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PubMed2004

Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening.

AIM: To ascertain the predictive values of thyroid autoantibodies and thyrotropin (TSH) levels for subsequent thyroid dysfunction in patients with diabetes. METHODS: Review of records of 467 patients who had attended diabetes clinics for a mean of 6.1 years. Baseline autoantibody and TSH results and thyroid status at annual review were determined. RESULTS: Thyroid disorders were known in 29 patients (6.2%), and newly identified in 32 (6.9%), at presentation. Of 406 patients with normal baseline thyroid status, 24 (5.9%) developed thyroid dysfunction during 6.1 years of mean follow-up. Higher baseline TSH concentration was associated with subsequent hypothyroidism; a threshold of 1.53 mU/L, approximately defining the top quartile, provided 75% sensitivity and specificity. Both TSH greater than 1.53 mU/L and positive autoantibody status predicted thyroid dysfunction, but only TSH was significant in multivariable analysis (odds ratio, 7.74, p < 0.001). No overt thyroid dysfunction developed in 293 patients with baseline TSH levels less than 1.53 mU/l. CONCLUSIONS: Baseline TSH level may be a better predictor of thyroid dysfunction than thyroid autoantibodies in people with diabetes. Patients with TSH levels below the top quartile have a risk of thyroid dysfunction similar to the general population. It may be appropriate to stop annual thyroid screening in this group, although confirmation is required.

Adolescent↗
PubMed2002

Cyclooxygenase-2 expression in human thyroid carcinoma and Hashimoto's thyroiditis.

OBJECTIVES: Cyclooxygenases (COX) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. COX-2, unlike the constitutively expressed COX-1, is an inducible enzyme upregulated during cell proliferation and inflammation. More recently, COX-2 has been implicated in the development of numerous types of epithelial cancers. In addition, COX-2 is highly expressed in several inflammatory diseases. Because of its dual role in inflammation and cancer, we were interested in determining if COX-2 plays a role in the development of human thyroid carcinoma and Hashimoto's thyroiditis, an autoimmune condition frequently associated with thyroid malignancy. MATERIALS AND METHODS: Twenty paraffin-embedded human tissue specimens, including normal, inflammatory, and neoplastic thyroid sections, were analyzed by immunohistochemical staining for expression of human COX-2. In addition, COX-2 protein expression was verified by Western blot in two specimens. RESULTS: Immunohistochemical staining confirmed the presence of COX-2 in thyroid epithelial neoplasms, including papillary and follicular carcinomas. Moreover, COX-2 expression was observed in patients with Hashimoto's thyroiditis. COX-2 expression, however, was not observed in normal thyroid tissue, multinodular goiter, or anaplastic carcinoma. CONCLUSIONS: We have shown that cyclooxygenase-2 is expressed in thyroid carcinoma and thyroid epithelium from patients with Hashimoto's thyroiditis but not in normal thyroid. The expression of COX-2 in both of these thyroid pathologies may provide a basis for the relationship between carcinogenesis and autoimmunity.

Adult↗
PubMed2004

Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice.

Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 x CBA)F(1) mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3(+) mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

Animals↗
PubMed2003

Development of a murine model of autoimmune thyroiditis induced with homologous mouse thyroid peroxidase.

