A 2013 European survey of clinical practice patterns in the management of Graves' disease.

OBJECTIVE: Management of Graves' disease (GD) in Europe was published in 1987. Aim of this survey was to provide an update on clinical practice in Europe, and to compare it with a 2011 American survey. DESIGN: Members of the European Thyroid Association (ETA) were asked to participate in a survey on management of GD, using the same questionnaire of a recent American survey. RESULTS: A total of 147 ETA members participated. In addition to serum TSH and free T4 assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (85·6%) and thyroid ultrasound (70·6%) to confirm aetiology, while isotopic studies were selected by 37·7%. Antithyroid drug (ATD) therapy was the preferred first-line treatment (83·8%). Compared to the previous European survey, Europeans currently more frequently use TRAb measurement and thyroid ultrasound for diagnosis and evaluation, but first-line treatment remains ATDs in a similar percentage of respondents. Current clinical practice patterns differ from those in North America, where isotopic studies are more frequently used, and radioiodine (RAI) still is first-line treatment. When RAI treatment is selected in the presence of mild Graves' orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis is frequently used. The preferred ATD in pregnancy is propylthiouracil in the first trimester and methimazole in the second and third trimesters, similar to North America. CONCLUSIONS: Significant changes in clinical practice patterns in Europe were noted compared to the previous European survey, as well as persisting differences in diagnosis and therapy between Europe and North America.

Graves' ophthalmopathy: current concepts regarding pathogenesis and management.

Referring to the hyperadrenergic theory on the pathogenesis of Graves' ophthalmopathy, a 1934 JAMA editorial (513) stated "the mechanism of exophthalmos is well understood though the knowledge would seem to be poorly disseminated." Several subsequent theories on pathogenesis, stated equally emphatically, have experienced a similar fate to that prompting this remark, but not before negatively impacting upon the management of patients suffering from this disorder. Thus, it is with an element of caution that we conclude that the sequence of events contributing to the pathogenesis of Graves' ophthalmopathy has become progressively more lucid, due to the assiduous efforts of many investigators in this field. Demonstration of an inextricable link between the eye and the thyroid in Graves' ophthalmopathy seems limited only by our ability to detect subtle involvement of one or the other of these two organs in exceptional cases, although not all authors share this viewpoint (514). The factors modulating the degree of expression of the thyroid component, such as concurrent lymphocytic thyroiditis or qualitative differences in TRAb seem more tangible than those affecting the clinical expression of eye involvement. Environmental factors such as smoking are associated, to a degree that matches or surpasses that known for genetic predisposition to this disorder. Local anatomy, including such factors as vulnerability to obstruction of venous drainage, must play a role as evidenced by asymmetric eye involvement and rapid relief of inflammatory changes after orbital decompression surgery. The transition from palliative to curative measures in Graves' ophthalmopathy will require further advances in our understanding of the putative shared thyroid-eye antigens, demonstration that these antigens are etiologically important and concomitant advances in antigen-specific immune therapy.

The effect of antithyroid drug pretreatment on acute changes in thyroid hormone levels after (131)I ablation for Graves' disease.

