Long-term Effect of Thyrotropin-binding Inhibitor Immunoglobulin on Atrial Fibrillation in Euthyroid Patients.

OBJECTIVE: Individuals with hyperthyroidism are at an increased risk of atrial fibrillation (AF), but the association between autoantibodies and AF or cardiovascular mortality in individuals who have returned to normal thyroid function remains unclear. METHODS: The study utilized electronic medical records from National Taiwan University Hospital between 2000 and 2022. Each hyperthyroidism patient had at least 1 thyrotropin-binding inhibiting immunoglobulin (TBII) measurement. The relationship between TBII levels and the risk of AF and cardiovascular mortality was assessed using multivariable Cox regression models and Kaplan-Meier survival analysis. RESULTS: Among the 14 618 enrolled patients over a 20-year timeframe, 173 individuals developed AF, while 46 experienced cardiovascular mortality. TBII values exceeding 35% were significantly associated with an elevated risk of AF for both the first TBII (hazard ratio {HR} 1.48 [1.05-2.08], P = .027) and mean TBII (HR 1.91 [1.37-2.65], P < .001). Furthermore, after free T4 levels had normalized, a borderline association between first TBII and AF (HR 1.59 [0.99-2.56], P = .056) was observed, while higher mean TBII increased AF (HR 1.78 [1.11-2.85], P = .017). Higher first and mean TBII burden continued to significantly impact the incidence of cardiovascular mortality (HR 6.73 [1.42-31.82], P = .016; 7.87 [1.66-37.20], P = .009). Kaplan-Meier analysis demonstrated that elevated TBII levels increased the risk of AF and cardiac mortality (log-rank P = .035 and .027, respectively). CONCLUSION: In euthyroid individuals following antithyroid treatment, elevated circulating TBII levels and burden are associated with an elevated risk of long-term incident AF and cardiovascular mortality. Further reduction of TBII level below 35% will benefit to clinical outcomes.

Comparison of two different TSH-receptor antibody assays: A clinical practice study.

Background: Graves' disease (GD) is caused by the production of TSH-receptor (TSHR) stimulating auto-antibodies. Over the years various TSHR-antibody (TRAb) detection assays have been developed. Most clinical laboratories use competitive TSH-binding inhibitory immunoglobulin (TBII) assays, which measure the total amount of stimulating and blocking auto-antibodies. Selective detection of TSHR stimulating auto-antibodies (TSI) was previously only possible with functional cell-based bioassays. However, more recently an automated bridge-based binding assay to more specifically measure TSI has become available. The aim of our study was to compare the third-generation automated competitive immunoassay (TBII) with the automated bridge immunoassay (TSI) in clinical practice in an academic thyroid expert center. Methods: A retrospective study in 356 patients with Graves' disease, Graves orbitopathy (GO), and other (thyroid) disease treated in an academic thyroid center was performed. All samples were analyzed for TBII and TSI. For both assays, sensitivity, specificity, positive predictive value (PVV), negative predictive value (NPV) and diagnostic odds ratios were calculated using different cut-offs for negativity. Results: Using the provided cut-off, the overall sensitivity appeared similar between TBII and TSI, but TSI showed higher overall specificity, PPV, NPV and diagnostic odds ratio. Using two or three times the cut-off for negativity resulted in a decrease in sensitivity, but an increase in specificity and PPV, which was most pronounced for the TBII-assay. Analysis in a subgroup of newly diagnosed treatment naïve GD/GO patients also revealed overall favorable results for the TSI-assay. Increasing the cut-off for negativity resulted in increased specificity for both assays, with similar results using two or three times the cut-off. Most patients with concordant positive results for TBII and TSI suffered from GD or GD + GO (n = 110, 95.6 %), while patients negative for both TBII and TSI mostly suffered from other (thyroid) disease (n = 143, 77.3 %). From patients with positive TBII but negative TSI only 42.1 % had GD/GO (n = 16), whereas 57.9 % (n = 22) had other (thyroid) disease. In contrast, 88.9 % of patients with positive TSI but negative TBII had GD/GO (n = 16), whereas 11.1 % (n = 2) had other (thyroid) disease. Conclusion: In our academic thyroid center, the diagnostic performance of the TSI-assay outperformed the TBII-assay. Using a higher cut-off value for negativity can be helpful in assessing clinical relevance.

Painful Subacute Thyroiditis is Commonly Misdiagnosed as Suspicious Thyroid Nodular Disease.