Autoimmune thyroid disease (AITD) is a common autoimmune disease. Thyroid peroxidase (TPO) is a well characterized autoantigen in AITD. Autoantibodies and autoreactive T lymphocytes to TPO are believed to play a major role in the pathogenesis of lymphocytic thyroiditis. To understand the pathogenic mechanisms of AITD and the role of TPO, we have established a mouse model of lymphocytic thyroiditis by immunizing C57Bl/6 (H-2(b)), CBA (H-2(k)), and C57Bl/6 x CBA F1 mice with recombinant murine TPO (rmTPO) ectodomain comprising amino acid residue 1-837 produced in Escherichia coli. Mice were immunized with 30 microg purified ectodomain in complete Freund's adjuvant. Antibodies against rmTPO were detected in the serum of all mice from day 21 onward. Draining lymph node cells from rmTPO-immunized animals showed dose-dependent proliferation to TPO stimulation. Mice killed at d 50 and 90 revealed variable degrees of thyroiditis with infiltration of mononuclear cells and destruction of thyroid follicles. C57Bl/6 and the F1 mice, in comparison with CBA mice, showed a greater degree of thyroiditis. There was a lack of correction between the intensity of thyroiditis and the anti-TPO response. Immunotyping of the thyroid cellular infiltrates showed predominantly CD4+ T cells and B220+ B cells but scanty CD8+ T cells. None of the control mice injected with the purified fusion partner developed anti-TPO antibodies and thyroiditis. In conclusion, a genuine autoimmune mouse model of lymphocytic thyroiditis was established using autologous mouse TPO. This new model induced with autologous TPO will lead to a better understanding of the mechanisms in destructive thyroiditis and will assist in the development of new strategies for modulating the pathogenic immune response.

Animals↗
PubMed1994

Preservation of functioning human thyroid "organoids" in the severe combined immunodeficient mouse. III. Thyrotropin independence of thyroid follicle formation.

The severe combined immunodeficient (scid) mouse allows the in vivo reconstitution of thyroid follicles from thyroid monolayer cells when transplanted sc within an extracellular basement membrane matrix. After 2-3 weeks, these human thyroid organoids show an active microfollicular histology and secrete human thyroglobulin into the murine serum in response to the administration of recombinant human TSH. Furthermore, such organoids survive for more than 3 months in this functional state. To assess whether thyroid follicular reconstitution was TSH dependent, we examined organoid follicular reconstruction in T3-induced hyperthyroid scid mice, in which endogenous murine TSH was presumed to be totally suppressed. By providing water with 12 micrograms/ml T3, we increased the murine serum T3 levels from a mean of 1.9 nmol/liter in controls to greater than 12.0 nmol/liter. After 3 weeks, thyroid cells derived from normal human thyroid monolayers were suspended in an extracellular basement membrane matrix, and the suspension was transplanted sc into scid mice (with or without T3-induced hyperthyroidism) and allowed to reconstitute. Histological examination 4 weeks later showed a similar degree of thyroid follicle formation in mice treated with or without T3, indicating that the hyperthyroid state had caused no interference with thyroid follicle reconstitution. This was further confirmed by transmission electron microscopy, which demonstrated normal human thyroid follicle cell polarity in the organoids of both euthyroid and hyperthyroid mice. In addition, using an extracellular basement membrane preparation with reduced growth factor (epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor) levels also allowed normal thyroid follicle formation in T3-fed mice. These data demonstrate that in vivo thyroid follicle formation is TSH independent and that extrathyroidal epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor may be relatively unimportant. The factors and molecular mechanisms leading to follicular reorganization of adult human thyroid cells remain to be determined, but are likely to depend largely on intrathyroidal growth factor secretion and cell-cell interaction.

Animals↗
PubMed2003

Additional phenotypic abnormalities with presence of cysts within the empty thyroid area in patients with congenital hypothyroidism with thyroid dysgenesis.

Congenital hypothyroidism (CH) is most frequently caused by thyroid developmental abnormalities, and it has recently been shown to have a familial component with members affected by either CH or asymptomatic thyroid developmental abnormalities. The pathogenesis of the disease is unknown, but it seems possible that a common genetic mechanism underlies these heterogeneous phenotypic expressions. Associations among these anomalies in the same individuals have occasionally been described. The aim of this study was to investigate whether cysts of the thyroglossal duct could be shown by ultrasonography in patients with CH caused by thyroid dysgenesis. Children with CH (n = 57) who were diagnosed by newborn TSH screening were prospectively evaluated by ultrasonography at the age of 10.5 +/- 4.5 yr. The etiology of CH (ectopic thyroid tissue, n = 42; athyreosis, n = 15) was established before treatment initiation on the basis of thyroid radioiodine scanning and the absence of any thyroid tissue in the normal location confirmed by ultrasonography. Cysts were found in 39 patients (68% of cases) with either ectopic thyroid tissue (n = 29) or athyreosis (n = 10). All cysts were located in the empty thyroid area in the left (57%) or right (43%) side and were mostly closer to the midline. Patients had either a single cyst (n = 16 patients) or multiple cysts (n = 23 patients). The cysts were bilateral in 17 of the 39 patients. Most of them were vertically oval or round, with a size ranging in diameter from 2-21 mm (mean, 3.5 +/- 2). In conclusion, the presence of cysts within the empty thyroid area in 68% of patients with CH due to thyroid dysgenesis is a novel observation that is part of the developmental anomaly of this disease. Several explanations can be put forward to explain the presence of these cysts. They might be due to the persistence of the ultimobranchial bodies as a cystic structure or part of the thyroid-forming material, which may migrate along the normal pathway of the usual course of the thyroglossal duct, giving rise to cell residues within the empty thyroid area.