Acute changes in thyroid hormone levels before and after radioiodine therapy for Graves' disease were compared in 42 patients randomized to receive either antithyroid drug pretreatment or no pretreatment. Five patients (11.9%), including 3 in the pretreatment arm and 2 in the no pretreatment arm experienced a late exacerbation of thyrotoxicosis after radioiodine therapy. The majority (19 of 21, 90.5%) of pretreated patients experienced a transient increase in free T(4) and free T(3) after discontinuation of antithyroid drugs, with little further elevation after radioiodine therapy. After stopping antithyroid drugs and before radioiodine administration, mean serum free T(4) values rose from 14.7 +/- 6.9 to 21.6 +/- 12.1 pmol/L, representing a 46.9% increase, whereas serum free T(3) levels rose from 4.9 +/- 1.7 to 8.1 +/- 6.3 pmol/L, representing a 65.3% increase. The average pretreated patient experienced a 52.4% increase [95% confidence interval (CI), +26.4% to +78.5%] in free T(4) and a 61.8% increase (95% CI, +23.5% to +100.0%) in free T(3). Conversely, the majority (19 of 21, 90.5%) of nonpretreated patients experienced a rapid decline in thyroid hormone levels after radioiodine treatment. Over the 14 days after radioiodine therapy mean free T(4) values in nonpretreated patients fell from 85.8 +/- 60.4 to 58.0 +/- 76.5 pmol/L, representing a 32.4% decrease, whereas mean free T(3) levels fell from 16.1 +/- 8.0 to 10.8 +/- 11.1 pmol/L, representing a 32.9% decrease. The average nonpretreated patient experienced a 20.6% decrease (95% CI, -47.3% to +7.0%) in free T(4) and a 24.3% decrease (95% CI, -1.2% to -47.4%) in free T(3) during this time period. Excluding 2 patients with a late exacerbation after radioiodine, 19 nonpretreated patients experienced a decrease in mean free T(4) values from 76.8 +/- 46.6 to 36.6 +/- 19.8 pmol/L, representing a 52.3% decrease, whereas mean free T(3) levels fell from 15.5 +/- 7.7 to 7.8 +/- 3.6 pmol/L, representing a 49.7% decrease. The average decrease in free T(4) levels among this subgroup of patients was 30.1% (95% CI, -4.6% to -55.6%), whereas the average decrease in free T(3) was 34.4% (95% CI, -13.7% to -55.1%). High levels of TSH receptor autoantibodies at diagnosis were associated with an acute worsening of thyrotoxicosis after stopping antithyroid drug pretreatment. We conclude that pretreatment with antithyroid drugs does not protect against worsening thyrotoxicosis after radioiodine, but may allow such patients to start from a lower baseline level should an aggravation in thyrotoxicosis occur. The findings support the recommendation that most patients with Graves' disease do not require antithyroid drug pretreatment before receiving radioiodine.

Thyrotropin receptor antisera for the detection of immunoreactive protein species in retroocular fibroblasts obtained from patients with Graves' ophthalmopathy.

Autoimmunity against the TSH receptor (hTSH-R) is known to be the proximate cause of thyroidal activation in Graves' disease, but has not been definitively linked to extrathyroidal manifestations of this disorder, such as ophthalmopathy and pretibial myxedema. In an effort to increase our knowledge concerning mechanisms responsible for Graves' ophthalmopathy, we used antiserum directed against a highly immunogenic portion of the hTSH-R (amino acids 352-367; P1) to assess the presence of this receptor or immunologically related protein in cultured human retroocular fibroblasts obtained from patients with Graves' ophthalmopathy. Immunoenzymatic and immunofluorescent studies revealed specific staining of both cytoplasmic and cell membrane-associated protein in discrete vesicles. To further evaluate the immunoreactive species present in these cells, immunoblotting experiments were performed using hTSH-R-specific antisera (anti-P1) and sera obtained from patients with Graves' disease. Several protein bands were identified using both anti-P1 and Graves' disease patient sera, including species at mol wt of 95, 71, and 18 kilodaltons, the possible significance of which is discussed. The results support the hypothesis that immunity against the hTSH-R or related proteins contributes to the ophthalmopathy of Graves' disease.

Expression polymerase chain reaction for the in vitro synthesis and epitope mapping of autoantigen. Application to the human thyrotropin receptor.

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.

Reactive hypoglycemic coma due to insulin autoimmune syndrome: case report and literature review.

Recurrent episodes of postprandial hypoglycemic symptoms culminated in hypoglycemic coma in a hypertensive but otherwise healthy man while he was taking hydralazine. The patient was found to have an extreme elevation in the immunoreactive insulin level, leading to the discovery of insulin antibodies in the absence of prior exposure to exogenous insulin. Negative results of an anatomic study of the pancreas and an inability to reproduce hypoglycemia during a prolonged fast helped to exclude insulinoma. In contrast, symptomatic hypoglycemia developed in response to oral glucose loading and was associated with an elevation in total and free insulin as well as C-peptide levels. The patient was diagnosed with insulin autoimmune syndrome, which, although a common source of hypoglycemia in Japan, has been well documented in only 15 cases from other countries. HLA typing revealed the patient to be positive for groups Cw4 and DR4, a combination that has been preliminarily associated with insulin autoimmune syndrome in Japan. Unlike the majority of cases previously reported, this patient had no clinical or serologic evidence of an underlying autoimmune disorder and had not been exposed to drugs containing sulfhydryl groups. This case adds to the world literature on insulin autoimmune syndrome, lends support to a postulated HLA association, and documents the presence of insulin autoantibodies in the absence of another underlying autoimmune disorder.

