Henry B. Burch

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.

Expression of the Sodium Iodide Symporter and Thyroglobulin Genes Are Reduced in Papillary Thyroid Cancer

Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 ± 41 picogram equivalents [pg Eq]), than did benign nodules (829 ± 385 pg Eq), or normal tissues (1907 ± 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40–96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2–96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 ± 245 pg Eq vs. 1854 ± 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.

The Utility of Serum Thyroglobulin Measurement at the Time of Remnant Ablation for Predicting Disease-Free Status in Patients with Differentiated Thyroid Cancer: A Meta-Analysis Involving 3947 Patients

CONTEXT Decisions regarding initial therapy and subsequent surveillance in patients with differentiated thyroid cancer (DTC) depend upon an accurate assessment of the risk of persistent or recurrent disease. OBJECTIVE The objective of this study was to examine the predictive value of a single measurement of serum thyroglobulin (Tg) just before radioiodine remnant ablation (preablation Tg) on subsequent disease-free status. DATA SOURCES Sources included MEDLINE and BIOSYS databases between January 1996 and June 2011 as well as data from the authors tertiary-care medical center. STUDY SELECTION Included studies reported preablation Tg values and the outcome of initial therapy at surveillance testing or during the course of long-term follow-up. DATA EXTRACTION Two investigators independently extracted data and rated study quality using the Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews-2 (QUADAS-2) tool. DATA SYNTHESIS Fifteen studies involving 3947 patients with DTC were included. Seventy percent of patients had preablation Tg values lower than the threshold value being examined. The negative predictive value (NPV) of a preablation Tg below threshold was 94.2 (95% confidence interval = 92.8-95.3) for an absence of biochemical or structural evidence of disease at initial surveillance or subsequent follow-up. The summary receiver operator characteristic curve based on a bivariate mixed-effects binomial regression model showed a clustering of studies using a preablation Tg below 10 ng/ml near the summary point of optimal test sensitivity and specificity. CONCLUSION Preablation Tg testing is a readily available and inexpensive tool with a high NPV for future disease-free status. A low preablation Tg should be considered a favorable risk factor in patients with DTC. Further study is required to determine whether a low preablation Tg may be used to select patients for whom radioiodine remnant ablation can be avoided.

The Impact of Thyroid Nodule Size on the Risk of Malignancy and Accuracy of Fine-Needle Aspiration: A 10-Year Study from a Single Institution

BACKGROUND False-negative rates for thyroid fine-needle aspiration (FNA) vary from 0.4% to 13%, but the effect of nodule size on the accuracy of thyroid FNA remains controversial. We hypothesized that large thyroid nodule size does not contribute to the risk of malignancy or the risk of a false-negative FNA. METHODS All thyroid FNAs performed at the Walter Reed Army Medical Center during September 2001-August 2011 were reviewed. A strict correlation between the biopsy site, location, and size of nodule on ultrasound (US) and pathology report was ensured. FNA results were classified as benign, atypical, follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), suspicious for malignancy (SM), or malignant, and the pathology result was categorized as either benign or malignant. Nodules were analyzed by size: 0.5-0.9 cm (group A), 1.0-3.9 cm (group B), and ≥ 4 cm (group C). Incidental thyroid cancer was not included. RESULTS Of 3013 patients undergoing FNA, 667 (22.1%) had surgery. Patients were excluded for nodules <0.5 cm, nondiagnostic FNA, or no preoperative US, leaving 540 patients with 695 nodules. Among patients referred for surgery, FNA results were benign in 417 nodules (60%), atypical in 22 (3.2%), FN/SFN in 122 (17.6%), SM in 77 (11.1%), and malignant in 57 (8.2%). Postoperative malignancy rates by FNA result were 7% if benign, 4.5% if atypical, 23% if FN/SFN, 33.8% if SM, and 78.9% if malignant. FNA accuracy was 60% in group A, 68.5% in group B, and 80.3% in group C (p=0.01). False-negative rates for FNA were 7.0% overall, 15.8% in group A, 6.3% in group B, and 7.1% in group C (p=0.25). Sensitivity and negative predictive value were highest in group B at 81.6% and 93.7%, respectively. The prevalence of malignancy was not different between groups. CONCLUSION Our results show that the thyroid nodule size ≥ 4 cm increases neither the risk of false-negative FNA results, nor the overall risk of malignancy. We also show a tendency toward a higher false-negative rate in subcentimeter nodules. We conclude that a large nodule size should not prompt automatic referral for thyroidectomy. An increased awareness of potential sampling error in subcentimeter nodules is warranted.

