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.

The pure-science ideal and democratic culture.

These early experiences of pure scientists will have an unmistakable ring of familiarity to anyone familiar with the current situation. Charles Sanders Peirce, with characteristic insight, had stated the fundamental dilemma of the pure scientist operating within a democratic framework. How can one ask the public to provide support, much less facilities, for the intellectual gratification of one select group? A part of the answer, of course, is simply that one cannot. As long as a group is dependent upon public support it must seek some means of contact with the values of the enveloping society, and the moment it does this it departs in some measure from the ideal purity. The schizophrenic attitude described by Dubos therefore became a professional necessity as soon as the new ideal was adopted. Since the time of Gould, scientists have been able to tell each other that the man who based science's claim to support on grounds of immediate practical utility was "no loyal follower and true friend of science" and, at the same time, to trust that the popularizers and technicians would convey a different message to the public. On the whole, they have not been disappointed in their expectation, and there has been little need for them to go beyond the standard formula : Utility is not to be a test of scientific work, but all knowledge will ultimately prove useful. Since the continued existence of scientists in this society depends upon the believability of that vague claim, there is little likelihood hood that the schizophrenia will disappear.

Triiodothyronine-induced thyrotoxicosis in ophthalmic Graves disease.

A euthyroid woman with ophthalmic Graves disease developed endogenous hyperthyroidism coincident with T3 suppression test. There is a putative role of liothyronine administration in precipitating or activating hyperthyroidism. Aberrancies in T3 suppression testing in graves disease occur.

Myocardial function in hypothyroidism. Relation to disease severity and response to treatment.

Systolic time intervals (ST) were used to evaluate myocardial function prospectively in 29 hypothyroid patients. The patients were divided into three categories of disease severity: (1) severe hypothyroidism, (2) mild hypothyroidism, and (3) decreased thyroid reserve or "prehypothyroidism." Groups 1 and 2 showed decreased myocardial contractility with a prolonged preejection period (PEP), shortened left ventricular ejection time (LVET), and increase PEP/LVET, compared with normal controls. The STI were more abnormal (P less than .05) in group 1 than in group 2, suggesting that the severity of myocardial dysfunction correlates with the severity of the hypothyroidism. Group 3 had normal STI. Ten patients were restudied when euthyroid and showed complete normalization of their STI, supporting the thesis that hypothyroidism was the sole cause of the initial myocardial dysfunction.

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.

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.

The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an out-patient endocrine clinic.

A chemiluminescent TSH assay (detection limit, less than 0.01 mU/L) allows for accurate measurement of subnormal TSH concentrations. We retrospectively analyzed serum TSH and the free T4 (fT4) index of 460 consecutive endocrine clinic visits to determine the usefulness of TSH measurements alone in the assessment of thyroid function. Additionally, case histories were presented nonconsecutively to one of us (TSH alone or TSH with fT4) to determine if knowledge of the fT4 level would alter management. Of hypothyroid patients on replacement therapy (n = 127), 60% had concordant fT4 and TSH, 14% had subnormal TSH with normal fT4, 18% had high TSH with normal fT4, and 4% normal TSH with high fT4; only 4% were managed differently when the fT4 level was known in addition to TSH. Of the patients receiving suppressive therapy with TSH levels above 0.05 mU/L (n = 81), only 4% were managed differently when fT4 was known; 4% had high fT4. With TSH levels below 0.05 mU/L (n = 64), knowledge of fT4 was felt to be necessary for management in all cases; 53% had high fT4. Twenty-three of 46 (50%) patients being treated for hyperthyroidism had discordant TSH and fT4, including 7 patients with low TSH and low fT4. Two of 21 (10%) patients screened with pituitary/hypothalamic disease had discordant TSH and fT4, and 4 of 9 (44%) patients treated with L-T4 for secondary hypothyroidism had subnormal TSH. Knowledge of fT4 was felt to be necessary in all these cases. We conclude that TSH alone is sufficient for screening and monitoring L-T4 replacement or suppression therapy if TSH levels are above 0.05 mU/L. These patients account for the majority of visits to our endocrine clinic. TSH alone is misleading in pituitary disease and during the treatment of hyperthyroidism. fT4 is needed if TSH levels are less than 0.05 mU/L to assess the degree of hyperthyroidism.

