THERAPEUTIC PROBLEMS OF NON-TOXIC NODULAR GOITER

The crucial point regarding non-toxic nodular goiter is the early diagnosis of neoplasm. A neoplasm may be suspected if a nodular goiter has shown recent growth with the concurrent appearance of pressure symptoms, if it is found in a patient under the age of 20, if vocal cord paralysis is present, or emphatically, if a solitary nodule is discovered. Such non-toxic nodular goiters should be promptly removed regardless of the presence or absence of pressure symptoms. If significant pressure symptoms are present, this in itself is an adequate reason for thyroidectomy.     

Cyclic AMP in non-toxic nodular goiter

Cyclic AMP concentrations in a non-toxic nodular goiter were measured by means of the radiocompetitive protein-binding assay. It has been shown that cold thyroid nodules contain a higher concentration of cAMP than the macroscopically normal, extra-nodular thyroid tissue.     

Serum levels of the cytokines IL-1beta, IL-6 and ICAM-1 after 131I-treatment of Graves' disease and nodular goiter.

Cytokines might be involved in the immunological flare up, seen in some patients after 131I-treatment. Therefore, we measured serum levels of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), interleukin-6 soluble receptor (IL-6sR) and Intercellular-adhesion-molecule-1 (ICAM-1) as well as tumor necrosis factor (TNF-alpha) after 131I-treatment of Graves' disease and nodular goiter. Seven patients with Graves' disease, eight with toxic nodular goiter and seven with non-toxic nodular goiter, were followed after 131I-treatment. The patients were treated in the euthyroid state. Blood samples were drawn at day 0, 4, 7, 21 and after 3 months. Significant increases were seen in free T4 index (FT4I), free T3 index (FT3I) and thyroglobulin (Tg) within the first weeks, and TSH simultaneously decreased. None of the cytokines demonstrated any change during follow-up, neither in the entire group nor in subgroups. FT4I and FT3I correlated significantly to ICAM-1. In conclusion, our data suggest that there does not seem to be prolonged cytokine activation after 131I-treatment for thyroid disorders.     

表皮生长因子及受体在甲状腺肿瘤中的表达

目的:研究表皮生长因子(Epidermal Growth Factor,EGF)及受体(Epidermal Growth Factor Receptor,EGFR)及在甲状腺肿瘤中的表达。方法:应用免疫组织化学法检测91例甲状腺病变组织中EGFR和EGF的表达情况。结果:结节性甲状腺肿、甲状腺腺瘤、分化型甲状腺癌标本中EGFR表达的阳性率分别为15%、25%、68.62%,EGF表达的阳性率分别为10%、15%、68.62%,其中EGFR、EGF在分化型甲状腺癌与其余两组间差异均有统计学意义(P<0.05)。EGFR和EGF在甲状腺乳头状癌中的表达与性别、年龄、肿瘤大小、淋巴结转移、临床分期等临床因素无明显相关。结论:EGF和EGFR的表达可作为鉴别甲状腺肿瘤良恶性的一个指标。     

Does Unilateral Lobectomy Suffice to Manage Unilateral Nontoxic Goiter?

