Analysis of risk factors of rapid thyroidal radioiodine-131 turnover in Graves’ disease patients

Rapid iodine-131(131I) turnover in the thyroid gland is an important feature of Graves’ disease (GD) and also a strong predictor of radioiodine therapy failure. The aim of this study was to explore the predictors of rapid 131I turnover. The clinical data on 2543 patients were retrospectively reviewed. Patients were divided into 2 groups depending on present or absent with rapid 131I turnover defined as a 4-hour to 24-hour 131I uptake ratio of ≥1. Overall, 590 cases (23.2%) had a rapid 131I turnover. In the univariate analysis, gender, age, FT3/FT4 concentration, disease duration, with or without antithyroid drugs (ATD), time of ATD, thyroid weight and thyroid textures displayed significant differences. Cutoff values of age, FT3 and thyroid weight to predict rapid 131I turnover were 38 years, 35 pmol/l and 56 g by receiver operating characteristic curves. Binary logistic regression analysis further revealed higher probability of rapid 131I turnover in patients with thyroid weight ≥56 g (odds ratio [OR]:3.7, 95% confidence interval [CI]: 3.032–4.559), age <38 years (OR:2.3, 95%CI: 1.906–2.856), FT3 concentration ≥35 pmol/l (OR:7.6, 95%CI: 5.857–8.563) and females (OR:2.2, 95%CI: 1.757–2.791). In conclusion, larger goiters, younger age, higher FT3 concentration and females are independently associated with rapid 131I turnover in GD patients.


Comparison of patient characteristics between groups. Demographic and clinical characteristics
of the 2 group patients studied are displayed in Table 2. We found subjects with rapid 131 I turnover had a higher first-dose failure rate (12.0% vs. 6.3%, OR = 2.018, 95%CI: 1.484-2.744, P < 0.0001). When we compared the categorical variables between groups using the chi square test, we found no statistically significant association in the complications (P = 0.782) and thyroid nodules (P = 0.643). However, there was significant difference in the gender composition (P < 0.0001), thyroid textures (P = 0.004) and with or without ATD (P < 0.0001).
Similarly, we found no statistically significant difference in the disease duration (P = 0.109), 4 h/24 h thyroid 131 I uptake (P = 0.206 and 0.534, respectively) when comparing the continuous variables in the 2 groups using the Mann-Whitney U test. However, we found younger patients, cases with higher FT 3 /FT 4 concentration and heavier thyroid weight, and those with longer time of ATD use more likely had rapid 131 I turnover (all P < 0.01).  (Fig. 1). The optimal cutoffs were the values yielding maximum sums of sensitivity and specificity from the ROC curves 17,18 . The results demonstrated that the optimal cutoff values for age and FT 3 concentration were 38 years old and 35 pmol/l, at which the sensitivity and specificity were 63.3%, 63.2% (for age) and 75.3%, 73.1% (for FT 3 ), respectively (area under curve [AUC]: 0.672; 95% CI: 0.646-0.697 and AUC: 0.815; 95% CI: 0.796-0.834, P < 0.001, respectively). Similarly, we found a thyroid weight threshold of 56 g, with a sensitivity of 67.3% and specificity of 65.6% for rapid 131 I turnover (AUC: 0.710; 95% CI: 0.687-0.733, P < 0.001). Table 3 shows a multivariate logistic regression analysis of the potential risk factors of rapid 131 I turnover. Variables that were significant in the univariate analysis were entered into the stepwise method. The multivariate logistic regression analysis revealed that patients with thyroid weight ≥56 g and FT 3 concentration ≥35 pmol/l demonstrated a 3.7-fold and 7.6-fold higher probability of rapid 131 I turnover, respectively, and cases with age < 38 years old showed a 2.3-fold higher probability. Additionally, female patients had a 2.2-fold higher probability of rapid 131 I turnover.

Logistic regression analysis.
Comparison of rapid 131 I turnover in patients with thyroid weight <56 g or ≥56 g, age <38years or ≥38years and FT 3 concentration <35 pmol/L or ≥35 pmol/L. A comparative analysis of the percent of rapid 131 I turnover, using the chi square test, between the patients with thyroid weight <56 g or ≥56 g, age <38 years or ≥38years and FT 3 concentration <35 pmol/l or ≥35 pmol/l was performed (Fig. 2).
We found a rapid 131 I turnover rate of 37.1% among patients with thyroid weight ≥56 g and 13.1% with thyroid weight <56 g (P < 0.0001). Additionally, the rapid 131 I turnover rates in patients with age <38 years and ≥38years were 33.2% and 14.6%, respectively (P < 0.0001). Similarly, we also found a rapid 131 I turnover rate of 40.3% among patients with FT 3 concentration ≥35 pmol/l and 8.2% with FT 3 concentration <35 pmol/l (P < 0.0001).  Table 2. Comparison of patient characteristics between the 2 groups. Data are presented as count (percentage) or median (range). *P value < 0.01 using chi square test. **P value < 0.01 using Mann-Whitney U test. FT 3 = free triiodothyronine, FT 4 = free thyroxine, SD = standard deviation, ATD = antithyroid drugs.

