2025 年 72 巻 5 号 p. 487-494
We investigated the association between a 500 MBq dose of radioactive iodine treatment (RAIT) and both thyroid nodule volume and thyroid function in patients with a single autonomous functioning thyroid nodule (AFTN). We retrospectively studied 201 patients with an AFTN who received RAIT at a dose of 500 MBq and were followed up for more than 2 years. Thyroid function at diagnosis, thyroid antibody positivity, treatment with antithyroid drugs before RAIT, cystic components of the nodule, and 131I uptake outside the nodule were assessed. Nodule enlargement was observed in 18 patients (9%), persistent hyperthyroidism in 13 patients (6.5%), and hypothyroidism in 45 patients (22.3%). Nodule volume before RAIT was significantly larger in the nodule enlargement group compared to the non-enlargement group. The risk factors for persistent hyperthyroidism were larger nodule volume and absence of a cystic component in multivariate analysis. The cutoff nodule volume before RAIT for predicting nodule enlargement was 15.5 mL, and for predicting persistent hyperthyroidism was 16.6 mL. Nodule volume decreased to 47% in the first year and continued to gradually decrease thereafter. This study provided long-term outcome data regarding nodule volume change and thyroid function in AFTN patients following single fixed-dose RAIT, and it identified risk factors for nodule enlargement and persistent hyperthyroidism after RAIT. Nodule volume before treatment was a good predictor of treatment response.
A single autonomous functioning thyroid nodule (AFTN) has been reported to occur at a lower incidence among thyrotoxicosis patients in regions with adequate iodine intake than among thyrotoxicosis patients in low-iodine-intake regions [1]. Autonomous functional thyroid nodules (AFTNs) are common in older age groups of thyrotoxicosis patients, and they are more common in women, in whom incidences 4 to 10 times higher than in men have been reported [2, 3]. In Japan, AFTNs in thyrotoxicosis patients have been treated surgically, by radioactive iodine treatment (RAIT), or with antithyroid drugs (ATDs). Definitive treatment by surgery or RAIT is recommended since thyrotoxicosis recurs after discontinuation of ATD therapy. Radiofrequency ablation is not a widely used treatment method in Japan, because it is not covered by the national health insurance policy. Since July 2002, Ito Hospital has been using a fixed 500 MBq dose of RAIT to treat most AFTN cases. However, to date, evidence is lacking regarding how nodule volume and thyroid function varies after RAIT among patients with AFTN in Japan.
Therefore, we aimed to describe the long-term outcome (i.e., nodule volume and thyroid function) after a single RAIT in a large AFTN case series. We also investigated possible risk factors for developing hyperthyroidism, nodule enlargement, and hypothyroidism after RAIT, using information on the size of the nodule before RAIT, thyroid hormone levels before RAIT, TgAb and/or TPOAb positivity, and ATD treatment before RAIT.
This was a retrospective cohort study conducted at Ito Hospital. We reviewed the medical records of 247 patients diagnosed with AFTN between March 2005 and December 2020 who had undergone RAIT at a dose of 500 MBq at least once. The definition of AFTN in this study was based on the laboratory findings in the form of a suppressed thyrotropin (TSH) level, a negative TSH receptor antibody (TRAb) test, and increased single nodular radioactive iodine uptake and decreased uptake in the surrounding extranodular thyroid tissue (Fig. 1a, b). No patients with toxic multinodular goiter were included. All subjects had been diagnosed with overt hyperthyroidism or subclinical hyperthyroidism. After the diagnosis was established, patients were informed that they had two treatment options: surgery and RAIT. Surgery was recommended for patients with a large AFTN and RAIT was provided as an option for those who did not wish to undergo surgery. ATDs were used to treat patients with severe symptoms of hyperthyroidism or with cardiac complications. After RAIT, a diagnosis of hypothyroidism was made when fT4 level was below the lower limit of the assay’s reference range, and/or TSH level was higher than 10 μIU/mL. We excluded the 46 patients with <2 years of follow-up after RAIT, resulting in the final analytical sample of 201 patients.
