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Brief report: Use and misuse of thyroid ultrasound in the initial workup of patients with suspected thyroid problems referred by primary care physicians to an endocrine clinic.

BACKGROUND AND OBJECTIVES: Thyroid ultrasound (TUS) plays an important but limited role in the evaluation of some complaints related to the thyroid gland. This study was designed to examine how primary care physicians use TUS before referring patients to an endocrine clinic. DESIGN: We audited all charts of first-time referrals for appropriateness of TUS use. Recommendations in practice guidelines and current textbooks defined appropriate indications for TUS: (1) patients with a thyroid nodule and a history of head or neck irradiation; (2) follow-up of patients with nodules not surgically removed; and (3) evaluation of patients with amiodarone-induced thyrotoxicosis. SETTING: Endocrine referral clinic in a teaching hospital in Israel. RESULTS: Two hundred and eight unselected referrals were reviewed. Sixty-nine (33%) of the patients presented with a TUS. Documented reasons for TUS were suspected thyroid mass (n=35, 51%), thyroid dysfunction (n=21, 30%), neck pain (n=5, 7%), dyspnea (n=4, 6%), and dysphagia (n=2, 3%). Of the 69 TUS reviewed, 64 (93%) were not appropriate. CONCLUSIONS: Primary care clinicians obtain TUS studies in patients without recommended indications prior to referral to an endocrinologist.

Adult↗

A novel thyroid hormone receptor-beta mutation, not anticipated to occur in resistance to thyroid hormone, causes variable phenotypes.

Resistance to thyroid hormones (RTH) is a syndrome characterized by a variable tissue hyposensitivity to thyroid hormones and is linked to mutations in the thyroid hormone receptor-beta (TRbeta) gene. We report here for the first time in vivo the mutation R429W (CCG-->TCG) located in the exon 10. The artificial mutant obtained in vitro displayed a normal T(3)-binding affinity and transactivation function. Therefore, it was thought to produce little, if any, clinical effect and to escape to clinical detection. The present report is at least in part discordant with this prediction since the propositus and his grandmother had an authentic hyperthyroidism with high FT(4) plasma level in the presence of inappropriate TSH. On the other hand, spontaneous variations of clinical features and - interestingly - of plasma FT(4) concentrations with time in the propositus, and the phenotype observed in his mother who never complained with thyrotoxic symptoms, confirmed the in vitro binding and functional predictions. The most intriguing is the clinical course of the grandmother as she first presented with predominant pituitary RTH and a diffuse goiter and finally with a toxic multinodular goiter with normal T(3) and T(4) plasma concentrations and suppressed TSH. In conclusion, we report a novel mutation in the gene encoding the thyroid hormone receptor responsible for predominant pituitary RTH already described in vitro but not in vivo. The fluctuant phenotype of the propositus suggests that other factors modulate the degree of tissue resistance that is under genetic control. Toxic multinodular goiter, possibly due to chronic TSH stimulation during RTH, in addition to the phenotype variability, increases the difficulty to diagnose this thyroid disorder.

Adult↗

The thyroid hormone receptors: molecular basis of thyroid hormone resistance.

Major progress has been achieved in the mechanism of action of thyroid hormones thanks to the identification of the T3 receptor as the product of the proto-oncogene c-erbA. Recognition of subsets of receptors with and without T3-binding properties and of the interaction of different receptors with each other leads to new insights in cell regulation and development. In thyroid hormone resistance, distinct mutations in the T3-binding domain of thyroid hormone receptor (TR)beta have been identified in unrelated families. No correlation between the type of mutation and tissue resistance has been established. Mutant TRs bind to thyroid hormone response elements (TREs) on both negative or positive T3-controlled genes. Subjects with heterozygous TR beta gene deletion are not affected, supporting the hypothesis that mutant TRs act through a dominant negative effect. In generalized thyroid hormone resistance, mutated TR beta may interfere through competition for TREs and/or formation of inactive dimers. Finally, deficiency in T3 receptor auxiliary protein or other accessory proteins or competition between mutant and normal TRs for these factors is not excluded.

