LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations.

AIMS: To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. METHODS: The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤ 50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥ 20 ng/l. RESULTS: The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2). The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. CONCLUSIONS: In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations.

Overexpression of type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels.

Thyroid function is normally undisturbed in patients with thyroid carcinoma. We have identified three patients with large or widely metastatic follicular thyroid carcinoma who had a persistently increased ratio of serum T(3) to T(4) in the absence of autonomous production of T(3) by the tumor. To investigate the possibility of tumor-mediated T(4) to T(3) conversion, we assayed types 1 and 2 iodothyronine selenodeiodinase (D1 and D2) activity in a 965-g follicular thyroid carcinoma resected from one of these patients. The V(max) for D2 was 8-fold higher than in normal human thyroid tissue. Resection of this tumor, leaving the left thyroid lobe intact, normalized the serum T(3) to T(4) ratio. In two other patients, treatment with sufficient levothyroxine to suppress TSH was associated with a high normal T(3) and a subnormal free T(4) index. In one, concomitant administration of the D1 inhibitors, propylthiouracil and propranolol, did not decrease the elevated serum T(3) to T(4) ratio. These data illustrate that increased T(4) to T(3) conversion in follicular thyroid carcinomas, probably by D2, can cause a significant perturbation in peripheral thyroid hormone concentrations.

Association between lithium use and thyrotoxicosis caused by silent thyroiditis.

OBJECTIVE: To determine the incidence of silent thyroiditis in lithium users and characterize lithium-associated thyrotoxicosis. DESIGN: Retrospective record review. PATIENTS: 400 consecutive patients (300 with Graves' disease and 100 with silent thyroiditis) who underwent radioiodine scanning of the thyroid. MEASUREMENTS: Odds of lithium exposure. RESULTS: The odds of lithium exposure were increased 4.7-fold in patients with silent thyroiditis compared with those with Graves' disease (95% CI: 1.3, 17). Lithium-associated silent thyroiditis occurred with an incidence rate of approximately 1.3 cases per 1000 person-years, and lithium-associated thyrotoxicosis occurred with an incidence rate of approximately 2.7 cases per 1000 person-years, higher than the reported incidence rates of silent thyroiditis (< 0.03-0.28 cases per 1000 person-years) and of thyrotoxicosis (0.8-1.2 cases per 1000 person-years) in the general population. CONCLUSION: Thyrotoxicosis caused by silent thyroiditis might be associated with lithium use.

Atypical subacute thyroiditis: preliminary observations.

Nine patients with painless or minimally painful subacute thyroiditis were seen between late June and October 2000. Six had a history of antecedant viral symptoms. Thyroid peroxidase antibodies were negative in eight patients tested; none had a family history of autoimmune thyroid disease. It is possible that these patients represent examples of postviral painless subacute thyroiditis (atypical subacute thyroiditis). In order to establish the nature of the syndrome, cytological examination, HLA typing, and long-term follow-up are necessary.

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.

Risperidone-associated hyperprolactinemia.

OBJECTIVE: To compare the prolactogenic effects of risperidone, clozapine, and typical antipsychotic agents in an outpatient community-based psychiatric population. METHODS: Prolactin and thyroid-stimulating hormone (TSH) concentrations were measured in 68 outpatients with schizophrenia who were receiving antipsychotic medications and were recruited from a community mental health clinic. RESULTS: The percentage of women with increased prolactin concentrations was significantly greater in the risperidone group (100%, 12 of 12 patients) than in the clozapine group (25%, 1 of 4) (P = 0.0071) but not in comparison with the typical antipsychotic agent group (83%, 5 of 6) (P = 0.333). The percentage of men with increased prolactin concentrations was significantly greater in the risperidone group (94%, 17 of 18) than in the clozapine group (18%, 3 of 17) (P<0.0001) and in comparison with the typical antipsychotic agent group (27%, 3 of 11) (P = 0.0003). The mean prolactin concentration (all ng/mL +/- standard deviation) was also significantly higher in patients taking risperidone (women, 125.0 +/- 56.6; men, 37.3 +/- 23.9) than clozapine (women, 22.0 +/- 25.9; men, 13.3 +/- 22.4) (female patients, P = 0.0004; male patients, P<0.0001) or typical antipsychotic agents (women, 69.0 +/- 59.8; men, 13. 3 +/- 9.1) (female patients, P = 0.036; male patients, P = 0.0003). In the risperidone group, gender affected prolactin level, with women having higher concentrations than men, but the duration of therapy did not. In this group, prolactin was inversely dependent on age. No difference was noted in TSH concentrations between medication groups. CONCLUSION: Risperidone is a potent inducer of hyperprolactinemia in outpatients with schizophrenia in a community population. The higher and more frequently increased prolactin concentrations caused by risperidone could adversely affect patient health and compliance.

A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer.

Recombinant human TSH has been developed to facilitate monitoring for thyroid carcinoma recurrence or persistence without the attendant morbidity of hypothyroidism seen after thyroid hormone withdrawal. The objectives of this study were to compare the effect of administered recombinant human TSH with thyroid hormone withdrawal on the results of radioiodine whole body scanning (WBS) and serum thyroglobulin (Tg) levels. Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS were studied. Radioiodine WBS and serum Tg measurements were performed after administration of recombinant human TSH and again after thyroid hormone withdrawal in each patient. Radioiodine whole body scans were concordant between the recombinant TSH-stimulated and thyroid hormone withdrawal phases in 195 of 220 (89%) patients. Of the discordant scans, 8 (4%) had superior scans after recombinant human TSH administration, and 17 (8%) had superior scans after thyroid hormone withdrawal (P = 0.108). Based on a serum Tg level of 2 ng/mL or more, thyroid tissue or cancer was detected during thyroid hormone therapy in 22%, after recombinant human TSH stimulation in 52%, and after thyroid hormone withdrawal in 56% of patients with disease or tissue limited to the thyroid bed and in 80%, 100%, and 100% of patients, respectively, with metastatic disease. A combination of radioiodine WBS and serum Tg after recombinant human TSH stimulation detected thyroid tissue or cancer in 93% of patients with disease or tissue limited to the thyroid bed and 100% of patients with metastatic disease. In conclusion, recombinant human TSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer persistence and recurrence.

