Correlation Between TRAb and Early Onset Hypothyroidism After ¹³¹I Treatment for Gravesʼ Disease

Abstract

The aim of the study was to explore the clinical features related to early hypothyroidism and the relationship between the changes of thyrotropin receptor antibodies (TRAb) and early hypothyroidism in the course of ¹³¹I treatment for Graves’ disease. This study was a retrospective observation, including 226 patients who received the first ¹³¹I treatment. The general information and laboratory tests were collected before and after ¹³¹I treatment, and the laboratory data affecting the difference in disease outcome were analyzed. According to the changes of antibodies in the third month, whether the changes of antibodies were involved in the occurrence of early-onset hypothyroidism was analyzed. Early onset hypothyroidism occurred in 165 of 226 patients, and the results showed that the incidence of early hypothyroidism was higher in patients with low baseline TRAb level (p=0.03) and increased TRAb after treatment (p=0.007). Both baseline TRAb levels (p<0.001) and the 24-hour iodine uptake rate (p=0.004) are significant factors influencing the changes in TRAb. The likelihood of a rise in TRAb was higher when the baseline TRAb was less than 18.55 U/l and the 24-hour iodine uptake level exceeded 63.61%. Low baseline and elevated post-treatment levels of TRAb were significantly associated with early-onset hypothyroidism after ¹³¹I treatment. Monitoring this index during RAI treatment is helpful in identifying early-onset hypothyroidism and mastering the clinical outcome and prognosis of Graves’ disease.

Keywords

early onset hypothyroidism - ¹³¹I treatment - thyrotropin receptor antibody - Gravesʼ disease - retrospective observation

Introduction

Graves’ disease (GD) is an organ-specific autoimmune disorder characterized by excessive secretion of thyroid hormones. Its hallmark is the presence of thyroid-stimulating hormone receptor antibody (TRAb) in serum, which targets the thyroid-stimulating hormone receptor (TSHR) and is a key pathogenic component [1]. Its detection rate in untreated Graves’ disease patients can exceed 90%, showing a close relationship with the onset, recurrence, and course of the disease [2].

Radioactive iodine (RAI) therapy is increasingly used as a first-line treatment for GD. The mechanism involves the use of β radiation generated by ¹³¹I to damage thyroid tissue. Due to the short average range of β particles, the proposed method is safe and effective. RAI therapy boasts a high cure rate and relatively minor adverse reactions. Simultaneously, this approach is simple, economical, and preferred for patients with concurrent drug allergies, impaired liver function, and leukopenia.

However, the high rate of hypothyroidism following RAI treatment limits its widespread use. Over the last decade, RAI use has decreased even in the United States, in part due to patients’ tendency to avoid hypothyroidism and lifelong hormone replacement [3]. Hypothyroidism after RAI can be divided into early-onset hypothyroidism and late-onset hypothyroidism within 1 year, with the former having a high incidence. Previous studies reported that the incidence of hypothyroidism 1 year after RAI was about 80.9% [4]. Regarding treatment outcomes, age, sex, thyroid volume and mass, ATD treatment, iodine uptake rate, and ¹³¹I dose may be the influencing factors [5] [6] [7] [8] [9] [10], but the results are different. For example, high doses of ¹³¹I have been reported to be associated with success and hypothyroidism [11], while others have not [12].

Hypothyroidism is a common side effect of RAI therapy, and many patients with indications refuse this method, which leads to disease delay and aggravation. Furthermore, some patients neglect follow-up appointments, leading to delay diagnosis and treatment of early-onset hypothyroidism, which can result in severe or even permanent hypothyroidism. Therefore, studying the related factors of hypothyroidism after RAI therapy, optimizing the application of ¹³¹I, and identifying the occurrence of hypothyroidism at an early stage are the goals pursued by the majority of physicians. This article aims to identify predictive factors for early-onset hypothyroidism through a retrospective study, assisting clinicians in recognizing early-onset hypothyroidism and optimizing patient treatment.