a: A thyroid scintigraphy image showing strong radioactive iodine accumulation in a single nodule and slight, sparse accumulation in the surrounding area
b: A thyroid scintigraphy image showing radioactive iodine accumulation in a single nodule alone and no accumulation in the surrounding area
RAIT was performed after confirming that the nodule was benign based on the aspiration cytology findings. Iodine intake restriction was initiated 8 days prior to RAIT. If a patient was being treated with ATDs before RAIT, they were discontinued 8 days prior to RAIT. This study was approved by the Ethics Committee of Ito Hospital (Approval No. 359, 2021).
Laboratory and ultrasonography measurementsThyroid function was assessed monthly for four months after RAIT, then six months and one year after RAIT, and often on an annual basis thereafter. TSH, fT3, and fT4 levels were measured by electrochemiluminescence immunoassays (Elecsys TSH, Elecsys fT3, and Elecsys fT4, respectively; Roche Diagnostics GmbH, Basel, Switzerland). The manufacturers’ reference ranges were: TSH 0.2–4.5 μIU/mL, fT3 2.2–4.3 pg/mL, and fT4 0.8–1.6 ng/dL. TSH receptor antibody (TRAb) levels were determined with a commercial radioimmunoassay kit (TRAb-CT; RSR, Cardiff, UK) and expressed as percentage (%) inhibition of binding according to the manufacturer’s instructions (reference values <10%) until September 30, 2008, and since October 1, 2008, they have been determined with an electrochemiluminescence immunoassay kit (Elecsys TRAb; Roche Diagnostics GmbH, Basel, Switzerland; reference values <2.0 IU/L). Anti-thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were determined by solid-phase RIA kits (Cosmic Corp., Tokyo, Japan, until May 31, 2006, and Roche Diagnostics GmbH, Basel, Switzerland since June 1, 2006).
Ultrasonography was performed in 95 cases (47.3%) at six months post-RAIT and in 141 cases (70.1%) at one year post-RAIT, and on an annual basis thereafter. Thyroid nodule volume was estimated by measuring the length, width, and depth of each nodule in millimeters, and calculating the volume by the following formula: thyroid nodule volume = (0.52 × length × width × depth) [4]. The definition of tumor growth was determined as an increase in the tumor volume, calculated by ultrasound after treatment, to a volume greater than 100% compared to the tumor volume before treatment.
Statistical analysisBaseline characteristics between presence and absence of nodule enlargement were analyzed by the Wilcoxon rank-sum test for continuous variables and Fisher exact test for categorical variables. Characteristics between the three groups (Euthyroid, Hyperthyroid, Hypothyroid) were analyzed by the Kruskal-Wallis test and Dunn-Bonferroni-Test for continuous variables and chi-square test for categorical variables. We then conducted a multivariable logistic regression analysis to identify independent risk factors for nodule enlargement, persistent hyperthyroidism, and hypothyroidism. We selected age, sex, and other explanatory variables with a p value <0.10 in the univariate analysis to insert as risk factors in the model. A receiver operating characteristic (ROC) curve analysis was performed to determine cutoff values. The Kaplan-Meier method was used to evaluate cumulative incidence. The comparisons of the tumor volume ratios at each subsequent year relative to the baseline volume (the baseline volume was set equal to 100%) were performed using the Kruskal-Wallis Test and Dunn-Bonferroni-Test. All statistical analyses were performed with JMP software version 14.0. (SAS Institute, Inc., Cary, NC), and p values <0.05 were defined as statistically significant.