Binding Sites↗

Comparative findings of lymphocytic thyroiditis and thyroid lymphoma.

OBJECTIVE: To compare the cytologic features of histologically proven lymphocytic (Hashimoto's) thyroiditis (Hashimoto's thyroitidis) and primary thyroid lymphomas (TL). STUDY DESIGN: Clinical histories, smears (stained with Diff-Quik, Papanicolaou stain or hematoxylin and eosin [HE]) and surgical specimens (HE slides) were reviewed in 25 cases of lymphocytic thyroiditis and 12 of thyroid lymphomas. RESULTS: Surgical specimens of thyroiditis were obtained for other medical reasons: goiter and compressive symptomatology in 21 cases and neoplasms in 4 (2 papillary carcinomas, 1 follicular carcinoma and 1 oncocytic adenoma). Seven cases were primary lymphomas, and 5 were secondary. Histologically there were 6 large B-cell lymphomas, 2 mantle cell lymphomas, 1 Burkitt lymphoma, 2 mucosal-associated lymphoid tissue lymphomas in blastic transformation and 1 of unknown type. Sensitivity for the diagnosis was 67.5% for HT and 92.3% for lymphoma. CONCLUSION: A heterogeneous population of small and large lymphocytes was the most frequent pattern in both diseases. The presence of a monotonous population of large lymphocytes or, more rarely, of small cells indicates a probable TL. Plasma cells favor HT. Other techniques are mandatory for the differentiation of cases with inconclusive diagnoses.

Adult↗

Compensatory role of thyroid hormone receptor (TR) alpha 1 in resistance to thyroid hormone: study in mice with a targeted mutation in the TR beta gene and deficient in TR alpha 1.

Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor beta (TR beta) gene. Almost all RTH patients are heterozygous with an autosomal dominant pattern of inheritance. That most are clinically euthyroid suggests a compensatory role of the TR alpha1 isoform in maintaining the normal functions of thyroid hormone (T3) in these patients. To understand the role of TR alpha1 in the manifestation of RTH, we compared the phenotypes of mice with a targeted dominantly negative mutant TR beta (TR betaPV) with or without TR alpha1. TR betaPV mice faithfully recapitulate RTH in humans in that these mice demonstrate abnormalities in the pituitary-thyroid axis and impairment in growth. Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice, and severe impairment of postnatal growth was manifested in TR betaPV mice deficient in TR alpha1. Furthermore, abnormal expression patterns of T3-target genes in TR betaPV mice were altered by the lack of TR alpha1. These results demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH. This compensatory role may be especially crucial for postnatal growth.

Animals↗

Hashimoto's thyroiditis and carcinoma of the thyroid: optimal management.

Several authors have noted a high incidence of thyroid carcinoma in patients with Hashimoto's thyroiditis (HT), and some have even considered HT a premalignant condition. The authors evaluated all patients with surgically proven HT at Beth Israel Medical Center in New York from 1985 through 1990. Of these 48 patients, 8 (17%) had thyroid carcinoma in addition to HT. No statistically significant difference between patients with and without concurrent carcinoma was noted in the percentage of patients with a dominant mass, irregular thyromegaly, compressive symptoms, suspicious fine needle aspiration biopsies (FNABs), or a cold nodule on thyroid scintigraphy. However, patients with neither a positive FNAB nor a cold nodule were much less likely to have carcinoma than patients with one or both of these tests positive (0% vs. 26%, P < or = .05). A management scheme for patients with HT is proposed to adequately and efficiently evaluate and treat patients for concurrent thyroid carcinoma.

Adenoma↗

Zn concentration in thyroid tissue and whole blood of women with different diseases of thyroid.

