The changing role of scintigraphy in the evaluation of thyroid nodules.

Nodular thyroid disease is common. Most nodules are asymptomatic and benign, but some are malignant. Fine needle aspiration (FNA) biopsy should be the cornerstone of the evaluation of thyroid nodules. Radionuclide scans and other imaging procedures should be considered adjunctive tests and should not be performed until after determination of thyroid function and results of cytology are available.

Maltoma of the thyroid in a man with Hashimoto's thyroiditis.

We report the case of a 42-yr-old man with primary thyroid lymphoma arising from mucosa-associated lymphoid tissue (MALT-lymphoma, maltoma). The patient underwent a hemithyroidectomy for a growing mass in the right lobe of the thyroid while being treated with 1-thyroxine for Hashimoto's thyroiditis. The clinical diagnosis of Hashimoto's disease was confirmed by aspiration biopsy of the mass during the course of L-thyroxine treatment. Postoperatively, histology showed atypical lymphoproliferative infiltrates suspicious of low-grade non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue-type, coexisting with a reactive process typical of chronic lymphocytic thyroiditis. Immunophenotyping showed a mixed B- and T-lymphocyte population, which was nondiagnostic. However, Southern blot analysis revealed a clonal rearrangement of the Ig heavy chain gene. This case demonstrates that cytology or histology may not distinguish between reactive or low-grade lymphomatous thyroid processes. The use of molecular technique was essential to prove clonality and the presence of lymphoma.

Recognizing the faces of hypothyroidism.

Physicians may not recognize hypothyroidism if they rely on the stereotypical picture of the disorder. The age of the patient, stage of the disease, and other illnesses or conditions such as pregnancy can change the clinical presentation. The signs and symptoms of hypothyroidism are remarkably diverse. Instead of a single picture, physicians need a mental gallery.

Effect of early referral to an endocrinologist on efficiency and cost of evaluation and development of treatment plan in patients with thyroid nodules.

Radionuclide uptake and scan and sonogram, frequently ordered before referral to an endocrinologist, are expensive and poor predictors of thyroid nodule malignancy. We estimated costs of excessive imaging and other studies by reviewing the records of all patients (n = 70) referred to a single, consulting endocrinologist, for thyroid nodule evaluation in a 2-yr interval and subsequently, presenting only pertinent histories and results of physical examinations, thyroid function tests, and thyroid autoantibodies, to a second, reviewing endocrinologist (RE) who was blinded to diagnosis and management. Concordance in diagnosis and management between consulting endocrinologist and RE was 87.1% and 93.4%, respectively. Accuracy of diagnosis, loss of patient's time (8.7 h, average), and cost of unnecessary testing, defined as tests not required by the RE for diagnosis and management according to published guidelines, were determined. Unnecessary testing included 153 physician's office or diagnostic laboratory visits, 44 sets of thyroid function tests, 32 radionuclide uptake and scan, 39 thyroid sonograms, and 3 computed tomography scans. The total direct cost of unnecessary tests was estimated at $27,290 ($390/patient) in addition to costs of 30 unnecessary physician's office visits. Only 2 of 8 surgical referrals required surgery, whereas 6 other patients required surgery, including 3 with papillary carcinoma. We conclude that early referral to an endocrinologist of patients with suspected thyroid nodules results in significant savings in cost of evaluation, patient's time, and increased diagnostic precision. Six of the 8 patients referred for surgery before endocrine consultation had benign thyroid disease that did not require surgery. Six additional patients were referred to surgery, 3 of whom had papillary thyroid carcinoma. Early referral of patients with suspected thyroid nodules to an endocrinologist results in significant savings in both cost and patient's time as well as increased precision of diagnosis.

Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropin-suppressive doses of L-thyroxine.