Subjects and Methods

Study population

The study population consisted of Graves patients who were hospitalized in the Department of Endocrinology, the Second Affiliated Hospital of Soochow University from December 2010 to December 2022. Informed consent forms were signed before treatment, and precautions such as radiation protection and follow-up time were informed. The study has been approved by the Ethics committee of the Second Affiliated Hospital of Soochow University.

Inclusion criteria: 1. Patients meeting the Graves’ disease diagnostic criteria established by the American Thyroid Association in 2016 [13]; 2. Patients without contraindications to radioactive iodine and undergoing their initial isotope therapy; 3. Follow-up duration of 6 months to 1 year or longer; 4. Age ranges from 18 to 70 years.

Exclusion criteria: 1. Previous RAI or surgical treatment; 2. Incomplete or lost follow-up data 3. Patients with severe cardiac, hepatic, renal dysfunction, or concurrent malignancies.

Data collection

Clinical characteristics include gender, age, duration of disease (the months from the onset of the disease to treatment), 3-hour and 24-hour iodine uptake rates (3h-RAIU, 24h-RAIU), iodine intake, and the reason for RAI therapy. Serum markers include alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cre), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin receptor antibodies (TRAb), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TGAb). Measurements for TSH, FT3, and FT4 were conducted using a BECKMAN Dxl80 fully automated chemiluminescence analyzer. TRAb determination employed the Elecsys Anti-TSHR (Roche Diagnostics).

The dose of the isotope was calculated using the following formula:

(The dose of ¹³¹iodine was determined by nuclear medicine experts in our hospital and the thyroid mass was calculated based on clinical palpation or/and combined with thyroid color ultrasound. The expected dose per gram of thyroid tissue was determined according to the severity of the patient’s disease and thyroid mass).

Statistical analysis

All data were processed by SPSS27.0 statistical software. Normal continuous variables were represented by mean±standard deviation (SD), and inconsistencies were represented by median and upper and lower quartile distance M (P25,75). The measurement data of normality were compared by independent sample T-test; otherwise, Wilcoxon Mann–Whitney and Kruskal–Wallis rank sum tests were used. Univariate and multivariate logistic regression analyses were performed to find factors affecting TRAb, p<0.05 was statistically significant. Receiver operating characteristic (ROC) curves were generated to predict TRAb changes based on the examined indicators.

The study primarily encompasses: 1) Comparing disease outcomes among patients with different characteristics. 2) Comparing the baseline data of TRAb under different trends and exploring the association between TRAb changes and the occurrence of early-onset hypothyroidism.

Results

Characteristics of the patients

A total of 226 patients were qualified for the study based on the inclusion and exclusion criteria. Their basic characteristics are presented in [Table 1]. The reasons for RAI therapy were categorized into five groups, as illustrated in [Fig. 1] (Other reasons encompassed patients unwilling or unable to take medication long-term, joint pain after medication, thyroid enlargement of Grade II or higher, concurrent toxic multinodular goiter Mixed factors are defined as having two or more causes).

Fig. 1 Reasons for patients choosing ¹³¹I therapy in the last decade. The reasons why patients with hyperthyroidism choose isotope therapy mainly include the above six conditions.

Table 1 Characteristics of all patients.

Variables	Range
Male:Female	70 (30.97%):156 (69.03%)
Age (years)	40 (31,51)
Duration of disease (months)	12 (2,72)
3-h RAI uptake	60.64±18.36
24-h RAI uptake	71.91±13.18
Dose of RAI	7.5 (6.5, 8.5)

The basic characteristics of the patients were included in the article.

Effectiveness of RAI treatment and patient regression

The patients were divided into hypothyroidism group, remission group, and secondary treatment group according to the prognosis within 1 year. Comparison of baseline data among the three groups ([Table 2]) showed significant differences in duration of disease, ALT, and TRAb.

Table 2 Baseline comparison of outcomes.

