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PubMed2004

Association of the T-cell regulatory gene CTLA4 with Graves' disease and autoimmune thyroid disease in the Japanese.

Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigen. The cytotoxic T-lymphocyte antigen-4 ( CTLA4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. Recently, AITD susceptibility in the Caucasians was mapped to the 6.1-kb 3'UTR of the CTLA4 gene, in which the three single-nucleotide polymorphisms (SNPs) CT60, JO31, and JO30 were strongly associated with AITD. In order to determine the association of the CTLA4 gene with AITD in the Japanese, case-control association analysis for the four SNPs of the CTLA4 gene using 380 AITD patients and 266 healthy controls was done. Among the SNPs examined, the SNP JO31 was most significantly associated with AITD in the Japanese, whereas the association of the JO30 with AITD was not observed. The frequency of the disease-susceptible G allele of the JO31 of the Japanese control was higher than that of the Caucasians (67.1% vs 50.2%); however, the G allele of the JO31 was associated with Graves' disease (GD) (67.1% vs 76.3%, P=0.0013) and AITD in the Japanese (67.1% vs 74.2%, P=0.0055). Furthermore, the G allele of the JO31 was associated with the increased risk for GD [ P=0.0051, odds ratio (OR)=1.7] and AITD ( P=0.016, OR=1.5) in a dominant model. These results suggested that the CTLA4 gene is involved in the susceptibility for GD and AITD in the Japanese.

Alleles↗
PubMed1995

Expression of intercellular adhesion molecule-1 on human thyroid cells from patients with autoimmune thyroid disease: study of thyroid xenografts in nude and severe combined immunodeficient mice and treatment with FK-506.

It has been suggested that intercellular adhesion molecule-1 (ICAM-1) may play an important role in the initiation, localization, and perpetuation of autoimmune thyroid diseases (AITD). In an effort to clarify its role, we have investigated the expression of ICAM-1 on thyroid epithelial cells (TEC) of patients with AITD, patients with nontoxic goiter (NTG), and normal subjects (PN) by flow cytometric analysis under basal conditions and after modulation with cytokines, before and after 8 weeks of thyroid tissue xenotransplantation in nude athymic mice (which lyses all passenger lymphocytes), and in severe combined immunodeficient (SCID) mice where these cells survive. Before xenografting, ICAM-1 was expressed on 56% of TEC from Hashimoto's thyroiditis (n = 5), 54% of Graves' disease (n = 6), 15% of NTG (n = 5), and 12% of PN TEC. After the xenografts had been 8 weeks in nude mice, ICAM-1 expression decreased markedly in AITD TEC [from 56% to 10% in Hashimoto's thyroiditis (P < 0.001) and from 54% to 8% in Graves' disease (P < 0.01)], but did not change significantly in NTG or PN. After the xenografts had been 8 weeks in SCID mice, the expression of ICAM-1 was significantly higher on TEC of AITD compared with the same tissue in nude mice. When the SCID mice engrafted with AITD tissue were treated with the anti-CD4+ T (helper) cell agent FK-506, the expression of ICAM-1 was reduced significantly compared with that in the original tissue or that in nontreated mice engrafted with the same tissue. The proportion of TEC that were ICAM-1 positive was up-regulated in all cases by certain cytokines (e.g. interferon-gamma and tumor necrosis factor-alpha applied alone or in combination). We also detected the presence of ICAM-1 in AITD frozen tissues using an immunohistochemical technique. These data suggest a role for ICAM-1 in human AITD. However, the expression of ICAM-1 appears to be a secondary phenomenon in response to the immune assault, rather than a primary event. Our results support the idea that TEC may act as passive captives to immunological events in human AITD.

Animals↗
PubMed1990

Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalities.