Biondi, Fazio, and colleagues recently reported that long term T4 treatment to suppress serum TSH markedly affects cardiac function. T4-treated patients had more symptoms [12.2 +/- 3.9 (+/-SD) vs. 4.2 +/- 2.3 by quantitative questionnaire], higher mean heart rate, increased incidence of atrial extrasystoles, increased interventricular septal thickness and left ventricular mass index (LVMi), and significant diastolic dysfunction. The severity of cardiac abnormalities was highly correlated with scores of a rating scale used for assessing symptoms of thyrotoxicosis. We have duplicated their studies in 17 athyreotic patients (mean age, 45 +/- 10 yr; range, 27-63 yr) without heart disease or hypertension whose dose of T4 was titrated to suppress serum TSH to less than 0.01 microU/mL. The mean duration of T4 treatment was 9.2 +/- 5.4 yr. Controls were healthy volunteers matched for sex and age (+/-3 yr). The mean T4 dose was 2.8 +/- 0.9 micrograms/kg (0.192 +/- 0.058 mg/day). By questionnaire, patients had minimal symptoms, although their symptom score was significantly greater than the control value (4 +/- 3 vs. 2 +/- 1; P < 0.05; maximum score, 36). No differences in mean heart rate or in atrial or ventricular extrasystoles were noted. In patients, indexes of systolic and diastolic function and interventricular septal thickness were similar to control values. The mean LVMi was normal in both groups. However, the mean LVMi in patients (117 +/- 35 g/m2) was higher than that in controls (92 +/- 31; P < 0.05). In conclusion, patients were minimally affected by TSH-suppressive doses of T4. They had few symptoms and no increase in extrasystoles or basal heart rate. Based on current knowledge, the increase in LVMi observed in patients without associated significant systolic or diastolic abnormalities does not have clinical or prognostic importance. Therefore, in the absence of symptoms of thyrotoxicosis, patients treated with TSH-suppressive doses of L-T4 may be followed clinically without specific cardiac laboratory studies.

Graves' disease and autoimmune factor VIII deficiency.

A patient with longstanding Hashimoto's thyroiditis who was treated with L-thyroxine at a dosage of 0.05 mg/day developed a decreased serum TSH concentration. L-Thyroxine was discontinued. Within 1 month, the patient developed mild hyperthyroidism due to Graves' disease. A hemorrhagic disorder occurred simultaneously with bleeding into muscle, joints, and skin. The bleeding disorder was identified as an acquired factor VIII deficiency due to a factor VIII inhibitor. The bleeding disorder resolved after treatment with prednisone, cyclophosphamide, and intravenous gamma globulin. Graves' disease also resolved but without specific treatment with either antithyroid drugs or radioactive iodine. The development of these two autoimmune disorders in this patient simultaneously suggests an underlying derangement in immune regulation common to both diseases.

Normal serum free thyroid hormone concentrations in patients treated with phenytoin or carbamazepine. A paradox resolved.

OBJECTIVE: To address the paradox that phenytoin- and carbamazepine-treated patients have decreased serum free thyroxine (T4) and triiodothyronine (T3) concentrations but appear clinically euthyroid and have normal serum thyroid-stimulating hormone (TSH) concentrations. DESIGN: In vitro studies comparing measurements of total and free T4 and T3 by ultrafiltration assay (undiluted serum) and a commercial free T4 estimate kit in control serum samples or serum samples containing added therapeutic levels of phenytoin or carbamazepine. These measurements were made in serum samples diluted 1:5 with either identical serum or phospate buffer, pH 7.4, and in serum samples from patients with seizure disorders who were treated with phenytoin or carbamazepine. SETTING: A 650-bed teaching hospital. PATIENTS: Selected patients (n=19) who were in good health except for seizure disorder, with stable anticonvulsant drug levels in the upper half of the therapeutic range, and were not taking any other drugs that could affect thyroid parameters. MAIN OUTCOME MEASURE: Serum concentrations of free T4 and free T3 in patients taking phenytoin or carbamazepine vs normal controls. RESULTS: Addition of phenytoin or carbamazepine to normal human serum in vitro resulted in a significant increase in free T4 fraction and free T4 (P<.001). In patients taking phenytoin or carbamazepine, serum total T4 decreased significantly to 60% and 74%, respectively, of the control serum concentration (P<.001 for both phenytoin and carbamazepine); free T4 fraction (by ultrafiltration assay) increased 65% and 44%, respectively (P<.001 for phenytoin, P<.01 for carbamazepine); and free T4 remained unchanged. Free T4 concentration measured by a commercial kit (1:5 serum dilution) was significantly lower than the control concentration in both phenytoin- and carbamazepine-treated patients. Serum free T3 and serum TSH were also normal in phenytoin- and carbamazepine-treated patients. CONCLUSIONS: Therapeutic levels of phenytoin and carbamazepine displace T4 and T3 from serum binding proteins. When added to serum, the drugs effect an increase in free hormone fractions and free T4 and T3. In drug-treated patients, increased free T4 and T3 fractions offset the significant decrease in serum T4 and T3, resulting in normal free T4 and free T3 concentrations. Since currently available clinical tests will continue to show decreased free T4 concentrations in patients taking phenytoin or carbamazepine, clinicians should rely on serum TSH measurements to confirm the euthyroid status of these patients.

Subclinical thyroid disease.

