Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter?

PURPOSE: Thyroid receptor antibodies can quantify thyroid eye disease activity, predict outcomes and aid timing of interventions. The type and generation of assay is frequently unspecified, complicating meta-analyses. To determine the clinical and biochemical relationships between a second-generation thyrotropin receptor-binding inhibition antibody (TRAb) immunoassay, detecting stimulatory and blocking antibodies, with the thyroid stimulating immunoglobulin (TSI) bridging immunoassay detecting the stimulatory component only. METHODS: Retrospective review of 100 consecutive patients attending a regional specialist service. For each patient and visit, both a TRAb and TSI were performed, and a clinical activity score (CAS) recorded. RESULTS: A significant positive correlation between TRAb and TSI (rho = 0.828, p < 0.01) but a weaker correlation between the assays and CAS (TRAb: rho = 0.439, p < 0.01; TSI: r = 0.357, p < 0.01) were found. In 10% of the episodic data, patients had a TRAb level that was disproportionately high (39.41 ± 52.84 IU/L), compared to their TSI levels (9.53 ± 12.10 IU/L) with a higher-than-average CAS (2.47 ± 1.78; range, 0-5). Within 12 months of diagnosis, a significant positive correlation between CAS and TRAb (rho = 0.503, p < 0.01) as well as between CAS and TSI (rho = 0.329, p < 0.01) were found. In patients with a diagnosis over 12 months, the correlation with CAS for both TSI and TRAb were Spearman rank correlation coefficient of 0.347 (p < 0.01) and 0.327 (p < 0.01), respectively. CONCLUSIONS: TRAb and TSI correlate strongly and to a lesser extent with the CAS. For most patients, TRAb can be replaced with the more economical TSI. TRAb also correlates better with newly diagnosed, more active patients than TSI. In a subset of patients, blocking antibodies may play a significant pathogenic role, requiring different treatment and monitoring. Further studies are required to investigate this relationship.

Hyperthyroidism is Underdiagnosed and Undertreated in 3336 Patients: An Opportunity for Improvement and Intervention.

OBJECTIVE: The aim of this study was to determine the prevalence of undiagnosed and untreated hyperthyroidism among patients with suppressed thyroid-stimulating hormone (TSH). BACKGROUND: Hyperthyroidism can significantly diminish patient quality of life and increase the financial burden on patients and health systems. We hypothesized that many patients with hyperthyroidism remain undiagnosed because physicians fail to recognize and evaluate suppressed TSH as the first indication of disease. METHODS: We reviewed administrative data on 174011 patients with TSH measured at a tertiary referral center between 2011 and 2017 to identify individuals with hyperthyroidism (TSH <0.05 mU/L) and their subsequent outcomes: evaluation (measurement of T4, T3, radioactive iodine (RAI) uptake scan, thyroid-stimulating immunoglobulin, thyroid peroxidase antibodies) diagnosis, referral and treatment. We used Kaplan-Meier methods and multivariable time-related parametric hazard modeling to measure our outcomes. RESULTS: We found 3336 patients with hyperthyroidism. The mean age of our cohort was 52 ±â€Š17 years, with 79% females and 59% whites. Only 1088 patients (33%) received any appropriate evaluation and hyperthyroidism remained undiagnosed in 37% of patients who had the appropriate workup. Among those diagnosed with hyperthyroidism, only 21% were referred for surgery and 34% received RAI. Predictors for hyperthyroidism diagnosis include lower TSH (0.01u/L), younger age, African-American race, private commercial insurance, being seen in an outpatient setting, absence of medical comorbidities, presentation with ophthalmopathy, or weight loss. CONCLUSIONS: Hyperthyroidism is frequently unrecognized and untreated, which can lead to adverse outcomes and increased costs. Improved systems for detection and treatment of hyperthyroidism are needed to address this gap in care.

TSI assay utilization: impact on costs of Graves' hyperthyroidism diagnosis.

