Abstract
Background
Excess iodine intake due to iodinated contrast media (ICM) infusion during medical examinations is considered as a potential cause of thyroid abnormalities. However, the short-term effects of ICM exposure on patients in a Chinese population are not well elucidated.
Methods
In total, 200 patients who received intravenous ICM were enrolled, and their thyroid function was determined before ICM exposure (baseline) as well as 1 week and 1 month after the ICM infusion. The relationship between the peak urinary iodine concentration (UIC) and the contrast agent (CA) dose was then investigated. Three months after ICM exposure, the patients who developed thyroid dysfunction within 1 month of ICM exposure were followed up.
Results
This study included 125 males and 75 females, with a mean age of 56.56 ± 13.89 years old and an average CA dose of 26.93 ± 8.35 g. Patients with thyroid nodules had an increased risk of subclinical hyperthyroidism (OR = 2.1491, 95% CI: 1.0335–71.1880, p = 0.0465). Additionally, the urinary iodine level (1658.37 ± 527.47 μg/L) peaked at 1 week after ICM exposure, and the peak level was weakly positively correlated with free thyroxine (FT4) level (r = 0.1531, p = 0.0317). Meanwhile, CA dose weakly negatively correlated with anti-thyroid peroxidase antibody (TPOAb) (r=-0.2077, p = 0.0035). The follow-up results at 3 months after ICM exposure showed that the newly developed abnormal thyroid function within 1 month of ICM exposure had mostly returned to normal.
Conclusions
Patients with thyroid nodules had an increased risk of subclinical hyperthyroidism 1 month after iodine contrast imaging. The effect was transient, and most patients self-recovered without any intervention.
Keywords: Iodinated contrast media, thyroid function, subclinical thyroid dysfunction, urinary iodine, contrast agent dose
Introduction
It is well known that iodine, one of the most important components of thyroid hormones, is necessary for normal thyroid function. However, superfluous intake of iodine can affect the normal functions of the thyroid [1]. Nowadays, iodinated contrast media (ICM) is widely applied in clinical examinations including computed tomography and vascular intervention surgery [2]. According to a report released by IPSOS Healthcare [3], contrast-enhanced CT made up, on average, 17% of total CT examinations conducted at a medium-sized hospital in China. The volume of CT per year at a tertiary-care hospital was 49,807 examinations in 2017. However, a recent epidemiological survey conducted across 31 provinces and cities in China, involving 78,470 cases, showed that the overall prevalence of thyroid diseases in the Chinese population is 50.96% [4].
The application of ICM means excessive iodine intake, which may potentially impair thyroid function [5–8]. The mechanism may be that (1) the disruption of the thyroid’s own regulation mechanism by excessive iodine, autonomous secretion occurs, leading to the occurrence of thyroid toxicosis (Jod-Basedow effect) [9]; (2) excess serum iodine inhibit iodine organification, thereby inhibiting the biosynthesis and release of hormones in the thyroid (Wolff-Chaikoff effect). It is normally followed by resumption of normal thyroid function within 2 days. However in patients with potential thyroid dysfunction (such as a history of nontoxic nodular goitre, mild Graves’ disease), Wolff-Chaikoff effect cannot be successfully escaped, leading to hypothyroidism [10].
Nevertheless, due to insufficient studies of ICM-induced thyroid dysfunction, its prevalence and clinical significance is not well characterized. Several large retrospective studies have deeply investigated the correlation between ICM intake and thyroid function, and they consistently found that patients who once received ICM have a 46% increased risk of developing thyroid dysfunction and nodular goitres [11–13]. However, several prospective observational studies conducted in various countries have shown different results, with the incidence of ICM-induced hyperthyroidism ranges from 0% to 9%, and the incidence of hypothyroidism reaches up to 15% [14–18]. These discrepancies may be mainly attributed to the heterogeneity of study design, racial specificity, and variations in iodine intake levels, among other factors [19]. Although iodine is excreted via the urine and the urinary iodine concentration (UIC) is one of the most important factors that reflects iodine intake, most studies have not observed the effects of the UIC or the contrast agent (CA) dose on thyroid function. Furthermore, there are currently no recognized standards for monitoring thyroid function in the Chinese population after ICM intake. Measuring thyroid function before or after ICM exposure is not recommended by European Thyroid Association Guidelines, and advocated its routine monitoring only in high-risk individuals [18]. Therefore, a more comprehensive prospective study needs to be performed. In this study, we aimed to provide evidence for the prevention and monitoring of thyroid diseases after ICM exposure.