	Hypothyroidism (n=165)	Remission (n=40)	Re-treatment (n=21)	p
Age	39 (330.5, 49.5)	41.5 (33.25,55.75)	48 (30,58)	0.154
Duration	10 (2,66)	24 (2.25,45)	54 (12,120)	0.017
3h-RAIU	58.85 (44.76,74.89)	59.28 (48.69,69.33)	74.53 (54.93,82.62)	0.187
24h-RAIU	72.67±12.55	69.29±13.55	73.89±15.53	0.34
Dose of RAI	7.5 (6.5,8.5)	7 (6,8)	7 (6,8.75)	0.287
ALT	31 (22,56.75)	34 (22,70)	16.5 (14,41)	0.013
AST	24.5 (18,40)	25 (14,34)	19 (13.25,29.75)	0.344
Cre	38.5 (32.25,48.75)	48 (35,55)	52 (35.75,62.5)	0.804
FT3	16.36 (8.58,20.15)	14 (9.08,20.4)	13.31 (8.12,16.99)	0.714
FT4	6.41 (3.63,47.14)	43.85 (5.2,53.11)	5.25 (2.44,33.84)	0.128
TSH	0.0065 (0.001,0.012)	0.001 (0.001,0.01)	0.02 (0.0093,0.036)	0.823
TRAb	7.53 (4.59,16.36)	8.63 (2.78,16.4)	16.36 (7.13,27.99)	0.03
TPOAb	171.12 (37.3,600)	212 (56.3,600)	481.65 (40.3,909.48)	0.4
TGAb	9.9 (0.8,48.5)	2.02 (0.3,73.24)	82.63 (44.68,950)	0.185

Age: The age of the patient at the time of treatment. Duration: duration of disease (month). This refers to the months from the onset of the disease to treatment According to the clinical prognosis, the patients were divided into three groups: Hypothyroidism, Remission and Re-treatment. There were significant differences in disease course, ALT, and TRAb among the three groups.

Hypothyroidism group: Patients with hypothyroidism at any time within one year were divided into hypothyroidism group.

Secondary treatment group: Those who needed re-treatment within 1 year were divided into the secondary treatment group.

Remission group: The remission group was defined as those with reduced hyperthyroidism severity.

Analysis of variation affecting antibody changes

The difference between baseline data and the time distribution of hypothyroidism in different antibody trends were analyzed, and the indexes affecting antibody changes were explored.

Elevated group: TRAb increased at month 3 compared to baseline data.

Reduced group: TRAb decreased at month 3 compared to baseline data.

The results showed that there were significant differences in 24hRAIU, FT3, TSH, and TRAb between the two groups at baseline ([Table 3]). TRAb changes were primarily influenced by 24-hour RAIU and baseline TRAb, according to single-factor and multiple-factor logistic models ([Table 4]). Higher 24-hour RAIU and lower baseline TRAb were associated with a greater likelihood of TRAb elevation. The ROC curve ([Fig. 2]) demonstrated an Area Under the Curve (AUC) of 0.725 for baseline TRAb, with a critical value of 18.55 IU/l; The AUC for 24-hour RAIU was 0.612, with a critical value of 63.61%. Analyzing the time of hypothyroidism, we found that the incidence of hypothyroidism was highest in the first 4 months, including 76.76% of the total number of patients in the elevated group and 56.09% in the reduced group. Drawing a bar chart based on the duration of hypothyroidism ([Fig. 3]), it was found that the first two months of hypothyroidism occurred in the reduced group (43%), while the highest proportion of hypothyroidism occurred in the elevated group at 3–4 months (55%).

Fig. 2 The ROC curve of TRAb influencing factors. All patients were divided into two groups based on antibody changes: Reduced group and Elevated group. The ROC curve indicated that TRAb baseline and 24 h RAIU were the main factors affecting TRAb variation.

Fig. 3 Percentage of hypothyroidism in each time period. The picture shows the proportion of hypothyroidism occurring in the two groups in different time periods. It can be seen that the proportion of hypothyroidism occurring in the first four months is the highest, and the occurrence of hypothyroidism decreases with the progress of time.

Table 3 Baseline difference in antibody change.