OBJECTIVES: Thyroid-stimulating immunoglobulins (TSIs) are autoantibodies that bind to the thyroid-stimulating hormone (TSH) receptor on thyroid cells, resulting in Graves' disease (GD), the most common cause of hyperthyroidism. Recently published guidelines recognize the value of anti-TSH receptor antibodies, and a TSI test with high sensitivity and specificity for GD, recently cleared by the US Food and Drug Administration, is now available. Despite this, existing diagnostic algorithms for hyperthyroidism do not currently include TSI testing except in specific cases like pregnancy. The objectives of this analysis are to understand whether incorporating a test that specifically detects TSIs into existing algorithms results in cost savings and reduces time to diagnosis for payers and managed care organizations. STUDY DESIGN: An evidence-based economic model was developed to determine the average time to diagnosis and annual costs associated with various diagnostic algorithms for GD in a population of 100,000 managed care enrollees. Diagnostic algorithms used in current practice and hypothetical algorithms that include the TSI test were identified using published clinical guidelines and interviews with practicing endocrinologists. The model estimates costs of current and TSI test-based diagnostic algorithms using payment amounts for laboratory tests, procedures, and physician visits. RESULTS: Compared with non-TSI algorithms, 100% use of algorithms that include the TSI test result in 46% faster time to diagnosis and generate 47% overall cost savings due in large part to reductions in costly procedures and specialist office visits. CONCLUSIONS: Incorporation and early utilization of the TSI in vitro diagnostic test into current diagnostic algorithms confers cost savings and shortens time to diagnosis.

Assessment of iodine and non-iodine deficiency hypothyroidism in women of reproductive ages in the sub-Himalayan plains of West Bengal.

Indian women of reproductive age groups commonly suffer from hypothyroidism which may be due to iodine or non iodine deficiency causes. This study was undertaken with a view to ascertain the leading cause of hypothyroidism in women of reproductive age group residing in the sub-Himalayan plain areas of Darjeeling district of West Bengal. Serum TSH, T4, T3 and Urinary Iodine Excretion (UIE) levels were measured in 101 non pregnant women. Our results reveal that among 37.62% (n=38) of bio-chemically established hypothyroid women; majority 76.32% (n=29) are suffering from iodine deficiency and the rest 23.68% (n=9) have Hypothyroidism due to other causes. Moreover, iodine deficiency persists among 57.42% (n=58) of the women in our study. We conclude that iodine deficiency disorders are still a major problem in this region and hypothyroidism due to iodine deficiency is more prevalent than the non iodine deficiency causes. Hence lacunae in the iodine supplementation process needs to be reviewed.

Subclinical hypothyroidism in lithium-treated psychiatric patients in Tehran, Islamic Republic of Iran.

We investigated thyroid function in 46 (20 female & 26 male) psychiatric outpatients on lithium treatment by assessing triiodothyronine, thyroxine and thyroid stimulating hormone (TSH) levels. The presence of thyroid antibodies (anti-thyroid peroxidase and anti-thyroglobulin) was also assessed. Out of the 46 patients, 8 (17%) displayed overt hypothyroidism. Of the remaining patients, subclinical hypothyroidism was found in 16 patients (35%) and euthyroidism in 22 (48%). Thyroid antibodies were present in 6 patients in the euthyroid group and 5 patients in the hypothyroid group. The Pearsor product-moment correlation results indicated positive association between TSH level and duration of lithium use and age of the patients with subclinical hypothyroidism. Duration of lithium use and age could be a reasonable indicator for screening asymptomatic patients for subclinical hypothyroidism after starting lithium treatment.

Subclinical hypothyroidism in lithium-treated psychiatric patients in Tehran, Islamic Republic of Iran

We investigated thyroid function in 46 [20 female and 26 male] psychiatric outpatients on lithium treatment by assessing triiodothyronine, thyroxine and thyroid stimulating hormone [TSH] levels. The presence of thyroid antibodies [anti-thyroid peroxidase and anti-thyroglobulin] was also assessed. Out of the 46 patients, 8 [17%] displayed overt hypothyroidism. Of the remaining patients, subclinical hypothyroidism was found in 16 patients [35%] and euthyroidism in 22 [48%]. Thyroid antibodies were present in 6 patients in the euthyroid group and 5 patients in the hypothyroid group. The Pearsor product-moment correlation results indicated positive association between TSH level and duration of lithium use and age of the patients with subclinical hypothyroidism. Duration of lithium use and age could be a reasonable indicator for screening asymptomatic patients for subclinical hypothyroidism after starting lithium treatment

Antithyroid drugs and Graves' disease--prospective randomized assessment of long-term treatment.