Materials and methods
Study subjects
This study was a multicentre, prospective, cohort study that included patients of at least 18 years of age who conducted intravenous ICM at Sun Yat-sen Memorial Hospital affiliated with Sun Yat-sen University and Huizhou People’s Hospital from January 2022 to October 2022. Exclusion criteria were as follows: (a) patients with any of the following diseases: malignant tumours, critical illness (admitted to the Intensive Care Unit), mental illness, hypothalamic-pituitary diseases, Active thyroid disease (such as overt hypothyroidism, hyperthyroidism, or thyroid cancer, past history of thyroid cancer or thyroid surgeries); (b) patients who received ICM in the past 6 months; (c) patients who have used any of the following drugs within the past 6 months: methimazole, propylthiouracil, levothyroxine, compound iodine solution, amiodarone, immune checkpoint inhibitors, tyrosine kinase inhibitors, interferon, interleukin-6, lithium, glucocorticoids, dopamine, and dobutamine; and (d) pregnant or lactating patients. The flowchart of the patients is shown in Figure 1.
Figure 1.
Flowchart of patient screening.
A total of 298 patients were recruited, but 98 patients were excluded due to dropping out or failing to complete the follow-up. Finally, 200 patients were included in this study. Among the 200 patients, 183 patients received iodixanol (350 mg/mL), 10 patients received iopamidol (370 mg/mL), 5 patients received iopromide (370 mg/mL), and 2 patients received iohexol (350 mg/mL).
Study measures
On the day of computed tomography scanning and prior to the administration of ICM, serum and urine samples (a spot fasting first-morning urine sample) were collected from the patients for the baseline measurements. In addition, patient information was gathered using standard questionnaires, including age, sex, history of diseases like hypertension, diabetes, and cardiovascular disease, alcohol and smoking history, and current medications. Then, thyroid ultrasound examination was performed. Diagnoses of hypertension, diabetes mellitus, and cardiovascular disease were based on the medical history and the list of current medications.
Serum and urine samples (a spot fasting first-morning urine sample) were obtained again from the patients at 1 week and 1 month after the application of ICM. Patients who had thyroid function abnormalities within 1 month after receiving ICM were recorded and followed up 3 months later, and their Serum sample was collected for measuring thyroid function. At each follow-up visit, a short survey was given to collect details on thyroid dysfunction-related symptom and any recent occurrences of excessive iodine exposure since the last visit. The follow-up tests were performed the exact day in most situations, with a margin of 2 days on either side of the organized follow-up date allowed in exceptional situations.
Serum from patients was utilized for detecting thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-thyroid peroxidase antibody (TPOAb), thyroglobulin autoantibody (TgAb), and thyrotropin receptor antibody (TrAb); while urine was used for detecting the UIC.
Laboratory measurements
Serum tests were performed by using a direct chemiluminescence immunoassay (Siemens Healthcare Diagnostics, Inc.). Urine testing was conducted by using inductively coupled plasma mass spectrometry (Agilent Technologies Co.). The reference ranges were as follows: FT4, 11.50–22.70 pmol/L; FT3, 3.50–6.50 pmol/L; TSH, 0.550–4.780 μU/mL and UIC 100–300 μg/L. Concentrations of TPOAb and TgAb that were greater than 34 IU/mL and 115 IU/mL, respectively, were considered as a positive test result.