The median (interquartile range) age was 53 (41–64), and 90% were females (Table 1). Four of the 201 patients followed up for more than two years had undergone RAIT twice (all four had persistent hyperthyroidism, and one had nodule enlargement), and three had undergone RAIT three times (three had persistent hyperthyroidism, and two had nodule enlargement). In addition, four patients had undergone surgery after RAIT (three had persistent hyperthyroidism, and two had nodule enlargement). The median follow-up period was 1,484 days (IQR 959–2,267 days), and nodule enlargement was observed in 18 (9%) of these 201 patients. Sustained hyperthyroidism in 13 (6.5%), and hypothyroidism in 45 (22.3%) at the end of the follow up period.
| Age (yr) | 53 (19–83) |
| Sex (female/male) | 181/20 |
| FT3 (pg/mL) [reference range: 2.2–4.3] | 5.3 (3.0–22.4) |
| FT4 (ng/dL) [reference range: 0.8–1.6] | 1.7 (0.93–7.01) |
| TSH (μIU/mL) [reference range: 0.2–4.5] | 0 (<0.01–0.17) |
| TgAb-positive | 26 (12.9%) |
| TPOAb-positive | 17 (8.5%) |
| Volume of the AFTN (mL) | 11.2 (0.7–113.6) |
| Maximum diameter (mm) | 38.1 (14.6–75.2) |
Median (range)
Table 2 shows the characteristics of cases according to whether nodule enlargement was present or absent after a single RAIT. Nodule volume and maximum nodule diameter before RAIT were significantly larger in the nodule enlargement group compared to the non-enlargement group (nodule volume: median 17.8 mL vs. 10.7 mL, p = 0.003; maximum nodule diameter: median 40.5 mm vs. 38.0 mm, p = 0.02). No association was found between age, sex, thyroid hormone levels, TgAb positivity, TPOAb positivity, uptake outside the nodule, or treatment with ATDs and nodule enlargement. Based on the results of the univariate analysis, nodule volume before RAIT and FT4 at diagnosis were included in addition to age and sex as explanatory variables in the multivariable regression models. Although nodule volume and FT4 at baseline tended to be associated with nodule enlargement, none of the correlations with the predictors were statistically significant. The ROC curve analysis showed that the cutoff nodule volume and cutoff maximum nodule diameter before RAIT for predicting nodule enlargement were 15.5 mL (sensitivity 61%, specificity 71%, area under the ROC curve [AUC] 0.70) and 53.4 mm (sensitivity 33%, specificity 95%, AUC 0.61), respectively.
| Nodule enlargement | Present | Absent | p |
|---|---|---|---|
| Number of patients | 18 | 183 | |
| Age (yr) | 55 (32–74) | 52 (19–83) | 0.59 |
| Sex (female/male) | 14/4 | 167/16 | 0.09 |
| FT3 (pg/mL) | 4.85 (3.0–22.4) | 5.3 (3.0–18.2) | 0.83 |
| FT4 (ng/dL) | 1.75 (1.28–6.61) | 1.7 (0.93–7.01) | 0.1 |
| TSH (μIU/mL) | 0 (<0.01–0.12) | 0 (<0.01–0.17) | 0.95 |
| TgAb-positive | 1 (5.6%) | 25 (13.7%) | 0.47 |
| TPOAb-positive | 2 (11.1%) | 15 (8.2%) | 0.65 |
| Volume of the AFTN (mL) | 17.8 (5.7–92.6) | 10.7 (0.7–113.6) | 0.0031 |
| Maximum diameter (mm) | 40.5 (33.3–55.7) | 38 (32.6–44.7) | 0.02 |
| RAI uptake outside the nodule | 7 (38.9%) | 62 (33.9%) | 0.79 |
| Cystic component within the nodule | 8 (44.4%) | 92 (50.3%) | 0.80 |
| Prior ATD treatment | 6 (33.3%) | 40 (28.9) | 0.41 |
| Post-RAIT follow-up period (days) | 1,343 (794–2,661) | 1,525 (732–6,079) | 0.07 |
| Follow-up period from RAIT to the final ultrasound examination | 1,265 (176†–3,053) | 1,566 (791–4,532) | 0.06 |
| Final Outcome: Euthyroid | 12 | 131 | |
| Hyperthyroid | 4 | 9 | |
| Hypothyroid | 2 | 43 |
Median (range)
†The shortest interval between RAIT and the final thyroid ultrasound examination was 176 days, as the patient required surgery following RAIT.