Twenty-two apparently euthyroid patients with endocrine ophthalmopathy not associated with goiter, antithyroid microsomal or antithyroglobulin antibodies, or overt thyroid disease (so-called ophthalmic Graves' disease) were tested for subclinical hyperthyroidism or hypothyroidism. We measured 131I uptake and scan, serum T3 (by RIA), and serum TSH using a sensitive (by immunoradiometric assay) assay. Three patients were found to be hyperthyroid, and 1 was hypothyroid. The remaining 18 patients, who remained euthyroid throughout the study period, were investigated for evidence for antibody-mediated immunity against thyroid antigens. We measured antibody-dependent cell-mediated cytotoxicity against fresh thyroid cells using a 51chromium release assay, thyroid membrane-reactive antibodies in an enzyme-linked immunosorbent assay incorporating solubilized thyroid membranes, and TSH receptor-binding antibodies using a RRA and carried out sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting with patient sera for antibodies reactive with 64 and 110 kDa (thyroid peroxidase) membrane proteins. Bands were demonstrated, on SDS-PAGE, at 64 or 110 kDa in 13 patients, antibody-dependent cell-mediated cytotoxicity tests were positive in 7 patients, and enzyme-linked immunosorbent assay was positive in 4 of the 17 patients tested. In addition, TSH receptor antibody tests were positive in 5 patients, none of whom had other evidence for hyperthyroidism. Finally, significant lymphocyte infiltration was demonstrated on aspiration biopsy in 3 patients. All 18 patients had positive tests in at least 1 of the immunological assays. We believe that these data support the hypothesis that endocrine ophthalmopathy always occurs in patients with overt or subclinical Graves' hyperthyroidism, Hashimoto's thyroiditis, or thyroid immunological abnormalities. Those patients previously described as having euthyroid Graves' disease should, thus, be considered to have associated thyroid immunological abnormalities even though histological confirmation (from aspiration needle biopsy) may be obtained in only a minority of the patients. The possibility that the mechanism for this close association is cross-reactivity of cytotoxic antibodies against a thyroid/eye muscle cell surface shared antigen is discussed in the context of recent evidence from the authors' laboratory.

Adult↗
PubMed2005

Non-thyroid autoantibodies in autoimmune thyroid disease.

Autoimmune thyroid disease is frequently accompanied by other organ-specific and non-organ-specific diseases, most likely because there is sharing of genetic and possibly environmental susceptibility factors. These associations are well recognized in the autoimmune polyglandular syndromes; autoimmune thyroid disease is one of the three major endocrinopathies in the type 2 syndrome and occurs in around 4% of type 1 patients. This review considers the frequency of disease-specific autoantibodies in patients with thyroid autoimmunity and briefly examines the role of such antibodies in performing screening for the associated conditions. Recommendations are made for using such autoantibody tests in the setting of patients with autoimmune thyroid disorders, and also for the utility of screening for thyroid autoimmunity in patients with pernicious anaemia, Addison's disease, coeliac disease, primary biliary cirrhosis, myasthenia gravis, lymphocytic hypophysitis, systemic lupus erythematosus and rheumatoid arthritis. At present, however, there are no large-scale trials that have shown the cost-benefit ratio of autoantibody screening for autoimmunity screening, and clinicians must use individual judgement combined with heightened awareness to identify who to test.

Autoantibodies↗
PubMed1991

Previous thyroid disease and risk of thyroid cancer in Switzerland.

A hospital-based case-control study of 86 cases of thyroid cancer and 317 controls was done in the Swiss Canton of Vaud. Patients with thyroid cancer tended to be better educated (odds ratio [OR] 2.1 for greater than or equal to 14 vs. less than or equal to 8 years of education 95% CI 1.1-4.1) and of higher social class than controls. Cases more often had a history of benign thyroid nodules (OR 25.2, 95% CI 7.6-83.6) and non-toxic goitre (OR 5.3, 95% CI 2.5-11.2). Furthermore, patients with thyroid cancer were more likely to have resided in endemic goitre areas (OR 1.7, 95% CI 1.0-3.0) and to have had first-degree relatives affected by benign thyroid disease (OR 3.9, 95% CI 2.1-7.1). Therefore, this study offers quantitative evidence of the association between various thyroid diseases and the risk of thyroid cancer which, despite difficulties in the classification of benign and malignant thyroid diseases, is remarkably consistent in studies from different countries.

Adolescent↗
PubMed1995

Thyroperoxidase microsatellite polymorphism in thyroid diseases.