Adolescent↗
PubMed1981

Triiodothyronine generation from thyroxine in human thyroid: enhanced conversion in Graves' thyroid tissue.

Conversion of T4 to T3 was studied in normal, Graves', and neoplastic thyroid tissues obtained at surgery. Homogenates of human thyroid follicular adenoma and carcinomas were incubated with [125I]T4 and dithiothreitol (DTT) at 37 C for 60 min under N2 gas. T3 formation was assessed by measuring [125I]T3 formed, using paper chromatography. In the second series of experiments, the suspensions of the 100,000 X g pellet of normal thyroid tissues adjacent to the tumor and Graves' thyroid tissues were incubated with unlabeled T4 and DTT at 37 C for 60 min under N2 gas. T3 generated was measured by RIA. T3 generation in the thyroid tissue was dependent on incubation time, amount of the tissue used, concentration of DTT, temperature, and pH. Propylthioracil inhibited T3 formation, while methimazole had no effect. A kinetic study with the homogenate of a thyroid adenoma and 100,000 X g pellet suspensions of two normal and three Graves' thyroids gave apparent Km values of 2.7, 4.9, and 4.1 microM for T4, respectively, and Vmax values of 0.8, 3.0, and 10.9 pmol T3/mg protein.min, respectively. Conversion of T4 to T3 was observed in two of three tumor tissues studied and was markedly enhanced in Graves' thyroid tissues (mean +/- SE, 11.9 +/- 2.0 pmol/mg protein.min) compared to that of normal thyroid tissues (3.2 +/- 0.6 pmol/mg protein.min; P less than 0.01). It is concluded that T4 is enzymatically converted to T3 in normal and Graves' thyroids and differentiated thyroid neoplasms. Moreover, enhanced conversion of T4 to T3 was found in Graves' thyroid tissue.

Adenoma↗
PubMed2002

Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations.

In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells. Selenium-dependent enzymes also have several modifying effects on the immune system. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases. We performed a blinded, placebo-controlled, prospective study in female patients (n = 70; mean age, 47.5 +/- 0.7 yr) with autoimmune thyroiditis and thyroid peroxidase antibodies (TPOAb) and/or Tg antibodies (TgAb) above 350 IU/ml. The primary end point of the study was the change in TPOAb concentrations. Secondary end points were changes in TgAb, TSH, and free thyroid hormone levels as well as ultrasound pattern of the thyroid and quality of life estimation. Patients were randomized into 2 age- and antibody (TPOAb)-matched groups; 36 patients received 200 microg (2.53 micromol) sodium selenite/d, orally, for 3 months, and 34 patients received placebo. All patients were substituted with L-T(4) to maintain TSH within the normal range. TPOAb, TgAb, TSH, and free thyroid hormones were determined by commercial assays. The echogenicity of the thyroid was monitored with high resolution ultrasound. The mean TPOAb concentration decreased significantly to 63.6% (P = 0.013) in the selenium group vs. 88% (P = 0.95) in the placebo group. A subgroup analysis of those patients with TPOAb greater than 1200 IU/ml revealed a mean 40% reduction in the selenium-treated patients compared with a 10% increase in TPOAb in the placebo group. TgAb concentrations were lower in the placebo group at the beginning of the study and significantly further decreased (P = 0.018), but were unchanged in the selenium group. Nine patients in the selenium-treated group had completely normalized antibody concentrations, in contrast to two patients in the placebo group (by chi(2) test, P = 0.01). Ultrasound of the thyroid showed normalized echogenicity in these patients. The mean TSH, free T(4), and free T(3) levels were unchanged in both groups. We conclude that selenium substitution may improve the inflammatory activity in patients with autoimmune thyroiditis, especially in those with high activity. Whether this effect is specific for autoimmune thyroiditis or may also be effective in other endocrine autoimmune diseases has yet to be investigated.