Table 3 shows the characteristics of patients who had persistent hyperthyroidism after a single RAIT. The univariate analysis identified older age, higher FT4 level at diagnosis, and larger nodule volume (indicated by a larger maximum diameter) as factors associated with persistent hyperthyroidism post-treatment. The absence of a cystic component was also associated with the persistent hyperthyroidism. No association was found between TgAb positivity, TPOAb positivity, uptake outside the nodule, or treatment with ATDs and persistent hyperthyroidism. Based on the results of the univariate analysis, age, FT4 at diagnosis, nodule volume before RAIT, and a cystic component within the nodule were included in the multivariable regression models. We found a statistically significant association of the volume of the AFTN (p = 0.00006), absence of a cystic component (p = 0.008) and older age (p = 0.02) with persistent hypothyroidism after a single RAIT. The ROC curve analysis showed that the cutoff nodule volume and cutoff maximum nodule diameter before RAIT for predicting persistent hyperthyroidism was 16.6 mL (sensitivity 84%, specificity 76%, AUC 0.84) and 46.2 mm (sensitivity 69%, specificity 83%, AUC 0.79), respectively.
| Euthyroid | Hyperthyroid | Hypothyroid | |
|---|---|---|---|
| Number of patients | 143 | 13 | 45 |
| Age (yr) | 53 (20–80) | 67 (43–76)* | 47 (19–83) |
| Sex (female/male) | 129/14 | 11/2 | 41/4 |
| FT3 (pg/mL) | 5.2 (3.0–16.8) | 5.5 (3.9–18.2)* | 5.3 (3.0–22.4) |
| FT4 (ng/dL) | 1.67 (0.93–4.39) | 2.04 (134–7.01)* | 1.74 (1.09–6.61) |
| TSH (μIU/mL) | 0 (<0.01–0.17) | <0.01 | 0 (<0.01–0.13) |
| TgAb-positive | 19 (13.3%) | 0 (0%) | 7 (15.6%) |
| TPOAb-positive | 12 (8.4%) | 0 (0%) | 5 (11.1%) |
| Volume of the AFTN (mL) | 11.3 (0.7–113.6) | 20.9 (8.3–92.6)* | 8.8 (0.8–28.1) |
| Maximum diameter (mm) | 37.8 (14.6–74.3) | 46.9 (30.5–75.2)* | 38 (14.9–58.1) |
| RAI uptake outside the nodule | 44 (30.8%) | 4 (30.7%) | 21 (46.7%) |
| Cystic component within the nodule | 73 (51.0%) | 2 (15%)* | 25 (55.6%) |
| Prior ATD treatment | 25 (28.7%) | 5 (38%) | 16 (48.5%)** |
| TSH when RAIT performed in prior ATD treatment cases | 0 (<0.01–0.1) n = 18 |
0 (<0.01–0.01) n = 5 |
0.02 (<0.01–0.46) n = 8 |
| Post-RAIT follow-up period (days) | 1,483 (732–6,079) | 1,323 (773–3,213)* | 1,615 (818–5,116) |
Median (range)
*Significant difference between the euthyroid group and hyperthyroid group; **significant difference between the euthyroid group and hypothyroid group.
Table 3 shows the characteristics of the patients with hypothyroidism after a single RAIT. There were no significant differences between the groups in antibody positivity or follow-up period after RAIT, and there were no significant differences in pre-treatment nodule volume, RAI uptake outside the nodule, or the presence of a cyst. Prior ATD treatment was significantly more common in the hypothyroidism group (p = 0.02). The TSH level of 31 of the 46 patients who received ATD treatment prior to RAITs was measured on the day RAIT was performed. The median TSH level in the hypothyroidism group was 0.02 μIU/mL, but there were no statistically significant differences from the values in the euthyroid group and hyperthyroidism group. These findings are shown in Table 3. To identify risk factors for hypothyroidism, we further analyzed 190 patients who received a single RAIT and no additional treatment. In three patients, persistent hyperthyroidism was present. Based on the results of the univariate analysis, FT4 at diagnosis, nodule volume before RAIT, RAI uptake outside the nodule, and prior ATD treatment was included in the multivariable regression models. We identified pre-treatment nodule volume alone as a predictor of hypothyroidism, but the AUC was only 0.59 (sensitivity 67%, specificity 51%). The cutoff nodule volume for predicting hypothyroidism was 11.2 mL.