Autoimmune thyroid diseases (AITD) cluster in families, although the nature of this phenomenon is still poorly understood. One possible approach to the identification of genetic factors contributing to the pathogenesis of AITD is the study of association between polymorphic markers and AITD themselves. In the present study we have analyzed the allelic distribution of sRA-1, a TPO tetranucleotide repeat, among patients with AITD, in comparison with patients with nonautoimmune thyroid diseases and the general population. The polymorphic marker was analyzed by PCR followed by electrophoresis on polyacrylamide denaturant gel. Our data show that no association exists between AITD and any of sRA-1 alleles, despite the important role that TPO plays as a thyroid autoantigen.

Adult↗
PubMed2003

Autoimmune thyroid disease associated with environmental thyroidal irradiation.

Reports of increased rates of thyroid disease in populations exposed to radiation as a result of the Chernobyl accident have increased awareness and concern about the risk of autoimmune-related thyroid disease possibly associated with environmental radiation exposure. While the association between thyroidal irradiation and an increased risk of thyroid neoplasia is well established, much less attention has been devoted to the potential effects of environmental irradiation on the function of the thyroid. However, since the Chernobyl accident new studies have been published that appear to link radiation exposure to an increased risk of autoimmune thyroiditis. In order to assess the plausibility of this association, we reviewed published studies that evaluate the possible association between environmental thyroidal radiation and the presence of antithyroid antibodies as well as autoimmune thyroid disease (hypothyroidism and hyperthyroidism). These data have not been summarized elsewhere. Although some epidemiologic evidence of an association exists, long-term, well-designed studies are needed to accurately evaluate the complex association between low-dose environmental radiation exposure and clinically significant non-neoplastic thyroid disease. The results of these studies will be important in determining the appropriate clinical follow-up of persons exposed to environmental thyroidal irradiation.

Autoimmune Diseases↗
PubMedDate not supplied

[Indications for preventive tracheostomy in the surgical treatment of non-neoplastic thyroid disease].

In thyroid surgery, an emergency tracheostomy is mandatory, as is well known, in acute pre- and postoperative asphyxia due to obstruction of the upper airways, especially in cases of malignant tumours. In particular conditions, in the presence of benign thyroid disease and when there is no reduction in the laryngo-tracheal lumen, tracheostomy has an important precautionary function following total thyroidectomy. The authors describe their experience with 6 patients treated by precautionary tracheostomy after total thyroidectomy for benign thyroid disease, analysing the indications and the advantages of this method.

Humans↗
PubMed1987

Prevalence of thyroid disease and abnormal thyroid tests in older hospitalized and ambulatory persons.

To determine the utility of laboratory tests for diagnosing thyroid disease in the hospitalized elderly, we measured serum thyroid-stimulating hormone (TSH), thyroxine (T4), free thyroxine index (FT4I), triiodothyronine (T3), and free triiodothyronine index (FT3I) in 125 geriatric inpatients, mostly men, and compared the results to those in elderly ambulatory patients. Hypothyroidism (TSH greater than 10 microU/mL with a low T4 and FT4I or clinical findings) was present in 7.8% (nine of 116) of male inpatients compared to only 0.7% of male ambulatory controls (P less than 0.01). Only a few women were studied but 17% (two of 12) were hypothyroid compared to 2.4% of ambulatory elderly women. Three of the hypothyroid inpatients had no clinical clue to their hypothyroidism. Further, decreased thyroid reserve or subclinical hypothyroidism (TSH greater than 10 microU/mL with a normal T4 and FT4I and no overt clinical findings), a condition which may lead to overt hypothyroidism, was more common in male inpatients (4.3%) than in male ambulatory controls (1.8% [P less than 0.01]). Thus, a clearly elevated serum TSH (greater than 10 microU/mL) was more common in inpatient (12.1%) than in ambulatory (2.4%) elderly men (P less than 0.01). Four inpatients and nine ambulatory controls had an elevated T4 and FT4I, but in only one (0.8%) inpatient and one (0.6%) control was a final diagnosis of hyperthyroidism made; the others had no clinical findings and a normal or low T3 and FT3I.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

[Exophthalmometry and thyroid disease. The value of the Hertel measurement evaluated by a group of patients with thyroid diseases and a control group].