ObjectiveTo evaluate the effectiveness of ipsilateral lobectomy to treat unilateral, nontoxic, benign nodular goiter and to define predictive factors for recurrence.MethodsPatients undergoing thyroid lobectomy for unilateral, nontoxic, benign nodular goiter between 2002 and 2007 were included. Patients were excluded if coincidental thyroid cancer was detected at histopathologic examination and completion thyroidectomy was performed. Potential predictors of recurrence including age; sex; family history; preoperative volume of the thyroid gland; preoperative number, size, and ultrasonography characteristics of the nodules; duration of postoperative follow-up; postoperative use of thyroxine; and histopathologic diagnoses were recorded at baseline. Follow-up visits were scheduled every 3 months during the first year and every 6 months thereafter. Recurrent disease was defined as a hypoechogenic or hyperechogenic nodule larger than or equal to 3 mm detected in the remaining contralateral lobe during ultrasonography. Patients with a thyrotropin value greater than 5 mIU/L received thyroxine. Fineneedle aspiration biopsy was performed for nodules greater than 10 mm or for nodules with characteristics suggestive of malignancy. Reoperation was indicated if a nodule was greater than 3 cm in diameter, posed a risk of malignancy, or caused compression signs or symptoms.ResultsA total of 104 patients were included. Histopathologic diagnoses at initial operation were adenoma in 45 patients, colloidal nodular goiter in 45 patients, and chronic lymphocytic thyroiditis in 14 patients. Average duration of follow-up was 39.75 ± 21.75 months (range, 5-87 months). Recurrence was seen in 63 patients (60.6%). Histopathologic characteristics of the lobectomy material (P <.001), preoperative volume of the thyroid gland (P <.006), and multinodularity (P <.011) were significant predictors of recurrence.ConclusionsHigher preoperative thyroid volume, histopathologic characteristics of nodules, and multinodular disease are associated with an increased risk of recurrence in patients with unilateral nodular goiter. Unilateral lobectomy is an effective therapeutic option with low reoperation rates in unilateral benign thyroid disease. (Endocr Pract. 2010;16:36-41)     

Arterial hypertension associated with hyper and hypothyroidism]

45 patients with hyper and hypothyroidism in the time 1989-1990 were observed. The Graves' disease was diagnosed in 29 and rather in the younger patients, but 16 had the toxic nodular goiter and those were elderly. In 27 the hypertension was secondary (symptomatic) and after the successful treatment of the hyperthyroidism was completely controlled. In 14 cases the hypertension was primary (essential) and the application of the hypotensive drugs was also necessary. Among 4 patients with primary hypothyroidism and associated hypertension and coronary insufficiency the early treatment by the thyroid preparation was successful: the blood pressure was lowered and the coronary insufficiency was improved; but if the replacement therapy was stopped and the hypothyroidism was relapsed, the blood pressure was increases and the coronary insufficiency was aggravated. Conclusions: 1. The secondary (symptomatic) hypertension associated with the hyperthyroidism may be controlled by successful treatment of the thyrotoxicosis, but the primary (essential) must be treated by the hypotensive drugs also. 2. The early treatment of the hypothyroidism may control the associated hypertension and the coronary insufficiency. 3. Graves' disease is associated mostly with symptomatic hypertension, in nodular toxic goiter in most of the cases the essential hypertension was established.     

Cytologic appearance of toxic nodular goiter after thyrostatic treatment. A karyometric study

OBJECTIVE: To assess whether the cytologic appearance of aspirates from toxic nodular goiter is substantially modified during the course of therapy with thyrostatic drugs. STUDY DESIGN: Morphometric features of thyrocyte nuclei in aspirates obtained from nontoxic nodular goiter (NTNG), toxic nodular goiter before treatment (TNG-untreated) and toxic nodular goiter during thyrostatic administration (TNG-treated) were examined. The relationship between the degree of morphologic changes and the duration of therapy was evaluated. An analysis of the composition of aspirates was also performed. RESULTS: The sizes of thyrocyte nuclei in the TNG-untreated group were larger than in the NTNG and TNG-treated groups, and treatment with thyrostatics was accompanied by a gradual decrease in the sizes of thyrocyte nuclei. However, karyometric features showed a tendency to increase again in patients treated for longer than 1 year, with the variability of nuclear size in a smear (anisokaryosis) increasing more markedly than the mean size of nuclei. Moreover, in those patients, nuclei with visible nucleoli were found. CONCLUSION: Only long-term therapy with thyrostatic drugs leads to changes in the microscopic appearance of smears obtained by fine needle aspiration biopsy (FNAB) of the thyroid relevant to cytologic diagnosis. Thus, FNAB can be performed successfully after the onset of treatment with thyrostatics if the cytologist is informed of the time scale of treatment in each case.     