Adult↗
PubMed1975

[Studies on hypophyseo-thyroid function in patients with chronic thyroiditis (author's transl)].

It is well known that serum TSH levels are elevated in most patients with chronic thyroiditis, even if the patient exhibits normal thyroid function tests. The determination of serum TSH levels in these patients is thought to be the most sensitive indicator of subclinical hypothyroidism. In this study, the hypophyseo-thyroid functions of untreated euthyroid patients with chronic thyroiditis were evaluated. Serum T3 levels in most of these patients were raised or at high normal levels, although serum T4 levels were in the low normal range. Serum T4 levels in patients with raised basal TSH were distributed in the low normal range. Hence, it is suggested that the decreased serum T4 stimulates TSH secretion which in turn stimulates T3 (and T4) secretion from the thyroid and the elevated T3 maintains the patient's euthyroid condition. Basal TSH levels in these patients varied from 2.5 to 37.0 muU/ml and mean +/-SD was 12.9+/-9.6 muU/ml. Thirteen out of 30 patients (43%) with normal free T4 indices showed elevated basal TSH levels. TSH responses to TRH injection were exaggerated in all euthyroid patients with raised basal TSH levels, as well as in 11 out 14 patients (78.6%) with normal basal TSH levels as well. But the maximum TSH responses after TRH injection were well correlated with basal TSH levels (gamma=0.79). The percent increases of serum T3 after TRH injection in those patients were less than those of the normal person, and there was no difference in T3 response between the normal TSH group and the group with raised TSH. Eight patients who suffered from collagen diseases (SLE:6, RA:1, PSS:1) without any evidence of thyroid disease also exhibited exaggerated TSH responses to TRH. In five out of these eight patients (62.5%) antithyroglobulin antibody was positive. This may indicate the presence of the so-called asymptomatic autoimmune thyroiditis in these patients. It is suggested that the elevated basal TSH levels in euthyroid patients with chronic thyroiditis are a much more sensitive indicator of thyroid failure than any other routine thyroid function tests. Moreover, the exaggerated TSH responses to TRH in patients with normal basal TSH levels indicated that the TRH-test is more useful for the detection of minimal thyroid failure, especially in patients having such conditions as asymptomatic automimune thyroiditis.

Collagen Diseases↗
PubMed2001

Transcriptional activation of the thyroglobulin promoter directing suicide gene expression by thyroid transcription factor-1 in thyroid cancer cells.

