Abstract
Objective
To investigate the impact of urinary iodine concentration (UIC) and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of differentiated thyroid cancer (DTC) patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors.
Methods
A total of 213 DTC patients received initial radioiodine therapy from June 2022 to September 2023. Demographic data and UIC were collected before and after therapy. Thyrotropin, thyroglobulin (Tg), and thyroglobulin antibody levels were assessed. Iodine uptake rate was measured, and therapeutic efficacy was evaluated 6 months post-therapy. Statistical tests were used for data comparison, and logistic regression analysis for response factors.
Results
Post-therapy UIC and pre-post UIC difference were significantly correlated with Tg levels but not with reaching excellent response (ER) indicated by suppression of Tg levels below 0.2 ug/L. Ps-Tg levels related to therapeutic efficacy, while UIC did not correlate with outcomes. ROC curve analysis found optimal ps-Tg cut-off points for the low-intermediate and high-risk groups classified by primary tumor size, invasion, metastasis, and pathological type.
Conclusion
Post-treatment UIC and pre-post UIC difference correlate with ps-Tg levels. Ps-Tg levels are an associated factor for DTC, but UIC changes, despite correlation with ps-Tg, are not significantly related to outcomes and cannot be used as a prognostic factor.
Plain Language Summary
Objective
To investigate the impact of urinary iodine concentration (UIC) and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of differentiated thyroid cancer (DTC) patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors.
Methods
213 DTC patients received initial radioiodine therapy from June 2022 to September 2023. Demographic data and UIC were collected before and after therapy. Thyrotropin, thyroglobulin, and thyroglobulin antibody levels were assessed. Iodine uptake rate was measured, and therapeutic efficacy evaluated 6 months post-therapy. Statistical tests were used for data comparison and logistic regression analysis for response factors.
Results
Post-therapy UIC and pre-post UIC difference were significantly correlated with thyroglobulin levels but not with reaching excellent response (ER) where suppression of Tg levels below 0.2ug/l. Ps-Tg levels related to therapeutic efficacy, while UIC did not correlate with outcomes. ROC curve analysis found optimal ps-Tg cut-off points for low-intermediate and high-risk groupsclassified by primary tumor size, invasion, metastasis, and pathological type.
Conclusion
Post-treatment UIC and pre-post UIC difference correlate with ps-Tg levels. Ps-Tg levels are an associated factor for DTC, but UIC changes, despite correlation with ps-Tg, are not significantly related to outcomes and cannot be used as a prognostic factor.
Keywords
Introduction
Thyroid cancer is the most common endocrine malignancy, with four main histological types: papillary thyroid cancer (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma, and anaplastic thyroid carcinoma. Approximately 85% to 90% of all thyroid cancers are PTC.1-3 PTC and FTC are collectively referred to as differentiated thyroid carcinoma (DTC), for which the standard treatment regimen typically includes surgery, radioactive iodine-131 (131I) therapy, and thyroid hormone replacement therapy.
Due to the unique anatomy of the thyroid gland, even total thyroidectomy may leave residual thyroid tissue. Differentiated thyroid cancer cells possess the ability to concentrate iodine, allowing 131I to specifically target these cells via their beta radiation effects, resulting in a proven clinical efficacy. Extensive research has demonstrated that postoperative 131I therapy for DTC patients can prolong survival and improve prognosis. 4 Postoperative 131I therapy, recognized internationally as an effective method for treating thyroid papillary cancer, eliminates residual cancer cells or thyroid tissue, reducing recurrence rates. Studies have shown that using 131I for clearance therapy after thyroidectomy can effectively reduce disease recurrence rates in patients. The primary roles of postoperative 131I therapy include: reducing local lesion recurrence, lowering mortality, identifying previously unknown metastases through whole-body 131I scanning; and enhancing the sensitivity of thyroglobulin (Tg) testing. Therefore, postoperative 131I therapy for differentiated thyroid cancer patients facilitates improved tumor staging and further treatment, significantly improving quality of life, making it a simple, safe, and effective treatment option. 5
Patients undergoing 131I therapy for differentiated thyroid cancer must adhere to a low-iodine diet, reduce their body’s iodine pool levels, stop taking thyroid hormones, and increase their thyroid-stimulating hormone levels to enhance thyroid iodine uptake capacity. Understanding patient iodine levels is therefore crucial, as iodine is a raw material for thyroid hormone synthesis and plays a regulatory role in metabolism and development. Most iodine in the human body is absorbed from the digestive tract, with over 80% excreted by the kidneys. Thus, urinary iodine concentration(UIC) closely correlate with iodine salt intake, 6 making urinary iodine testing the most specific and sensitive indicator for monitoring iodine nutrition status.