Hyperthyroidism: multiple possibilities in the female patient.

Hyperthyroidism is a clinical syndrome characterized by an excess of thyroid hormone, and its clinical consequences. A suppressed serum TSH concentration is the earliest biochemical manifestation of hyperthyroidism. Subclinical hyperthyroidism, characterized by suppressed serum TSH concentration alone, has important clinical consequences. These include bone loss in postmenopausal women and atrial fibrillation. A twenty-four hour radioiodine uptake and radionuclide scan are indispensable in the differential diagnosis of hyperthyroidism. Graves' Disease, an autoimmune disorder, demonstrates a strong female prevalence; the twenty-four hour radioiodine uptake is normal or elevated. Therapeutic options, including anti-thyroid drugs, radioactive iodine (131I) and surgery are utilized in all age groups. These include use in women during the reproductive years. Toxic nodular goiter and "hot" nodules are less common forms of hyperthyroidism; these too have normal or elevated radioiodine uptake, with characteristic radionuclide scans. Hyperthyroidism with a near-zero radioiodine uptake also has important clinical implications. Factitious (exogenous) hyperthyroidism is characterized by a low serum thyroglobulin concentration. Treatment consists of decreasing the dosage of, or withdrawing, thyroid hormone. Painful subacute thyroiditis, a post-vital syndrome, causes spontaneously resolving hyperthyroidism, which is often followed by hypothyroidism. The most common cause of hyperthyroidism with a low radioiodine uptake is painless, lymphocytic subacute thyroiditis. Here too, hyperthyroidism spontaneously resolves and often passes through a hypothyroid phase. This phase often requires therapy, and permanent mild or severe hypothyroidism may result.

Amiodarone and the thyroid.

OBJECTIVE: To review the amiodarone-associated alterations in thyroid hormone metabolism and thyroid function and compare them with the effects of inorganic iodide. To clarify the pathophysiologic features and treatment of amiodarone-associated hypothyroidism and thyrotoxicosis. SUMMARY: Amiodarone, an iodinated benzofuran, is an important antianginal and antiarrhythmic medication. It also alters thyroid hormone metabolism and may precipitate hypothyroidism or hyperthyroidism. Amiodarone-associated hypothyroidism (AAH) is similar to iodine-induced hypothyroidism. Amiodarone-associated thyrotoxicosis (AAT) has a complex pathophysiology. Type I AAT is due to increased thyroid hormone synthesis and release and occurs in patients with multinodular goiter or Graves' disease. Therapeutic interventions may include discontinuation of amiodarone, thionamide therapy, perchlorate, or surgery. In type II AAT, hyperthyroidism is the consequence of a destructive thyroiditis with release of preformed thyroid hormone. Prednisone therapy is the treatment of choice. The distinction between these two entities is of considerable clinical and therapeutic importance.

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND: To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS: One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS: Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS: Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

Fine needle aspiration biopsy of the thyroid gland in patients with prior Graves' disease treated with radioactive iodine. Morphologic findings and potential pitfalls.

OBJECTIVE: To evaluate the morphologic findings and their potential pitfalls in fine needle aspiration biopsies (FNAB) of thyroid glands obtained following radioactive iodine (RaI) (131I) treatment for Graves' disease. STUDY DESIGN: Study of thyroid FNAB specimens from six patients with prior Graves' disease treated with RaI who developed palpable nodules and had subsequent thyroid resections. RESULTS: The cytologic changes attributed to radiation were quite variable among the six cases and were so pronounced in one case that a false positive diagnosis of papillary carcinoma was made even though a history of RaI had been provided. The FNAB specimen from the second case, submitted without a history of RaI treatment, was diagnosed as suspicious for papillary carcinoma. The smears from patient 3 were signed out descriptively because the pertinent clinical history had not been provided. The FNAB specimens from the last three patients were correctly interpreted because of the history of RaI therapy provided. All six thyroid surgical specimens showed changes consistent with radiation injury, and none contained evidence of malignancy. CONCLUSION: The study's findings demonstrate that the atypia produced by RaI may be severe, leading to an erroneous diagnosis of malignancy. Provision of the appropriate clinical history of Graves' disease treated with RaI may prevent this pitfall.

Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association.

A set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with thyroid nodules or thyroid cancer was developed by consensus by an 11-member Standards of Care Committee (the authors of the article) of the American Thyroid Association, New York, NY. The participants were selected by the committee chairman and by the president of the American Thyroid Association based on their clinical experience. The committee members represented different geographic areas within the United States, to reflect different practice patterns. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information. Each committee participant was initially assigned to write a section of the document and to submit it to the committee chairman, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. Several of the committee members further revised and refined the document, which was then submitted to the entire membership of the American Thyroid Association for written comments and suggestions, many of which were incorporated into a final draft document, which was reviewed and approved by the Executive Council of the American Thyroid Association.