Low Iodine in the Follicular Lumen Caused by Cytoplasm Mis-localization of Sodium Iodide Symporter may Induce Nodular Goiter

Iodine is a key ingredient in the synthesis of thyroid hormones and also a major factor in the regulation of thyroid function. A local reduction of iodine content in follicular lumen leads to overexpression of local thyroid-stimulating hormone receptor (TSHr), which in turn excessively stimulates the regional thyroid tissue, and result in the formation of nodular goiter. In this study, we investigated the relationship between iodine content and sodium iodide symporter (NIS) expression by using the clinical specimens from patients with nodular goiter and explored the pathogenesis triggered by iodine deficiency in nodular goiter. In total, 28 patients were clinically histopathologically confirmed to have nodular goiter and the corresponding adjacent normal thyroid specimens were harvested simultaneously. Western blot and immunohistochemistry were performed to assay NIS expression and localization in thyrocytes of both nodular goiter and adjacent normal thyroid tissues. NIS expression mediated by iodine in follicular lumen was confirmed by follicular model in vitro. Meanwhile, radioscan with iodine-131were conducted on both nodular goiter and adjacent normal thyroid. Our data showed that NIS expression in nodular goiter was significantly higher than that in adjacent normal tissues, which was associated with low iodine in the follicular lumen. Abnormal localization of NIS and lower amount of radioactive iodine-131 were also found in nodular goiter. Our data implied that low iodine in the follicular lumen caused by cytoplasm mis-localization of NIS may induce nodular goiter.     

Métastase du tissu mou révélant un carcinome folliculaire différencié de la thyroïde

Differentiated thyroid cancer occupies a very important place within the framework of thyroid pathology, representing 90% of thyroid cancers. A nodular goiter generally summarizes the clinical picture. Nevertheless, remote metastases can be revealing. The elective localizations of these metastases are by descending order of frequency: lung, bone, mediastinal lymph nodes, kidney, liver and adrenal glands. Soft tissue metastases are extremely rare and exceptionally revealing of the neoplasm. We report one case of follicular thyroid carcinoma revealed by soft tissue metastases of the arm.     

Ultrasonographic pattern and levels of thyrotropin and antithyroid antibodies in patients with recurrent neutral goiter after subtotal thyroidectomy]

The study comprised 65 women (mean age 43 years) with the recurrent goiter after subtotal strumectomy. All patients were subjected to ultrasonographic examination using a sonograph Sonoline LM (Siemens) with 7.5 MHz head. The study was aimed at: 1) assessment of etiology of goiter recurrence, 2) assessment of changes in the thyroid parenchyma, 3) detection of the occurrence of heterogeneous structures, such as nodules, cysts and calcifications. It was found that goiter recurrence appeared mainly in the patients subjected to surgery because of neutral nodular goiter. The observed changes in the thyroid stump, such as heterogeneous structure of parenchyma, generalized cyst-like spaces and nodular structures mainly of mixed type or of solid, normo-echogenic or hyper-echogenic type, were associated with high levels of THS and the presence of antithyroid antibodies in blood serum. In patients with evidently high TSH levels and positive with respect to occurrence of antithyroid antibodies, the nodular structures were more numerous and of larger size. In can be concluded that ultrasonography provides a valuable noninvasive tool for the evaluation of morphological structure of the recurrent goiter.     

Melatonin concentrations in patients with large goiter before and after surgery

OBJECTIVES: Surgical removal of a very large goiter may traumatize adjacent anatomical structures. The manipulations that involve superior cervical ganglia may alter melatonin secretion. To test this hypothesis we decided to study diurnal serum melatonin profiles in patients with a very large goiter before and after the surgery. MATERIAL AND METHODS:The study was performed on 10 women (mean age-46.5+/-1.6 years; mean+/-SEM; range 39-54 years) with very large non-toxic nodular goiter (mean thyroid volume-125.8+/-25.9 cm (3); mean+/-SEM; range 82.6-326.7 cm(3)). Diurnal serum melatonin profiles were estimated two days before the operation and 10 days after the surgery. Blood samples were collected at 08:00, 12:00, 16:00, 20:00, 22:00, 24:00, 02:00, 04:00, 06:00 and 08:00 h. Melatonin concentration was measured using RIA kit. RESULTS: Nocturnal serum melatonin concentrations (at 24, 02, and 04 hours) were significantly higher after the surgery than before the operation. CONCLUSIONS: Very large goiter may compress the superior cervical ganglia altering indirectly the melatonin synthesis. It cannot be excluded, however, that the presence of the large goiter in some other way affects melatonin secretion.     