OBJECTIVE: To investigate and characterize the clinical and radiologic features of 10 patients with painful subacute thyroiditis with ultrasound findings considered suspicious for malignancy or for whom biopsy of a suspicious area was recommended by an attending radiologist. PATIENTS AND METHODS: Ten patients with painful subacute thyroiditis were seen from June 1, 2016, through January 1, 2019. All 10 patients presented to an endocrine or thyroid clinic with a neck ultrasound report stating findings suspicious for malignancy or nodular disease. Clinical, laboratory, radiographic, and pathologic data were (retrospectively collected and) reviewed. RESULTS: The mean ± SD patient age was 49.0±15.0 years at diagnosis; 8 patients were female. All the patients presented with a low or undetectable serum thyrotropin level. Six of 7 patients with available inflammatory markers had elevated levels. Thyrotropin receptor antibodies were absent in all 6 patients tested. On follow-up imaging, 8 patients had complete resolution or improvement of described findings, 1 was lost to follow-up, and 1 had an incidental nodule that was biopsied after the episode of thyroiditis and found to be papillary thyroid carcinoma. CONCLUSION: Painful subacute thyroiditis demonstrates specific sonographic patterns that may be misdiagnosed as suspicious thyroid nodular disease. Recognition of the innocent and transient nature of these findings is important for the proper management and monitoring of these patients.

Conversion to Graves disease from Hashimoto thyroiditis: a study of 24 patients

ABSTRACT Objective: The conversion of Hashimoto's thyroiditis (HT) to hyperthyroidism due to thyrotropin receptor antibodies is intriguing and considered rare. The contribution of TSH receptor blocking antibodies (TRAb), which may be stimulators (TSAb) or blockers (TBAb), is suspected. We describe clinical and biological variables in a series of patients switching from Hashimoto's thyroiditis to Grave's disease. Subjects and methods: Retrospective case study of 24 patients with Hashimoto's thyroiditis followed during 48 ± 36 months that developed later Graves' disease (GD). These variables were analysed in the hypo and hyperthyroid phase: age, sex, initial TSH, free triiodothyronine (fT3), free thyroxine (fT4), anti-TPO, TBII antibodies, parietal cell autoantibodies, time between hypo and hyperthyroidism, thyroid volume and levothyroxine doses (LT). Results: In HT, mean TSH was 9.4 ± 26.1 UI/L and levothyroxine treatment was 66.2 ± 30.8 µg/day. The switch to GD was observed 38 ± 45 months after HT diagnosis. As expected, we found significant differences on TSH, FT3, FT4 and TBAb levels. Three out of 14 patients had parietal cell autoantibodies. In two of these three cases there was an Helicobacter pylori infection. There were no significant differences between HT and GD groups with respect to thyroid volume. Conclusions: To our knowledge, large series documenting the conversion of HT to GD are scarce. Although rare, this phenomenon should not be misdiagnosed. Suspicion should be raised whenever thyroxine posology must be tapered down during the follow-up of HT patients. Further immunological and genetic studies are needed to explain this unusual autoimmune change.

Usefulness of TSH receptor antibodies as biomarkers for Graves' ophthalmopathy: a systematic review.

PURPOSE: Over the past several decades, many papers have been published about the usefulness of thyrotropin receptor antibodies (TRAbs) as biomarkers of Graves' ophthalmopathy (GO). However, results have been inconsistent. The purpose of this analysis is to determine a possible cause of these discrepancies and to examine the usefulness of TRAbs as biomarkers for GO, especially 'thyrotropin-binding inhibiting immunoglobulin (TBII)' and 'thyroid-stimulating antibody (TSAb)'. METHOD: 26 articles discussing the association between TRAbs and GO were selected which were then divided into three groups based on the study method and whether or not the patients had been treated for hyperthyroidism. From the results of the papers reviewed, a provisional conclusion was made and a theoretical model on the TBII-TSAb coordinate plane was developed to confirm that conclusion. RESULTS: TSAb is reported to be significantly or strongly associated with GO in the studies of pre- and post-treated patients for hyperthyroidism. TBII is positively correlated, negatively correlated or uncorrelated with GO in studies of pre-treated patients. However, it is generally agreed upon that TBII and GO are closely correlated in studies of post-treated patients. CONCLUSION: We conclude that the level of TBII may not be a reliable indicator of the current state of GO in pre-treated patients. Whereas, in post-treated patients, due to changes in the correlation between TBII and TSAb due to the effect of hyperthyroidism treatment, the level of TBII can be a more reliable indicator of GO. Furthermore, the current level of TBII is closely associated with the onset and severity of GO in the future and it can be a valid predictor of GO. However, the TSAb level appears to be more reliable.

