficient area, and undergoing thyroid surgery for nontoxic multinodular goitre, was enrolled. Patients were assigned randomly to two different therapeutic regimens: 70 patients received L-T4 therapy alone (Gr. L-T4), while the remaining 69 patients took iodized salt on a daily basis in addition to L-T4 treatment (Gr. L-T4 + I). In both groups, the initial L-T4 dose was 1.5 microg/kg/day, which, in our experience, has been shown to be intermediate between suppressive and replacement doses. To avoid the risks of mild thyrotoxicosis and to limit the excessive TSH stimulation of the thyroid remnant, the L-T4 dose was adjusted in those patients with serum TSH levels outside the lowest two-thirds of the normal range (0.3-2.5 mU/l). An ultrasound evaluation of thyroid remnant size was performed after thyroid surgery and 12 months later. RESULTS: After surgery, the median thyroid remnant volume was 3.5 ml (range 0.4-13.9 ml) in Gr. L-T4 and 4.6 ml (range 0.5-12.7 ml) in Gr. L-T4 + I (P = 0.06). After 1 year of follow-up, the patients treated with L-T4 + I obtained a remnant volume reduction (-39.7%, range -87.0% to +91.2%) significantly (P = 0.006) greater than that observed in patients assuming L-T4 alone (-10.2%, range -89.4% to +85.0%). However, the percentage of patients showing an increase in remnant size in the months following surgery was higher in Gr. L-T4 than in Gr. L-T4 + I (22/60 vs. 9/66; P = 0.01). In Gr. L-T4 patients the thyroid remnant volume variation throughout 12 months of treatment was correlated significantly with the size of the thyroid remnant found at the first ultrasound evaluation (R(2) = 0.3; P < 0.001). No such correlation was found in Gr. L-T4 + I patients, for whom the therapy maintains a similar effectiveness in patients with either a large or a small postsurgery thyroid remnant. In patients treated with L-T4 alone, the remnant volume variation was correlated significantly with the median serum TSH values attained in the course of treatment (R2 = 0.4; P < 0.001). The highest reduction in remnant volume was observed only by lowering the serum TSH concentrations. In patients treated with L-T4 plus iodine, instead, the thyroid remnant volume reduction occurred independently of the plasma TSH levels attained in the course of treatment. CONCLUSIONS: Our short-term prospective and randomized study leads us to conclude that, in patients living in a moderate iodine-deficient area and undergoing thyroid surgery for nontoxic goitre: (1) the iodine prophylaxis improves the effects of postsurgery nonsuppressive L-T4 therapy on thyroid remnant size. (2) In patients treated with L-T4 alone the therapeutic effectiveness decreases in the presence of a large postsurgery thyroid remnant. With the addition of iodine, the L-T4 maintains a similar efficacy in patients with either a large or a small remnant. (3) During treatment with L-T4 alone the highest therapeutic effectiveness is attained by lowering the plasma TSH concentration. With the addition of iodized salt to the daily diet the effects of L-T4 on remnant size are relevant independently of the TSH levels.

[Multinodular goiter. Epidemiology and prevention]. / Gozzo multinodulare. Epidemiologia e prevenzione.

Nodular goiter is the natural evolution of nontoxic goiter, that may be endemic, sporadic or familiar. Iodine deficiency is the cause of endemic goiter, while genetical defects, impairing the thyroid hormone biosynthetic efficiency or altering the number and/or activity of growth factor receptors, play the major role in the pathogenesis of sporadic and familiar nontoxic goiter. The prevalence of nodular goiter is directly related to the degree of iodine deficiency that is still present in several areas of the world. In iodine deficient areas such as some Italian regions, nodular goiter is present in 25-33% of the population, its frequency increasing with age. In iodine sufficient areas the prevalence of nodular goiter is comprised between 0.4 and 7.2% high in iodine deficient areas and about 4% in iodine sufficient countries, its frequency increasing with the age. Dysphagia, dyspnea and coarsening of the voice may occur for esophagous, tracheal or laryngeal nerve compression, respectively. Iodine deficiency has little if any effect on the frequency of thyroid carcinoma, while, with regard to the histological pattern, it leads to an increased ratio papillary/follicular. Thyroid function is normal in uncomplicated nontoxic goiter. However, the evolution of nodular goiter is toward the functional autonomy of nodules that may result in thyrotoxicosis. Hypothyroidism is rare and is usually the result of thyroid autoimmunity. All the cases due to iodine deficiency can be prevented by an adequate iodine prophylaxis that can be accomplished in industrialized countries by the use of sale enriched in iodine.