Expression of Bcl-2 family proteins in thyrocytes from young patients with immune and nonimmune thyroid diseases

The Bcl-2 family proteins that control homeostasis of cells play an important role in apoptosis. This group consists of antiapoptotic (Bcl-2, Bcl-XL) and proapoptotic (Bcl-2 associated protein X, Bax; B-cell homologous antagonist/killer, Bak) molecules. In the thyroid, abnormal apoptotic activity may be involved in a variety of diseases such as autoimmune thyroid diseases. The aim of the current study was to estimate the expression of pro- and antiapoptotic proteins in thyroid tissues from young patients with Graves' disease (GD), nontoxic nodular goiter and toxic nodular goiter using Western Blot and immunohistochemistry. Identification of the antiapoptotic Bcl-2 and Bcl-XL molecules in the thyrocytes revealed higher expression of both proteins in patients with GD (assessed as +++/++ and ++/+, respectively). In adolescents with toxic and nontoxic nodular goiter, this expression was lower (Bcl-2 ++/+ , ++/+; Bcl-XL +, +). The tissue material was additionally subjected to Western Blot analysis, which in GD patients showed the presence of Bcl-2 and Bcl-XL in one band p26 kDa. In patients with toxic and nontoxic nodular goiter, the intensity of expression for these two antiapoptotic proteins was lower (referred to band 26 kDa for Bcl-2 and Bcl-XL). Identification of the proapoptotic proteins Bax and Bak revealed their predominance in thyrocytes of GD patients (+, ++/+, respectively) as compared to patients with toxic and nontoxic nodular goiter (0/+, 0/+ for Bax and 0/+, 0/+ for Bak). In GD patients, Western Blot analysis showed Bax expression in one band 21 kDa and Bak in two bands p50, p24 kDa. In patients with nodular goiter, the degree of expression of both proapoptotic proteins was lower and referred to band 21 kDa for Bax (toxic and nontoxic goiter) and 24 kDa for Bak (toxic goiter only). Patients with GD showed a statistically significant correlation between Bcl-2 expression and antibodies against receptor for thyroid stimulating hormone (R = 0.47, p < 0.03); however, such a correlation was not observed in patients with nodular goiter. In conclusion, our findings suggest that the changes in the expression of regulatory proteins of the Bcl-2 family in the thyroid follicular cells indicate the involvement of apoptosis in the pathogenesis of GD.     

The treatment of multinodular large non-toxic goiter using repeated doses of radioiodine (preliminary report)

INTRODUCTION: The aim of study was to establish the effectiveness of radioiodine therapy using 131I in the group of patients with multinodular large non-toxic goiter. MATERIAL AND METHODS: Therapy was undertaken in female patients disqualified from surgery due to high risk and these patients who didn't agree to surgery. Studies were performed in 7 women (age range: 62-82 yrs) with large goiters (2nd degree according to WHO classification and goiter volume assessed by USG over 100 cm(3)). Serum TSH, fT4, fT3, antithyroid antibodies (TPOAb, TgAb, TRAb) levels, urinary iodine concentration (UIE) were estimated in all patients parallel with radioiodine uptake test (after 5 and 24 hours), 131I thyroid scintigraphy and fine needle biopsy to exclude neoplasmatic transformation. These studies and therapy with 22 mCi 131I were repeated every 3 months. RESULTS: Before therapy median thyroid volume was approximately 145 cm(3) and during therapy gradually decreased to 76 cm(3) after 6 months and to 65 cm(3) after 12 months. Increase of TRAb can be a inhibiting factor of thyroid volume reduction. Other antithyroid antibodies showed marked tendency to rise but without significant correlation with radioiodine uptake and goiter reduction. After 12 months we found 2 patients with clinical and laboratory hypothyroidism. CONCLUSIONS: In some cases of multinodular large non-toxic goiter, the radioiodine therapy can be the best alternative way for L-thyroxine treatment or surgery therapy. The fractionated radioiodine therapy of multinodular large non-toxic goiter is safe and effective method but continuation of nodules observation is necessary.     