Thyroid function tests during the early phase of subacute thyroiditis.

Six patients with subacute thyroditis were followed with serial measurements of T4, FT4, TSH and RAI uptake. Five of the six underwent TRH stimulation early in the course of their illness. All six patients had elevated or high normal values for T4 and FT4 at the time of their clinical presentation (mean = 13.8 microgram per 100 ml and 3.9 ng per 100 ml, respectively). RAI uptakes were 1% or less in all six. TRH testing revealed a suppressed TSH response (mean deltaTSH less than0.1 muU/ml) in all five patients tested, suggesting hyperthyroidism. After initial studies were performed, five patients were treated with L-triiodothyronine (L-T3) and one with aspirin. All patients improved over a two to four week period of time, no relapses being noted.

Use of adjunctive potassium iodide after radioactive iodine (131I) treatment of Graves' hyperthyroidism.

One hundred and nineteen patients with Graves' hyperthyroidism who were treated with 131I alone or 131I followed by potassium iodide (131I + KI) were studied retrospectively. Patients in both groups who required only a single dose of 131I for successful treatment of hyperthyroidism had similar age, gland size, 24-h radioactive iodine uptake, pretreatment serum T4 concentrations, and radioactive iodine treatment dose. Seven weeks after 131I, mean serum T4 concentrations were 12.3 +/- 6.1 micrograms/dl (mean +/- SD) in patients who received 131I alone and 8.0 +/- 3.9 micrograms/dl in patients who received 131I + KI (p less than 0.001). Sixty percent of the patients who received 131I + KI and remained euthyroid 1 yr after 131I treatment developed documented transient hypothyroidism while receiving KI (serum T4, 1.4 +/- 0.9 micrograms/dl). Patients with transient hypothyroidism receiving KI had larger estimated thyroid gland weights when hypothyroid than patients whose hypothyroidism was permanent (32 +/- 6 vs. 16 +/- 11 g; P less than 0.001). The overall incidence of hypothyroidism 1 yr after treatment with 131I was 58% in each of the two groups. Sixteen percent of each group were not successfully treated by a single dose of 131I and required further therapy. Adjunctive KI effectively treated thyrotoxicosis more rapidly than 131I alone without adversely affecting outcome at 1 yr; however, patients taking KI more often develop transient hypothyroidism.

The pituitary-thyroid axis in adults with phenylketonuria.

Serum thyroxine and triiodothyronine levels in 15 adult phenylketonuric patients on an unrestricted diet were normal despite reduced circulating tyrosine levels. Serum thyrotropin levels were normal in the basal state or in response to thyrotropin-releasing hormone in selected patients tested. These results support and extend previous observations of normal thyroid function in phenylketonuria.

Medullary thyroid carcinoma identified by cell-free translation of tumor messenger ribonucleic acid in a patient with a neck mass and the syndrome of ectopic adrenocorticotropin.

We report a patient who presented with a lateral neck mass and Cushing's syndrome secondary to the ectopic production of ACTH. The initial diagnosis was a nonchromaffin paraganglioma based on conventional light and electron microscopic studies. However, during this patient's hospital course, we determined that mRNA extracted from the tumor directed the translation of a calcitonin precursor in a cell-free system. This finding led to a consideration of the diagnosis of medullary thyroid carcinoma, which was then confirmed by further endocrine and histological evaluations. This is a report of the identification of a tumor type using techniques of molecular biology.

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.

Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study).