Evaluation and management of the solid thyroid nodule.

A tremendous effort has been applied to the determination of optimum management strategies in patients with solid thyroid nodules. The systematic acquisition of experience with historical and physical examination features suggestive of malignancy and the careful crafting of noninvasive techniques to assist in this determination have each contributed to improvements in the safety and cost-effectiveness of management in these patients. Despite this progress, significant difficulties await resolution, including the preponderance of patients still subjected to thyroidectomy for benign follicular lesions and the reluctance of clinicians to abandon the use of diagnostic techniques that offer little useful information, such as routine scintillation scanning and diagnostic trials of suppressive therapy. An exciting area now in its infancy is the identification of useful molecular markers for the selection of the few malignant thyroid nodules from among the multitudes of benign lesions. As is true in diagnostic evaluation, uncertainty continues to be experienced by clinicians charged with proper nonsurgical management of the solid thyroid nodule. The use of thyroid hormone suppressive therapy, once considered a cornerstone of conservative management, has been cast in a new light revealing both the limited utility and potential harm associated with this approach. These uncertainties should not be viewed as impediments, but rather, as opportunities for growth, as it is controversy rather than complacency that stimulates new investigation and fresh approaches to old problems.

Serum thyroglobulin measurement. Utility in clinical practice.

Serum thyroglobulin measurement has greatly facilitated the clinical management of patients with differentiated thyroid cancer and a variety of other thyroid disorders. Thyroglobulin autoantibodies remain a significant obstacle to the clinical use of thyroglobulin measurement. The interpretation of any given thyroglobulin value requires the careful synthesis of all pertinent clinical and laboratory data available to the clinician. The diagnostic use of rhTSH-stimulated thyroglobulin levels has greatly facilitated the follow-up of low-risk patients with thyroid cancer. Although the measurement of thyroglobulin mRNA from peripheral blood is likely to affect the future management of these patients, it is expected that serum thyroglobulin measurement will continue to have a principal role in the care of patients with differentiated thyroid cancer.

Life-threatening thyrotoxicosis. Thyroid storm.

Although important strides in recognition and therapy have significantly reduced the mortality in this disorder from the nearly 100% fatality rate noted by Lahey, survival is by no means guaranteed. More recent series have yielded fatality rates between 20% and 50%. Although some authors have attributed this improvement, in part, to a relaxation of the diagnostic criteria for thyroid storm, it more likely represents improvements in early recognition and the beneficial effects of the serial addition of antithyroid, corticosteroid, and antiadrenergic therapies to the treatment of this disorder. Thyroid storm is a dreaded, fortunately rare complication of a very common disorder. Most cases of thyroid storm occur following a precipitating event or intercurrent illness. Effective management is predicated on a prompt recognition of impending thyroid storm which is, in turn, dependent on a thorough knowledge of both the typical and atypical presentations of this disorder. An unwavering commitment to an aggressive, multifaceted therapeutic intervention as outlined herein is critical to the obtainment of a satisfactory outcome.

Progressive enzyme changes within anatomically defined segments of rabbit nephron: demonstration with a new technique.

