American Thyroid Association guidelines for detection of thyroid dysfunction.

OBJECTIVE: To define the optimal approach to identify patients with thyroid dysfunction. PARTICIPANTS: The 8-member Standards of Care Committee of the American Thyroid Association prepared a draft, which was reviewed by the association's 780 members, 50 of whom responded with suggested revisions. EVIDENCE: Relevant published studies were identified through MEDLINE and the association membership's personal resources. CONSENSUS PROCESS: Consensus was reached at group meetings. The first draft was prepared by a single author (P.W.L.) after group discussion. Suggested revisions were incorporated after consideration by the committee. CONCLUSIONS: The American Thyroid Association recommends that adults be screened for thyroid dysfunction by measurement of the serum thyrotropin concentration, beginning at age 35 years and every 5 years thereafter. The indication for screening is particularly compelling in women, but it can also be justified in men as a relatively cost-effective measure in the context of the periodic health examination. Individuals with symptoms and signs potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent serum thyrotropin testing.

Distinct regions of thyroglobulin control the proliferation and suppression of thyroid-specific lymphocytes in obese strain chickens.

The effect of thyroglobulin (Tg)iodination on the proliferation and suppression of thyroid-specific lymphocytes was examined in vivo in the obese strain (OS) and Cornell strain chicken models of autoimmune thyroiditis. Spleen cells from OS chickens were able to transfer disease to Cornell strain recipients. The ability to transfer disease was markedly reduced if the donors were raised on an iodine-depleting regimen. This deficiency was corrected by immunization of donor chickens with iodinated Tg. Immunization with low iodine Tg was ineffective. Neonatal tolerance induction with either iodinated or low iodine Tg reduced thyroiditis in 2-week-old OS chickens. Spleen cells from these tolerized chickens transferred to 4-day-old OS chickens were less thyroiditogenic. These results indicate that thyroid autoreactive cells are responsive to iodinated Tg, but not to low iodine Tg. Both of the Tg preparations, however, can induce tolerance to the disease. We conclude that distinct regions of the Tg molecule regulate the proliferation and suppression of thyroid-reactive lymphocytes, respectively. Only the former is dependent on the iodination of Tg. These results emphasize the importance of Tg as a self-antigen and provide one mechanism by which iodine may induce autoimmune thyroiditis.

The obese strain chicken as a model for human Hashimoto's thyroiditis.

The OS and the related Cornell C strain are interesting animal models for the study of the etiology of autoimmune thyroiditis. They are especially valuable for studying the etiologic role of thyroid abnormalities and abnormalities in the processing of iodine. Limitations of the model are the scarcity of immunological reagents for chickens, the absence of avian cloned thyroid-specific genes, minimal amounts of microsomal antibody and some differences between OS chickens and Hashimoto's patients in the types of thyroid abnormalities observed.

Thyroid cell injury is an initial event in the induction of autoimmune thyroiditis by iodine in obese strain chickens.

The present study examines the role of thyroid cell injury in the initiation of autoimmune thyroiditis by iodine in Obese strain (OS) chickens, a strain genetically susceptible to spontaneous autoimmune thyroiditis. OS and normal strain chickens were placed on an iodine depletion regimen started in ovo. This regimen is known to prevent thyroiditis in OS chickens. The chickens were injected with NaI every 24 h for up to 7 days starting at 3 weeks of age. Both strains showed evidence of mild thyrocyte injury 12 h after NaI. However, significant and sustained infiltration, beginning 24 h after NaI, was seen only in the OS. The infiltrating cells were primarily mononuclear. Polymorphonuclear cells were not observed. Immunohistological analysis showed the infiltrate to be composed of CD8 T cells, CD4 T cells, B cells, and macrophages in the ratio 40:20:22:17. The infiltration was sustained and progressive for at least 7 days. Thyroid infiltration after NaI repletion was significantly reduced in OS chickens tolerized to thyroglobulin at hatching. Prior treatment with the antioxidant drug ethoxyquin completely prevented both the thyrocyte injury and the infiltration induced by iodine. Treatment with antioxidant drugs had no effect on the uptake and incorporation of iodine by the thyroid. In summary, 1) iodine caused thyrocyte injury in both OS and normal chickens. 2) The injury was followed by cellular infiltration in the OS but not in normal chickens. 3) The infiltration appeared to be immune mediated in being primarily lymphocytic and at least partially thyroglobulin sensitive. 4) Prevention of thyroid injury by antioxidant drug treatment also prevented infiltration. We conclude that thyroid cell injury may be an initial event in the induction of autoimmune thyroiditis by iodine.

Adjunctive treatment with propylthiouracil or iodine following radioiodine therapy for Graves' disease.

