Biomedical subjects
Publications and source records attributed to L Wartofsky.
Antithyroid drugs induce sustained remission in only 55% of cases. Radioiodine, the overwhelming choice of specialists, may pose risks, including aggravation of ophthalmopathy. Surgical ablation should be considered only if a highly skilled surgeon is available. Thyroid storm requires aggressive management, and definitive treatment is needed for toxic adenoma or toxic multinodular goiter.
This article discusses several unusual forms of primary thyroid neoplasms. The TCV of PTC and insular thyroid carcinoma appears to have a more aggressive clinical behavior than DTC in most patient groups and may respond to thyroid hormone suppression and radioiodine. Anaplastic thyroid carcinoma, which may develop from differentiated thyroid tumors, has a poor prognosis which may be altered by surgery and radiation therapy but not typically by radioiodine and thyroid hormone suppression. Primary squamous cell carcinoma of the thyroid is an unusual entity that may be associated with a clinical syndrome that includes leukocytosis, fever, and hypercalcemia. Primary thyroid lymphoma is frequently associated with Hashimoto's thyroiditis and should be considered especially in older patients with rapidly enlarging thyroid masses. Although there are no studies assessing this issue, it seems reasonable that patients who have undergone thyroidectomy for neoplasms of thyroid cells that are poorly differentiated and do not concentrate radioiodine (e.g., squamous cell, anaplastic) should receive sufficient thyroid hormone suppression, if tolerated, to reduce TSH (third-generation assay) to approximately 0.1 to 0.3 mu U/mL, because TSH may be a growth factor. If, however, the tumor concentrates or responds to radioiodine, suggesting more differentiated cells (e.g., TCV, insular carcinoma), the target TSH level (third-generation assay) should range from 0.01 to 0.1 mu U/mL, as tolerated. Patients with primary thyroid neoplasms arising from cells other than thyrocytes (e.g., lymphoma) can be maintained at a TSH level of 0.5 to 1.5 mu U/mL. Our conclusions and analyses are often based upon small, retrospective, poorly controlled reports, and further studies are required to allow a better understanding of the evaluation and treatment of these neoplasms.
Clinical members of the American Thyroid Association were surveyed in regard to their diagnostic assessment, treatment, and long term assessment of differentiated papillary thyroid carcinoma. For a 39-yr-old female with a 2-cm solitary nodule and no history of radiation (index patient), respondents were asked to provide their preferences for diagnostic evaluation, treatment assuming a papillary carcinoma was focal, and follow-up. Of 408 surveys mailed, 233 (57.1%) were analyzed. Diagnostic studies included thyroid scan (56%), fine needle aspiration (96%), total serum T4 (49%), and third generation TSH (56%). Treatment included surgery (99%), with 86% preferring near-total/total thyroidectomy. After surgery, 61% recommended 131I ablation; long term therapy using L-T4 alone was recommended by 97%, with most preferring suppression to a target TSH level of less than 0.01 microIU/mL (22%), 0.01-0.05 (38%), or 0.06-0.50 (32%). For variations from the index patient, respondents' treatment were not different for a history of radiation, age of either 16 or 60 yr, nodule size of 1.5 cm, male sex, the presence of less than 1-cm multiple foci in the contralateral lobe, or capsular invasion of the nodule. Treatment and follow-up did change if there was blood vessel invasion or distant metastasis. In summary, our survey indicated consensus on diagnostic assessment of the index patient by fine needle aspiration and management by surgery and 131I therapy. However, management varied widely for the ablative dose of 131I, the target TSH level after ablation, and the frequency and type of follow up.
Aspects of the incidence and demographics of common thyroid disorders in the US (and elsewhere, to a lesser extent) are reviewed. The impact of healthcare reform and the efforts of managed care organizations to impose cost-effective management for the diagnosis and treatment of thyroid disorders are bringing unusual pressures to bear on both clinical laboratories and practicing endocrinologists. I discuss the potential dangers of utilization of suboptimally focused diagnostic approaches and of the inefficiencies in clinical management by primary-care providers, who often lack sufficient expertise, as opposed to endocrinologists. More than dollars are at stake, and the suboptimal management of common thyroid disorders presents several significant risks. Finally, I propose a general blueprint for the ongoing development of a structure for continuing quality improvement of the laboratory and clinical diagnosis, treatment, and long-term follow-up of patients with thyroid disease.