The kidney is an extremely heterogeneous organ, with morphological, physiological, and metabolic changes occurring from segment to segment along each nephron. To determine the heterogeneity that might exist within discrete anatomical segments of rabbit nephron, we developed a technique for making quantitative enzyme assays in serial samples, about 100 micron long, along identified segments of the nephron. Results for three enzymes in proximal convoluted and straight tubules show that adenylate kinase, an enzyme of high-energy phosphate metabolism, gradually decreases along the S1 and S2 segments of the proximal tubule, with no abrupt changes. Fructose bisphosphatase, a gluconeogenic enzyme, is high along the major portion of the proximal tubule but plummets along the final millimeter of S3. Conversely, phosphofructokinase, a glycolytic enzyme, is very low along the proximal tubule but increases sharply within the final millimeter. These data underscore the biochemical heterogeneity of the nephron, illustrating the enzyme levels may change markedly even within anatomically defined regions. They also suggest the importance of further studies of this type and demonstrate a practical means for such studies.

The distribution of six enzymes of oxidative metabolism along the rat nephron.

Using quantitative methods, citrate synthase (CS), fumarase, beta-hydroxyacyl-coenzyme A (CoA) dehydrogenase (beta OAC), 3-keto-acid CoA transferase (KCT), malic dehydrogenase (MDH), and malic enzyme were measured in seven defined parts of the nephron and in thin limb and papilla areas dissected from freeze-dried microtome sections of rat kidney. The results not only show a wide range of activity along the nephron for each of the enzymes, but that the proportions between the enzymes vary markedly among the different parts of the nephron. This suggests the existence of major regional differences in the capacity to oxidize specific metabolites. The ratio between two citrate cycle enzymes, fumarase and CS, was 4- or 5-fold higher in proximal segments than in the glomerulus or thin limb areas. The ratio between beta OAC (an enzyme of fatty acid oxidation) and CS was 3- to 5-fold higher in the middle proximal segments than in glomeruli or thin limb and papilla areas. The key enzyme for ketone body metabolism, KCT, was essentially confined to the thick tubule segments. Malic enzyme, in contrast to the other five enzymes, was highest in the proximal straight segments. New methods, sufficiently sensitive for this histochemical study, are described for malic enzyme and 3-keto-acid CoA transferase.

Distribution of two aminotransferases and D-amino acid oxidase within the nephron of young and adult rats.

In the adult rat kidney, alanine aminotransferase (EC 2.6.1.2), aspartate aminotransferase (EC 2.6.1.1) and D-amino acid oxidase (EC 1.4.3.3) were measured in glomeruli, 4 parts of the proximal tubule, 2 parts of the distal tubule and in patches from the thin limb area and the papilla. These enzymes were measured in more limited parts of the nephron during postnatal development. Adult aspartate aminotransferase activities (percentage of the highest) ranged from 100 in the distal straight segment to 25 in the late part of the proximal straight segment to 10 in the thin limb and papillary area. Alanine aminotransferase (lower by a factor of 100 in absolute terms) was distributed as the mirror image of aspartate aminotransferase within proximal and distal tubules. D-Amino acid oxidase was 850-fold higher in proximal straight segments than in medullary structures. During development alanine aminotransferase increased 6-fold and D-amino acid oxidase, 4.5-fold in proximal straight tubules but aspartate aminotransferase increased in distal straight tubles 8-fold.

Immunoglobulins from Graves' disease patients stimulate phospholipase A2 and C systems in FRTL-5 and human thyroid cells.

We have studied the effects of immunoglobulin G from Graves' disease patients on phospholipase A2 (PLA2) and C(PLC) systems in FRTL-5 and human thyroid cells. Immunoglobulin G (IgG) from Graves' disease patients stimulated arachidonic acid (AA) release in a time- and dose-dependent manner. In FRTL-5 thyroid cells, removal of external calcium had no significant effect on the IgG (20 micrograms/ml)-induced AA release in FRTL-5 thyroid cells. U-73122 (3 mumol/l), a PLC inhibitor, and quinacrine (100 mumol/l) but not U-26384 (5 mumol/l), PLA2 inhibitors, blocked the IgG-induced (20 micrograms/ml) AA release in FRTL-5 thyroid cells. Immunoglobulin G (100 micrograms/ml) also stimulated accumulation of inositol-1,4,5-triphosphate (IP3) in a time- and dose-dependent (20-300 micrograms/ml) manner in FRTL-5 cells. Immunoglobulin G from Graves' disease patients induced a significant increase of IP3 production (p = 0.01) compared to IgG from normal subjects. Removal of external calcium had no significant effect on the IgG-induced IP3 production. The PLC inhibitor U-73122 completely blocked IgG-induced IP3 production from FRTL-5 thyroid cells. Also, in human thyroid cells, IgG from Graves' disease patients induced a significant increase of AA release (p = 0.001) and IP3 production (p = 0.004) compared to the IgG from normal subjects. These data indicate that IgG from Graves' disease patients induced PLA2 activity that was PLC dependent, a pattern referred to as sequential activation. Our studies suggest that IgG from Graves' disease patients activates PLA2 and PLC systems in FRTL-5 and human thyroid cells. These signal transduction pathways could be involved in the pathogenesis of Graves' disease and future studies are warranted to investigate this area.