This study aims to investigate the impact of UIC and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of DTC patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors. 7 Specific objectives include evaluating the correlation between post-treatment UIC, pre-post UIC changes, and ps-Tg levels, as well as the relationship between Ps-Tg levels and therapeutic efficacy, while determining the optimal Ps-Tg cut-off points for different risk groups.
Patients and Methods
Patients
We collected data from 213 differentiated thyroid cancer patients who underwent initial iodine therapy between June 2022 and September 2023. For all participants, age, gender, TNM staging, and risk stratification were recorded, and all patient details were de-identified. The study was approved by the Ethics Committee of China National Nuclear Corporation 416 Hospital (approval no. YJ-2024-037), and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The requirement for informed consent was waived by our Institutional Review Board because of the retrospective nature of the study. All patients were divided into two groups: low-intermediate risk and high-risk. The assessment of efficacy in DTC can be divided into excellent response (ER) and non- excellent response (non-ER). Suppression of Tg levels below 0.2 ug/L is considered indicative of ER, while levels above this threshold are considered non-ER.8,9
Inclusion Criteria
Patients who have undergone total or subtotal thyroidectomy, whose pathological reports meet the diagnostic criteria for differentiated thyroid cancer, are scheduled for their first iodine therapy, have stopped taking thyroid hormone for at least 3 weeks and have a TSH > 30 mIU/ml, and have been on a low-iodine diet for 1 month are included in the study.
Exclusion Criteria
Patients with incomplete clinical data, those undergoing second or subsequent iodine therapies, those with other autoimmune diseases, those taking medications that clearly affect thyroid hormone levels, those with rheumatological immune diseases, anemia, chronic diseases (e.g., hepatic and renal insufficiency, cirrhosis, nephrotic syndrome, chronic cardiac insufficiency, chronic infectious diseases, malignancies), or a history of hypothalamic or pituitary diseases are excluded from the study.
Urinary Iodine Measurement
On the day of admission and 3 days after iodine therapy, 10 mL of first-morning urine was collected from each patient to measure urinary iodine using the arsenic-cerium catalytic spectrophotometry method described in “Determination of Iodine in Urine” (WS/T 107—2006). These values were recorded as the pre-iodine therapy UIC and the post-iodine therapy UIC.UIC were expressed as the median urinary iodine (MUI).Radiation safety precautions have been implemented when collecting urine samples following radioiodine therapy.
Serum Thyroid Stimulating Hormone, Thyroglobulin, and Antithyroglobulin Antibody Determination
Fasting venous blood samples of 5 mL were collected 1 day before and 6 months after iodine-131 therapy to determine the levels of thyroid stimulating hormone (TSH), thyroglobulin (Tg), and anti-thyroglobulin antibodies (TgAb). using chemiluminescent immunoassay (LiCA200 fully automatic electrochemical luminescence immunoassay analyzer from Kemeida Company).
Thyroid Iodine Uptake Rate
After an overnight fast, patients orally administered sodium iodide (2uCi,0.074MBq), and the thyroid iodine uptake rate was measured 24 hours later using a thyroid iodine uptake function measuring device.
The reporting of this study conforms to REMARK guidelines. 10
Statistical Analysis
All experimental data were analyzed using SPSS 26.0 statistical software. The measurement data were expressed as x ± s or median (M). For the comparison of quantitative data between groups, the independent sample t-test or Mann-Whitney U test was used before treatment; for the comparison of patient composition between groups, the chi-square test or Fisher’s exact probability method was used. univariate linear model analysis and multivariate models was performed, incorporating variables such as sex, age, disease stage, and risk stratification. Logistic regression analysis was used to analyze the influencing factors of ER and non-ER. A P value of <0.05 was considered statistically significant.