Discussion
Radioactive iodine ( 131 I) therapy is the most common modality for treatment of hyperthyroidism in the United States 2 . About 80-95% of GD patients could be controlled after first dose of 131I therapy, which is a relatively safe, simple and effective form of therapy 4,7,9 . In our institution, only 195 patients (7.7%) remained hyperthyroid after first-dose RIT. Rapid 131 I turnover in the thyroid gland is an important feature of GD and can be observed in 12-32% of patients with GD [12][13][14] . In the present study, we reviewed a large-sample GD patients and found the prevalence of rapid 131 I turnover is 23.2% in our patient population. Some investigators reported that rapid 131 I turnover was a strong predictor of RIT failure 12,14,15 , and Aktay et al. 12 found up to 55% of the GD patients with rapid 131 I turnover failed to respond to the initial 131 I therapy. Similarly, our study showed patients with 131 I uptake ratio of ≥1 have a higher first-dose RIT failure rate when comparing against those with 131 I uptake ratio of <1 (12.0% vs. 6.3%, P < 0.0001), although we delivered a higher concentration of 131 I per gram of thyroid tissue to patients with rapid 131 I turnover in our routine work. The higher failure rate of 131 I therapy among patients with rapid 131 I turnover might be explained by the rapid clearance or turnover of iodine-131 from the thyroid gland, which results in a shorter effective half-life of 131 I with less radiation subsequently delivered to the gland 12 . Therefore, patients with rapid 131 I turnover should receive a larger dose of 131 I in order to obtain higher RIT success rates.
The relatively high rapid 131 I turnover and first-dose RIT failure rate in patients with GD highlight the importance of identifying predictors of rapid 131 I turnover in this patient population. In our study, no differences were found in the disease duration, 4 h or 24 h thyroid 131 I uptake, and complications. Meanwhile, gender, age, FT 3 / FT 4 concentration, antithyroid medication, time of ATD, thyroid textures and thyroid weight could be used as the potential variables to predict rapid 131 I turnover in the univariate analysis. Female patients had a higher rapid 131 I turnover rate than males (26.5% vs. 15.9%). The FT 3 and FT 4 concentrations were higher in cases with rapid 131 I turnover (38.2 pmol/l vs. 31.3 pmol/l, and 86.5 pmol/l vs.78.9 pmol/l, respectively). The values of thyroid weight in patients with 131 I uptake ratio of ≥1 were heavier than those with 131 I uptake ratio of <1 (68.0 g vs. 48.5 g), and patients with rapid 131 I turnover were younger (33yrs vs. 42yrs). Furthermore, using multivariate logistic analysis, we found that gender, FT 3 concentration, thyroid weight and age were the independent factors related to rapid 131 I turnover. In our patient population, we verified that female patients had a 2.2-fold higher probability of rapid 131 I turnover. Moreover, patients with thyroid weight ≥56 g and FT 3 concentration ≥35pmol/l had a 3.7-fold and 7.6-fold higher probability of rapid 131 I turnover, with an accuracy of 71.0% and 81.5%, respectively. Additionally, we verified that patients with age <38 years old showed 2.3 times more risk of rapid 131 I turnover (accuracy 67.2%).
Rapid 131 I turnover has been ascribed to the so-called "small iodine pool syndrome, " which can be seen in patients pretreated with ATD 19,20 . Although ATD have short half-lives in blood, there is a high concentration and   Table 3. Comparison of predictors for rapid 131 I turnover by multivariate logistic regression analysis. FT 3 = free triiodothyronine, FT 4 = free thyroxine, OR = odds ratio, CI = confidence interval.
retention in the intra-thyroid environment, which may lead to a reduction in 131 I uptake and effective half-life of 131 I in the thyroid 19 . Thus, the 131 I turnover is faster in comparison to patients who were not treated. Additionally, patients who maintained anti-thyroid drug use during RIT also had a 4.9-fold higher risk of treatment failure in comparison to those who discontinued the medication 21 . In our study, 74.9% patients with rapid 131 I turnover had received antithyroid medications, comparing to 66.6% without rapid 131 I turnover (P < 0.001). However, a significant different finding in the univariate analysis was not upheld in the multivariate model, indicating that antithyroid medication prior to RIT is not considered to be a significant factor predicting rapid 131 I turnover.
As with most retrospective studies, this study has certain shortcomings. Firstly, the main weakness is the lack of data on thyroid autoantibodies titers, especially anti-thyrotrophin receptor antibody (TRAb) level which could be helpful in predicting disease severity and chance of RIT failure, whereas it was not available as a routine laboratory assessment during the time of data collection and we were unable to include it in our statistical analysis. Secondly, in this study, we only defined multiple 131 I therapies as first-dose RIT failure, however, although few, some patients lost to follow-up or chose other forms of treatment such as antithyroid medication or surgery after the initial RIT. Therefore, first-dose failure rate in this study was slightly lower.
In conclusion, the 4-to 24-hour 131 I uptake ratio appears to be a practical index for predicting early peaking of 131 I uptake in GD patients. The incidence of rapid 131 I turnover was high, which was expected in patients presenting larger goiters, younger age, higher FT 3 concentration and females, particularly those with thyroid weight ≥56 g, age <38 years, FT 3 concentration ≥35 pmol/l.