Clinical characteristics	Reduced group	Elevated group	p-Value
TRAb Before treatment	23.29±12.9	12.58±9.6	–
TRAb after treatment	17.74±11.69	33.4±10.05	–
Age (years)	50 (33,57)	39 (29,49.75)	0.254
3h-RAIU	64.42 (50.92,77.14)	63.33 (44.17,75.78)	0.453
24h-RAIU	72.02±11.75	72.26±13.53	0.009
Dose of RAI (mCi)	7.5 (6,8)	8 (6.5,9)	0.643
ALT	23 (19,34)	32.5 (21.25,62,5)	0.259
AST	24 (18,28)	24 (16.25,40)	0.787
Cre	35 (30,55)	40 (33,50.75)	0.309
FT3	15.84 (11.45,20.16)	15.48 (8.56,20)	0.046
FT4	30.38 (4.4,44.18)	8.76 (3.79,48.42)	0.056
TSH	0.002 (0.001,0.01)	0.008 (0.001,0.02)	0.014
TPOAb	302.5 (164,468.3)	107.5 (31.23,480)	0.83
TGAb	4.64 (0.9,48.5)	4.15 (0.51,44.14)	0.518

Table 4 Single-factor and multi-factor analysis.

Variables	Univariate analysis			Multivariate analysis
	B	OR (95% CI)	p	B	OR (95% CI)	p
24h-RAIU	0.036	1.037 (1.008,1.066)	0.011	0.048	1.049 (1.015,1.083)	0.004
FT3	–0.032	0.968 (0.937,1.000)	0.051	0.015	1.015 (0.962,1.071)	0.589
TSH	–1.314	0.269 (0.023,3.119)	0.306
TRAb	–0.084	0.919 (0.89,0.949)	<0.001	–0.090	0.913 (0.88,0.949)	<0.001

All patients were divided into two groups based on antibody changes: Reduced group and Elevated group. Univariate and multivariate analyses suggested that 24 h RAIU and TRAb baseline values were the main factors influencing the change of TRAb.

Discussion

In China, the prevalence rate of hyperthyroidism is high. Drug therapy is the first choice, but there are adverse reactions such as high recurrence rate, long course of treatment, and allergy. The failure of medication therapy in this trial was the primary factor in the decision to use RAI therapy. RAI therapy has the advantage of being rapid and simple, but the risk of hypothyroidism is high, which will increase the risk of cardiovascular disease, arrhythmia, and fracture. So, in this retrospective study, we looked for predictors of early hypothyroidism.

The 2016 edition of the Guidelines for the Diagnosis and Treatment of Hyperthyroidism of the American Thyroid Association clearly states that non-hyperthyroidism in patients with Graves’ disease after RAI therapy, including normal thyroid function and hypothyroidism, is considered a successful treatment. To reduce hypothyroidism, doctors always carefully formulate therapeutic doses. However, an analysis [14] has shown that there is no significant difference in outcome between the formula method and fixed dose. The differences in disease course, TRAb, and ALT indexes in patients with different treatment outcomes have attracted our attention, and this paper focuses on the analysis of TRAb. We found a significantly higher incidence of early hypothyroidism in patients with low baseline TRAb levels. It has been reported that a higher level of TRAb has a significant effect on iodine metabolism, which can enhance the ability of thyroid cells to take up iodine, accelerate the synthesis of thyroid hormone [15], and reduce the half-life of ¹³¹I. Therefore, we speculated that when TRAb levels were low before treatment, the synthesis function of thyroid hormone and the ability to cope with radiation damage were weak in this individual, and they could not “respond” better when they encountered radiation damage, so the incidence of hypothyroidism was relatively increased. Therefore, before RAI therapy, we need to pay attention to the baseline level of TRAb to help predict early onset hypothyroidism.