OBJECTIVE: Although antithyroid drugs (ATD) are widely used in the treatment of Graves' disease, management protocols, especially treatment duration, remain a subject of debate. The rate of relapse after short-term regimens of less than 6 months with ATD at decreasing doses is higher than after longer treatments from 12 to 24 months. As no prospective study has provided data on even longer protocols exceeding 2 years, we conducted a prospective trial to determine potential benefits of a 42-month treatment compared with an 18-month treatment. DESIGN, PATIENTS AND MEASUREMENTS: The aim of this prospective randomized trial was to compare relapse rates achieved two years after treatment withdrawal in patients who received carbimazole at decreasing doses for 18 months (n = 62) vs 42 months (n = 72). In addition to clinical relapse rate, the percentage of patients who normalized antithyroperoxidase (TPO) antibody and anti-TSH receptor stimulating antibody (TSAb) levels and early iodine uptake at the end of treatment were assessed as outcome criteria. RESULTS: The relapse rate two years after discontinuation of treatment did not differ significantly in patients treated for 18 months from those treated for 42 months (36% vs 29%, NS). At the end of treatment, there was no significant difference between the two groups in the percentage of anti-TPO positive patients (53% vs 46%, NS) or early iodine uptake (27% vs 21%, NS). Although the percentage of patients with TSAb was significantly lower in the 42-month treatment group (18% vs 42%, P = 0.004) at treatment withdrawal, the percentage of TSAb-positive patients did not significantly decrease between 18 and 42 months in this group (27% vs 18%, NS). CONCLUSION: Treatment duration greater than 18 months did not improve remission rate determined 2 years after treatment withdrawal or immunological variables or early iodine uptake measured at the time of discontinuation of treatment. These findings would indicate that, when a defined duration treatment is planned, prolonging treatment beyond 18 months does not provide any additional benefit.

Serum leptin levels and bioelectrical impedance assessment of body composition in patients with Graves' disease and hypothyroidism.

We investigated whether thyroid status modulates serum leptin concentrations and body composition as determined by bioelectric impedance analysis (BIA). The percent body fat mass (%FM) in male Graves' disease was significantly lower than that in age- and sex- matched normal subjects, at the levels of 11.4+/-6.4% (mean+/-SD) vs 19.9+/-9.2% for men (n=12, P<0.05) but not for women (22.6+/-7.6% vs 24.9+/-13.1%, n=28). In contrast, in female hypothyroidism (n=11) %FM was significantly higher than that in normal subjects (32.9+/-11.5%, P<0.01). Among other body composition parameters, the percentage of body water (%BW), and lean body mass (LBM) were significantly lower in hypothyroid patients, and the ECM (extracellular mass)/BCM (body cell mass) ratio was significantly (P<0.0001) increased in Graves' disease which was the result of marked depletion of BCM with concomitant expansion of ECM. The serum leptin levels were significantly decreased in male Graves' patients (2.3+/-0.7 ng/ml, P<0.05), whereas in female Graves' patients (8.8+/-5.9 ng/ml) and patients with hypothyroidism (9.5+/-7.6 ng/ml), the levels were not different from those of normal controls matched for BMI or %FM. There was a positive correlation between serum leptin levels and %FM in female Graves' patients (r=0.635, P=0.001) and in hypothyroid patients (r=0.801, P=0.014) but not in male Graves patients. There was no significant relationship between serum leptin levels and thyroid hormones, TRAb, or TSAb. In euthyroid obese subjects there was a positive relationship between serum leptin levels and serum TSH levels (r=0.37, P<0.01). These results suggest that hyperthyroidism is characterized by the decreased fat mass and serum leptin levels in men, but female patients appear to be resistant to the effect of thyroid hormones. Together with previous reports, thyroid status has a minor role in the regulation of serum leptin levels.

Assessment of thyroid growth stimulating activity of immunoglobulins from patients with autoimmune thyroid disease by cytokinesis arrest assay.