Study definitions
Overt hyperthyroidism was defined as low serum TSH concentrations and raised serum concentrations of thyroid hormones: FT4, FT3, or both [20]. Subclinical hyperthyroidism was defined as a subnormal serum TSH level along with serum FT4 and FT3 concentrations within the normal reference ranges [21]. Overt hypothyroidism was defined as TSH concentrations above the reference range and free thyroxine concentrations below the reference range [22]. Subclinical hypothyroidism was defined as an elevated serum thyrotropin level and a serum-free thyroxine level within the reference range [21]. Hashimoto’s thyroiditis was defined as high serum concentrations of TPOAb and TgAb [23]. Isolated thyroid antibody elevation was defined as TPOAb or TgAb concentrations above the reference range and isolated FT3/FT4 abnormalities was defined as FT3 or FT4 concentrations outside the normal reference ranges, either elevation or reduction.
Statistical analyses
Data were analyzed with the use of the statistical packages R (The R Foundation; http://www.r-project.org, version 4.2.0) and EmpowerStats (www.empowerstats.net, X&Y solutions, Inc. Boston, MA, USA). Continuous variables that conform to a normal distribution are recorded as mean ± standard deviation (SD), while those that do not conform to a normal distribution are represented using quartiles. The inter-group distribution differences of continuous data were analyzed using Friedman Test, while the distribution differences of categorical data were analyzed using the chi-squared test. After adjusting for confounding factors such as sex, age, body mass index, aspartate transaminase level, alanine transaminase level, hypertension, diabetes, cardiovascular disease, smoking, and alcohol consumption, Generalized Estimating Equations was used to estimate the effects of ICM on thyroid function and diseases. Pearson’s correlation analysis and Spearman’s correlation analysis were used to statistically analyze the correlations between the peak UIC we measured and CA dose with thyroid function. To explore the impact of thyroid nodules on the short-term changes in thyroid function following exposure to ICM, we conducted a stratified analysis of patients based on the presence of thyroid nodules. This stratification helps us to more accurately assess the specific effects of ICM on patients with different thyroid function statuses and provides a scientific basis for thyroid function monitoring in clinical practice for these patients. p < 0.05 indicated a statistically significant difference.
Results
Characteristics of the subjects
Among the 200 subjects included in this study, 125 (62.50%) were male, 75 (37.50%) were female, 30.50% were smokers, and 17.50% drank alcohol. The mean age of the subjects was 56.16 ± 13.89 years old, and the mean CA dose was 26.93 ± 8.35 g. All patients included had baseline thyroid function assessments. Among them, 7 cases were diagnosed with Hashimoto’s thyroiditis, and 13 cases had isolated thyroid antibody elevation. No cases of overt or subclinical hyperthyroidism, nor of overt or subclinical hypothyroidism, were identified. All patients we included underwent a thyroid ultrasound at baseline. Under ultrasound, 52.50% of the subjects had at least one thyroid nodule. The medical history showed that 45.50% of the patients had hypertension, 24.50% had diabetes, and 30.50% had cardiovascular disease (Table 1).
Table 1.
Characteristics of the subjects.
| Demographic characteristics | |
|---|---|
| Age (years) | 56.56 ± 13.89 |
| Height (cm) | 162.19 ± 9.01 |
| Weight (kg) | 66.61 ± 13.56 |
| Body mass index (kg/m2) | 25.22 ± 4.18 |
| Sex | |
| Male | 125 (62.50%) |
| Female | 75 (37.50%) |
| Behavioural habits | |
| Smoking | |
| No | 139 (69.50%) |
| Yes | 61 (30.50%) |
| Alcohol consumption | |
| No | 165 (82.50%) |
| Yes | 35 (17.50%) |
| Laboratory measurements | |
| Scr (μmol/L) | 88.33 ± 27.10 |
| Ucr (mmol/24 h) | 5.91 ± 3.31 |
| ALT (U/L) | 29.03 ± 71.73 |
| AST (U/L) | 26.50 ± 38.43 |
| eGFR (mL/(min × 1.73 m2)) | 79.34 ± 19.35 |
| CA dose (g) | 26.93 ± 8.35 |
| Thyroid nodes | |
| No | 95 (47.50%) |
| Yes | 105 (52.50%) |
| Medical history | |
| Hypertension | |
| No | 109 (54.50%) |
| Yes | 91 (45.50%) |
| Diabetes | |
| No | 151 (75.50%) |
| Yes | 49 (24.50%) |
| Cardiovascular disease | |
| No | 139 (69.50%) |
| Yes | 61 (30.50%) |
Scr: Serum creatinine, Ucr: Urine creatinine, ALT: Alanine transaminase, AST: Aspartate transaminase, eGFR: estimated glomerular filtration rate. The data are presented as the mean ± SD/N (%).