Exophthalmometry values from routine referrals to a hospital eye clinic are analysed, including adult patients with and without thyroid disease. In thyroid disease without eye motility complaints (n = 90) the median exophthalmometry value was 18 mm (range 12-28 mm). Thyroid patients with eye muscle involvement (diplopia, n = 47) had significantly higher values (median 22 mm, range 15-31 mm) but did not differ significantly from a subgroup of 51 patients without thyroid disease, but with "big eyes" as a (presumably) physiological finding (median value 20 mm, range 16-25 mm). The above three categories were all excluded from the control group (n = 203) which had 16 mm as median value, range 11-23 mm. Mean values were 16.0 +/- 1.8 mm in the females and 16.5 +/- 2.3 mm in the male controls. A side difference in exophthalmometry value > or = 2 mm appeared in 34% of thyroid patients with eye muscle involvement. This appeared in only a few per cent in the three other groups. Due to the wide overlap between groups, the solitary exophthalmometry reading is of limited diagnostic value, while the importance of exophthalmometry is evident when following the individual patient with orbital disease.

Adolescent↗
PubMed1996

A primary care approach to the adult patient with nodular thyroid disease.

Nodular thyroid disease can be defined as the presence of one or more nodules in a thyroid gland of normal or increased size. To diagnose and treat patients with nodular goiters cost-effectively is often challenging because many thyroid illnesses present with a nodule; often the patient is unaware of its presence. Although most thyroid nodules are benign, it is occasionally difficult to exclude malignant neoplasm in an enlarged gland. It is essential for the primary care physician to be comfortable with examining and treating patients with thyroid nodules. A rational, stepwise approach to the evaluation of nodular thyroid disease was developed.

Adult↗
PubMed1992

Assessment of antibody dependent cell cytotoxicity in autoimmune thyroid disease using porcine thyroid cells.

Antibody Dependent Cell Cytotoxicity (ADCC) appears to be involved in Autoimmune Thyroid Disease (AITD). Homologous system may trigger non-specific reactions which might obscure specific ADCC. Heterologous target cells may be useful for studying ADCC, provided relevant antigen(s) are expressed. We therefore tested the capacity of porcine thyroid cells to elicit ADCC reaction in the presence of sera from various patients with AITD. Porcine thyroid cells were used in a 4-hr chromium release assay in the presence of 1/10 heat inactivated human sera and human peripheral blood lymphocytes at a 30:1 effector-target ratio. There was a significant correlation (r = 0.64; P < 0.01) between ADCC activities tested on human or porcine thyroid cells. Serum or IgG effects on porcine thyroid ADCC were dose-dependent between 1/10 to 1/10,000 dilutions. Non-thyroid cell systems were unaffected by thyroid cytotoxic sera. Porcine thyrocyte susceptibility to ADCC peaked at the fourth day of culture and was enhanced by addition of TSH or TSH and methimazole in the culture medium. Using this heterologous system, we demonstrated ADCC activity in a significant proportion of patients with thyroiditis (14/19), Graves' opthalmopathy (19/44) or of mothers of children with congenital hypothyroidism (14/39) and in the children themselves (15/39). Discrepancies observed in some sera between ADCC activity and antithyroperoxidase antibody suggest that thyroperoxidase is not the only antigen involved in ADCC. These results indicate that porcine thyroid cells appear suitable for ADCC assay in patients with AITD. Also this system should be helpful to characterize the antigen-antibody involved.

Adult↗
PubMed2005

[Differentiated thyroid carcinoma in previously manifested autoimmune thyroid disease].