The Zn concentration in thyroid tissue and whole blood of patients with Graves' disease, thyroid cancer, and nodular goiter disease was determined using the total-reflection X-ray fluorescence method. The dependence of obtained concentrations on the clinical stage of the examined disease, histopathological grading, and kind of analyzed material (thyroid tissue and blood) was studied. The determined concentration of Zn was the lowest in the thyroid tissue of patients with thyroid cancer (23.1 microg/g) and it was the highest in the case of Graves' disease (41.7 microg/g), whereas in the blood samples, the reverse results were found (7.1 microg/g and 4.8 microg/g, respectively). The physical basis of the method used, the experimental setup, and the procedure of sample preparation are described.

Adolescent↗

Correlation between thyroid peroxidase activity and histopathological and ultrastructural changes in various thyroid diseases.

A morphological and biochemical study was performed on thyroid tissue with various thyroid diseases. The thyroid peroxidase (TPO) activity of normal thyroid tissues ranged from 2.6 to 7.0 mGU/mg DNA. The activity was low in adenomas and extremely low in carcinomas, and there was no significant relationship between the histological subclassification of follicular adenomas (simple, colloid, oxyphil) and TPO activity. The activity was various in the cases of chronic thyroiditis, ranging from non-detectable to 9.8 mGU/mg DNA, and the TPO activity showed a close correlation with the degree of lymphoid cell infiltration of the diseases. In the seven cases of Graves' disease, the values were high, though the elevation was not so remarkable in three cases which had already been euthyroid or slightly hypothyroid after long-term treatment. By means of subcellular fractionation, more than 50% of peroxidase activity was shown to be localized in the microsomal pellets, and this result well coincided with the electron microscopic findings of prominent development of rER.

Adenoma↗

Disappearance of blocking type thyrotropin binding inhibitor immunoglobulin (TBII) during thyroid and steroid medication in a patient with autoimmune thyroiditis.

A 55 year-old female had suffered from 3 consecutive diseases for a year. The diseases were ulcerative colitis, primary hypothyroidism and idiopathic thrombocytopenic purpura, and had been treated with L-thyroxine (50 micrograms daily) and betamethasone (0.5 to 1.5 mg daily). On examination, the thyroid gland was not palpable at all, thyroid 99 mTc pertechnetate uptake was 0%, and an echogram revealed the existence of an atrophic gland. Thyrotropin binding inhibitor immunoglobulin (TBII) in the serum was elevated to 58.0% and her IgG almost completely inhibited the in vitro cAMP increase due to bTSH. After 5 months TBII turned out to be negative and the inhibitory IgG activity was reduced significantly. The thyroid gland also became visible scintigraphically. Thyroid medication was then stopped. Four months after the cessation of thyroxine, she felt quite well and her thyroid functions remained within the normal ranges. Antibody to Yersinia enterocolitica was positive at a low titer (X20) in the early stages, but elevated reciprocally with the fall in TBII and finally reached X320. In conclusion, evidence of the disappearance of blocking type TBII from the serum was demonstrated for the first time. Steroid might have caused some favorable effects, and this clinical report indicates the possibility that remission of hypothyroidism due to blocking type TBII can be expected.

Antibodies, Bacterial↗

Identification of thyroid hormone residues on serum thyroglobulin: a clue to the source of circulating thyroglobulin in thyroid diseases.