Thyroid function and diseases before and after ICM exposure
The baseline concentrations of serum FT3, FT4, and TSH as well as the UIC are shown in Table 2. At 1 month after the ICM infusion, the concentration of serum FT3 (5.09 ± 0.68 pmol/L) was slightly greater compared to that at baseline (4.87 ± 0.60 pmol/L) and at 1 week post ICM exposure (4.87 ± 0.61 pmol/L). The UIC achieved a peak at 1 week after the ICM infusion and rapidly declined until 1 month post ICM application (Table 2).
Table 2.
Thyroid function and diseases before and after ICM exposure.
| Baseline | 1 week | 1 month | p-value | |
|---|---|---|---|---|
| FT3 (pmol/L, Mean ± SD) | 4.87 ± 0.60 | 4.87 ± 0.61 | 5.09 ± 0.68a | 0.0034 |
| FT4 (pmol/L, Mean ± SD) | 15.97 ± 2.42 | 15.84 ± 2.37 | 15.98 ± 2.74 | 0.7869 |
| TSH (mIU/L, M (Q1, Q3)) | 1.50 (1.07, 2.20) | 1.62 (1.03, 2.23) | 1.34 (0.92, 2.06)b | 0.0273 |
| UIC (μg/L, M (Q1, Q3)) | 143.80 (98.00, 231.50) | 2001.00 (1315.10, 2001.00)a | 197.60 (123.30, 285.40)a,b | <0.001 |
| Subclinical hyperthyroidism (%) | 0.0013 | |||
| No | 199 (99.50%) | 194 (97.98%) | 187 (93.50%) | |
| Yes | 1 (0.50%) | 4 (2.02%) | 13 (6.50%) | |
| Subclinical hypothyroidism (%) | 0.134 | |||
| No | 200 (100.00%) | 198 (99.00%) | 200 (100.00%) | |
| Yes | 0 (0.00%) | 2 (1.00%) | 0 (0.00%) | |
| Isolated thyroid antibody elevation (%) | 0.604 | |||
| No | 187 (93.50%) | 186 (93.00%) | 182 (91.00%) | |
| Yes | 13 (6.50%) | 14 (7.00%) | 18 (9.00%) | |
| Hashimoto’s thyroiditis (%) | 0.947 | |||
| No | 193 (96.50%) | 190 (95.96%) | 193 (96.50%) | |
| Yes | 7 (3.50%) | 8 (4.04%) | 7 (3.50%) | |
| Isolated FT3/FT4 elevation (%) | 0.023 | |||
| No | 200 (100.00%) | 197 (98.50%) | 193 (96.50%) | |
| Yes | 0 (0.00%) | 3 (1.50%) | 7 (3.50%) | |
| Isolated FT3/FT4 reduction (%) | 0.029 | |||
| No | 200 (100.00%) | 198 (99.00%) | 194 (97.00%) | |
| Yes | 0 (0.00%) | 2 (1.00%) | 6 (3.00%) |
The data are shown as the mean ± SD/N(%). p-value < 0.05 indicates statistical significance.
aIndicates statistical significance compared to the baseline.
bIndicates statistical significance compared to the 1-week group.
FT3: free triiodothyronine; FT4: free thyroxine; TSH: thyroid-stimulating hormone.
Overt hyperthyroidism or hypothyroidism was not detected in any subjects at 1 week or 1 month post ICM exposure. At 1 month after the ICM infusion, 13 patients had subclinical hyperthyroidism, 18 patients had isolated thyroid antibody elevation, 7 patients had isolated FT3/FT4 elevation, and 6 patients had isolated FT3/FT4 reduction. At the 1-month follow-up, 6.50% of the patients had subclinical hyperthyroidism, whereas there was no statistical difference in the percentage of subclinical hypothyroidism patients between baseline and the 1-week follow-up. Also, we found there were no patients who had subclinical hypothyroidism after 1 month of ICM exposure (Table 2). Among all subjects, TPOAb and TgAb showed no obvious distribution differences at each follow-up time point (Table S1).