The effect of radioiodine therapy in Graves' disease is gradual in onset and the subjects continue to be hyperthyroid for several weeks after such therapy. In a prospective study of 112 patients, we compared the usefulness of two commonly employed antithyroid drug regimens in controlling hyperthyroidism in the period immediately following radioiodine therapy. They received propylthiouracil (PTU, 100 mg orally three times a day), saturated solution of potassium iodide (10 drops once a day) or no drugs starting 5 days after radioiodine therapy. Thyroid status was monitored clinically and by serum thyroxine index and TSH measured at 4-6 week intervals over a 6-month period. The control or drug-treated groups did not differ in thyroid status 6 weeks after radioiodine. The PTU-treated group had greater incidence of hyperthyroidism and a lower incidence of hypothyroidism at 6 months. However, the differences were explained on the basis of a greater incidence of large goiters that appeared to confer relative radioresistance in the PTU group. We conclude that patients with mild to moderate hyperthyroidism do not benefit from adjunctive treatment with PTU or potassium iodide immediately after radioiodine therapy.

Triiodothyronine (T3) improves cardiovascular function during hemorrhagic shock.

Prior work showed that an intact thyroid axis augments survival from hemorrhagic shock (HS); this study assesses the effects of specific thyroid-related hormones on cardiovascular (CV) function during HS. Following thyroidectomy, 32 conditioned male dogs were subjected to HS to a mean arterial pressure (MAP) of 60 mm Hg for 90 min then to 40 mm Hg for 30 min. Postshock (PS), the dogs received thyroid-releasing hormone (TRH; 2 mg/kg), thyroid-stimulating hormone [control (TSH; 10 IU)], T3 (12 micrograms/kg), or T4 (40 micrograms/kg). Thirty minutes following treatment (PTX), they were resuscitated with shed blood and 50 ml/kg saline. CV and hormonal parameters were measured PS, PTX, postresuscitation (PR), and on day 2 (D2). There were no PS differences in CV parameters between groups. Following treatment, T3 significantly increased MAP (59.0 +/- 13 vs, 39.9 +/- 2.2 mm Hg) and cardiac output (CO; 0.92 +/- 0.1 vs. 0.80 +/- 0.1 liter/min; P < 0.05 by ANOVA). TRH treatment significantly improved PTX MAP (62.7 +/- 10 vs. 40.8 +/- 2.1; P < 0.05 by ANOVA). TSH and T4 did not significantly change PTX MAP or CO. There were no significant CV differences in the four groups following resuscitation or on D2. In conclusion, T3 improves MAP and CO during hemorrhagic shock. TRH transiently improved PTX blood pressure. Further study of the mechanism of this beneficial response afforded by T3 administration is warranted.

What makes silica toxic?

Published data suggest that particle charge could be related to its toxicity. Respirable particles containing silica were therefore collected in foundries and their charge measured. These particles carried high levels of positive charge that were related to low humidity. Incubating these particles with pulmonary macrophages from mice produced detectable activities of collagenase, a precursor of silicosis. These experiments confirm that the toxicity of silica particles is likely to be because of the positive charge they carry.

The role of iodine in thyroid autoimmunity: from chickens to humans: a review.

Evidence has been presented to support the idea that iodine plays an important role in autoimmune thyroiditis. Excessive amounts induce thyroiditis in genetically susceptible animal strains, while intrathyroidal depletion of iodine prevents disease in strains susceptible to severe thyroiditis. While the mechanisms by which iodine promotes thyroiditis is unknown, several hypotheses have been proposed. (1) T and/or B cells may react specifically to iodinated portions of thyroglobulin (Tg) so that severe iodine depletion renders Tg non-immunogenic. (2) A defect in the iodine processing machinery in thyroid epithelial cells of a susceptible person or animal may, in the presence of iodine, result in elevated levels of oxygen or iodine radicals, which could damage membrane lipids or proteins. (3) Defective iodine processing may result in the iodination of lipid or proteins (other than Tg) which could act either as immunogens or polyclonal activators.

Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens.

To assess the importance of the role of thyroidal iodine in the pathogenesis of thyroiditis in the obese strain (OS) chicken, a model of spontaneous and severe disease, we studied the effect of antithyroid drugs that reduce thyroidal iodine or prevent its metabolism. Reduction of thyroidal iodine was achieved with KClO4, an inhibitor of iodine transport and mononitrotyrosine (MNT), a drug that promotes loss of thyroidal iodine as iodotyrosines. A regimen consisting of KClO4 and MNT administration beginning in ovo and continuing after hatching reduced thyroidal infiltration to 2% of control values and decreased thyroglobulin antibody (TgAb) production for as long as 9 wk. Untreated birds had severe disease by 5 wk of age. The suppression of disease was independent of TSH, not mediated by generalized immunosuppression and reversed by excess dietary iodine. Two drugs that inhibit the metabolism of iodine, propylthiouracil (PTU) and aminotriazole, reduced thyroidal infiltration and TgAb levels, although to a lesser extent. When splenocytes from OS chickens with thyroiditis were transferred to Cornell strain (CS) chickens, a related strain that develops late onset mild disease, only the recipients that were iodine supplemented developed thyroiditis. In conclusion, autoimmune thyroiditis in an animal model can be prevented by reducing thyroidal iodine or its metabolism and optimal effects require intervention at the embryonic stage.