Analysis of human TSH receptor gene and RNA transcripts in patients with thyroid disorders.

Human TSH receptor (hTSH-R) gene and RNA transcripts were analyzed by Southern and Northern blots in patients with various thyroid disorders, and in tissue cell lines. A 1.4 Kb cDNA encoding the extracellular human TSH-R domain was used as a probe. Southern analysis revealed two constant bands of 11.0 and 5.0 Kb (hTSH-R) in the thyroid and human white cell samples studied, regardless of the disease process. Northern analysis showed a predominant band at about 4.4 Kb in the thyroid tissues but not in non-thyroid tissue or cell lines tested. There were no gene rearrangements or abnormal transcripts in Graves' disease or multinodular goiter samples. In contrast, the labelled cDNA TSH-R probe did not bind to RNA isolated from 1 of 2 papillary cancer samples. A portion of the unique area of the h-TSH receptor (approximately nucleotides 1100-1230) was directly sequenced in thyroid glands from patients with Graves' disease, multinodular goiter, and differentiated thyroid cancer. No mutations or polymorphisms were identified in these samples, as compared to normal thyroid or control placenta, although further definition of sequence variation in other areas of the TSH receptor, as well as in more samples, needs to be performed. The present study indicates the normal patterns of DNA and RNA hybridization in a variety of thyroid tissues and disease states, and demonstrates that pathologic thyroid samples, with the possible exception of thyroid cancer, were not associated with specific nucleotide abnormalities in the unique area of the TSH receptor that was studied.

Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration.

The application of fine-needle aspiration (FNA) to the evaluation of the thyroid nodule has greatly enhanced the ability of the clinician to appropriately select patients for thyroidectomy. However, despite extensive experience with thyroid FNA, the cytological distinction of benign from malignant follicular neoplasia remains problematic. As a result, most patients with FNA findings of a follicular neoplasm are referred for thyroidectomy. The goal of the present study was to develop clinical criteria capable of predicting malignancy in patients with an FNA diagnosis of follicular neoplasm. Among 1121 patients undergoing thyroid FNA at two large teaching centers during the period 1990 to 1995, 149 patients had cytological findings consistent with a follicular neoplasm. Among 103 patients referred for thyroidectomy, 22 (21%) were found to have a malignancy in the biopsied nodule. Among patients subjected to thyroidectomy, the risk of malignancy was significantly higher when follicular neoplasia was present in a male (43% vs. 16% for females, p = 0.007), when the nodule was greater than 4 cm to palpation (40% vs. 13% for nodules less than 4 cm, p = 0.03), or when the nodule was judged to be solitary by palpation (25% vs. 6% for a dominant nodule in a multinodular goiter, p = 0.02). Bayesian analysis of the data reveals that after an FNA showing a follicular neoplasm, the risk of malignancy in males with large nodules was nearly 80%, compared with a rate of only 3% in females with small nodules. These results suggest that clinical features including gender, nodule size, and character of the gland by palpation can be systematically integrated into the decision analysis, thereby improving the selection of patients for surgical referral.

Diagnosis and management of the autonomously functioning thyroid nodule: the Walter Reed Army Medical Center experience, 1975-1996.