Generalized estimating equations of thyroid function after the ICM infusion
The thyroid hormone levels were adjusted for potential confounding factors, and the results were shown in Table 3. In all subjects, the FT3 concentration was positively correlated with the ICM intake at 1 month (β = 0.2230, 95% CI: 0.1411–0.3049, p < 0.0001), whereas it was not significantly correlated at 1 week (β = 0.0058, 95% CI: −0.0486–0.0603, p = 0.8340) post ICM exposure. Of note, the risk of subclinical hyperthyroidism was significantly greater at 1 month (OR = 2.6271, 95% CI: 1.7741–107.8761, p = 0.0122) post ICM exposure, while there was no significant risk of subclinical hyperthyroidism at the 1-week follow-up (OR = 0.7224, 95% CI: 0.1810–23.4372, p = 0.5604) after the ICM infusion, compared to the baseline value. Additionally, whether or not the patients had thyroid nodules did not affect the correlation between the change of FT3 concentration and ICM exposure. Interestingly, compared with patients without thyroid nodules, those with thyroid nodules had a slightly negative correlation with the TSH level (β=-0.2763, 95% CI: −0.4060–0.1467, p < 0.0001) and a significant positive correlation with an increased risk of subclinical hyperthyroidism (OR = 2.1491, 95% CI: 1.0335–71.1880, p = 0.0465) at 1 month after the ICM infusion. The correlation between ICM administration and thyroid antibodies is shown in Table S2.
Table 3.
Generalized estimating equations of thyroid function after ICM exposure, stratified by the presence of thyroid nodules.
| FT3 |
FT4 |
TSH |
Subclinical hyperthyroidism |
Subclinical hypothyroidism |
||||||
|---|---|---|---|---|---|---|---|---|---|---|
| β (95% CI) | p-value | β (95% CI) | p-value | β (95% CI) | p-value | OR (95% CI) | p-value | OR (95% CI) | p-value | |
| Total | ||||||||||
| 1 week | 0.0058 (-0.0486, 0.0603) | 0.8340 | −0.1298 (-0.3483, 0.0887) | 0.2442 | 0.1000 (-0.0059, 0.2058) | 0.2861 | 1.4117 (0.4504, 37.3756) | 0.2104 | – | – |
| 1 month | 0.2230 (0.1411, 0.3049) | <0.0001* | 0.0133 (-0.3152, 0.3418) | 0.9367 | −0.1539 (-0.2623, 0.0455) | 0.0054* | 2.6271 (1.7741, 107.8761) | 0.0122* | – | – |
| Thyroid nodules | ||||||||||
| No | ||||||||||
| 1 week | −0.0025 (-0.0777, 0.0728) | 0.9491 | −0.1928 (-0.5120, 0.1264) | 0.2364 | 0.0489 (-0.0830, 0.1808) | 0.4672 | – | – | – | – |
| 1 month | 0.2323 (01157, 0.3490) | 0.0001* | −0.1003 (-0.6013, 0.4007) | 0.6947 | −0.0186 (-0.1921, 0.1549) | 0.8337 | – | – | – | – |
| Yes | ||||||||||
| 1 week | 0.0130 (-0.0655, 0.0914) | 0.7457 | 0.0707 (-0.3698, 0.2283) | 0.6429 | 0.1473 (-0.0151, 0.3098) | 0.1921 | 0.7224 (0.1810, 23.4372) | 0.5604 | – | – |
| 1 month | 0.2146 (0.0998, 0.3294) | 0.0002* | 0.1161 (-0.3142, 0.5464) | 0.5969 | −0.2763 (-0.4060, −0.1467) | <0.0001* | 2.1491 (1.0335, 71.1880) | 0.0465* | – | – |
Adjusted for sex, age, body mass index, aspartate transaminase, alanine transaminase, hypertension, diabetes, cardiovascular disease, smoking, alcohol consumption.
*Indicates statistical significance; p < 0.05.
FT3: free triiodothyronine 3, FT4: free triiodothyronine 4, TSH: thyroid-stimulating hormone, OR: odds ratio, CI: confidence interval.