Thyroidal iodine metabolism in obese-strain chickens before immune-mediated damage.

Several studies have shown that iodine plays a role in spontaneous autoimmune thyroiditis in man and other animals. In addition, abnormalities of iodine metabolism have been found in patients with Hashimoto's thyroiditis and in chickens of the obese strain (OS), an animal model of spontaneous autoimmune thyroiditis. We have examined several parameters of iodine metabolism before immune damage in this model and in the related Cornell strain (CS), a strain which develops a late-onset mild thyroiditis, to discover a possible causal relationship between altered iodine metabolism and the initiation of autoimmunity. Thyroglobulin was purified from individual chicken thyroid glands and analysed for iodine by the ceric sulphate method. Analogous to the thyroglobulin of Hashimoto's patients, the iodine content of OS thyroglobulin (27 atoms/molecule) was lower than that of normal-strain thyroglobulin (46 atoms/molecule) when the chickens were provided with a normal diet. Also, under conditions of TSH suppression, the iodine content of OS thyroglobulin (18 atoms/molecule) was lower than that of CS thyroglobulin (36 atoms/molecule) and of normal-strain thyroglobulin (32 atoms/molecule). In contrast with Hashimoto's patients, however, the OS and CS chickens had practically no inorganic iodide in their thyroid glands; electrophoretic analysis of thyroid homogenates revealed that essentially all (greater than 99.62%) 125I was organified by 16 h in all strains of birds tested. Despite the relatively poor iodination of thyroglobulin exhibited by OS chickens, they did not iodinate additional 'unique' proteins, when examined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of thyroid proteins labelled with 125I in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants delay the onset of thyroiditis in obese strain chickens.

Dietary iodine has been shown to be important in the induction of thyroiditis in susceptible chicken strains although the underlying mechanism remains unknown. Iodine may exert its effects through the formation of reactive oxidative radicals which would cause thyroidal injury and initiate infiltration. We have tested this hypothesis by examining the ability of butylated hydroxyanisole (BHA), ethoxyquin, and other antioxidants to prevent thyroiditis in Obese strain (OS) chickens, a strain that develops severe disease by 4 weeks of age. BHA, when administered from hatching until death at 5 weeks of age, reduced thyroidal infiltration and serum levels of antibodies binding thyroglobulin, T3, T4. Similar effects were observed with the antioxidant ethoxyquin. Weaker antioxidants such as vitamins C and E and beta-carotene had only slight or negligible effects on these parameters. BHA reduced thyroiditis in OS chicks killed at 3 and 5 weeks of age, but not at 8 weeks. When BHA treatment was initiated after the development of severe disease, it did not reduce thyroglobulin antibody levels. To determine the mechanism by which BHA reduces thyroiditis, studies were performed to assess the effect of BHA on thyroid function and on the immune responses to exogenous antigens. BHA had no effect on thyroid function in normal strain chickens since thyroidal radioiodine uptake and organification and serum T3 and T4 levels were unaffected. BHA did not alter immune responses to exogenous antigens such as sheep red blood cells or Brucella abortus in OS chickens. In summary, potent antioxidant drugs delayed the onset of thyroiditis when treatment was initiated before the onset of disease, suggesting that reactive oxygen intermediates are involved in the early stages of pathogenesis. However, the site of action remains unknown since they had no detectable effects on thyroid function or general immune responses.

Amiodarone-induced changes in lipid metabolism.