[Clinical screening after thyroid gland diseases: contribution of orienting ultrasound examination]. / Klinisches Screening nach Schilddrüsenerkrankungen: Beitrag der orientierenden Ultraschalluntersuchung.

AIM: Of this study was to define the significance of approximate ultrasound explorations of the thyroid gland for the clinical screening for thyroid diseases. METHOD: 918 patients in the medical service of a general hospital were screened for thyroid diseases by means of clinical, functional and sonomorphological methods. A sonographic screening scan with a 5 MHz probe provided data concerning structure and dimension of thyroid gland. Maximal sagittal diameter (SDm, normal range < 18 mm) was taken as a measure for thyroid size. RESULTS: Echogenicity has no essential meaning for thyroid dysfunction screening, but is indispensable for the detection of circumscript or general echo deficiency. SDm has proved to be a simple and well reproducible measure for thyroid size. Among 41 patients with thyrotoxicosis 40 had enlarged SDm, which means a sensitivity of 97.6%. However, a high rate of false positives makes TSH-screening of all enlarged thyroid glands obligatory. Moreover, SDm allows the estimation of a lack of thyroid mass as the most common cause of hypothyroidism. CONCLUSION: We recommend that an approximate ultrasound exploration of the thyroid gland including measuring of SDm should be part of every diagnostic procedure for thyroid disease, as it is precise and not time consuming.

Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency.

In 1980 the iodide content of salt was increased in Switzerland from 7.5 to 15 mg/kg. This raised the mean urinary iodine excretion from 90 (indicating mild iodine deficiency) to 150 micrograms/g creatinine. We examined whether this public health measure was followed by a change of the incidence of hyperthyroidism in a defined catchment area of 109,000 persons. Except for a 27% rise in the first year of the new salt, the total incidence of hyperthyroidism declined steadily to reach 44% of the control level in 1988/89. This was due to a decrease mostly of toxic nodular goitre (minus 73%), less so of Graves' disease (minus 33%). We conclude that correction of mild iodine deficiency has beneficial effects on the incidence of hyperthyroidism, contrary to what is seen initially after correction of severe deficiency.

Effectiveness of prophylactic therapy on goiter recurrence in an area with low iodine intake--a sonographic follow-up study.

There is no agreement as to whether or not drug treatment after surgery for nodular goiter is effective in preventing recurrence of goiter. Data about recurrences in areas of marginally low iodine intake (like Germany) vary widely. Therefore, we performed a retrospective study in 104 patients who had been treated surgically because of benign uninodular or multinodular goiter. The mean follow-up period was 6.4 years (minimal 1 year) with at least three examinations. Thyroid ultrasound with volumetric analysis was recorded in each patient. Thirty-two patients did not receive any prophylaxis, 50 patients were treated with L-thyroxine, 17 patients with a combination of L-thyroxine and iodine and 5 patients with iodine alone. Recurrence of goiter was documented in 28.0% of the untreated patients and in 8.9% of the patients on prophylaxis (P < 0.05). The mean increase of thyroid volume was 7.3 ml versus 3.1 ml in patients without versus with prophylactic drug treatment (not significant). No significant correlation was found between the increase of thyroid volume and age of the patients, follow-up time, or initial thyroid volume, respectively. These data clearly demonstrate the effectiveness of prophylactic drug therapy to prevent recurrence of goiter after thyroid surgery in an iodine-deficient area.