Widespread use of improved measurements for serum thyroid hormones and thyroid-stimulating hormone (TSH) has resulted in characterization of the syndromes of subclinical hypothyroidism, characterized by normal free T4 estimate and raised serum TSH, and subclinical hyperthyroidism, in which patients have normal serum free T4 estimate and decreased serum TSH. Therapy for these two disorders in generally recommended but must be individualized according to the patient's general medical condition. Additional studies are needed to assess the benefits of treatment. This report reviews subclinical hypothyroidism and subclinical hyperthyroidism, describing their causes, diagnostic criteria, complications, and indications for treatment. A brief review of testing for thyroid function is presented, and each of the subclinical disorders is compared with the classic syndromes of hypothyroidism and hyperthyroidism.

Down-regulation of type II L-thyroxine, 5'-monodeiodinase in cultured GC cells: different pathways of regulation by L-triiodothyronine and 3,3',5'-triiodo-L-thyronine.

The current consensus is that iodothyronines down-regulate type II T4 monodeiodinase (5'-DII) by an extranuclear acceleration of enzyme inactivation. We have investigated 5'-DII regulation in cultured GC cells, in which thyroid hormone responses are mediated by nuclear thyroid receptor (TR). GC cells actively converted T4 to T3, independent of propylthiouracil and with a Km of 1.4 nM, which are characteristics of 5'-DII. When GC cells were incubated with 10 nM T3, the Km was not affected. However, the maximum velocity was significantly down-regulated by 10 nM T3, from 0.15 to 0.018 pmol/mg protein.min. Dose-response studies showed that a 50% reduction in enzyme activity was achieved with either 0.25 nM T3 or 12 nM rT3. Time-course studies showed that a 50% reduction in enzyme activity occurred after 40 min of incubation with 100 nM rT3 and after 160 min of incubation with 10 nM T3. The down-regulation of 5'-DII by physiological concentrations of T3 has the characteristics of an effect that is mediated by nuclear TR. Our studies, therefore, suggest that down-regulation of 5'-DII by these iodothyronines in GC cells may occur by different mechanisms: enzyme inactivation for rT3, in agreement with the current consensus, and decreased enzyme production for T3, probably mediated by TR.

Congenital adrenal hyperplasia diagnosed in a man during workup for bilateral adrenal masses.

We studied an asymptomatic 55-year-old man who was found to have markedly enlarged adrenal glands on an abdominal computed tomographic scan and was scheduled to have adrenal biopsy because of suspicious findings on an adrenal magnetic resonance image. However, hormonal studies revealed congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Treatment with dexamethasone decreased the size of the adrenal glands. This is, we believe, the first report of congenital adrenal hyperplasia in an adult, diagnosed during the evaluation of an incidental adrenal lesion. Although congenital adrenal hyperplasia can present with varying severity and remain undiagnosed into adulthood, it is usually not considered in the evaluation of asymptomatic adult adrenal masses. We emphasize the need for proper hormonal studies in the evaluation of incidental adrenal lesions.

c-erb-A mRNA correlates with T3-receptor levels in liver and pituitary of tumor rats.

In the rat tumor model of the sick euthyroid syndrome, differential regulation of T3-induced cellular responses have been demonstrated in liver and anterior pituitary. These effects occur with a concomitant decrease in nuclear thyroid hormone receptor (TR) number as measured by the binding of 125I-labeled T3. To explore the possibility that these altered responses to T3 in tumor rats resulted from changes in the expression of different TR forms, we correlated the relative abundance of mRNAs encoding each receptor form with the concentration of TR measured by specific T3 binding. In anterior pituitary of tumor rats, TR beta-1 and beta-2 mRNA levels decreased to 51 and 45%, respectively, compared to controls; rat c-erb A alpha-2 mRNA, which encodes a TR-related DNA alpha-binding protein that does not bind T3, decreased to 46% of control. These findings correlate with a decrease in nuclear T3 binding capacity that has been shown to be 63% of control. The level of TR beta-1 mRNA, the only quantifiable TR form in liver, was decreased to 61% of control in the same hepatic tissue that revealed a 50% decrease in TR as measured by specific T3 binding. The coordinate down-regulation of all TR mRNA forms to a degree that parallels the decrease in TR number as measured by specific T3 binding suggests that the differential regulation of T3-mediated effects in illness is by a mechanism other than changing concentrations of specific receptor forms.(ABSTRACT TRUNCATED AT 250 WORDS)

Heat stress of cultured GC cells enhances triiodothyronine-induced growth hormone production by action within the 5'-flanking region of the rat growth hormone gene.