Outcomes of RAIT: Achievement of Euthyroidism, Development of Hypothyroidism, Nodule Volume ReductionThe median time to the achievement of euthyroidism after RAIT among the 201 patients included in our study was 90 days (Fig. 2), and improvement in function was observed in 88.8% of the patients within one year. The median time to the development of hypothyroidism among the 190 patients who received a single RAIT and no additional treatment was 178 days (Fig. 3). Fig. 4 and Graphical Abstract shows a plot of the nodule volume ratios each year, with nodule volume before treatment set equal to 100%. Nodule volume decreased to 47% in the first year. The tumor volume showed a statistically significant reduction (p = 0.0002). Dunn test revealed that the tumor volume showed a statistically significant reduction between the first and third years and between the first and seventh years of treatment. Although the number of patients who underwent ultrasonography decreased, there was an overall trend of reduction in nodule size.
The median interval between RAIT and the achievement of euthyroidism (n = 201). The y-axis represents euthyroidism probability.
The median interval between RAIT and the development of hypothyroidism (n = 190; patients who received a single RAIT and no additional treatment). The y-axis represents hypothyroidism probability.
A plot of the nodule volume ratio each year, with the volume before treatment set equal to 100%. Median nodule volume had decreased to 47.0% of the pre-treatment volume at 1 year, to 36.9% at 2 years, and to 29.8% at 3 years.
In this retrospective cohort study using long-term follow-up data after RAIT, nodule enlargement and persistent hyperthyroidism were observed in 9% and 6.5% of patients after treatment by RAIT. The volume of the AFTN was associated with nodule enlargement and persistent hyperthyroidism after a single RAIT. The absence of a cystic component was also associated with persistent hyperthyroidism after RAIT. These findings suggest that the nodule volume could be a useful indicator to assess future nodule enlargement and persistent hyperthyroidism when applying RAIT for patients with AFTN.
To date, there have been several reports regarding the RAIT for AFTN. Nygaard et al. reported persistent hyperthyroidism in 6% and hypothyroidism in 8% of a group of 62 patients with AFTN treated by RAIT, and final tumor volume was reduced to 45%. Several RAITs were required in 14% of the patients in their cohort, and the median RAIT dose was 322 MBq (148–1,576 MBq) [5]. Ceccarelli et al. reported a study of 346 patients with AFTN treated with RAIT and that 60% of the patients were hypothyroid after a 20-year follow-up period (11% required several RAITs). The RAI dose was 481 ± 181 MBq for nodules less than 4 cm and 629 ± 255 MBq for nodules larger than 4 cm, and the total dose in the cases treated more than once was 999 ± 300 MBq. The factors that increased the risk of hypothyroidism in their study were older age, RAI uptake, and pretreatment with ATDs. They did not investigate thyroid nodule volume reduction [6]. Yano et al. studied 50 patients with functioning nodules (15 patients with AFTN, 35 patients with TMNG) who received a RAIT dose of 500 MBq of RAIT. In their study 14% of the patients remained hyperthyroid, and 18% became hypothyroid. Thyroid nodule volume change was not investigated [7].
In the present study, among the 201 patients who received a single RAIT dose of 500 MBq, 6.5% were hyperthyroid, 71.2% had normal thyroid function, and 22.3% were hypothyroid at the end of the follow-up period (Graphical Abstract).