THE PATHOLOGY OF THE NODULAR GOITER

Pathologic studies of thyroid nodules indicate that a definite percentage of nodular goiters are malignant, and that an even higher percentage are true neoplasms. Malignant tumors may arise from adenomas, involutionary nodules or possibly from nodules of the unclassified type. Some carcinomas of the thyroid gland are undoubtedly malignant processes from the start. Because of the high incidence of neoplasms, benign and malignant, in a group of single nodules of the thyroid gland, the presence of such nodules should warrant radical resections of the involved lobe and adjacent isthmus. The high incidence of epithelial growth activity in nodular involutionary goiters may revise the accepted practice of removing non-toxic nodular goiters only when clinical evidence of growth or local pressure is present.     

The pathology of the nodular goiter

Pathologic studies of thyroid nodules indicate that a definite percentage of nodular goiters are malignant, and that an even higher percentage are true neoplasms. Malignant tumors may arise from adenomas, involutionary nodules or possibly from nodules of the unclassified type. Some carcinomas of the thyroid gland are undoubtedly malignant processes from the start. Because of the high incidence of neoplasms, benign and malignant, in a group of single nodules of the thyroid gland, the presence of such nodules should warrant radical resections of the involved lobe and adjacent isthmus. The high incidence of epithelial growth activity in nodular involutionary goiters may revise the accepted practice of removing non-toxic nodular goiters only when clinical evidence of growth or local pressure is present.     

The problem of goitre with particular consideration of goitre resulting from iodine deficiency (I): classification,diagnostics and treatment

In the present review paper, the following problems have been brought up: 1) types of nontoxic goitre and applied classification, 2) physiological periods or states predisposing to non-toxic goitre development, 3) evaluation of excessive stimulation of the thyroid gland, 4) the treatment of iodine deficiency consequences (non-toxic diffuse vs. non-toxic nodular goitre), 5) autoimmunologically-induced non-toxic goitre, and 6) positive effects of iodine prophylaxis with respect to goitre prevalence. The management of non-toxic nodular goitre, as well as of thyroid nodules is a separate and very complex issue, and--at the same time--the subject of our next review paper, published in the same issue of NEL.     

结节性甲状腺肿circRNA-miRNA-mRNA调控网络的构建

基于生物信息分析筛选结节性甲状腺肿中差异表达的环状RNA(circRNA),并揭示circRNA-miRNA-mRNA调控网络在结节性甲状腺肿中的作用。从GEO数据库中检索结节性甲状腺肿组织基因芯片数据,利用R软件筛选出差异表达的circRNA。联合多个生物信息数据库预测差异表达circRNA下游的miRNA及mRNA, 并对靶mRNA进行GO及KEGG富集分析。利用STRING在线数据库及Cytoscape软件筛选核心基因。确定了2个circRNA,42个miRNA及546个mRNA。GO及KEGG富集分析表明靶mRNA主要涉及细胞生长及基因表达调控过程。基于Cytoscape软件筛选出了14个核心基因(SP1、IGF1R、RPS6KB1、SMAD2、SMAD3、SMAD4、VEGFA、CCND1、CDK2、HSPA4、HIF1A、CREB1,NR3C1和STAT5A)。最终基于2个circRNA、11个miRNA和14个核心mRNA构建了circRNA-miRNA-mRNA调控网络。结节性甲状腺肿组织中异常表达的circRNA及相关的circRNA-miRNA-mRNA调控网络可能成为结节性甲状腺肿诊断与治疗的新靶点。     