TSH receptor gene expression in retroocular fibroblasts

RNA was isolated from fibroblasts from the retroocular area, from endomysial fibroblasts obtained from orbital lateral rectus muscle, and from abdominal skin fibroblasts. The RNA was reverse transcribed into cDNA which was then used as a template for PCR with primers encompassing a portion (nucleotides 989–1235) of the extra-cellular domain of the human TSH receptor (hTSH-R). A definite 247 BP product was detected from fibroblast RNA by ethidium bromide staining, and was confirmed by hybridization with labelled hTSH-R cDNA. The product had homology with the known TSH-R cDNA. These studies indicate that human fibroblasts can express hTSH-R, and they suggest that a cross reactive immunologic response between anti-hTSH-R and these fibroblast TSH receptors may play a role in the genesis of Graves’ ophthalmopathy.

Discontinuing Antithyroid Drug Therapy before Ablation with Radioiodine in Graves Disease

Table. SI Units and Abbreviations Radioactive iodine has been used to treat hyperthyroidism associated with Graves disease for nearly 50 years [1]. The efficacy, safety, and low cost of this therapy have made it the preferred definitive treatment in most patients with this disorder [2]. Radioiodine (Iodine-131) produces an intense radiation thyroiditis followed by progressive interstitial fibrosis and glandular atrophy, resulting in the destruction of the synthetic capacity of the gland [3]. Thyroiditis after Iodine-131 therapy is believed to peak between 10 and 14 days after ablation and may be associated with an exacerbation of hyperthyroidism as early as 1 to 7 days after therapy [4-6]. This exacerbation has been presumed to be caused by the release of hormones from the damaged thyroid and may occasionally be of sufficient severity to precipitate a life-threatening thyroid crisis or storm [6, 7]. Concern over the rapid release of glandular hormone stores after Iodine-131 ablation represents a rationale for adjunctive therapy with antithyroid drugs before or after ablation, a practice adhered to by 20% to 40% of thyroidologists according to a recent international survey [2]. However, because these agents inhibit the organification of iodine within the thyroid, they may limit the effectiveness of radioiodine therapy and therefore are generally stopped 4 to 7 days before treatment with Iodine-131 [8]. The discontinuation of antithyroid therapy might be expected to be associated with a rebound in thyroid hormone synthesis, such as to exacerbate thyrotoxicosis; in fact, discontinuation of antithyroid therapy is a frequently cited but probably rare precipitant of thyroid storm [7, 9, 10]. To the best of our knowledge, a systematic study of short-term changes in thyroid hormones after discontinuation of antithyroid therapy has not been previously published. Little information exists regarding short-term changes in thyroid hormones after administration of Iodine-131. Further, the existing literature in this area provides conflicting information: Some studies show short-term elevation in thyroid hormones after Iodine-131 therapy [11-13], others show no consistent short-term changes in hormone levels [14, 15], and still others show short-term decreases in these levels after radioiodine therapy [16]. None of the above studies compared the relative effects of discontinuing antithyroid therapy and administration of Iodine-131, and no study has measured changes in free thyroid hormone levels, which, as opposed to total thyroid hormone levels, may have predictive value for the development of thyroid storm [17]. We sought to determine prospectively the relative effects of stopping antithyroid therapy and subsequent radioiodine administration on free and total thyroid hormone levels in patients with Graves disease who have received thyroid ablation therapy. We also studied a subgroup of patients not receiving antithyroid therapy to evaluate short-term changes in thyroid hormone levels that occurred in the absence of pretreatment. Finally, we did an analysis of patient characteristics associated with the biochemical and clinical course after antithyroid therapy was discontinued and radioiodine was administered. Methods Patient Selection Patients were diagnosed as having hyperthyroidism caused by Graves disease on the basis of elevated thyroid hormone levels and suppressed thyroid-stimulating hormone levels by sensitive assay in the setting of diffuse goiter, elevated 24-hour radioiodine uptake, and in most cases, detectable levels of antibodies against the thyroid-stimulating hormone receptor. Patients with other causes of hyperthyroidism or cold nodules on pertechnetate scanning were excluded from the study. Unless contraindicated, patients had been treated with the antithyroid medications methimazole or propylthiouracil until they showed biochemical improvement or returned to a euthyroid state before referral for radioiodine ablation. Baseline Assessment At baseline, the presence and duration of antithyroid drug therapy were noted, a smoking history was obtained, and thyroid size was assessed by a single examiner. Levels of thyroid-stimulating immunoglobulins and thyroid-stimulating hormone-binding inhibiting immunoglobulins and basal levels of free and total thyroxine (T4) and triiodothyronine (T3) were measured. Treatment Protocol and Serial Evaluation Six days before patients were given Iodine-131, antithyroid therapy was discontinued in patients