In order to characterize the clinical and laboratory features of autonomously functioning thyroid nodules (AFTNs), and to assess optimal diagnosis and management of patients with this disorder, we performed a retrospective analysis of 49 such patients over a 22-year period encompassing January 1975 to November 1996. The following data were analyzed: thyroid hormone levels, thyroid scintiscan, radioiodine uptake, fine-needle aspiration biopsy, triiodothyronine (T3) suppression testing, thyrotropin-releasing hormone (TRH) stimulation test, and thyroid ultrasound. Clinical outcomes assessed included persistent hyperthyroidism, hypothyroidism, and nodule shrinkage after treatment, or in patients followed without definitive therapy, nodule growth, spontaneous degeneration, and progression to hyperthyroidism. Biochemical hyperthyroidism, often subclinical, was found in 73.5% of patients at presentation and in an additional 24.4% of patients during subsequent follow-up. The introduction of sensitive thyrotropin (TSH) testing during the period of study resulted in a decrease in the use of the T3-suppression test and TRH stimulation test from 100% and 20%, respectively, in the period from 1976-1980, to 4% each in the period from 1991-1996. T3-thyrotoxicosis occurred in 12.2% of patients. Thyrotoxicosis at any time during the course of follow-up was positively correlated with nodule size at diagnosis. Definitive therapy, used in 42.8% of patients, consisted of radioiodine ablation (38.1%) or thyroidectomy (61.9%). No patient had recurrence of thyrotoxicosis after definitive therapy, but 25% became hypothyroid. During follow-up for a mean of 30.9 months, nodules enlarged in 25% of patients overall, or 33% of patients not receiving definitive therapy. Cystic degeneration was documented in 26.5% of patients, although this change rarely reversed subclinical hyperthyroidism. The diagnosis of an AFTN requires a demonstration of TSH-independent nodular hyperfunction. The introduction of sensitive TSH assays has simplified the evaluation of AFTN patients and revealed a high prevalence of subclinical thyroid hyperfunction in this disorder. In view of current increased awareness of adverse consequences associated with subclinical hyperthyroidism and the rarity of spontaneous resolution of hyperthyroidism in AFTN patients (despite a propensity for spontaneous hemorrhage), definitive therapy is recommended. Both radioiodine and hemithyroidectomy have high cure rates and a low posttreatment incidence of hypothyroidism.

Lymphocytes express thyrotropin receptor-specific mRNA as detected by the PCR technique.

Human lymphocytes are known to play a critical role in autoimmune diseases both by producing antibodies and by participating in lymphokine-cellular interactions. TSH, a classic pituitary hormone, may be secreted by human lymphocytes, and controversy has existed whether a specific, authentic TSH receptor also was present on the surface of these cells. The objective of our study was to identify TSH receptor transcripts after designing specific oligonucleotides that would recognize a unique putative TSH binding area of the thyroidal TSH receptor. The existence of TSH receptor transcripts was probed by employing these primers in a PCR reaction with cDNA derived from normal peripheral human lymphocytes and human thyroid tissue, as well as with cDNA from a medullary cancer cell line and rat liver. Human lymphocytes and thyroid tissue, but not medullary cancer cells or rat liver, demonstrated specific TSH receptor amplification product both by ethidium bromide staining and by Southern blot hybridization with labeled TSH receptor cDNA. The lymphocyte cDNA was partially sequenced and found to be identical to the thyroid-derived cDNA. These findings indicate that normal, nonactivated, human lymphocytes produce transcript for a TSH receptor that appears identical to that in thyroid tissue. Future studies should focus on the regulation of this transcript, as well as on the role TSH and TSH receptor may play in modulating local lymphokine activation of T and B cells, both in normal conditions and in autoimmune thyroid disease.

Thyroid cancer yield in patients with Graves' disease.