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OBJECTIVE: To determine the relative effects on thyroid hormone levels of discontinuing antithyroid drug therapy and subsequent ablation with radioiodine in patients with hyperthyroid Graves disease. DESIGN: A clinical trial with a prospective analysis of the relative change in thyroid hormone levels over time in response to therapy in two study groups. SETTING: An outpatient endocrine clinic at a tertiary care hospital. PATIENTS: 21 patients with a clinical diagnosis of hyperthyroid Graves disease scheduled to receive ablation therapy with radioiodine (131I): 17 patients were pretreated with antithyroid drugs, and 4 were not. METHODS: Antithyroid drugs were stopped 6 days before radioiodine therapy. Patients were monitored clinically and biochemically with measurement of free and total levels of thyroxine (T4) and triiodothyronine (T3) on days -6, -3, -1; the day of radioiodine therapy; and days 1, 2, 3, 4, 5, 7, and 14. RESULTS: Before radioiodine treatment and compared with baseline measurement, the mean increase in free T4 levels after discontinuation of antithyroid therapy was 86% (95% CI, 16.1% to 156%), with a concurrent mean increase in free T3 levels of 71.6% (CI, 31% to 112%). Radioiodine therapy resulted in a mean decrease in free T3 levels of 28.7% (CI, -44.1% to -13.2%), a mean decrease in total T3 levels of 22.9% (CI, -39.4% to -6.4%), and stability in free and total T4 levels rather than aggravation of thyrotoxicosis. A smaller group of patients not receiving antithyroid drugs experienced a course qualitatively similar to that of pretreated patients after 131I treatment, with a mean reduction in free T4 levels of 39.8% (CI, -69.9% to -9.7%) and a mean decrease in free T3 levels of 49.4% (CI, -93.7% to -5.1%). CONCLUSION: Short-term increases in thyroid hormone levels in patients with Graves disease receiving radioiodine ablation occur primarily as a result of discontinuing antithyroid therapy rather than as a result of treatment with 131I. Stability or decrease in thyroid hormone levels, rather than further elevation, occurs during the 2-week interval after ablation therapy with 131I. Antithyroid drug therapy before radioiodine ablation may have little effect on the short-term biochemical course after 131I therapy for Graves disease. The homogeneity of our sample regarding age, diagnosis, and general health may prevent application of these findings to other populations without further study.
Reports of reduced bone mineral density (BMD) in patients receiving long-term replacement and suppression therapy with L-thyroxine have generated considerable interest and controversy. A substantial literature has evolved, with interpretation of conflicting results obscured by a variety of confounding factors. We examined the BMD measurements of 202 white women who were taking thyroid hormone to determine the contribution to BMD of a number of clinical characteristics and parameters associated with thyroid hormone therapy. Measurements of BMD (N = 335 over 2.6 +/- 1.6 years) of the spine (L2-L4) were performed in 195 subjects. The BMD of three sites of the hip was measured (N = 247 over 1.8 +/- 1.1 years) in 157 subjects. The BMD of the proximal radius was also measured (N = 172 over 1.8 +/- 1.2 years) in 124 subjects. Increasing age and a history of previous thyrotoxicosis had a deleterious effect on spine BMD. Body mass index (BMI) was positively correlated with spine BMD. Dose of thyroid hormone, duration of therapy, type of underlying thyroid disease, history of thyroidectomy, or serum-free thyroxine index did not influence either the initial BMD or the change in spine BMD over time. In the hip, age correlated with a decrease, and BMI with an increase in BMD. A history of previous thyrotoxicosis was associated with a decrease in hip BMD at all three sites (0.05 < p < 0.10). No other clinical parameters significantly influenced either the initial BMD or the change in hip BMD over time. Increasing age and dose of thyroid hormone, and a prior history of thyrotoxicosis had a deleterious effect on the BMD at the proximal radius. In summary, thyroid hormone therapy was not associated with a significant effect on BMD of the spine or hip, but a decreased BMD of the proximal radius was related to both previous thyrotoxicosis and to dose of thyroid hormone.