The median time to achieving euthyroidism after RI therapy was 90 days, which was consistent with the results of a previous study [5]. The risk factors for persistent hyperthyroidism were lack of a cystic component in the nodule and large nodule volume. Nine patients had a solid tumor containing a cystic component less than 5 mm in size, and none of them exhibited persistent hyperthyroidism. Even when the cases with a cystic component less than 5 mm in size were analyzed together with the cases without a cystic component, the results remained consistent, indicating that their presence had no impact on the results of the analysis. The cutoff nodule volume and cutoff maximum nodule diameter before RAIT for predicting persistent hyperthyroidism were 16.6 mL and 46.2 mm, respectively. Ronga et al. reported a high incidence of persistent hyperthyroidism after RAIT of 12.7% in patients with large nodules (50 g or larger) and concluded that surgery should be recommended in such patients [8]. In previous reports it was estimated that patients who underwent radioiodine therapy for autonomous thyroid disease had a 1.1% risk of developing post-radioiodine immunogenic hyperthyroidism or Graves’ disease (GD) [9]. There was no evidence suggesting a rapid exacerbation of hyperthyroidism indicating the onset of GD in the cohort analyzed in our study, and TRAb levels were not measured.
The only factor for hypothyroidism after RAIT identified in their study was small nodule volume, but the AUC was only 0.59, and the cutoff nodule volume for predicting hypothyroidism was 11.2 mL. The same had been reported in previous studies; there was no correlation between either TgAb positivity or TPOAb positivity and thyroid function outcome [6, 7, 10, 11], and the results of our study were consistent with the findings in previous studies. Pre-treatment with ATDs has been reported to be a risk factor for hypothyroidism after RAIT [6], but we found no association between pretreatment with ATDs treatment and hypothyroidism after RAIT. ATDs were prescribed for patients with severe symptoms of thyrotoxicosis. There was no association observed between the history of MMI administration and the minimal presence of RAI uptake outside nodules. The limited number of patients treated with MMI, with only 46 cases, may have affected the statistical significance of the findings.
The RAIT protocols have varied from study to study, and the doses of 131I have also varied. Zakavi et al. compared four different RAIT doses: a fixed low dose (481 MBq), fixed high dose (832 MBq), calculated low dose (3.33–3.70 MBq/g), calculated high dose (6.66–7.4 MBq/g), and they found that high dose treatment resulted in hypothyroidism after RAIT [12]. In our study, the administered activity was 500 MBq in all cases, and administered dose for large AFTN might have been insufficient according to the Dr. Zakavi’s regimen.
RAI uptake outside the nodule has been reported to be a risk factor for post-treatment hypothyroidism [13], but we did not find any association between the presence of RAI uptake outside nodules and post-treatment hypothyroidism. The reason for this discrepancy was the clearly higher treatment dose in the previous study (mean dose 1,167 MBq) than in our own study (500 MBq).
In our own study, nodule volume decreased in most patients, and the maximum volume reduction occurred in the first year after RAIT. By contrast, nodule volume increased in 9% of the patients, and the risk of an increase in nodule volume was greater when nodule volume was above 15.5 mL.
Our study had several limitations. First, due to the nature of the retrospective cohort study design, we cannot rule out the possibility of unmeasured variables (e.g., metabolic disorders and other treatments patients might have received during the study period) that might influence our findings, and we did not have information on overall thyroid gland size, which might have influenced RI uptake. Second, ultrasound images were not available for all years of follow-up for every patient, which could introduce selection bias. Third, thyroid antibodies were tested at their first visit to our hospital, not when RAIT was performed, and thus our findings might suffer from measurement error. Lastly, a single-center study design also limits the generalizability of our findings.
In conclusion, our study provided long-term outcome data following a single fixed-dose RAIT in terms of thyroid function and nodule volume change in AFTN patients, and it identified risk factors associated with persistent hyperthyroidism and nodule enlargement after RAIT. Nodule size less than 15 mL can be considered a reference value for choosing radioiodine therapy in the treatment of AFTNs.
We would like to extend our deep gratitude to the Ito Hospital staff for their unwavering dedication to patient care and diligent data collection.
The authors declare that they have no conflicts of interest to report in regard to this study.
Natsuko Watanabe and Kiminori Sugino are members of Endocrine Journal’s Editorial Board.
No funding was received for this article.