Gene therapy with thyroglobulin (TG) promoter and a prodrug/suicide gene combination may prove useful as a treatment for thyroid carcinoma. However, most poorly differentiated and anaplastic thyroid carcinomas have lost the ability to express the TG gene expression accompanied by loss of transcription factors [thyroid transcription factor-1 (TTF-1), TTF-2, or Pax-8] interacting with the TG promoter. In anticipation of developing transcriptionally targeted gene therapy of TG-nonproducing thyroid carcinomas, we investigated the effect of TTF-1 gene transfer on TG promoter activity and the cytotoxic effect obtained by the TG promoter-driven HSV-TK gene along with ganciclovir in thyroid carcinoma and nonthyroidal cells. Using a chimeric construct containing the 5'-flanking region of the rat TG gene between -826 and +39 bp and the luciferase gene, TG promoter activity was detected in a normal rat thyroid cell line (FRTL-5), but not in a dedifferentiated line of thyroid cells (FRT) expressing Pax-8 but not TTF-1, TTF-2, or TG [TTF-1(-)/TTF-2(-)/Pax-8(+)/TG(-)], or in a human papillary thyroid carcinoma cell line [BHP15-3; TTF-1(-)/TTF-2(-)/Pax-8(-)/TG(-)], a human pulmonary cell line [H441; TTF-1(+)/TTF-2(-)/Pax-8(-)/TG(-)], or a dog kidney epithelial cell line [MDCK; TTF-1(-)/TTF-2(-)/Pax-8(+)/TG(-)]. Cotransfection of the TTF-1 expression vector stimulated TG promoter activity in FRT and BHP15-3 dedifferentiated thyroid cells, but not in H441 pulmonary cells. Only weak activation was observed in MDCK kidney cells. We then constructed recombinant adenovirus vectors, AdTTF-1 and ADTGTK: AdTTF-1 contained cytomegalovirus promoter and rat TTF-1 cDNA; AdTGTK carried the TG promoter-driven HSV-TK gene. Infection with AdTGTK and combined with GCV treatment induced a cytotoxic effect in FRTL-5 cells but not in dedifferentiated thyroid or nonthyroid cells. Cotransduction of AdTTF-1 and AdTGTK permitted 90% cytotoxicity for BHP15-3 and >95% cytotoxicity for FRT, as well as for BHP7-13 and BHP18-21v thyroid cancer cell lines [both/TTF1(-)/TTF-2(-)/Pax-8(+)/TG(-)]. In contrast, little cytotoxicity was seen for H441 and MDCK cell lines even with 300 microg/ml of ganciclovir. These results suggest that cotransduction of a TG promoter-controlled suicide gene and the TTF-1 gene by adenoviral vectors confers transcriptionally targeted gene-mediated cytotoxicity in poorly differentiated thyroid carcinoma cells unable to express the TG gene.

Adenoviridae↗
PubMed2002

Diagnosis of thyroid metastasis in cancer patients with thyroid mass by fine needle aspiration cytology and ultrasonography.

BACKGROUND: Thyroid metastasis is generally thought to be infrequent. To evaluate its occurrence, fine needle aspiration cytology and ultrasound of the thyroid gland were performed in nonthyroid cancer patients with thyroid mass. METHODS: A total of 20 nonthyroid cancer patients (6 males and 14 females with a mean age of 55 +/- 7 years) with thyroid mass were examined with thyroid ultrasound and fine needle aspiration cytology. Their underlying malignancies included lung cancer in 10 patients, breast cancer in 7 patients, cervical cancer in 2 patients and colon cancer in 1 patient. RESULTS: Thyroid metastases were diagnosed in 4 patients (20%), 2 with breast cancer and 2 with lung cancer. For 3 of them, thyroid ultrasound showed solitary hypoechoic nodule, and in 1 case, multiple nodular lesions were demonstrated in each lobe. In addition, neck lymph nodes were noted in 3 patients. In the remaining 16 cancer patients, thyroid ultrasound showed either multiple or solitary nodular goiter change with no neck lymph node involvement. Fine needle aspiration cytology (FNAC) yielded nonthyroid adenocarcinoma in 4 metastatic cases. The 2 breast cancer patients received finally total thyroidectomy and were still alive 1 year after operation. While in the other 2 lung cancer cases, only supportive treatment were given due to advanced stages and the patients died within months. CONCLUSIONS: Thyroid metastases could occur at a high frequency in nonthyroid cancer patients with thyroid mass from our small series. By combining FNAC with ultrasound, a clinical diagnosis of thyroid metastasis is attainable in cancer patients with thyroid mass.

Adult↗
PubMed2003

The role of oxidative stress in physiological and pathological processes in the thyroid gland; possible involvement in pineal-thyroid interactions.