The Change of Pulmonary Artery Pressure in Graves'Disease Before and After Treatment / 대한내분비학회지

BACKGROUND: Exertional symptoms, dyspnea and impaired effort tolerance are common in patients with Graves' disease. Proposed explanations include: high-output left heart failure, ineffective oxygen utilization and respiratory muscle weakness. In addition, pulmonary hypertension has also been reported in patients with Graves' disease. A high prevalence of hypothyroidism and positive thyroid autoantibody were also observed in patients with pulmonary arterial hypertension. Therefore, the pulmonary artery pressure in patients with Graves' disease was evaluated. METHODS: Two-dimensional and Doppler echocardiographic examinations (Hewlett Packard Sonos 2500) were performed to determine the pulmonary artery (PA) pressure in 26 Graves' disease patients, both before and after treatment (23 patients with propylthiouracil and 3 with RAI), and in 10 euthyroid controls. The changes in the PA pressure after treatment were evaluated in 13 patients with Graves' disease, who became euthyroid after treatment. RESULTS: The pulmonary artery pressure was increased in the untreated Graves' disease patients compared to the normal controls (23.5+/-2.32 vs. 29.6+/-10.3 mmHg). 38.5% of the Graves' disease patients (10/26) showed pulmonary arterial hypertension (PA>30 mmHg) and the serum TBII levelwas higher in the Graves' disease patients with pulmonary arterial hypertension than in those with normal PA pressure (P<0.05). In the Graves' patients who became euthyroid after treatment, the PA pressure was significantly decreased. CONCLUSION: 38.5% of the untreated Graves' disease patients showed pulmonary arterial hypertension, and the pulmonary artery pressure was significantly decreased in those who became euthyroid after treatment. The pathogenesis and clinical importance of pulmonary arterial hypertension in Graves' disease requires further studies.

Differential Diagnostic Value of TSH Receptor Antibody Measurements in Thyrotoxic Postpartum Patients with History of Graves' Disease / 대한내분비학회지

BACKGROUND: It is known that pregnancy markedly influences the clinical course of autoimmune thyroid diseases. In the postpartum period, various kinds of autoimmune thyroid dysfunctions can be observed. Thyroid dysfunction is found in 5.5-7.1% of postpartum women in the general population. Among those who show thyroid dysfunction after delivery, some will develop Graves' disease and others will develop postpartum thyroiditis. It is also known that patients with Graves' disease may manifest thyrotoxicosis in the postpartum period because of postpartum thyroiditis or relapse of the Graves' disease itself. We evaluated the clinical features of postpartum thyrotoxicosis in Graves' disease patients to find diagnostic indices that could be used in differentiating between postpartum thyroiditis and relapse of Graves' disease. METHOD: We reviewed the cases with postpartum thyrotoxicosis in patients that had a history of Graves' disease between 1995 and 2000. The diagnosis of postpartum thyroiditis had been made by means of a 99mTc thyroid scan or by the observation of a typical triphasic thyroid function change, in cases where a 99mTc thyroid scan was not possible because of breast feeding. We measured the serum TSH, free T4, free T3, TSH binding inhibiting immunoglobulin (TBII), anti-thyroid peroxidase (TPO) antibody, and anti- thyroglobulin (Tg) antibody serially from the time of the diagnosis of Graves' disease to the time of postpartum thyroid dysfunction. RESULTS: Eleven patients, 5 patients in the postpartum thyroiditis (PPT group) and 6 patients with relapse of the Graves' disease (GD group), were identified. The mean values of TBII of two groups at the time of diagnosis of Graves' disease were 40.9+/-4.8 IU/mL (PPT group), 58.9+/-23.5 IU/mL (GD group) respectively, which were insignificant. The mean values of TBII of the two groups at early pregnancy were 3.2+/-1.9 IU/mL (PPT group), 41.6+/-22.6 IU/mL (GD group) and this difference was statistically significant (p=0.009). The mean values of TBII of the two groups at the time of postpartum thyrotoxicosis were 1.9+/-1.6 IU/mL (PPT group), 51.5+/-23.2 IU/mL (GD group) which were also statistically significant (p=0.003). The mean values of anti-TPO antibody, anti-Tg antibody, disease duration, and treatment duration between the two groups were not significantly different. The onsets of thyroid dysfunction after delivery in the two groups were 2.6+/-2.0 (PPT group), 4.0+/-3.9 (GD group) months which were statistically insignificant. CONCLUSION: These data suggest that the measurement of TBII at the time of the postpartum thyrotoxic period, could help to differentiate postpartum thyroiditis from a relapse of Graves' disease in those patients that have a history of Graves' disease especially when thyroid scan is not possible because of breast feeding.