The management of thyroid nodules in patients with Graves' disease remains an issue both of concern and controversy for those who care for these patients. At one time, thyroid cancer in patients with thyrotoxicosis was considered to be extremely rare, but this perception has proven to be incorrect. Several studies have demonstrated both an increased incidence of nodules and of thyroid cancer in patients with Graves' disease, with cancer rates varying from as low as 1% to as high as 9% of cases. These divergent estimates of malignancy rates in Graves' disease have predictably led to variability in management recommendations. Considerable controversy also exists as to whether or not thyroid cancer behaves more aggressively in patients with Graves' disease. Anecdotal experience and a number of studies have suggested an increased aggressiveness of papillary and follicular thyroid cancer in patients with Graves' disease, but these findings are not universal. Underlying both issues of the incidence and aggressiveness of thyroid cancer is the role of thyrotropin (thyroid stimulating hormone, TSH) in the development and stimulation of thyroid cancer. The association between TSH and thyroid cancer has long been known. TSH has a central role in thyroid growth and normal functioning and appears to play a similar part in the growth and development of thyroid cancer. The close relationship of TSH to the stimulating TSH-R antibodies (TSH-R AB) seen in Graves' disease has led to the perception that thyroid cancer occurring in the setting of Graves' disease may become more aggressive as a result of stimulation by these autoantibodies. This article will summarize the existing literature pertaining to thyroid cancer in Graves' disease, and suggest an evidence-based approach to the management of these patients.

Nuclear localization of thyroid transcription factor-1 correlates with serum thyrotropin activity and may be increased in differentiated thyroid carcinomas with aggressive clinical course.

Thyroid transcription factor 1 (TTF-1) is essential for thyroid differentiation and regulates expression of thyroglobulin, thyroid peroxidase, sodium/iodide symporter, and thyrotropin receptor (TSH-R) genes. Because thyrotropin (TSH) upregulates these same genes, we hypothesized TSH-R activation might increase TTF-1 and that TTF-1 might be differentially expressed in benign and malignant thyroid disease. TTF-1 expression and sub-cellular localization were determined by immunohistochemistry in 62 thyroid carcinomas, 15 benign lesions, and 2 normal thyroids. Nuclear TTF-1 was detected in benign (77%) and malignant lesions (69%), with similar intensity in both (1.1+/-0.19 versus 1.0+/-0.10). Nuclear TTF-1 staining correlated with the effective serum TSH level (p = 0.02) and patient age (p < 0.05). Nuclear TTF-1 was detected in 35 papillary thyroid carcinomas (PTC), of which 23% developed recurrent or persistent disease, and was absent from 18 PTC, of which only 6% recurred (p = 0.06). We conclude that nuclear TTF-1 correlates with serum TSH activity, increases with age, and may be increased in persistent or recurrent PTC.

Fine needle aspiration of thyroid nodules. Determinants of insufficiency rate and malignancy yield at thyroidectomy.

OBJECTIVE: To evaluate patient- and practice-specific determinants of the thyroid nodule fine needle aspiration (FNA) insufficiency rate and malignancy yield at a tertiary-care teaching hospital. STUDY DESIGN: All FNAs of thyroid nodules performed from August 1990 to October 1993 at the Walter Reed Army Medical Center Endocrinology Clinic were reviewed and the results analyzed for correlation with surgical outcome, scintiscanning result and operator experience. Provider-specific factors influencing the FNA insufficiency rate, surgical referral pattern and malignancy yield were evaluated. RESULTS: A total of 504 aspirations in 422 patients with thyroid nodules were included in the analysis. The sensitivity of FNA for detecting malignancy was 80%, specificity was 73.2%, and accuracy was 75.2%. A significant negative correlation was found between recent aspirator experience and the insufficiency rate. Repeat aspiration of nodules previously yielding benign cytology increased the malignancy yield. Surgical excision of nodules with insufficient aspirations gave a low malignancy yield, and aspiration of nodules that were "hot" on scintiscanning rarely yielded false positive FNA results. CONCLUSION: Specific limitations of thyroid nodule FNA include a large number of aspirates containing insufficient cytologic material and a variable malignancy yield. Specific recommendations based on the findings in this report are: the establishment of uniform criteria for judging specimen adequacy, the performance of repeat aspiration on thyroid nodules with previously benign aspirates, the abandonment of scintiscanning in the routine management of thyroid nodules and a conservative approach to clinically indolent nodules repeatedly found to have scant cellularity on FNA. Based on these findings, an algorithm for the diagnostic evaluation of a solid thyroid nodule can be constructed.