who received these agents. Serial clinical and laboratory assessment was done on days 6, 3, and 1 before therapy; the day of treatment; and days 1, 2, 3, 4, 5, 7, and 14 after treatment. In patients not receiving antithyroid drugs, assessment was initiated from the day before therapy with Iodine-131. On each morning listed, free and total levels of T4 and T3 were measured, as were pulse and estimated thyroid size by palpation. Patients graded their symptoms of heat intolerance, nervousness, confusion, insomnia, dyspnea, palpitations, and hyperdefecation on a scale ranging from 0 to 3 as follows: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. On the day of treatment, radioiodine uptake was measured to allow calculation of the dose of Iodine-131 according to the following formula: 200 to 250 microcuries/g of estimated thyroid weight/radioiodine uptake. Unless contraindicated, -adrenergic blocking agents (atenolol or metoprolol) were given to all patients throughout the study. No patient received antithyroid drug therapy during the 14 days after Iodine-131 treatment. Laboratory Testing Thyroid hormone assays were done at Hazelton Laboratories (Vienna, Virginia) on batched serum samples that had been stored at 20C pending study completion. Total T4 and T3 levels were measured using radioimmunoassay, and free T4 and T3 levels were measured using Coat-a-Count assay kits (Diagnostic Products, Los Angeles, California). Interassay coefficients of variation for values in the euthyroid range are as follows: total T4, 8.1%; free T4, 7.4%; total T3, 6.3%; and free T3,3.9%. For values in the hyperthyroid range, interassay coefficients of variation are the following: total T4, 5.9%; free T4, 6.8%; total T3, 5.7%; and free T3, 4.8%. Thyroid-stimulating hormone-receptor antibody assays were done at SmithKline Bio-Science Laboratories (Baltimore, Maryland). We measured thyroid-stimulating immunoglobulin levels using bioassay for production of cyclic adenosine monophosphate by cultured thyrocytes and expressed as thyroid-stimulating hormone equivalents. Thyroid-stimulating hormone-binding inhibiting immunoglobulin was measured with a radioreceptor assay and was expressed as the percentage inhibition of thyroid-stimulating hormone binding. Normal ranges for each of these assays are given in Table 1. Table 1. Characteristics at Study Entry of Patients Receiving or Not Receiving Pretreatment with Antithyroid Drugs* Statistical Analysis We used StatView statistical software (Abacus Concepts, Calabasas, California) for the statistical analyses. Changes in thyroid hormone levels over time were assessed for significance using repeated-measures analysis of variance. Post hoc testing was done using the Fisher protected least significant difference and the Scheffe F-test procedures. Whenever relevant, we calculated confidence intervals to supplement null hypothesis testing. Comparison of the rate of change in thyroid hormone levels after radioiodine therapy in patients who received and those who did not receive pretreatment was done by linear regression analysis of disappearance curves of individual patient hormone, followed by the Mann-Whitney U-test. Correlation between patient clinical measurements (duration of antithyroid drug therapy, current smoking status, goiter size, radioiodine uptake, dosage of Iodine-131, and basal thyroid hormone and thyroid-stimulating-receptor antibody levels) and change in thyroid hormone levels over time was assessed using Pearsons correlation procedure for continuous variables and analysis of variance for calculations involving discrete dependent variables. Results Patient Characteristics Twenty-one patients (12 women and 9 men) gave informed consent to participate in the study, which was approved by the Walter Reed Army Medical Center Human Use Committee. Patients ranged in age from 19 to 71 years (mean, 38.1 11.2 years). Seventeen patients received pretreatment with antithyroid drugs before receiving radioiodine: Nine patients received methimazole, 5 received propylthiouracil, and 3 received both agents sequentially because of rash or pruritus with the first agent used. Four patients could not receive either preparation because of rash (2 patients), a history of hepatitis (1 patient), and social circumstances (1 patient). Estimated baseline thyroid size ranged from 25 to 80 g, with a mean of 44 11 g. Duration of antithyroid therapy ranged from 4 to 52 weeks, with a mean duration of 14 weeks. Baseline clinical and laboratory characteristics are summarized in Table 1. Treatment doses of Iodine-131 ranged from 9.8 to 22.0 mCi, with a mean dose of 16.6 3.7 mCi. Clinical Course All patients remained clinically stable throughout the study. No consistent change occurred in symptoms during the study period; nearly equal numbers of patients experienced worsened and improved symptoms, either during preparation for Iodine-131 therapy or after therapy. Changes in Thyroid Hormone Levels Figure 1 shows the short-term changes in thyroid hormones after antithyroid therapy was discontinued in the 17 patients receiving this treatment before administration of Iodine-131. Two patients were missing a single time point for which data were derived by regression analysis. Compared with baseline measurements, levels of each of the hormones measured increased significantly during the 5 days after antithyroid therapy was discontinued and before patients received Iodine-131 ablation therapy.