Correlations between peak UIC we measured, CA dose, and thyroid function after ICM exposure
No significant correlations were detected between the peak UIC we measured or the CA dose and the FT3 or TSH level at 1 week or 1 month after the ICM infusion. Meanwhile, subclinical hyperthyroidism or subclinical hypothyroidism was not correlated with the UIC or the CA dose (Table 4). There was a moderate positive correlation between the FT4 level and the peak UIC we measured at 1 month after the ICM infusion (r = 0.1531, p = 0.0317). In addition, there was a moderate negative correlation between the CA dose and TPOAb (r=-0.2077, p = 0.0035) at 1 month after the ICM infusion (Table S3).
Table 4.
Correlations between peak UIC, CA dose, and thyroid function after ICM exposure.
| Time | Correlation | p-value | Correlation | p-value | |||||
|---|---|---|---|---|---|---|---|---|---|
| 1 week | Peak UIC | FT3 | 0.0903 | 0.2178 | 1 month | Peak UIC | FT3 | 0.0333 | 0.6423 |
| FT4 | 0.0192 | 0.7932 | FT4 | 0.1531 | 0.0317* | ||||
| TSH | −0.0775 | 0.2894 | TSH | – | – | ||||
| Subclinical hyperthyroidism | 0.0624 | 0.3936 | Subclinical hyperthyroidism | 0.1035 | 0.1476 | ||||
| Subclinical hypothyroidism | 0.0836 | 0.253 | Subclinical hypothyroidism | – | – | ||||
| 1 week | CA dose | FT3 | −0.0692 | 0.3392 | 1 month | CA dose | FT3 | 0.0075 | 0.9172 |
| FT4 | 0.0179 | 0.8039 | FT4 | 0.0577 | 0.422 | ||||
| TSH | 0.0647 | 0.3699 | TSH | 0.0041 | 0.9542 | ||||
| Subclinical hyperthyroidism | 0.1158 | 0.1079 | Subclinical hyperthyroidism | 0.0868 | 0.2261 | ||||
| Subclinical hypothyroidism | 0.057 | 0.4276 | Subclinical hypothyroidism | – | – |
Indicates statistical significance; p < 0.05.
UIC: urinary iodine concentration, CA: contrast agent, FT3: free triiodothyronine, FT4: free thyroxine, TSH: thyroid-stimulating hormone.
Thyroid function of subjects at 3 months after the ICM infusion
The outcomes of the thyroid function abnormalities in patients at 3 months after the ICM infusion are shown in Table S4. The data indicate that within 1 month post ICM exposure, all newly diagnosed subclinical hypothyroidism and Hashimoto’s thyroiditis patients recovered, except for the two newly diagnosed subclinical hyperthyroidism patients who did not recover. Most patients with isolated elevation or reduction of FT3/FT4 or isolated elevation of thyroid antibodies also recovered. However, for patients with baseline thyroid abnormalities such as Hashimoto’s thyroiditis or isolated elevation of thyroid antibody levels, their abnormalities did not recover by 3 months after ICM exposure.
Discussion
In this study, we explored within 1 month after receiving iodine contrast agents, the proportion of patients developing new-onset subclinical hyperthyroidism significantly increased. New-onset isolated increases and decreases in FT3/FT4 levels were noted. Compared to patients without thyroid nodules, those with thyroid nodules had a significantly higher risk of developing subclinical hyperthyroidism after 1 month. Patients with thyroid nodules also showed a notable decrease in TSH levels after 1 month. Follow-up at 3 months indicated that most patients with newly abnormal thyroid function within the month returned to normal; however, those with pre-existing thyroid abnormalities, such as Hashimoto’s thyroiditis, did not fully recover.