Reactive oxygen species (ROS) play an important role in physiological processes, but - when being in excess - ROS cause oxidative damage to molecules. Under physiological conditions, the production and detoxification of ROS are more-or-less balanced. Also in the thyroid, ROS and free radicals participate in physiological and pathological processes in the gland. For example, hydrogen peroxide (H2O2) is crucial for thyroid hormone biosynthesis, acting at different steps of the process. Additionally, H2O2 is believed to participate in the Wolff-Chaikoff's effect, undergoing in conditions of iodide excess in the thyroid. Much evidence has been accumulated indicating that oxidative stress is involved in pathomechanism of thyroid disease, e.g., Graves' disease, goiter formation or thyroid cancer. Melatonin (N-acetyl-5-methoxytryptamine) - the main secretory product of the pineal gland - is a well-known antioxidant and free radical scavenger, widely distributed in the organism. Mutual relationships between the pineal gland and the thyroid have - for a long time - been a subject of intensive research. The abundant to-date's evidence relates mostly to the inhibitory action of melatonin on the thyroid growth and function and - to a lesser extent - to the stimulatory effects of thyroid hormones on the pineal gland. It is highly probable that under physiological conditions melatonin and, possibly, other antioxidants regulate ROS generation for thyroid hormone synthesis. We believe that melatonin may protect against extensive oxidative damage in the course of certain thyroid disorders or in case of a harmful action of some external factors on the thyroid. Thus, oxidative damage and the protective action of antioxidants, melatonin included, may occur during both physiological and pathological processes in the thyroid, however, this assumption, requires further studies.

Animals↗
PubMed2005

[Detecting the API2-MALT1 fusion gene and its significance in Hashimoto's thyroiditis and thyroid lymphomas].

OBJECTIVE: To investigate the expression of API2-MALT1 fusion gene mRNA in Hashimoto's thyroiditis, thyroid MALT lymphoma and DLBCL, as well as the correlation between the expression and the pathogenesis and prognosis of two types of thyroid lymphoma. METHODS: Eight cases of Hashimoto's thyroiditis, 12 cases of MALT lymphoma and 3 cases of DLBCL in thyroid were selected and retrieved. API2-MALT1 transcripts were investigated in all cases by reverse transcript touchdown-PCR and nested PCR. The effect of API2-MALT1 fusion gene on the prognosis of thyroid lymphomas was assessed by analyzing the clinicopathological features and the follow-up findings. RESULTS: The variant 1446/1123 transcript was detected in 2 of thyroid lymphomas (1 MALT lymphoma, 1 DLBCL) but not in 8 cases of Hashimoto's thyroiditis and 5 cases of chronic lymphadenitis. Both of API2-MALT1-positive cases were accompanied with Hashimoto's thyroiditis, showing stage I E and no involvement of lymph node. CONCLUSION: The incidence of API2-MALT1 transcript in thyroid lymphomas was low; however, the correlation between API2-MALT1 fusion gene and the progression from Hashimoto's thyroiditis to lymphoma could not be excluded; the thyroid lymphoma with API2-MALT1 transcript seemed to develop on a more indolent clinical course.

Adult↗
PubMed1997

Thyroid-stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene.

Thyroid carcinomas from mice bearing a thyroid-targeted ret/PTC1 oncogene were studied for responsiveness to endogenous thyroid-stimulating hormone (TSH) to evaluate the effect of TSH on tumor progression. Mice of both sexes were maintained for either 3 or 6 months on a low-iodine diet (LID; < 0.05 ppm) to decrease thyroid hormone production and increase endogenous pituitary TSH secretion. Nontransgenic littermates served as controls. Lesions in mice on LID were observed only in the thyroid and pituitary glands. LID induced marked hyperplasia of thyroid follicular cells of nontransgenic control mice at both time points despite a return of TSH levels to normal values after 6 months of treatment. All transgenic mice had bilateral thyroid carcinomas with histologic features resembling human papillary thyroid carcinoma. The LID resulted in a progressive increase in thyroid area weight and tumor cellularity with the development of a prominent spindle-cell component in the thyroid carcinomas after 6 months. There was no evidence, however, of local or distant metastasis of the thyroid carcinomas. Despite the lack of histologic differentiation, the spindle-cell population retained focal immunoreactivity for thyroglobulin. Our results show that ret/PTC1-induced thyroid follicular cell carcinomas retain TSH responsiveness and maintain a benign biologic behavior despite histologic evidence of anaplasia.