We studied the effect of incubation at 41 C on a clone of GC cells that had previously been stably transfected with a gene construct, pGHXGPT, containing -1800 to +8 of the rat growth hormone promoter fused to the structural gene for E. Coli xanthine guanine phosphoribosyl-transferase. The effect of incubation of the clone containing pGHXGPT at 41 C was to enhance triiodothyronine induction of growth hormone secretion (2-fold, p < 0.01) and of xanthine quanine phosphoribosyl-transferase activity (3-fold, p < 0.01). We conclude that the increase in triiodothyronine-induced growth hormone production during heat stress occurs by stimulation of the growth hormone promoter.

The effects of chronic exposure to supraphysiological concentrations of 3, 5, 3' triiodo-L-thyronine (T3) on cultured GC cells.

We have characterized the effects of supraphysiological concentrations of T3 on GC cells, a cultured cell line in which physiologic concentrations of T3 regulate cell growth, protein content, and growth hormone (GH) production. GC cells were exposed to 3 times (1.0 nM) and 80 times (25.0 nM) the physiologic concentration of T3 (0.3 nM) for either 4 d or for greater than 3 months. Both short and prolonged exposure to supranormal T3 concentrations supported maximal cell growth rate and induced significant increases in total protein (P less than 0.025) and GH production (P less than 0.01) per cell when compared to measurements in control GC cells. In addition, exposure to 1.0 nM and 25.0 nM T3 for greater than 3 months enhanced the toxicity of heat shock in a manner similar to previously described effects on GC cells due to T3 exposure of shorter duration. Thus, initial responses to raised T3 concentrations in cultured GC cells persisted without alteration when hormone exposure was prolonged for greater than 3 months.

Role of L-thyroxine in nuclear thyroid hormone receptor occupancy and growth hormone production in cultured GC cells.

The contribution of L-thyroxine (T4) to nuclear thyroid receptor occupancy was studied in GC cells incubated with concentrations of 3,5,3'-triiodo-L-thyronine (T3) and T4 that resulted in free iodothyronine levels similar to those in serum of euthyroid rats. T4 accounted for 5.4-10% of the occupied receptors: T3 derived from T4 [T3(T4)] and T3 added to medium accounted for the remainder of receptor occupancy. Incubation with increasing medium free T4 resulted in a progressive increase in the contribution of T4 and T3(T4) to receptor occupancy. In incubations with 3.6-fold increased medium free T4, T4 accounted for 20.4%, and T3(T4) for 40.3% of receptor occupancy. These occupancy data and the experimentally determined Ka of thyroid receptor for T3 and T4 allowed calculation of nuclear free iodothyronine concentrations. Nuclear free T3 was 3-6-fold greater than medium free T3 and nuclear [corrected] free T4 was 12-19-fold greater than medium free T4. When GC cells were incubated with decreased medium free T3 and physiological medium free T4, both nuclear receptor occupancy and growth hormone production decreased as well. However, a twofold increase in medium free T4, in the presence of decreased medium free T3, restored receptor occupancy and growth hormone production to or near control values. These findings establish a role for T4 in addition to T3(T4) in nuclear receptor occupancy and biological activity in rat anterior pituitary tissue both in physiologic conditions and when medium free T4 is raised. The findings may have relevance to the sick euthyroid thyroid syndrome in which free T4 may be increased in some patients who have decreased serum free T3.

Heat stress and hydrocortisone are independent stimulators of triiodothyronine-induced growth hormone production in cultured rat somatotrophic tumour cells.

We have reported that, in cultured GC cells, the stress of incubation at 41 degrees C enhances thyroid hormone stimulation of growth hormone (GH) in a manner similar to the effects observed in a model of nonthyroidal disease in rats. Since glucocorticoids are potentially involved in stress responses both in vivo and in cell culture, we studied the role of glucocorticoid in the enhancement of (which are rat somatotrophic tumor cells) triiodothyronine (T3)-induced GH synthesis due to heat stress. Hydrocortisone addition increased T3-induced GH synthesis and GH mRNA content in cultured GC cells at both 37 degrees C and 41 degrees C. Depletion of glucocorticoid endogenous to serum supplement of the tissue culture medium did not prevent the enhancement of T3-induced GH synthesis that occurred during incubation at 41 degrees C. The levels and affinity of glucocorticoid cytosolic receptors were not enhanced during incubation at 41 degrees C. Lastly, no change in the sedimentation coefficient of the cytosolic glucocorticoid receptor or in its translocation into the nucleus occurred during incubation at 41 degrees C. Thus, the enhancement of T3-induced GH production in GC cells by heat stress appeared independent of the effect of glucocorticoids and not mediated through glucocorticoid receptors.