Thyroglobulin (Tg) present in the serum of normal individuals and patients with thyroid disorders could be partly newly synthesized non-iodinated Tg and partly Tg containing iodine and hormone residues originating from the lumen of thyroid follicles. With the aim of examining the contribution of the latter source of Tg to the elevation of serum Tg concentration in thyroid pathophysiological situations, we devised a procedure to identify thyroxine (T4) and tri-iodothyronine (T3) residues on Tg from unfractionated serum. A two-step method, basedon (i)adsorption of Tg on an immobilized anti-human Tg (hTg) monoclonal antibody (mAb) and (ii)recognition of hormone residues on adsorbed Tg by binding of radioiodinated anti-T4 mAb and anti-T3 mAb, was used to analyze serum Tg from patients with either Graves' disease (GD), subacute thyroiditis (ST) or metastatic differentiated thyroid cancer (DTC). Purified hTg preparations with different iodine and hormone contents were used as reference. Adsorption of purified Tg and serum Tg on immobilized anti-hTg mAb ranged between 85 and 90% over a wide concentration range. Labeled anti-T4 and anti-T3 mAbs bound to adsorbed purified Tg in amounts related to its iodine content. Tg adsorbed from six out of six sera from ST exhibited anti-T4 and anti-T3 mAb binding activities. In contrast, significant mAb binding was only observed in one out of eight sera from untreated GD patients and in 1 out of 13 sera from patients with DTC. The patient with DTC, whose serum Tg contained T4 and T3, represented a case of hyperthyroidism caused by a metastatic follicular carcinoma. In conclusion, we have identified, for the first time, T4 and T3 residues on circulating Tg. The presence of Tg with hormone residues in serum is occasional in GD and DTC but is a common and probably distinctive feature of ST.

Antibodies, Monoclonal↗

Incidental detection of familial medullary thyroid carcinoma by calcitonin screening for nodular thyroid disease.

Serum calcitonin screening has recently been found to be a useful supplement to fine-needle aspiration biopsy, ultrasound and radionuclide imaging in the evaluation of thyroid nodules. We describe a case where introduction of routine calcitonin screening in nodular thyroid disease led to the detection of a family with medullary thyroid carcinoma. The benefits and problems of basal and stimulated serum calcitonin testing and ret-proto-oncogene mutation studies are exemplified and we discuss the appropriate use and interpretation of these tests. We conclude that routine basal serum calcitonin measurement in nodular thyroid disease and thoughtful use of ret-mutation analysis is cost-effective in detecting medullary thyroid carcinoma and multiple endocrine neoplasia type II.

Adult↗

Receptors for thyroid-stimulating hormone in normal and pathological human thyroid tissues.

The receptors for TSH have been studied in human thyroid tissue to assess their density and binding characteristics in various disease states. A single set of similar independent receptors appeared to be present in both healthy and pathological thyroid tissue. Their binding affinity for bovine TSH averaged 1.1 X 10(10) l/mol in healthy tissue and, with the exception of papillary carcinoma which showed some reduction, was not significantly altered in the various disease states studied. No receptors with low binding affinity were found. The number of receptors was significantly greater in toxic diffuse goitre and in hyperfunctioning follicular adenoma (but these tissues came from patients given antithyroid drugs and often iodine preoperatively), and was reduced in Hashimoto's thyroiditis. In well-differentiated thyroid carcinoma, the number of receptors was similar to or greater than in normal tissue, but in undifferentiated and medullary carcinoma, and in lymphoma of the thyroid, receptors were completely absent. Tracer-binding data obtained with human TSH were uniformly lower than the corresponding data obtained with bovine TSH, but showed an analogous pattern of differences amongst the various normal and pathological tissues.

Humans↗

Overexpression of thyroid hormone receptor beta1 is associated with thyrotropin receptor gene expression and proliferation in a human thyroid carcinoma cell line.

To correlate the differentiation phenotype of two human thyroid cancer cell lines with their expression of various molecular markers, we analyzed the mRNA levels of four thyroid-specific genes, including thyrotropin receptor (TSHR), thyroglobulin (Tg), thyroid transcription factor-1 (TTF-1), and paired-box containing transcription factor-8 (PAX-8) genes. The results showed a differentiation-status-related pattern in which a well-differentiated cell line (WRO) expressed all the four genes, in contrast to an anaplastic cell line (ARO) that expressed TTF-1 and reduced levels of TSHR, but no Tg or PAX-8 genes. Furthermore, to verify the finding of concomitant loss of beta subtype thyroid hormone receptor (TRbeta) and TSHR gene expression in neoplastic thyroid tumors (Bronnegard et al. 1994), we examined the expression levels of TRbeta1 gene in these cell lines. Whereas the WRO cells produced an abundant amount of TRbeta1 protein detectable by immunoprecipitation, the ARO cells produced none. This new observation prompted us to investigate whether overexpression of TRbeta1 protein in ARO cells might produce changes in the differentiation phenotypes. We found that the level of expression of the TSHR gene and the proliferative index of ARO cells were significantly upregulated in the cells stably transfected with wild-type TRbeta1. These findings suggest that TRbeta1 protein overexpression can affect the differentiation phenotypes and induce more efficient cell proliferation of the anaplastic ARO cells.