Results
Patient General Clinical Information
From June 2022 to September 2023, we collected data from patients with differentiated thyroid cancer who underwent initial iodine therapy. A total of 213 patients were included, of which 7 were excluded due to incomplete data, resulting in a final cohort of 206 patients. There were 53 male and 153 female patients. The risk stratification for DTC, according to the American Thyroid Association 11 guidelines, is based on factors such as tumor size, lymph node metastasis, distant metastasis, patient age, and other clinical characteristics., there were 4 patients in the low-risk group, 105 in the intermediate-risk group, and 97 in the high-risk group. The stage distribution was as follows: 169 patients were Stage I, 27 were Stage II, 7 were Stage III, and 3 were Stage IVA.
Influencing Factors of Pre-treatment Urinary Iodine for DTC
Urinary Iodine Levels of DTC Patients Before Iodine treatment(ug/L).
Influencing Factors of Post-treatment Urinary Iodine for DTC
Urinary Iodine Levels of DTC Patients After Iodine Treatment(ug/L).
Influencing Factors of Difference in Urinary Iodine Pre- and Post-Treatment for DTC
We further analyzed the influencing factors of the difference in UIC before and after treatment. There was a significant correlation between the difference in UIC before and after treatment and ps-Tg (R = 0.335, P = 0.00), as well as thyroid iodine uptake rate (R = 0.154, P = 0.028). However, there was no correlation with TSH (R = −0.06, P = 0.932), TgAb (R = −0.46, P = 0.529), or 131I dose (R = −0.06, P = 0.927).
Efficacy Assessment Analysis
Comparison of Clinical Data Among Patients With Low-Intermediate Risk DTC.
*P < 0.05 is considered statistically significant.
Comparison of Clinical Data Among Patients With High Risk DTC.
*P < 0.05 is considered statistically significant.
Multivariate Logistic Regression Analysis of DTC.
*P < 0.05 is considered statistically significant.
Construction of a Prognostic Prediction Model for DTC
In the analysis of the ROC curve for ps-Tg levels in the low-intermediate risk group, the optimal cut-off point was found to be 1.415 ng/mL. This means that when the ps-Tg ≥ 1.415 ng/mL, the model tends to classify the patient as not achieving effective remission; conversely, if the ps-Tg < 1.415 ng/mL, the patient may be considered to have achieved effective remission. Despite these misclassifications, the overall performance of the model was quite good, with a sensitivity of 73.53%, a specificity of 92.31%, and an AUC of 0.9058, demonstrating a good classification effect (Figure 1). The analysis of the ROC curve for ps-Tg levels in different group DTC patients.
In the analysis of the ROC curve for ps-Tg levels in high-risk patients, with ER as the dependent variable, the optimal cut-off point was found to be 1.925 ng/mL. This means that when the ps-Tg level ≥ 1.925 ng/mL, the model tends to classify the patient as not achieving effective remission; conversely, if the ps-Tg < 1.925 ng/mL, the patient may be considered to have achieved effective remission. Despite these misclassifications, the overall performance of the model was quite good, with a sensitivity of 61.29%, a specificity of 86.84%, and an AUC of 0.8018 (Figure 1).
To further understand the impact of ps-Tg levels on patient outcomes, we conducted a comprehensive analysis of all differentiated thyroid cancer patients. Our findings revealed that the optimal cut-off point for ps-Tg levels was 1.85 ng/mL. While there were some misclassifications, the model’s overall performance was quite impressive, with a sensitivity of 67.94%, a specificity of 89.47%, and an AUC of 0.8563 (Figure 1). These results suggest that ps-Tg levels can be a valuable tool in predicting patient outcomes and guiding treatment decisions.