Animals↗
PubMed1999

Analysis of human sodium/iodide symporter, thyroid transcription factor-1, and paired-box-protein-8 gene expression in benign thyroid diseases.

The ability to concentrate iodide, a fundamental property of normally functioning thyroid tissue, is altered in various thyroid diseases. Given the critical role of the Na+/I- symporter (NIS) in controlling iodide access to the thyroid gland, altered expression of NIS may be responsible, at least in part, for an enhanced or diminished capacity to concentrate iodide. In this study, we used Northern blot analysis, a newly established quantitative polymerase chain reaction (PCR) assay and in addition hNIS-directed immunohistochemical analysis to assess the levels of hNIS mRNA and protein expression in various localized and diffuse benign thyroid abnormalities, including Graves' disease (GD), scintigraphically cold solitary benign thyroid nodule (CBTN), nontoxic multinodular goiter (NMNG), solitary autonomously functioning thyroid nodule (AFTN), and mild diffuse iodine deficiency goiter (IDG). In addition, in view of the recent identification of putative binding sites for the transcription factors thyroid transcription factor-1 (TTF-1) and human paired-box-protein-8 (Pax-8) in the human NIS gene promoter, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to assess in these same samples the levels of TTF-1 and Pax-8 gene expression. Northern blot analysis revealed high levels of hNIS gene expression in thyroid specimens derived from patients with GD and AFTN. In contrast, levels of hNIS mRNA expression were moderate in NMNG, low in diffuse IDG, and very low in CBTN. Quantitative RT-PCR analysis of hNIS mRNA transcripts revealed variable but generally low levels of hNIS gene expression in IDG and NMNG, and undetectable or very low levels of hNIS mRNA in all scintigraphically CBTN studied. In contrast, markedly elevated levels of hNIS mRNA transcripts were detected in active GD (up to 17-fold) and AFTN (up to 25-fold). Immunohistochemical analysis revealed abundant hNIS protein expression by thyroid follicular cells in GD, moderate and heterogeneous levels in NMNG, and very low levels in CBTN. hNIS mRNA levels were correlated with TTF-1 and Pax-8 gene expression in GD and, to a lesser degree, in AFTN, NMNG, and IDG, but not in CBTN. In general, hNIS gene expression was more closely correlated with TTF-1 as compared to Pax-8 gene expression. In conclusion, the abundance of hNIS mRNA and protein expression in a broad range of benign thyroid pathologies correlated well with their functional state as assessed by thyroid scintigraphy. In addition to TTF-1 and Pax-8, other transcription factors and enhancer elements may contribute to regulation of NIS gene promoter activity.

Carrier Proteins↗
PubMed1997

Maternal thyroid function: interpretation of thyroid function tests in pregnancy.

Thyroid status is frequently assessed during pregnancy, both to evaluate suspected thyroid abnormalities, and to monitor the status, of pre-existing thyroid disease. However, the production, circulation, and disposal of thyroid hormone are all altered in pregnancy. Interpretation of thyroid function studies in the pregnant patient must be performed based on an understanding of the normal physiologic changes at each stage of pregnancy. Examples of pregnancy-associated changes include, estrogen-stimulated increase in serum thyroxine binding globulin, chorionic gonadotropin stimulated T4 and T3 production from the thyroid gland, and accelerated degradation of thyroid hormone by the placenta. The serum-TSH alone is usually not adequate to assess thyroid status in pregnancy, and the various conditions that can effect this measurement are described. The pattern of thyroid studies in pregnancy is important in diagnosing thyroid disease, and it may indicate physiologic adaptations to optimize maternal thyroid status for fetal development.

Female↗
PubMed1993

Interindividual differences in the pituitary-thyroid axis influence the interpretation of thyroid function tests.