The relationship between the changes of TRAb and early hypothyroidism is still unclear. The biological requirements for thyroglobulin (TG) storage in thyroid follicular cells can be satisfied for three months. Why does hypothyroidism occur within three months of RAI treatment? Previous literature suggested that ionizing radiation produced by ¹³¹I could affect the apoptosis process of thyroid cells and lead to a decrease in thyroid hormone synthesis [16]. In addition, ¹³¹I can induce changes in the inflammatory response [17] and change the expression of Treg cells, B lymphocytes, and corresponding inflammatory factors. A number of studies [18] suggested that TRAb would increase immediately after RAI therapy and reach a peak value at about 3 months, which may be related to β rays destroying thyroid follicular cells and aggravating autoimmune reactions due to antigenic exposure to TSHR [19]. In our work, we also found that the duration of antibody elevation in most patients was about 3-6 months, followed by a slow decline for half a year. In addition, we found that the incidence of early onset hypothyroidism in the TRAb elevated group was 76.76%, whereas the reduced group was 56.09% (χ²=7.269, p=0.007<0.05), the difference was statistically significant. Does elevated TRAb indicate a stronger immune response, leading to more severe thyroid follicular cell damage? The β-rays produced by ¹³¹I affect the immune system and the process of apoptosis, the degree of influence of both, and the relationship with the therapeutic effect need to be further studied.

TRAb is a stimulatory thyroid antibody, which has a similar effect to TSH in promoting thyroxine production by thyroid follicular cells. When TRAb is reduced, thyroid hormone synthesis is diminished, and thyroid hormone levels are reduced, but why does an elevated TRAb accompany a higher incidence of hypothyroidism? Thyroid cells are highly specialized polarized epithelial cells that are highly sensitive to the stressful environment of the endoplasmic reticulum, the main site of protein synthesis. A large number of reactive oxygen species (ROS) generated by radiation damage can induce endoplasmic reticulum stress (ERS) [20], which is involved in down-regulating the expression of TSH receptor and the expression of sodium-iodide symporter (NIS), TPO, and TG, key molecules in thyroid hormone synthesis [21]. Therefore, we speculated that ¹³¹I radiation might interfere with the TSHR signaling pathway by inducing endoplasmic reticulum stress, leading to post-receptor defects. When thyroid hormone production is insufficient, it is manifested in the situation of increased antibody and hypothyroidism, which needs further verification.

In the process of RAI therapy, early prediction of hypothyroidism is helpful for timely detection and treatment. We found that both the baseline and the changing trend of TRAb had a certain predictive value in the occurrence of early-onset hypothyroidism. The baseline level of TRAb (p<0.001) and 24-hour iodine uptake rate (p=0.004) could affect the change of TRAb to some extent. By drawing the ROC curve, when the baseline serum TRAb was less than 18.55 U/l and the 24-hour iodine uptake rate level was more than 63.61%, the likelihood of TRAb elevation was higher. Therefore, for these patients, the relevant risks should be fully informed before treatment. After treatment, it is necessary to be especially vigilant about the occurrence of early hypothyroidism, and the follow-up time should be appropriately shortened, and follow-ups should be increased to better grasp the condition changes. This is a retrospective study, there is the problem of incomplete research data. The absence of thyroid ultrasound reports limits further studies of the association between thyroid volume and hypothyroidism. On the other hand, whether the disease course and ALT index are related to the prognosis of RAI therapy needs to be further verified. In addition, the relationship between long-term changes in TRAb and hypothyroidism needs further research.