Discussion
The international community commonly uses the median UIC to assess the general differences in iodine nutrition levels among populations. Some studies have also suggested that urinary iodine can be used as a indicator of individual iodine nutrition status. 12 Patients are required to follow a low-iodine diet before treatment to create a low-iodine state in their bodies, which helps the lesions better absorb the radioactive iodine-131 medication. Both dietary iodine and iodine-131 are excreted from the body through the urinary system. Therefore, the purpose of conducting urinary iodine tests before treatment and 3 days after treatment is to evaluate the patient’s iodine levels and understand the residual radiation dose in the patient’s body, explore the influencing factors of changes in urinary iodine levels, and investigate their relationship with treatment efficacy. Urine sampling is relatively simple and convenient, making it a viable indicator for assessing iodine levels in differentiated thyroid cancer patients before iodine treatment.
It should be noted that UIC are susceptible to fluctuations due to factors such as dietary iodine content, urine volume, and sweat loss. To overcome this limitation, many researchers have proposed using morning urine, 24-hour urine samples, consecutive random urine samples over multiple days, and creatinine correction methods instead of single random urine samples.13-15 Therefore, this experiment collected morning urine samples from patients to minimize the impact of other factors. And different restricted iodine diet protocols may affect urinary iodine excretion, which may affect treatment success.16-20 For example, in a study, there was no difference in TSH levels between the group whose radioactive iodine treatment was successful and the group whose treatment was unsuccessful. 17 In that study, contrary to the current study, all patients who failed radioactive iodine treatment were stage 1 patients.
This study analyzed the changes in UIC before and after iodine treatment in relation to factors such as age, sex, thyroid stimulating hormone, thyroid globulin, thyroid globulin antibodies, thyroid iodine uptake rate, TNM staging, and risk stratification. The results revealed that UIC were correlated with sex, age, stratification, staging, thyroid globulin, and thyroid iodine uptake rate. Moreover, the post-treatment UIC and the difference in UIC before and after treatment were significantly correlated with thyroid globulin levels. Tg is a large molecular glycoprotein complex specifically synthesized by thyroid follicular epithelial cells, composed of approximately 2768 amino acids. It is the most important and abundant protein in thyroid follicles. As a specific tumor marker for differentiated thyroid cancer patients undergoing total thyroidectomy + iodine-131 treatment, Tg has been shown to be a sensitive indicator of iodine deficiency and excess in a 2013 survey conducted by UNICEF and ICCID. 21 In 2016, Ma and Skeaf 22 reviewed 34 studies that used Tg as an iodine nutrition indicator and concluded that Tg can be used as an evaluation indicator for iodine deficiency, but there are still limitations, especially for adults and pregnant women, which require further research. The findings of this study support the conclusions of previous research, which indicated a significant correlation between Tg levels and UIC. This suggests that Tg levels could potentially be used to assess iodine levels in patients with iodine deficiency. Additionally, Tg has been proven to play an important role in predicting the prognosis and monitoring the efficacy of differentiated thyroid cancer. Therefore, this study aimed to determine whether Tg levels could serve as an indicator of iodine nutrition status in patients with DTC, while also examining whether UIC could serve as an independent prognostic factor for DTC.
The correlation between TgAb and Tg is primarily manifested in their roles in the diagnosis and monitoring of thyroid diseases. Tg is a protein produced by thyroid cells and is an essential component of thyroid hormone synthesis. In certain thyroid diseases, particularly DTC, Tg levels may elevate. TgAb are autoantibodies against Tg, and their presence may interfere with the measurement of Tg levels(10). If a patient has high levels of TgAb, it could lead to false negative or false positive results in Tg testing, thereby affecting the assessment and monitoring of the disease. For instance, in DTC patients, postoperative monitoring of Tg levels is a crucial indicator for evaluating recurrence and metastasis. However, if the patient also has high levels of TgAb, it could obscure the true Tg levels. This study also included TgAb and confirmed that regardless of whether in the low-intermediate risk or high-risk group, TgAb is associated with therapeutic efficacy. Therefore, in the detection of DTC patient diseases, it is necessary to simultaneously monitor the results of Tg and TgAb.
Based on their risk level, patients were divided into two groups: low-intermediate risk and high risk. The analysis focused on whether the patients achieved ER after a 6-month follow-up. The results revealed that ps-Tg was an associated factor, while UIC were not significantly correlated with treatment efficacy. Although this study could not prove that UIC could predict patient prognosis before treatment. The correlation analysis also confirmed a relationship between UIC and ps-Tg. However, due to the limited sample size in this study, further validation with larger, preferably multicenter clinical data is needed.