Autoimmune thyroid diseases are frequently associated with differentiated thyroid carcinomas. The role of autoimmune phenomena in the origin and clinical course of coexisting papillary and follicular carcinomas is still controversial. In Graves' patients, the prevalence of palpable thyroid nodules is 15.8%, and by using ultrasonography, the prevalence increases to 33.6%. Since the malignancy rate of palpable thyroid nodules in Graves' patients is 16.9%, approximately threefold higher than in general population, it seems that a thyroid nodule diagnosed in Graves' patients is at higher risk for malignancy. In addition, radioiodine therapy for Graves' disease was found to be associated with increased incidence of thyroid cancer in some studies. These studies however, were not able to confirm the carcinogenic effect of radioiodine therapy since the late growth of occult carcinomas could not be excluded. The frequency of the association of Hashimoto's thyroiditis and differentiated thyroid carcinomas is approximately 30%. The presence of coexistent Hashimoto's thyroiditis does not affect the diagnostic evaluation and management of papillary thyroid cancer. The frequent presentation of differentiated thyroid carcinomas in Graves' disease and Hashimoto's thyroiditis opens the possibility that some mutual pathogenethic mechanisms might be involved in the development of these diseases.

Adenocarcinoma, Follicular↗
PubMed2003

Musculoskeletal manifestations in patients with thyroid disease.

OBJECTIVE: Thyroid dysfunction may cause musculoskeletal symptoms. We have evaluated the prevalence of adhesive capsulitis, Dupuytren's contracture, trigger finger, limited joint mobility and carpal tunnel syndrome in a series of patients with various thyroid diseases and differing levels of function. DESIGN AND PATIENTS: Patients with euthyroid (diffuse and/or nodular) goitre, Hashimoto's thyroiditis, Graves' disease, toxic nodular goitre, toxic diffuse goitre and patients with goitre who had partial thyroidectomy were included in the study (n = 137). Neurological and musculoskeletal examinations were performed after a standardized symptom questionnaire. The prevalence of musculoskeletal problems was analysed with respect to thyroid function and thyroid autoantibody status. MEASUREMENTS: Serum concentrations of free T3, free T4, TSH and thyroglobulin and thyroperoxidase antibodies were determined. Serum levels of creatine kinase, lactate dehydrogenase, calcium and phosphate along with erythrocyte sedimentation rate were measured to exclude other causes of musculoskeletal complaints. RESULTS: When the study group (n = 137) was divided according to thyroid status, 30.6% (n = 42) were thyrotoxic, 16.8% (n = 23) had subclinical thyrotoxicosis, 28.5% (n = 39) were euthyroid, 7.3% (n = 10) had subclinical hypothyroidism and 16.8% (n = 23) were hypothyroid. Overall, adhesive capsulitis was found in 10.9% (n = 15), Dupuytren's contracture in 8.8% (n = 12), limited joint mobility in 4.4% (n = 6), trigger finger in 2.9% (n = 4) and carpal tunnel syndrome in 9.5% (n = 13) of the patients. The prevalence of adhesive capsulitis was highest in patients with subclinical thyrotoxicosis (17.4%); Dupuytren's contracture, limited joint mobility and carpal tunnel syndrome were commonest in hypothyroid patients (21.7%, 8.7% and 30.4%, respectively). Trigger finger occurred in 10% of patients with subclinical hypothyroidism. When these prevalences were analysed with respect to thyroid status, carpal tunnel syndrome was significantly more prevalent in the hypothyroid group (P = 0.004). When thyroperoxidase antibody-positive and -negative patients were compared, adhesive capsulitis negatively (P = 0.03, r =-0.18) and trigger finger positively correlated with (P = 0.03, r = 0.21) thyroperoxidase antibody existence. CONCLUSIONS: These results demonstrate that musculoskeletal disorders often accompany thyroid dysfunction. In addition to the well-known observation that these disorders are common in patients with hypothyroidism, they are also observed in patients with thyrotoxicosis. Patients with thyroid dysfunction should be questioned for musculoskeletal complaints and referred to a specialist if necessary.

Adult↗
PubMed1996

Relationship between breast cancer and thyroid disease: relevance of autoimmune thyroid disorders in breast malignancy.

