The Prediction Model Using Thyroid-stimulating Immunoglobulin Bioassay for Relapse of Graves' Disease

Han-Sang Baek; Jaejun Lee; Chai-Ho Jeong; Jeongmin Lee; Jeonghoon Ha; Kwanhoon Jo; Min-Hee Kim; Jae Hyoung Cho; Moo Il Kang; Dong-Jun Lim


J Endo Soc. 2022;6(5) 

In This Article

Abstract and Introduction


Objective: Thyroid-stimulating immunoglobulin (TSI) bioassay has a better ability to predict the relapse rate of Graves' disease (GD) than the thyroid-stimulating hormone (TSH)-binding inhibitory immunoglobulin method in terms of measuring the TSH receptor antibody. However, the optimal TSI bioassay cutoff for predicting relapse after antithyroid drug (ATD) withdrawal is not well evaluated.

Methods: This retrospective study enrolled GD patients who had been treated with ATD and obtained their TSI bioassay <140% from January 2010 to December 2019 in a referral hospital.

Results: Among 219 study subjects, 86 patients (39.3%) experienced relapse. The TSI bioassay value of 66.5% significantly predicted the relapse of GD (P = 0.049). The group with a TSI bioassay value > 66.5% were expected to show a 23.8% relapse rate at 2 from ATD withdrawal, and the group with a TSI < 66.5% had a 12.7% relapse rate based on Kaplan-Meier curves analysis. The TSI bioassay showed a good ability to predict relapse GD in the female group (P = 0.041) but did not in the male group (P = 0.573). The risk scoring based on the nomogram with risk factors for GD relapse, which was constructed to overcome the limitation, increased the predictive ability of GD relapse by 11.5% compared to the use of the TSI bioassay alone.

Conclusions: The cutoff value of the TSI bioassay to predict GD relapse should be lower than that for diagnosing GD. However, as the single use of the TSI bioassay has limitations, a nomogram with multiple risk factors including TSI bioassay could be helpful to predict GD relaps e.


Graves' disease (GD) is one of the most well-known autoimmune thyroid diseases.[1] It is well known that the thyrotropin receptor antibody (TSH-R-Ab) plays an important role in the pathogenesis of GD by causing thyroid stimulation and inducing hyperthyroidism.[2] However, this TSH-R-Ab has a different action from the thyroid-stimulating hormone (TSH) receptor: stimulation or blocking.[1–3] Stimulating TSH-R-Ab activates the 3',5'-cyclic adenosine 5'-monophosphate pathway to stimulate the TSH receptor, thus inducing thyroid growth and increasing thyroid hormone production.[2,4] On the other hand, blocking TSH-R-Ab acts as an antagonist to the TSH receptor.[2,3]

There are 2 assays for TSH-R-Ab detection: the competitive thyrotropin-binding inhibitory immunoglobulin (TBII) assay and the thyroid stimulatory immunoglobulin (TSI) bioassay.[1] Immunoglobulins that inhibit the binding of radiolabeled TSH to the TSH receptor could be detected by the TBII assay.[5,6] The problem is that this assay measures thyroid-blocking immunoglobulins as well as TSIs.[6] On the contrary, the TSI bioassay could differentiate between stimulating TSH-R-Ab and blocking TSH-R-Ab.[7,8] The TSI bioassay can measure the 3',5'-cyclic adenosine 5'-monophosphate produced when TSI stimulates the TSH receptor.[5] Although the TBII assay has limitations, TBII offers an accurate diagnosis of GD, and the TSI bioassay is predictive of extrathyroidal manifestations.[6,9,10]

For the treatment of GD, there are 3 options: surgery, radioactive iodine treatment (RAI), or antithyroid drug (ATD).[4,10] While surgery or RAI treats GD by destroying thyroid tissue, ATD inhibits the synthesis of thyroid hormone to treat GD without destroying the thyroid structure. This is an advantage of ATD and a limitation simultaneously; the relapse from remaining thyroid tissue is always a concern.[11] According to previous studies, the relapse rate after ATD withdrawal almost approached 50%.[12,13] In addition, many clinical factors such as male sex, younger age, smoking, severe hyperthyroidism, large goiter, and orbitopathy are associated with a high relapse rate.[14] In addition, there is debate about ATD use during pregnancy because it could be harmful for embryonic development.[15]

Furthermore, TSH-R-Ab levels showed a good ability to predict relapse and disease course in previous studies.[16,17] In these studies, the TBII assay was used to measure TSH-R-Abs. Because it measures both stimulating and blocking antibodies, the TSI bioassay method appeared to be more accurate in predicting the course of disease.[18,19] Kwon et al showed that the TSI bioassay could better predict relapse after withdrawal from ATD.[20] However, they did not measure 2 assays (TBII and TSI bioassay) simultaneously in 1 person and used a predetermined cutoff point of the TSI bioassay derived from the diagnosis of GD, not based on the prognosis of GD. Because they only used the positivity of the assay without quantitative measurement, the exact cutoff value to predict relapse was difficult to find.

Although the TSI bioassay has a better ability to predict relapse of GD, it is not known whether the TSI bioassay cutoff value for diagnosing GD and predicting relapse is the same. Therefore, in this study, we tried to achieve the optimal TSI bioassay cutoff value to predict relapse after withdrawal from ATD in patients with the results of 2 assays. Furthermore, we tried to make a prediction model with confounding factors for the relapse of GD.