OBJECTIVE: To develop a novel bioassay for the assessment of thyroid cell growth stimulating activity using cytochalasin B (CB) and to test immunoglobulins (IgGs) from patients with autoimmune thyroid diseases. DESIGN: The assay is based on the principle that growing cells during incubation with CB show an increased number of nuclei in a cell (N/C index), since CB, at appropriate concentrations, is known to inhibit cytoplasmic cleavage without affecting nuclear mitosis. The N/C index represents potential DNA production while cells are incubated with CB. METHODS: FRTL-5 thyroid cells were incubated with various thyroid stimulators in TSH-free medium containing 2 mg/J CB for 3 days. After the incubation, the cells were harvested in trypsin/EDTA to obtain single cell suspension, fixed, dropped onto a glass slide, stained and observed under a microscope to determine the N/C index. RESULTS: Bovine TSH at 10(-3)-1.0 U/I, forskolin at 1x10(-7)-10(-5) mol/l, cholera toxin at 10x10(-5)-10(-3) mg/l, or (Bu)2cAMP at 1 x 10(-5)-10(-3) mol/l increased the N/C index up to approximately 2.0 in a dose-dependent manner. IgGs not only from 27 patients with untreated goitrous Graves' disease but also from 14 patients with goitrous Hashimoto's thyroiditis elicited an increase in the N/C index, which exceeded the mean + 2 S.D. of the values for 17 normal subjects (mean +/- S.D., 1.063 +/- 0.014). Four patients with primary myxedema displayed a normal N/C index. In Graves' disease, the N/C index did not correlate significantly with thyroid stimulating antibodies (TSAb) activities but did correlate significantly with estimated goiter size (P < 0.05). IgGs containing blocking-type TSH-receptor antibodies inhibited the TSH- or Graves IgG-stimulated increase in N/C index almost completely, but did not influence the stimulatory effect of IgG from two patients with Hashimoto's thyroiditis. CONCLUSIONS: We have developed a sensitive and simple assay for thyroid growth stimulating activity by using CB, and found that all tested patients with goitrous Graves' disease and goitrous Hashimoto's thyroiditis have thyroid growth stimulating immunoglobulins whose activity does not correlate with TSAb.

Optimization and clinical assessment of a radioreceptor assay for thyrotropin-binding inhibitor immunoglobulins.

We tried to improve the sensitivity of a radioreceptor assay for thyrotropin-binding inhibitor immunoglobulins (TBII) by modifying assay conditions. About a twofold increase in sensitivity without a loss of reproducibility was obtained by prolonging the incubation of the receptors with test serum from 15 to 120 min before the addition of 125I-labeled thyrotropin. In 20 untreated, 49 treated patients with Graves' disease and 19 patients with euthyroid Graves' disease, TBII activities obtained using 120 min preincubation were significantly higher than those obtained using 15 min preincubation (p less than 0.005). No significant increase in TBII activities was observed in the presence of sera from patients with primary hypothyroidism (n = 17), simple goiter (n = 7), adenomatous goiter (n = 11), thyroid adenoma (n = 11) or cancer (n = 12). TBII were detectable in 15 (47%) of 32 triiodothyronine-nonsuppressible Graves' patients who were receiving maintenance antithyroid drug therapy using 120 min preincubation, while they were positive in only 6 patients (19%) using 15 min preincubation. The assay using a longer preincubation period was found to be sensitive, specific and useful for diagnosis and follow-up of Graves' disease.

Bioassay of thyroid-stimulating immunoglobulins using human thyroid cell cultures: optimization and clinical assessment.

Primary monolayer cultures of human thyroid cells have been used to investigate the intracellular cyclic AMP response to thyroid-stimulating immunoglobulins (TSIg) prepared from the sera of patients with Graves' disease. In particular, attention was directed towards dose-response characteristics obtained under differing incubation conditions, and an optimized incubation procedure based upon conditions consistent with the maximal precision of TSIg measurement was developed. The magnitude of the cyclic AMP response to a tested TSIg preparation was shown to be greatest after the longest incubation period investigated, 16 h, for all doses of TSIg investigated. The greatest precision of TSIg measurement, as determined by the lowest relative error, was obtained at an immunoglobulin (Ig) dose of 1 mg/ml, and when incubated at this dose level for 16 h, all Ig-enriched fractions prepared from the sera of 28 newly-diagnosed patients with Graves' disease significantly (P less than 0.05) raised the intracellular cyclic AMP level of thyroid cell monolayers. After thionamide drug therapy, the incidence of TSIg detection declined to 42% (5 of 12 patients). TSIg bioactivity was also found in 9 of 14 (64%) patients with euthyroid exophthalmos and in 4 of 11 (36%) cases of non-toxic goitre. In contrast, Ig's prepared from the sera of normal euthyroid volunteers were devoid of TSIg bioactivity.