The relationship between thyroid dysfunction and breast cancer (BC) is debated. To clarify this controversial issue, a prospective study on thyroid function in BC was performed. The prevalence of thyroid disease was examined in 102 consecutive BC patients with ductal infiltrating carcinoma after surgery and before starting any chemohormonal or x-ray therapy and in 100 age-matched control healthy women living in the same borderline iodine-sufficient geographic area. All subjects were submitted to clinical ultrasound thyroid evaluation and serum free T4, free T3, TSH, thyroperoxidase antibody, and thyroglobulin antibody determination. Fine needle aspiration was performed in all thyroid nodules. Estrogen and progesterone receptors (ER and PR, respectively) were assayed in 92 and 55 BC specimens, respectively. The overall prevalence of thyroid disease was 47 in 102 (46%) in BC patients and 14 in 100 (14%) in controls (P < 0.0001). The prevalence of nontoxic goiter was 27.4% in BC patients and 11% in controls (P = 0.003). Hashimoto's thyroiditis was found in 13.7% of BC patients and in only 2% of the controls (P < 0.005). Other thyroid disorders found in the BC group included 2 cases of Graves' disease, 2 of thyroid carcinoma, and 1 of subacute thyroiditis, whereas in the control group only 1 case of Graves' disease and none of the other disorders were found. Mean free T3, free T4, and TSH concentrations showed no difference between BC patients and controls. The prevalence of thyroperoxidase antibody was higher in BC patients than in controls (23.5% vs. 8%; P < 0.005), whereas the prevalence of thyroglobulin antibody was not different. In BC patients the presence of thyroid antibodies was more frequently associated with clinically detectable autoimmune thyroiditis (14 of 26, 51.8%; P = 0.03) and was more common in the younger group. The positivity of ER was found in 51 of 92 (55.43%) and that of PR was found in 26 of 55 (47.27%) BC specimens. No relationship was found among ER, PR status, and the presence of serum thyroid antibodies. In conclusion, 1) the present study provides evidence that the overall prevalence of thyroid disorders is increased in patients with breast cancer, and 2) thyroid autoimmune disorders, especially Hashimoto's thyroiditis, account to a large extent for the increased prevalence of thyroid disease in patients with breast cancer. This feature is independent from the ER and PR status of the primary tumor. The present findings call attention to the usefulness of screening for thyroid disease in any patient with breast cancer.

Adult↗
PubMed2006

[Acromegaly and thyroid disease: prevalence of thyroid cancer].

The relationship between cancer and acromegaly has been subject of study for many years. From a case of differentiated thyroid carcinoma in one of our acromegalic patients, we reviewed a series of 100 acromegalics and found two others cases of thyroid cancer, which are described in this work. From that point, we have got data from the literature about this last association and its possible pathogenesis. The prevalence of thyroid disease is increased among acromegalic patients, mainly due to nodular goiter. This association will be discussed, as well as the relation between insulin-like growth factor-I and cancer, in an effort to have a better understanding of its meaning for our cases. We concluded that it would be prudent to do periodic ultrasonographic evaluation of acromegalic patients, follow by fine needle aspiration biopsies of suspect nodules.

Acromegaly↗
PubMed2001

[Review of thyroid disease and recent progress in thyroid research].

Major thyroid diseases and recent progress in thyroid research are reviewed, including our clinical experiences and data on genetic analysis. Of the 19,944 patients receiving care in our endocrinology and metabolism department over the past 26 years(from 1974 to 2000), there were 4,471(22.4%) patients with thyroid diseases. Of these patients with thyroid disease, 37.3% had Graves' disease, 24.1% had Hashimoto's thyroiditis, and 22.2% had a benign thyroid tumor. Male-to-female ratio for Graves' disease was 1:3.2. The precise mechanism and genetic or environmental factors underlying the onset and progression of autoimmune thyroid disease need further investigation, although recent thyroid research, especially molecular level studies, has resulted in many new insights. Our genetic analysis of patients and experimental animals with thyroglobulin(Tg) abnormalities indicated the amino acids involved in the surface electric charge were important in maintaining the solid structure of Tg and thyroid hormone synthesis in addition to tyrosine and cysteine. In three patients with hyperthyroid Graves' disease, Hashimoto's thyroiditis or idiopathic hypothyroidism, followed by the author for 8 to 20 years, it was indicated that continued comprehensive care was needed for various episodes, even those arising from non-endocrine conditions, throughout the clinical course, although clinical and laboratory findings showed improvement of the thyroid disease itself.

Congenital Hypothyroidism↗