Current diagnostic studies [radioiodine uptake and serum thyroglobulin (Tg) levels] for residual or metastatic thyroid tissue in patients with differentiated thyroid carcinoma require a hypothyroid status necessary for adequate endogenous TSH stimulation. However, almost all patients have symptoms of clinical hypothyroidism during this period. As shown in the present study, recombinant human TSH (rhTSH) allows stimulation of 131I uptake and Tg release from residual thyroid tissue in euthyroid patients. To assess safety, dosage, and preliminary efficacy, comparison was made of the stimulation of 131I uptake and Tg release after rhTSH administration and after T3 withdrawal in 19 patients after a recent thyroidectomy for differentiated thyroid carcinoma. Various doses (10-40 U) of rhTSH were injected im for 1-3 days in patients receiving suppressive doses of T3. Twenty-four hours after the last dose of rhTSH, 1-2 mCi 131I were administered, followed by a neck and whole body scan 48 h later. After discontinuing T3 for a median period of 19 days (range, 15-28), endogenous serum TSH levels were markedly elevated, and the patients were given a second dose of 131I and rescanned 48 h later. The injections of rhTSH were tolerated well. No major adverse effects were reported; nausea was reported in 3 (16%) and vomiting in 1 of the patients treated with high doses. The quality of life, as measured by two psychometric scales, was far better during rhTSH treatment than after T3 withdrawal. The peak levels of serum TSH (mean +/- SD) after a single dose of 10, 20, or 30 U were 127 +/- 19, 309 +/- 156, and 510 +/- 156 mU/L, respectively, and occurred 2-8 h after injection. Twenty-four hours after the injection, TSH levels decreased to 83 +/- 31, 173 +/- 73, and 463 +/- 148 mU/L in these treatment groups, respectively. The quality of the thyroid scans and the number of sites of abnormal 131I uptake were similar after rhTSH treatment and in the hypothyroid scans in 12 (63%) patients. Two additional sites of uptake in the chest and one in the thyroid bed, not visible on the hypothyroid scans, were identified in 3 (16%) patients after rhTSH. In 1 patient a focus of uptake was better visualized after rhTSH than after withdrawal. In 3 (16%) other patients, 1 lesion in the chest and 2 in the neck were seen only after T3 withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Hormonal hyperthermia: endocrinologic causes of fever.

Although hyperthermia is a component of many endocrine diseases, it is uncommon for fever to be the presenting manifestation of hormonal disorders. During a four year period we encountered six patients, hospitalized principally because of fever, who were found to have endocrine causes for the fever. In all, the admitting diagnosis was infection; three were suspected of having tuberculosis, two of gram-negative bacteremia and one of endocarditis. Except for asymptomatic bacteriuria in one patient (who remained febrile despite appropriate antibiotic therapy) infection was ruled out in all cases, and fever was attributed to "masked" thyrotoxicosis, triiodothyronine (T3) toxicosis, subacute thyroiditis, primary adrenal insufficiency, secondary adrenal insufficiency and pheochromocytoma. In a seventh patient, extreme pyrexia developed in the setting of the thyroid storm. The importance of hormonal mechanisms in thermoregulation is discussed.

Subclinical hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-thyroxine.

Spontaneous hyperthyroidism and that due to excessive administration of thyroid hormone result in osteopenia. Bone density was measured in 28 white premenopausal female patients who were taking commonly prescribed suppressive doses of L-thyroxine (mean dose 0.171 +/- 0.035 g) for five or more years. The thyroxine level was 13.5 +/- 2.6 micrograms/dl (normal 8.0 +/- 2.4 micrograms/dl), the free thyroxine index was 4.4 +/- 1.0 (normal 2.4 +/- 0.8), and the triiodothyronine value was 154 +/- 26 ng/dl (normal 132 +/- 32 ng/dl). Basal thyrotropin was undetectable (less than 0.08 microIU/ml) in 23 patients, and thyrotropin measured 20 minutes after thyrotropin-releasing hormone administration was not demonstrable in 13 patients and subnormal in 10 patients. Women who had taken L-thyroxine for 10 or more years (n = 12, age 37 +/- 4 years) had a 9 percent reduction in bone density (0.667 +/- 0.044 g/cm2, p less than 0.01) compared with normal premenopausal age-matched control subjects (n = 56, age 35 +/- 6 years, bone density 0.733 +/- 0.055 g/cm2). It is concluded that prolonged suppressive L-thyroxine treatment may result in mild subclinical hyperthyroidism with adverse effects on bone. Patients requiring suppression of the pituitary-thyroid axis should be given the smallest dose of L-thyroxine necessary to achieve a satisfactory clinical response.

Complications of surgery in hypothyroid patients.