Conclusions

In summary, ¹³¹I treatment of Graves’ disease is a complex process of change. By paying attention to baseline TRAb and the level of 24-hour iodine uptake before treatment and dynamically monitor serum TRAb after treatment, we can predict the occurrence of early-onset hypothyroidism and intervene early, to reduce untreated early-onset hypothyroidism and benefit patients better.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Lantz M, Planck T, Asman P. et al. Increased TRAb and/or low anti-TPO titers at diagnosis of Graves' disease are associated with an increased risk of developing ophthalmopathy after onset. Exp Clin Endocrinol Diabetes 2014; 122: 113-117
• 2 Hargreaves CE, Grasso M, Hampe CS. et al. Yersinia enterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves' disease. J Immunol 2013; 190: 5373-5381
• 3 Seib CD, Chen J, Iagaru A. Shifting trends and informed decision-making in the management of Graves’ disease. Thyroid 2020; 3: 351-354
• 4 Gibb FW, Zammitt NN, Beckett GJ. et al. Predictors of treatment failure, incipient hypothyroidism, and weight gain following radioiodine therapy for Graves' thyrotoxicosis. J Endocrinol Invest 2013; 36: 764-769
• 5 Allahabadia A, Daykin J, Holder RL. et al. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000; 85: 1038-1042
• 6 Sabri O, Zimny M, Schulz G. et al. Success rate of radioiodine therapy in Graves' disease: the influence of thyrostatic medication. J Clin Endocrinol Metab 1999; 84: 1229-1233
• 7 Moura-Neto A, Mosci C, Santos AO. et al. Predictive factors of failure in a fixed 15 mCi ¹³¹I-iodide therapy for Graves' disease. Clin Nucl Med 2012; 37: 550-554
• 8 Murakami Y, Takamatsu J, Sakane S. et al. Changes in thyroid volume in response to radioactive iodine for Graves' hyperthyroidism correlated with activity of thyroid-stimulating antibody and treatment outcome. J Clin Endocrinol Metab 1996; 81: 3257-3260
• 9 Walter MA, Christ-Crain M, Eckard B. et al. Radioiodine therapy in hyperthyroidism: inverse correlation of pretherapeutic iodine uptake level and post-therapeutic outcome. Eur J Clin Invest 2004; 34: 365-370
• 10 Zantut-Wittmann DE, Ramos CD, Santos AO. et al. High pre-therapy (99mTc) pertechnetate thyroid uptake, thyroid size, and thyrostatic drugs: predictive factors of failure in (¹³¹I) iodide therapy in Graves' disease. Nucl Med Commun 2005; 26: 957-963
• 11 Boelaert K, Syed AA, Manji N. et al. Prediction of cure and risk of hypothyroidism in patients receiving ¹³¹I for hyperthyroidism. Clin Endocrinol (Oxf) 2009; 70: 129-138
• 12 Liu M, Jing D, Hu J. et al. Predictive factors of outcomes in personalized radioactive iodine (¹³¹I) treatment for Graves' disease. Am J Med Sci 2014; 348: 288-293
• 13 Ross DS, Burch HB, Cooper DS. et al. 2016 American thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. J Thyroid 2016; 26: 1343-1421
• 14 Chen DY, Schneider PF, Zhang XS. et al. Striving for euthyroidism in radioiodine therapy of Graves' disease: a 12-year prospective, randomized, open-label blinded endpoint study. J Thyroid 2011; 21: 647-654
• 15 Sundaresh V, Brito JP, Wang Z. et al. Comparative effectiveness of therapies for Graves' hyperthyroidism: a systematic review and network meta-analysis. J Clin Endocrinol Metab 2013; 98: 3671-3677
• 16 Rooij A, Vandenbroucke JP, Smit JW. et al. Clinical outcomes after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism: systematic review and meta-analysis. Eur J Endocrinol 2009; 161: 771-777
• 17 Bojarska-Szmygin A, Janicki K, Pietura R. et al Changes in TSH receptor antibody levels (TRAb) as markers of effectiveness of various therapies in Graves-Basedow's disease. J Ann Univ Mariae Curie Sklodowska Med 2003; 58: 248-253
• 18 Fangdu Li, Jimin Yuan, Zhongjia Wei. et al. Changes of apoptosis molecules in serum of patients with Graves' disease treated with ¹³¹I and their correlation. J Marker Immunoassay Clin 2005; 208: 208-210
• 19 Jones BM, Kwok CC, Kung AW. Effect of radioactive iodine therapy on cytokine production in Gravesʼ disease: transient increases in interleukin-4 IL-4, IL-6, IL-10, and tumor necrosis factor-alpha, with longer term increases in interferon-gamma production. J Clin Endocrinol Metab 1999; 84: 4106-4110
• 20 Panganiban RA, Mungunsukh O, Day RM. X-irradiation induces ER stress, apoptosis, and senescence in pulmonary artery endothelial cells. Int J Radiat Biol 2013; 89: 656-667
• 21 Wen G, Ringseis R, Eder K. Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes. Plos One 2017; 12: 61-78

Publication History

Received: 29 November 2023

Accepted after revision: 15 February 2024

Article published online:
04 April 2024