OBJECTIVE: We investigated interindividual differences in the shape, slope and setpoint of the pituitary-thyroid axis (PTA) in normal persons. Based on these physiological data we propose a novel bivariate concept for the interpretation of thyroid function tests which is less biased by interindividual differences in the PTA than the currently used univariate approach. DESIGN: In two separate trials (A and B), healthy volunteers were given small, increasing doses of T3 (7.5-45 micrograms/day orally) over 5 days. The regulation characteristics of the individual PTAs and the effects of age and gender were assessed by general linear regression models. In addition, serum samples were collected from normal persons to establish the proposed bivariate approach for the interpretation of thyroid function tests. SUBJECTS: The regulatory characteristics of the PTA were determined in a total of 21 normal volunteers (eight females, 13 males; age 24-49 years). Single blood samples were collected from 257 normal volunteers. The participants had no history of pituitary or thyroid disease. MEASUREMENTS: Free and total thyroid hormone and TSH concentrations were determined in the serum. All samples from one person were analysed in the same assay in duplicate. RESULTS: A log-linear relationship between T3 and TSH was found to describe best the individual PTA (multiple r = 0.96). However, significant differences in the setpoint (P < 0.001) and to a lesser degree in the slope (P < or = 0.05) of the PTA were detected; this variability was not dependent on age or gender. Since these findings invalidate the assumptions on which the current univariate interpretation of thyroid function tests is based, we propose a novel model for the evaluation of thyroid function tests derived from the experimentally determined shape and average slope of the PTA. CONCLUSIONS: The presence of significant age and gender-independent interindividual variations in the setpoint of the pituitary-thyroid axis raises conceptual problems with the current approach for interpreting thyroid function tests. An easy to use graphical bivariate representation of the normal ranges for thyroid function tests is presented and exemplified by the thyroid hormone and TSH measurements in a large reference population. This concept should improve the diagnostic accuracy in the borderline-normal, and particularly subclinical hypothyroid region of these hormone measurements.

Adult↗
PubMed1999

Thyroid function, morphology and prevalence of thyroid disease in a population-based study of Danish centenarians.

OBJECTIVES: To investigate thyroid function, morphology, and autoimmunity in relation to physical function in an unselected population of centenarians. DESIGN: A population-based survey. SETTING: Denmark. PARTICIPANTS: All persons living in Denmark who celebrated their 100th anniversary during the period April 1, 1995 to May 31, 1996, a total of 276 persons. MAIN OUTCOME MEASUREMENTS: Thyroid hormones (TSH, T4, FT4I, T3, FT3I, and T3RU), thyroid autoantibodies (TPOab and Tgab), thyroid volume, activities of daily living according to the Katz Index of ADL. RESULTS: In all, 207 (75%) of the 276 eligible subjects participated, and 148 agreed to blood tests. Among the participants, 2.9% had previously known hyperthyroidism, and the same proportion had previously known hypothyroidism. The blood tests did not reveal any undiagnosed cases of overt thyroid dysfunction. However 7.2% had a subnormal serum TSH, and 2.9% had an elevated serum TSH; all had normal serum T3 and serum T4 levels. Thyroid autoantibodies were detected in 26 (17.6%) centenarians (11.5% had Tgab and 9.5% had TPOab). Among relatively independent centenarians, low serum T3 was significantly associated with high comorbidity (P = .029), whereas both low serum T3 and thyroid autoantibodies were significantly associated with ADL-dependency (P < .001 and P = .030, respectively). Ultrasonography (n = 50) revealed a small gland with a median volume of 8.3 mL (range 3.2-27.9) compared with an expected volume of 20 mL (14-26) (P < .001). There was no significant relationship to body weight. When examined by ultrasound, only 26% had significant morphological alterations. CONCLUSIONS: Thyroid dysfunction does not seem to be more prevalent among centenarians than among younger old people. Low serum T3 is related to poor physical function and co-morbidity, whereas thyroid autoimmunity is related only to poor physical functioning. Despite atrophy of the thyroid gland, these findings suggest that thyroid function is well preserved in centenarians.

Activities of Daily Living↗