Hypothyroidism has generally been considered a contraindication to surgery. To determine the actual risks of perioperative complications in hypothyroid patients, the clinical courses of 40 hypothyroid surgical patients (serum thyroxine concentration 1.9 +/- 1.0 micrograms/dl) were retrospectively compared with those of 80 control patients matched for age, sex, and operative procedure. The two study groups were comparable in preoperative anesthetic physical class, prevalence of other medical conditions, and year of operation. During noncardiac surgery, intraoperative hypotension was encountered more frequently in the hypothyroid patients than in the control patients (61 versus 30 percent, p less than 0.05). Cardiac surgery was complicated by heart failure more often in the hypothyroid patients (29 versus 6 percent, p less than 0.05). Postoperatively, the hypothyroid patients more commonly had gastrointestinal (19 versus 1 percent, p less than 0.02) and neuropsychiatric (38 versus 18 percent, p less than 0.02) complications than control patients. Despite comparable rates of perioperative infection (38 versus 33 percent, p = NS), the hypothyroid patients less frequently manifested fever (35 versus 79 percent, p less than 0.001). There were no differences in perioperative blood loss, duration of hospitalization, or the prevalences of perioperative arrhythmia, hypothermia, hyponatremia, delayed anesthetic recovery, abnormal tissue integrity, impaired wound healing, pulmonary complications, or death. Preoperative clinical and chemical features of hypothyroidism were not useful in defining a subgroup of patients at special risk. Thus, surgery in hypothyroid patients is associated with an increased risk of several minor perioperative complications, which should be anticipated and preemptively managed in the course of their anesthetic and surgical care.

Hyperthyroxinemia in patients treated with high-dose propranolol.

Six patients with hyperthyroxinemia (five men and one woman) were evaluated for possible hyperthyroidism. All were taking large daily doses of propranolol--480 +/- 155 (+/- SE) mg--for treatment of angina pectoris. The patients had no clinical evidence of hyperthyroidism, although three had small goiters. Further evaluation of the patients revealed elevated serum free thyroxine levels and/or free thyroxine index, low-normal serum triiodothyronine levels, and elevated serum reverse triiodothyronine levels in all six. The thyroid-stimulating hormone response to thyrotropin-releasing hormone was normal in two patients, subnormal in three patients, and absent in one patient. One patient was restudied while receiving low-dose propranolol (80 mg a day), with normalization of all thyroid functional parameters. The data suggest that the abnormalities seen in patients taking high doses of propranolol were due to drug-induced blockade of iodothyronine deiodination. Signs and symptoms of hyperthyroidism are lacking in patients taking large doses of propranolol. If such a patient is discovered to have an elevated serum thyroxine level, a more complete evaluation of thyroid function is necessary before the diagnosis of thyrotoxicosis can be made. The thyrotropin-releasing hormone test may be of particular value in this circumstance.

Elevated thyroxine levels due to increased thyroxine-binding globulin in acute hepatitis.

Two patients are presented who had unexpected increases in serum thyroxine concentration due to acquired thyroxine-binding globulin excess associated with asymptomatic hepatitis. Serum hormone concentrations were also analyzed retrospectively in 10 outpatients with viral hepatitis. Acute hepatitis is associated with an increase in serum thyroxine and thyroxine-binding globulin concentrations and a corresponding decrease in the triiodothyronine resin uptake. In five patients, serum thyroxine concentration (mean +/- SD) was elevated at 21.08 +/- 5.86 micrograms/dl during illness, and decreased to 10.18 +/- 2.96 micrograms/dl during full recovery (p less than 0.05); serum thyroxine-binding globulin concentration was elevated at 2.14 +/- 0.36 mg/dl during illness, and decreased to 1.18 +/- 0.16 mg/dl during recovery (p less than 0.01). Interpretation of thyroid function test results can be difficult in patients with hepatitis. When serum thyroxine is elevated, careful attention to a decrease in the triiodothyronine resin uptake is essential to avoid the incorrect diagnosis of hyperthyroidism. Occasionally, this change in the triiodothyronine resin uptake may be the first evidence of occult hepatic inflammation.