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.

A 2015 Survey of Clinical Practice Patterns in the Management of Thyroid Nodules.

CONTEXT The management of thyroid nodules has changed dramatically over the past two decades. In the interim, technological advances including high-resolution ultrasound and molecular testing of thyroid nodules have been introduced. OBJECTIVE We sought to document current practices in the management thyroid nodules and assess the extent to which technological advances have been incorporated into current practice. We further sought to compare current practice to recommendations made in a recently updated American Thyroid Association (ATA) clinical practice guideline (CPG) and examine differences in thyroid nodule management among international members of U.S.-based endocrine societies. METHODS Members of The Endocrine Society, ATA, and American Association of Clinical Endocrinologists were invited to participate in a Web-based survey dealing with testing, treatment preference, and modulating factors in patients with thyroid nodules. RESULTS A total of 897 respondents participated in the survey, including 661 members of The Endocrine Society, 454 American Association of Clinical Endocrinologists members, and 365 ATA members. Thyroid fine-needle aspiration (FNA) in 2015 is generally performed by endocrinologists (56.6%) and radiologists (31.9%), most frequently using ultrasound guidance (83.3%). Respondents in general have a lower threshold for FNA of thyroid nodules than that recommended in the updated ATA CPG. Management depends on the FNA result, with follicular lesion of undetermined significance/atypia of undetermined significance resulting in molecular testing (38.8% of respondents), repeat FNA cytology (31.5%), or immediate referral for thyroid surgery (24.4%). Nodules showing follicular neoplasm by FNA are referred for thyroid surgery by 61.2% of respondents (46.6 % lobectomy, 14.6 % total thyroidectomy) or molecular testing (29.0 %). Nodules found suspicious but not conclusive for malignancy (Bethesda category V), are referred for thyroid surgery (86.0%) and rarely undergo molecular testing (9.5%). During pregnancy, only 47.6% of respondents would perform FNA in the absence of nodular growth, with most respondents deferring FNA until after pregnancy. Endocrinologists are 64.2% less likely to perform FNA in an octogenarian than a younger patient with a comparable thyroid nodule. Striking international differences were identified in the routine measurement of calcitonin and in the use of molecular testing of thyroid nodules. CONCLUSIONS In summary, our survey of clinical endocrinologists on the management of thyroid nodules documents current practice patterns and demonstrates both concordance and focal discordance with recently updated CPGs. Both international differences and a change in practice patterns during the past two decades are demonstrated.