A Case of Transient Neonatal Hypothyroidism Due to Maternal TSH-Binding Inhibitor Immunoglobulins / 대한소아내분비학회지

Recognition of transient forms of neonatal hypothyroidism is very important to prevent the complications of congenital hypothyroidism. Transplacental passage of TSH-binding inhibitory immunoglobulins(TBII) may result in transient congenital hypothyroidism. Transient neonatal hypothyroidism was found in a daughter of 25-yr-old mother who was receiving levothyroxine for primary hypothyroidism due to Hashimoto's thyroiditis. The neonate was treated with thyroxine which was discontinued at 24 months of age. Thyroid scanning during the neonatal period failed to identify functional thyroid tissue, suggesting thyroid agenesis, whereas thyroid scan performed on subsequent follow-up revealed a normal gland. Sequential measurements of serum autoantibodies directed towards the TSH receptor were made in the patient and her mother. High titers of blocking antibodies were present in the mother(TBII, 82.1%) and newborn(TBII, 85.5%) at 19 days after birth. The levels remained persistently high in the mother, whereas they declined and undetectable in the patient at 23 months of age. The above laboratory and clinical data were compatible with blocking nature of TBII, resulting in transient neonatal hypothyroidism and an athyreotic appearance on scan. The TBII measurement can be a useful predictor of neonatal hypothyroidism as well as confirming the nature of the disease in newborn.

The Changes of Serum Soluble Intercellular Adhesion Molecule-1(ICAM-1) According to the Clinical Course of Graves' Disease Treated with Antithyroid Drug / 대한내분비학회지

Background: TSH binding inhibiting imunoglobulins(TBII) are autoimmune antibody causing autoimmune thyroid diseases such as Graves disease or Hashimoto's thyroiditis, while intercellular adhesion molecule-1(ICAM-1) is known as a substance expressed at the site of autoimmune reaction in relation with lymphocyte infiltration. The serum TBII activity is used as an index of the disease course and prognosis of Graves disease treated with antithyroid drugs, propylthiouracil or methimazole. The aim of this study is to understand the change of serum ICAM-1 level according to the change of the degree of autoimmunity and clinical course of Graves disease. Methods: In order to study the change of soluble ICAM-1 and relationship to the immune mechanism of Graves' disease, we measured serum levels of TBII and ICAM-1 in patients(n 35) with Graves disease before and after treatment with antithyroid drugs and in relapsed patients using a highly sensitive ELISA method. Results: The serum levels of TBII and ICAM-1 were markedly elevated in patients with Graves disease before treatment than normal controls and there were good correlation between TBII and ICAM-1 level. In patients with normalized TBII levels after 22 months antithyroid drug treatment, the ICAM-1 levels became normal but in the patients with high serum TBII level showed high serum level of ICAM-1 even with clinical remission with same treatment. The serum levels of TBII and ICAM-1 in relapsed patients were elevated as those of patients before treatment. Conclusion: With the above results, we can conclude that not only the TBII level but seru ICAM-1 level also reflect the degree of autoimmune activity of Graves disease and may be used as an index of the disease course and prognosis of Graves disease treated with antithyroid drugs.

Clinical Characteristics of Graves' Disease Patients with Undetectable Thyrotropin Binding Inhibitor Immunoglubulin (TB2) / 대한내분비학회지

Background: Graves disease is an autoimmune disease caused by TSH receptor antibodies. Thyrotropin binding inhibitor immunoglobulins(TBII) are detected in most Graves patients, but some patients have no TBII activities in their sera. It is unknown whether the clinical features of TBII-positive patients are different from those of TBII-negative patients. Methods: To evaluate the prevalence of TBII-negative Graves' patients and its clinical differences from TBII-positive patients, we examined TBII by radioreceptor assay in 686 consecutive untreated Graves patients. We found 84 TBII-negative patients(15 men and 69 women, mean age ±EM: 40.9±.4 years) and compared their clinical characteristics with 87 TBII-positive patients (22 men and 65 women, mean age±EM: 39.9±.5 years) who were selected randomly from the same patients group. Results: In this study, TBII was undetectable in 12.2% of patients with Graves' disease(84 of 686). TBII-negative group had a less weight loss than TBII-positive group. However, there was no significant differences in age, sex ratio, prevalence of ophthalmopathy, duration of illness and positive rate of family history for thyroid diseases between TBII-negative and

A case of neonatal hypothyroidism due to maternal TSH-binding inhibitor immunoglobulin

No abstract available.

AN ANTl-TSH ANTI-IDIOTYPIC ANTISERUM WITH ACTIVITY OF THYROID-STIMULATING INHIBITOR IMMUNOGLOBULIN (TSH) / 中华内分泌代谢杂志

Rabbit anti-TSH anti-idiotypic antiscra were raised by immunization with auti-TSH antibody. The antiserum from rabbit No. 551 was found to have the activity of inhibiting the binding of TSH receptor on thyroid cell membrane and 125I-TSH, that is, TBII (TSH-binding inhibitor immunoglobulin) positive. This antiserum was also shown to inhibit cAMP release stimulated by 100 mU/L bTSH. The characteristics of No. 551 antiserum were similar to of patients with myxedema.