Regarding the correlation between UIC and thyroglobulin, some researchers have proposed that UIC may be associated with the efficacy of differentiated thyroid cancer treatment. Similar to the findings of this study, Cao et al found a correlation between UIC and treatment response in low-intermediate risk differentiated thyroid cancer patients. 23 In contrast, Jiang et al found that UIC were related to unsatisfactory efficacy in low-intermediate risk DTC patients, but not in high-risk patients, which contradicts the findings of this study. 24 The reasons for these discrepancies may include: the small number of low-risk patients, which may lead to bias in statistical analysis, the significant impact of dietary habits on UIC, despite efforts to maintain a low-iodine diet, variations in water intake during hospitalization and regional or dietary differences. These factors require further investigation and correction with larger clinical datasets.
Further analysis using ROC curves for ps-Tg in different risk groups of DTC patients, with ER as the dependent variable, revealed that the optimal cut-off points were 1.415 ng/mL for low-intermediate risk patients and 1.925 ng/mL for high-risk patients. This suggests that when the Tg level is below these cut-off points in stimulated states, patients are more likely to achieve ER, indicating a good classification effect for the model. The coefficient of ps-Tg was negative, indicating that the odds ratio was less than 1.This suggests that the smaller the Tg value, the more likely it is for ER to occur, that is, the better the efficacy. Conversely, the larger the Tg value, the worse the efficacy.
Conclusion
This study demonstrates a significant correlation between UIC and ps-Tg, but UIC is not significantly correlated with patient prognosis. It reaffirms that Tg can serve as an independent prognostic predictor for differentiated thyroid cancer, with Tg showing promise as an indicator of iodine nutritional status in differentiated thyroid cancer. However, it is important to note that while Tg is an important factor, it is just one of many that may influence treatment efficacy. A comprehensive evaluation of multiple factors is necessary to accurately assess and predict treatment outcomes. The role of UIC as a prognostic predictor for treatment efficacy requires further investigation with larger sample sizes.
Supplemental Material
Supplemental Material - Influencing Factors of Urinary Iodine Concentration Before and After Radioiodine Therapy for Differentiated Thyroid Cancer: An Initial Exploration of the Relationship With Therapeutic Efficacy
Supplemental Material for Influencing Factors of Urinary Iodine Concentration Before and After Radioiodine Therapy for Differentiated Thyroid Cancer: An Initial Exploration of the Relationship With Therapeutic Efficacy by Qian Liu, Huan Zhou, Yuxiao Xia, Ying Huang, Lina Liu, Xue Jiang, and Yuhong Shi, PhD in Cancer Control
Supplemental Material
Supplemental Material - Influencing Factors of Urinary Iodine Concentration Before and After Radioiodine Therapy for Differentiated Thyroid Cancer: An Initial Exploration of the Relationship With Therapeutic Efficacy
Supplemental Material for Influencing Factors of Urinary Iodine Concentration Before and After Radioiodine Therapy for Differentiated Thyroid Cancer: An Initial Exploration of the Relationship With Therapeutic Efficacy by Qian Liu, Huan Zhou, Yuxiao Xia, Ying Huang, Lina Liu, Xue Jiang, and Yuhong Shi, PhD in Cancer Control
Footnotes
Author Contributions
All authors contributed to the study conception and design. Yuhong Shi contributed to the conception of the study; Huan Zhou helped perform the analysis with constructive discussions. The data collection and first draft of the manuscript were written by Qian Liu. Xue Jiang, Yuxiao Xia, Ying Hua, and Lina Liu helped the organization of the data. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by China Baoyuan research fund project (CBY1202105), sichuan provincial medical youth innovation research project (021076), chengdu city technology innovation and research development project (2022-YF05-01418-SN) and sichuan provincial science and technology department general project (23NSFSC1849).
Poster’s Name of Primary Reviser
All authors have provided revision comments, and the revisions are to be handled by Qian Liu.
Ethical Statements
Data Availability Statement
The data that support the findings of this study are available in supplementary information.
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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