Blotting, Western↗

[Analysis of expression of LGALS3BP gene in thyroid tissues and peripheral blood lymphocytes in patients with papillary thyroid cancer].

INTRODUCTION: Galectin-3 (Gal-3), coding by LGALS3BP gene, is a protein of the lectin family that has been associated with neoplastic processes and seems to play an important role in a variety of cell biological processes. In the thyroid gland, the high expression of this protein has been described in differentiated carcinomas, especially in papillary thyroid cancer (PTC). AIM: Analysis of Gal-3 protein expression in PTC and nodular goiters; investigation of Gal-3 mRNA expression in peripheral blood lymphocytes (PBL) in patients with PTC and nodular goiter; analysis of correlation between Gal-3 protein expression in PTC and Gal-3 mRNA in PBL of the same patient. MATERIAL AND METHODS: Gal-3 protein was evaluated by immunohistochemistry in benign (27 multinodular goiters) and malignant (30 papillary carcinomas) thyroid tissues and galectin-3 mRNA expression by real-time PCR in peripheral blood lymphocytes (PBL) from 90 patients with multinodular goiter (n = 27), papillary carcinoma (n = 30) and healthy controls (n = 33). RESULTS: In PTC we observed increased expression of Gal-3 protein (all 30 cases) in cytoplasm, nucleus and cell membranes of cancer cells. 23 of 27 benign thyroid nodular goiters were negative for Gal-3 expression. In all examined blood samples we observed higher LGALS3BP gene expression than GAPDH (house keeping gene) with no difference between both groups, without relation to the Gal-3 expression in PTC. CONCLUSIONS: There is no difference in Gal-3 expression in peripheral blood lymphocytes in patients with papillary thyroid cancer in relation to nodular goiter.

Antigens, Neoplasm↗

Interference in thyroid-function tests in postpartum thyroiditis.

Three women are described from a study of patients with postpartum thyroiditis whose sera gave spuriously increased concentrations of free thyroid hormone because of antibody binding of radiolabeled thyroxin (T4) and triiodothyronine (T3) analogs. All of the women showed increased serum concentrations of thyroid autoantibodies. The antibody binding of radiolabeled analogs and its effect on free T4 and free T3 assays disappeared by 48 weeks postpartum. Postpartum women who develop thyroid autoantibodies have approximately 2% prevalence of increased binding of radiolabeled analogs, which can result in an interference in thyroid hormone assays involving T4 and T3 analogs.

Autoantibodies↗

Sclerosing mucoepidermoid thyroid carcinoma with eosinophilia. A distinctive low-grade malignancy arising from the metaplastic follicles of Hashimoto's thyroiditis.

Eight cases of a distinctive low-grade carcinoma of the thyroid gland occurring in a background of Hashimoto's thyroiditis are reported. The patients were women presenting with a painless thyroid mass. Grossly, the tumors were white, homogeneous, firm, and usually ill defined. Histologically, strands and small nests of squamoid tumor cells exhibiting mild to moderate nuclear pleomorphism, distinct nucleoli, and pale cytoplasm infiltrated an abundant, dense fibrohyaline stroma. Foci of definite squamous differentiation and small pools of mucin were often found within the tumor nests. The neoplastic cells were immunoreactive for cytokeratin, but not for thyroglobulin or calcitonin. The stroma and many of the tumor islands were infiltrated by eosinophils in all cases. Extrathyroidal extension occurred in five cases and lymph node metastases in one. This tumor seems to arise from the benign squamous nests sometimes associated with mucin deposition found in Hashimoto's thyroiditis and thought to be the result of metaplastic changes of the follicular epithelium. It shares several morphologic features with cases previously reported as mucoepidermoid carcinoma of the thyroid, but it differs from them in other respects. The differential diagnosis includes undifferentiated/squamous cell carcinoma, intrathyroidal thymic carcinoma, and direct extension or metastasis of carcinoma from other organs.