Analysis and prevention of recurrent goiter.

The current study was done to analyze our experience with recurrent goiter. Prevention must be stressed because reoperations of the thyroid gland present technical difficulties and are associated with an increased risk of hypoparathyroidism and permanent hoarseness. Nodular recurrences occurred in 36 of 1,456 patients (2.5 percent) who underwent thyroidectomy between 1968 and 1983. All patients had the initial operation at Jean Bernard Hospital, Poitiers, France, and had follow-up evaluation from five to 20 years. Multinodular goiter accounted for 70 percent of the recurrences. Sixty percent of the recurrences were in patients with multinodular goiters. Recurrent goiter was usually first detected about eight years after thyroidectomy. Thirty patients with recurrence had reoperations. Two patients had paralysis of the vocal cord and one patient had permanent hypoparathyroidism. Recurrent goiter may occur because of the development of new nodules (true recurrence) or because of the growth of "residual" or persistent macroscopic or microscopic nodules left at the previous thyroid operation. Intraoperative digital palpation of the entire thyroid gland is essential for detecting residual macroscopic thyroid nodules, and all enlarged nodules should be removed. Thyroid-stimulating hormone (TSH) suppressive therapy is recommended by some authorities to prevent "true" recurrences, although its efficacy is debated. Since recurrence is uncommon in the current series, perhaps TSH suppressive therapy should only be used in high-risk patients. In the current experience, only the multinodular character of the nodules in euthyroid patients has a significant correlation with subsequent development of recurrent goiter (p < 0.01), and one must consider patients with multinodular goiter at risk for recurrence. Once TSH treatment is begun, it will logically be continued for life. Total thyroidectomy has been recommended by some endocrine surgeons for treating patients with multinodular goiter. We prefer subtotal thyroidectomy and reserve total thyroidectomy for patients when no normal thyroid tissue can be preserved because only 2.5 percent of the patients in the current study had recurrent goiter. Prevention of residual nodules is probably best assured by systematic palpation during operation of the two thyroid lobes. This considerably lessens the risk of recurrence. Since nodular recurrences occurred in only 2.5 percent of the patients in the current study, although multinodular goiter must be considered at risk for recurrence, we do not recommend systematic total thyroidectomy in multinodular goiter.

Bócio multinodular atóxico: avaliaçäo da taxa de recidiva e funçäo após tiroidectomia parcial: análise retrospectiva de 39 casos / Nontoxic multinodular goiter: evaluation of recurrence rate and function after thyroidectomy partial: retrospective analysis of 39 cases

Realizou-se um estudo retrospectivo sobre a taxa de recidiva e funçäo hipofíseo-tiróidea em 39 pacientes com bócio multinodular atóxico, submetidos a tiroidectomia parcial, no período de 1970 a 1983, visando avaliar possíveis correlaçöes entre alteraçöes da funçäo tiróidea, extensäo da cirurgia e recidiva do bócio. A incidência da recidiva do bócio foi de aproximadamente 15%, sendo a maioria identificada dez ou mais anos após a cirurgia. Operaçöes mais radicais diminuíram a taxa de recidiva, às custas de um aumento do risco de hipotiroidismo subclínico. Näo foram encontradas diferenças estatisticamente significativas nos níveis plasmáticos de T3, T4, T4 livre e TSH (basal e após TRH) entre os pacientes com ou sem recidiva. Em uma paciente o tratamento pós-operatório com tiroxina näo evitou o aparecimento do bócio recidivante. Isto sugere que o aumento do TSH näo parece ser necessário para a manutençäo do bócio atóxico recidivante. Uma vez que a maioria dos pacientes submetidos a tiroidectomia permanece eutiróidea e apenas uma pequena proporçäo desenvolve recidiva, parece-nos questionável o uso pós-operaçäo rotineiro de hormônios tiróideos visando à profilaxia da recidiva do bócio multinodular