A 2013 Survey of Clinical Practice Patterns in the Management of Primary Hypothyroidism

CONTEXT In 2012, comprehensive clinical practice guidelines (CPGs) were published regarding the management of hypothyroidism. OBJECTIVE We sought to document current practices in the management of primary hypothyroidism and compare these results with recommendations made in the 2012 American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) hypothyroidism CPGs. In addition, we sought to examine differences in management among international members of U.S.-based endocrine societies and to compare survey results with those obtained from a survey of ATA members performed 12 years earlier. METHODS Clinical members of The Endocrine Society (TES), the ATA, and the AACE were asked to take a web-based survey consisting of 30 questions dealing with testing, treatment, and modulating factors in the management of primary hypothyroidism. RESULTS In total, 880 respondents completed the survey, including 618 members of TES, 582 AACE members, and 208 ATA members. North American respondents accounted for 67.6%, Latin American 9.7%, European 9.2%, Asia and Oceania 8.1%, and Africa and Middle East 5.5%. Overt hypothyroidism would be treated using l-T4 alone by 99.2% of respondents; 0.8% would use combination l-T4 and liothyronine (l-T3) therapy. Generic l-T4 would be used by 49.3% and a brand name by 49.9%. The rate of replacement would be gradual (38.5%); an empiric dose, adjusted to achieve target (33.6%); or a calculated full replacement dose (27.8%). A target TSH of 1.0 to 1.9 mU/L was favored in the index case, but 3.0 to 3.9 mU/L was the most commonly selected TSH target for an octogenarian. Persistent hypothyroid symptoms despite achieving a target TSH would prompt testing for other causes by 84.3% of respondents, a referral to primary care by 11.3%, and a change to l-T4 plus l-T3 therapy by 3.6%. Evaluation of persistent symptoms would include measurement of T3 levels by 21.9% of respondents. Subclinical disease with a TSH 5.0 to 10.0 mU/L would be treated without further justification by 21.3% of respondents, or in the presence of positive thyroid peroxidase antibodies (62.3%), hypothyroid symptoms (60.9%), high low-density lipoprotein (52.9%), or goiter (46.6%). The TSH target for a newly pregnant patient was <2.5 mU/L for 96.1% of respondents, with 63.5% preferring a TSH target <1.5 mU/L. Thyroid hormone levels would be checked every 4 weeks during pregnancy by 67.7% and every 8 weeks by an additional 21.4%. A hypothyroid patient with TSH of 0.5 mU/L who becomes pregnant would receive an immediate l-T4 dose increase by only 36.9% of respondents. CONCLUSION The current survey of clinical endocrinologists catalogs current practice patterns in the management of hypothyroidism and demonstrates 1) a nearly exclusive preference for l-T4 alone as initial therapy, 2) the widespread use of age-specific TSH targets for replacement therapy, 3) a low threshold for treating mild thyroid failure, 4) meticulous attention to TSH targets in the pregnant and prepregnant woman, and 5) a highly variable approach to both the rate and means of restoring euthyroidism for overt disease. Both alignment and focal divergence from recent CPGs are demonstrated.

Evaluation of adult papillary thyroid carcinomas by comparative genomic hybridization and microsatellite instability analysis

To clarify the mechanism of tumorigenesis in papillary thyroid carcinoma (PTC) and ascertain whether genomic changes correlate with histologic features, we conducted a comprehensive molecular evaluation of PTC using comparative genomic hybridization (CGH) and microsatellite instability (MSI) analysis in a set of 17 histologically well-characterized PTC specimens. To our knowledge, this is the first study that evaluates chromosomal and nucleotide instability in the same PTC tumor specimens. Four of 15 samples (27%) had aberrations detected by CGH. All four had a partial or complete gain of chromosome 20, and 3 of 4 had a partial or complete loss of chromosome 13. No MSI was detected in any of the PTC samples (n=16), and all samples examined by immunohistochemistry (n=9) expressed the DNA repair enzymes hmlh1 and hmsh2. All PTC samples with abnormal CGH had vascular invasion or invasion of the thyroid capsule, and there was a significant correlation between the presence of chromosomal aberrations and capsular/vascular invasion (P=0.026). We conclude that although chromosomal and microsatellite instability are uncommon in PTC, tumors with chromosomal aberrations are more likely to be associated with invasion.