Adult↗

[Study of thyroid function parameters and thyrotropin in general non-thyroid diseases].

The changes in the parameters of thyroid function and thyrotropin (TSH) have been evaluated in 5 groups of patients with general non-thyroid disease (GNTD): acute severe bacterial infection (16 patients), acute myocardial infarction (22 patients), diabetic ketoacidosis (24 patients), non-ketotic hyperosmolar decompensation (8 patients), protein-calorie undernutrition (12 patients), without associated conditions or drug therapies that might have modified the thyroid hormones. These patients were evaluated at the beginning of their GNTD and after recovery. Thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) were measured by radioimmunoassay (RIA), the TBC index by competitive analysis, the free T4 by a labeled T4 analogue and T4 by immunoradiometric analysis (IRMA). In all patients similar changes in thyroid hormones and in IRMA were found, and they returned to normal after recovery; the changes were most marked in diabetic ketoacidosis, followed by hyperosmolar decompensation and by undernutrition. When the 5 groups were evaluated together, T3 was the most commonly low value (57.3%), followed by T4 and TBC index (26.8%), free T4 (20.7%) and the free T4 index (10.9%). The level of rT3 was increased in 39% of cases. Baseline TSH was, initially, 1.05 +/- 1.05 microU/ml, and 1.36 +/- 0.85 microU/ml after recovery (p less than 0.001). It was only found to be suppressed in one patient (a female with diabetes mellitus and Graves disease); in 17 cases it had borderline values between 0.1 and 0.4 microU/ml, and in the remaining patients it was normal. GNTD induces profound changes in the thyroid functional parameters, with reductions below their normal range, including the analogue measured T4 and low TSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

c-myc expression in the thyroid. II: Thyrocytes and peripheral and intrathyroidal lymphocytes from patients with autoimmune thyroid disease.

Enhanced oncogene expression observed in lymphocytes from patients with systemic lupus erythematosus has suggested the importance of studying oncogene expression and regulation in the cellular events of autoimmune thyroid diseases (AITD). The present study examines oncogene expression in peripheral and intrathyroidal lymphocytes from patients with Hashimoto's disease (HD) and Graves' disease (GD). Intrathyroidal lymphocytes from a patient with primary thyroid lymphoma were also examined. Lymphocytes were isolated by Ficoll-Hypaque gradients, and total RNA was prepared by extraction with guanididium thiocyanate and ultracentrifugation through a cesium chloride cushion. RNA concentrations were determined by O.D. readings at 260/280 nm and each sample subjected to gel electrophoresis with ethidium bromide staining to assure the integrity of the RNA. 30 micrograms total RNA was size fractionated on a 1% (w/v) agarose/formaldehyde gel and transferred to nylon membranes. These membranes were hybridized with nick-translated 32P labelled c-myc DNA (exon III), washed at high stringency and subjected to autoradiography. Specific bands were quantitated by scanning densitometry. Five RNA samples from GD thyroids had 2.4 Kb bands corresponding to c-myc with a mean O.D. (+/- SD) of 0.76 +/- 0.23, whereas 7 from normal thyroid glands had mean O.D. of 1.0 +/- 0.26. Peripheral lymphocytes from 7 GD patients had a mean O.D. of 1.41 +/- 0.25, 4 HD patients had a mean O.D. of 1.05 +/- 0.10 and 2 normal patients had a mean O.D. of 1.4 +/- 0.14. The readings for a sample obtained from intrathyroidal lymphocytes of a patient with HD and thyroid lymphoma were 1.0 and 1.4, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune Diseases↗