425 例结节性甲状腺肿患者术后复发影响因素的分析

目的:探讨结节性甲状腺肿复发的影响因素。方法:分别对本院425例结节性甲状腺肿患者随访1年至8年;采用SPSS软件对复发相关因素进行单因素和多因素Logistic回归分析。结果:随访患者中有39例复发,复发率为9.18%。分析结果显示,两侧甲状腺结节数量越多,结节性甲状腺肿复发率越高(OR=2.631),双侧结节性甲状腺肿患者比单侧患者复发率高(OR=2.758),与接受正规替代治疗者相比,未接受替代治疗及接受非正规替代治疗者更易复发(OR=7.577/4.151),与单纯结节切除术相比,一侧加峡部全切、对侧部分/次全切除术术后复发率低(OR=0.209)。结论:结节性甲状腺肿患者术后复发率较高,针对上述各种影响因素,在临床上相应的治疗措施可有效预防结节性甲状腺肿的复发。     

分子生物学法分析青少年甲状腺肿物临床病理及特点

探讨青少年甲状腺肿物的临床病理学特点,甲状腺癌的复发、转移和结节性甲状腺肿复发的可能相关因素。按WHO病理分型标准和国际抗癌联盟(UICC)TNM分期标准回顾性分析青少年甲状腺肿物124例及其中部分甲状腺癌和结节性甲状腺肿的随访资料。124例甲状腺肿物患者男女比例约为1 3,甲状腺癌39例(31.5%),其中乳头状癌35例,滤泡癌3例,髓样癌1例;甲状腺腺瘤59例(47.6%),结节性甲状腺肿11例(8.9%),结节性甲状腺肿伴腺瘤7例(5.6%),甲状腺炎5例(4%),甲状舌管囊肿3例(2.4%)。本组资料显示,青少年甲状腺癌以乳头状癌为主,其复发、转移与组织学亚型为弥漫硬化型及甲状腺包膜和其外软组织受侵状态相关。虽然常见淋巴结转移、肺转移以及局部侵犯周围软组织,但患者总体预后较好。结节性甲状腺肿的复发与病变弥漫位于双叶有关,而与患者性别、年龄和是否伴有乳头样及腺瘤样增生关系不密切。     

Bocio intratorácico tóxico. Perfil clínico y morbilidad quirúrgica en una unidad de cirugía endocrina

BackgroundThe development of postsurgical complications is exacerbated when several risk factors coincide in the same patient. Objective: To analyze the results of surgery for toxic intrathoracic goiter in terms of (a) the need for sternotomy; (b) morbidity and mortality; and (c) remission of compressive symptoms.Material and methodsA review (1980–2002) was carried out of 43 cases of toxic intrathoracic multinodular goiter according to Eschapase's definition (3 cm below the sternal manubrium) occurring in patients without previous thyroid surgery who underwent total thyroidectomy. There were 2 control groups: I (non-toxic intrathoracic goiter, without recurrence and not requiring total thyroidectomy) and II (non-intrathoracic, non-toxic goiter without recurrence, requiring total thyroidectomy). The following variables were analyzed: sociopersonal, clinical and surgical characteristics, morbidity, mortality, and outcome.ResultsCompared with the control groups, the patient group had longer disease duration and was older. In 6 patients (14%) 1 was difficulty in intubation, and 2 patients required fiberoptic intubation. All goiters could be extirpated through the cervical route. The morbidity rate was 37% (n=16). Notably, 4 were recurrent lesions (9%), 1 of which was definitive, and 14 were hyperparathyroidism (33%), one of which was definitive. The only difference between the control groups and the patient group was a greater incidence of transitory hypoparathyroidism in the patient group than in control group II (33% versus 15%; p=0.0103). Surgical outcomes were excellent in terms of symptom remission.ConclusionsIn any unit with ample experience of endocrine surgery, total thyroidectomy in toxic intrathoracic goiter can be carried out with a low risk of postsurgical complications, a low incidence of sternotomies and complete symptom remission. In intrathoracic goiter surgery, the presence of associated hyperthyroidism does not increase postoperative morbidity.