Materials and Methods
Subjects. Between June 2007 and March 2014, the medical records of hyperthyroid patients consecutively referred to the Thyroid Clinic for 131 I therapy were reviewed. The 131 I dose (MBq) = 131 I dose for per gram of thyroid tissue (MBq/g) × thyroid weight (g)/24h-RAIU. Of all the 2940 patients, a total of 2543 patients (793 men and 1750 women; age, 10-80 years) with the clinical diagnosis of GD were selected and 350 cases with other etiologies for hyperthyroidism, including multinodular goiter, plummer's disease and hashimoto's thyroditis were excluded. Additionally, the remaining 47 patients who had received RIT before were also excluded. GD was diagnosed on the basis of diffuse goiter, elevated 4-or 24-hour RAIU of the thyroid gland, thyrotoxicosis, and/or positive TRAb. All medications that could interfere with thyroidal 131 I uptake, such as seafood and some drugs (methimazole, propylthiouracil, compound iodine solution, probanthine, and so on), were stopped at least one week before RAIU measurements.
This study was approved by the medical ethics research committee of Tianjin Medical University General Hospital and written informed consent was obtained from each patient. We confrmed that all methods were carried out in accordance with the relevant guidelines and regulations.
Data collection and grouping. Data on gender, age, disease duration, thyroid function tests, with or without ATD, time of ATD, thyroid weight, 4 h/24 h thyroid 131 I uptake, thyroid textures (soft, moderate or stiff), thyroid nodules or not, with complications or not prior to RIT were collected for all patients.
All the patients were divided into 2 groups depending on present or absent with rapid thyroidal 131 I turnover (early peaking of 131 I uptake), which was defined as an early (approximately 4 hour)/late (approximately 24 hour) 131 I uptake ratio of ≥1.  A comparative analysis of the percent of rapid 131 I turnover between the patients with age <38 years or ≥38years (A), thyroid weight <56 g or ≥56 g (B) and FT 3 concentration <35 pmol/l or ≥35 pmol/l (C).

RAIU, thyroid function tests
SCieNTifiC RepoRTs | 7: 8301 | DOI:10.1038/s41598-017-08475-z Diagnostics GmbH, Mannheim, Germany). Length, breadth, and depth of each lobe was measured respectively, the volume of each lobe was calculated using the formula for a prolate ellipsoid, and estimated thyroid weight(g) = length × breadth × depth × π/6. 22 Statistical analysis. Statistical analysis was performed using SPSS (Statistical Package for Social Sciences) 12.0 for windows (SPSS, Chicago, IL, USA). Continuous and categorical variables were expressed as mean ± standard deviation (SD) (median [range]) and count (percentage), respectively. A chi square test was used to verify association or compare proportions. To compare continuous variables in the 2 groups, the Mann-Whitney U test was performed due to non-normal distributions. ROC curves were plotted to identify the best threshold for the potential predictors of rapid 131 I turnover. AUC was used as an estimation of diagnostic accuracy. To identify associated factors of rapid 131 I turnover, we performed multivariate logistic regression analysis with a variable entrance criterion of 0.05 or less. All P values presented were two-tailed, and values <0.05 were considered to be statistically significant.