Hypothyroidism is a major cause of secondary hypercholesterolemia. Amiodarone treatment alters both the levels of serum lipids and thyroid hormones. We investigated whether the amiodarone-induced changes in lipid metabolism are related to the changes in thyroid hormone levels. Eighteen patients received amiodarone (31 +/- 3 g cumulative dose) for six weeks. Serum triglyceride, total-cholesterol, high density lipoprotein-cholesterol and its subfractions, apolipoproteins B and AI, and plasma post-heparin lipoprotein lipase and hepatic triglyceride lipase activities were determined. Amiodarone treatment caused significant increases in serum total-cholesterol (baseline 4.4 +/- 0.21 (SE), 6 weeks 5.12 +/- 0.26 mmol/l, P less than 0.01), in low density lipoprotein cholesterol (baseline 2.61 +/- 0.26, 6 weeks 3.36 +/- 0.21 mmol/l, P less than 0.05) and in apolipoprotein B (baseline 1.95 +/- 0.15, 6 weeks 2.26 +/- 0.13 mmol/l, P less than 0.01) concentrations. Serum high density lipoprotein and its subfractions, or apolipoprotein AI levels did not change. Plasma post-heparin lipoprotein lipase activity increased (baseline 137 +/- 21, 6 weeks 168 +/- 21 U/ml, P less than 0.01) while hepatic triglyceride lipase did not change. Amiodarone also caused an increase in serum thyroxine (baseline 110 +/- 8, 6 weeks 136 +/- 6 mmol/l, P less than 0.05), although values remained in euthyroid range. In summary, amiodarone therapy increased the concentrations of atherogenic lipoproteins in the serum similar to that seen in hypothyroidism. On the other hand the effect of amiodarone on lipoprotein lipase was opposite to that seen in hypothyroidism. Therefore, amiodarone-induced changes in lipid metabolism cannot be explained solely on the basis of the changes in circulating thyroid hormone levels.

Thyroid dysfunction in adults over age 55 years. A study in an urban US community.

The prevalence of thyroid dysfunction was determined in a healthy urban population over the age of 55 years. A highly sensitive serum thyrotropin assay was used initially to screen 968 subjects. Elevated values (greater than 6 mU/L) were found in 7.3%, while suppressed values (less than 0.1 mU/L) were present in 2.5% subjects. Protirelin stimulation testing demonstrated exaggerated responses in 95% of the subjects with elevated thyrotropin levels and subnormal responses in 81% of the subjects with suppressed thyrotropin levels. Thyroid dysfunction, as defined by abnormalities of both serum thyrotropin level and protirelin response, was calculated to be present in 8.9% of the population. The prevalence was greater in whites (vs blacks), in women, and in subjects older than 75 years as compared with the 55- to 64-year age group. Hypothyroidism was calculated to be present in 6.9% subjects. Despite an increased prevalence of thyroid autoantibodies in these subjects, only 8.5% of them had subnormal serum thyroxine concentrations. Hyperthyroidism was calculated to be present in 2.0% of the population, two thirds of whom were taking thyroid hormone preparations. These results suggest a significant prevalence of thyroid dysfunction in the elderly, with important sex and racial differences.

Comparison of the effects of amiodarone and ipodate on the rat heart.

Chronic treatment of rats with amiodarone has been shown to produce hypothyroid-like effects such as a reduction in body and heart weight and increased synthesis of the low ATPase V3-cardiac isomyosin (Bagchi, Brown, Schneider and Banerjee 1987). In this report, we have tested the hypothesis that amiodarone causes these effects through the inhibition of intracellular production of triiodothyronine (T3) from thyroxine (T4) by comparing the effects of amiodarone with those of ipodate, a potent inhibitor of T4 to T3 conversion. Separate groups of rats were given dietary ipodate and amiodarone respectively for six weeks. Both agents increased serum T4 and T4/T3 ratios, a finding consistent with the inhibition of peripheral T4 to T3 conversion. However, ipodate failed to produce hypothyroid-like effects on body weight, heart weight and isomyosin transitions similar to those found in the amiodarone group. These data indicate that the hypothyroid-like effects of amiodarone on the rat heart are not due to the inhibition of intracellular generation of T3 from T4.

Loss of pubic and axillary hair following treatment with glucocorticoids.

A woman with prior bilateral oophorectomy developed loss of pubic and axillary hair following treatment with glucocorticoids. Serum androgens were low while cortisol and aldosterone levels were normal. This unusual presentation, which continued for at least 3 years, was most likely attributable to the prolonged selective suppression of adrenal androgens by glucocorticoids.

Decreased thyroidal response to thyrotropin in type II diabetes mellitus.

The responses to TRH and bovine TSH (bTSH) were compared in 19 men with uncontrolled type II diabetes mellitus and eight healthy control subjects. Baseline serum TSH, T3 and T4 were similar in both groups and the rise of serum TSH, T3 and T4 following the intravenous (IV) administration of TRH (500 micrograms) was not significantly different. Diabetic subjects showed a blunted response to the subcutaneous (sc) administration of bTSH (5 U) when their maximal serum T3 and T4 values were compared with controls (T4, 9.4 +/- 0.3 v 12.3 +/- 1.1 micrograms/dL, P less than .005; T3, 185 +/- 9 v 233 +/- 17 ng/dL, P less than .025; diabetic v control). When the response to bTSH was examined in seven patients after 4 to 5 days of strict glycemic control, the maximal T3 response was found to increase in six, and the maximal T4 response in five. These data show that the thyroidal secretory response to large doses of TSH is decreased in uncontrolled diabetes mellitus and that strict glycemic control frequently improves the response.