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The clinical applicability of a newly described polymerase chain reaction directed protein expression system was assessed for the in vitro synthesis and partial epitope mapping of large radiolabeled human thyrotropin receptor (hTSH-R) protein segments. PCR amplification of targeted regions within the hTSH-R cDNA followed by in vitro transcription and translation permitted rapid synthesis of protein segments ranging in size from 18 to 62 kDa. Initial epitope mapping was directed at a 52 amino acid segment unique to the hTSH-R compared to otherwise homologous glycoprotein hormone receptors. Sera from Graves' disease patients known to have autoantibodies against the hTSH-R were used to immunoprecipitate two protein fragments differing only by the presence of the unique region in the larger fragment (E5) but not in the smaller fragment (E4). Dense precipitation bands were obtained using Graves' sera to immunoprecipitate E5 whereas little or no specific immunoprecipitation of E4 occurred. Normal sera gave only weak immunoprecipitation bands of E5. The technique provides significant advantages over conventional cloning methods and should have general applicability in the study of other protein targets of autoimmune disease.
We interviewed 300 white postmenopausal women (160 with thyroid disease, 140 without thyroid disease) to investigate whether having thyroid disease or taking thyroid hormone increased the prevalence of having a hip, vertebral, or forearm fracture. Thirty-seven (23%) women with thyroid disease and 45 (32%) women without thyroid disease had had a fracture, and there were no significant differences between these groups in the number or type of fractures. Dose of thyroid hormone and duration of therapy or disease did not affect fracture occurrence in women with thyroid disease. Women with a history of hyperthyroidism (9 of 32) or thyroid cancer (2 of 11) appeared to have their first fracture earlier (p < 0.01) than women without thyroid disease. In summary, women taking thyroid hormone for a variety of thyroid disorders do not appear to have an enhanced prevalence of a hip, vertebral, or forearm fractures, but women with a history of hyperthyroidism may have a propensity for their fractures to occur earlier in life.
In spite of an experience of almost 50 years of use of antithyroid drugs and radioiodine for the treatment of Graves' disease, the rationale for choice is often obscure. Early reports of high remission rates during thiourea therapy were followed by less optimistic ones, which along with other factors may have fueled the current major shift toward use of radioiodine. This review examines whether or not the use of antithyroid drugs indeed may have become obsolete. The intrathyroidal and extrathyroidal mechanisms of action of the drugs are reviewed with emphasis on their potential immunosuppressive effects. The latter may involve a direct effect on thyroid follicular cells, a direct suppression of TSH receptor antibody formation, or indirect effects mediated via heat shock proteins, oxygen free radicals, and the immune system. Potential factors associated with success or failure with antithyroid drug therapy are discussed, such as the effects of dose and duration of treatment, iodine milieu, and concomitant L-thyroxine therapy. The risks inherent to radioiodine therapy are only briefly described with emphasis on the possible aggravation by radioiodine of preexistent ophthalmopathy. The reader must decide whether the evidence marshalled convincingly indicates that the use of the thiourea compounds should be abandoned. The author thinks not, and is optimistic that imminent discovery of the yet elusive and enigmatic pathogenesis of Graves' disease will permit new and innovative treatment or more effective use of currently available therapies.
Production of neuroendocrine peptides by human lymphocytes is thought to facilitate control of the immune response. The presence of neuroendocrine peptide gene expression, specifically the TSH beta subunit gene, was studied in human lymphocytes using Northern blot analysis and polymerase chain reaction (PCR) techniques. Northern blot analysis of human lymphocyte RNA probed with a TSH beta cDNA probe failed to demonstrate TSH beta subunit steady state message levels. PCR amplification of lymphocyte-derived cDNA using TSH beta subunit complementary primers resulted in amplification of a .38 Kb DNA fragment, confirming expression and initial exonic splicing of TSH beta subunit gene exons 2 and 3 in human lymphocytes. Sequence analysis of this .38 Kb DNA fragment demonstrated conservation of exon borders after splicing (exons 2 and 3) and predicted an amino acid translation product similar, if not identical, to human TSH beta peptide sequence. Hybridization with a TSH beta subunit cDNA probe of PCR-amplified reverse-transcribed lymphocyte RNA suggested that: (1) the abundance of TSH beta subunit gene transcripts in human lymphocytes is less than the relative abundance in T3-treated pituitary; and (2) this messenger RNA may be modulated by the presence of certain thyromimetic compounds (T2, T3, TRIAC).