As is well known, iodine is an essential element for the thyroid gland. Inversely, excessive iodine intake may cause thyroid dysfunction. With the increasing popularity of computed tomography angiography and other examinations, more patients receive iodine CAs, leading to short-term excessive iodine intake [24]. Such excessive iodine intake may cause a variety of diseases [25,26]. The number needed to harm for ICM-induced hyperthyroidism or hypothyroidism was one in every 250 patients [11]. Investigating the alterations in thyroid function after contrast agent administration is beneficial for patients to receive appropriate medical observation during hospitalization and effectively prevent potential thyroid diseases caused by ICM exposure, especially for high-risk populations. To the best of our knowledge, several retrospective studies in China have focused on the risk of thyroid diseases within at least 1 year after CA administration [12,27]. However, the duration of metabolism of free iodine in the body may be much shorter than 1 year, which may result in the gradual disappearance of thyroid damage during the observation period. Therefore, we still need to further investigate the short-term effects of CA administration on thyroid function, which would be more helpful for monitoring patients.
Our study did not find the occurrence of hyperthyroidism after ICM exposure which is consistent with findings from other populations that similarly report a low incidence of hyperthyroidism after ICM administration. An observational study of 788 cases in a German population found that only 2 cases (0.25%) developed overt hyperthyroidism within 3 months after ICM exposure [28]. Similarly, a study conducted in Italy reported that hyperthyroidism occurred in just 2% of 1,572 patients undergoing coronary angiography [29]. Additionally, Si et al. investigated the effect of ICM in a short-term, they found the risk of subclinical thyroid dysfunction occurred with a single large dose of ICM, but no severe thyroid dysfunction occurred [30]. However, in our study, the incidence of subclinical hyperthyroidism was significantly increased at 1 month after ICM exposure, as indicated by the fact that half of the subjects (52.50%) in this study had thyroid nodules, which may cause a potentially higher prevalence of focal autonomy, while the remaining patients could suppress thyroid hormone secretion through negative feedback mechanisms to maintain the thyroid function balance. Our findings are consistent with a long-term study in a Chinese population that found patients with euthyroid nodular goitre had a higher risk of thyroid dysfunction than those who did not have it [12]. A similar trend was observed in an Italian study, where patients with euthyroid nodular goitre were also at higher risk of thyroid dysfunction [31]. Another short-term study conducted in the German population did not observe hyperthyroidism in any patient after ICM exposure 3 weeks, but thyroid function parameters were significantly altered in patients with nodular goitre [32]. Patients with nodular goitre are considered to be at risk of developing thyrotoxicosis after iodine load. It should be noted that epidemiological surveys have shown a high prevalence of thyroid nodules in the Chinese population (45.2% in women and 31.2% in men), so much attention should be paid to the risk of thyroid dysfunction in patients with thyroid nodules after ICM exposure [33]. Additionally, we found that patients with thyroid nodules after ICM exposure tended to have a decrease in the TSH level, whereas patients without thyroid nodules did not exhibit this tendency. Similarly, it has been reported that patients with normal thyroid nodules tended to have a lower TSH level at 42 days after ICM exposure in a German population [34]. Inversely, Terumi et al. found that the TSH level increased at 4 weeks after ICM exposure in their study of a Japanese population [35]. This discrepancy may be related to the fact that they did not divide the subjects based on the presence of thyroid nodules. Here, we speculated that ICM exposure reduced the TSH level in patients with thyroid nodules, thereby increasing the risk of subclinical hyperthyroidism. It should be noted that we did not include patients with subclinical thyroid dysfunction. However, studies have shown that patients with subclinical hyperthyroidism are more likely to develop thyroid dysfunction after ICM exposure due to increased iodine load [31]. Clinicians need to more closely monitor thyroid function in these patients after ICM exposure, and our future studies will also specifically investigate the effects of ICM in this clinically relevant group.
In the current study, no overt or subclinical hypothyroidism cases were found after 1 month of ICM exposure, we speculated that Chinese patients routinely consume iodine [36], which is consistent with findings from other studies conducted in iodine-sufficient regions, such as a recent study in Sweden reported that ICM-associated hypothyroidism is rare and typically mild in populations with sufficient iodine levels [37]. Also, the exclusion of patients with previous history of thyroid dysfunction can account for the low rate of hypothyroidism in our study. Mekaru et al. observed that patients with baseline subclinical hypothyroidism tended to develop clinical hypothyroidism [38], which demonstrated that the occurrence of hypothyroidism after ICM tends to be more common in patients who already had subclinical hypothyroidism, rather than those with normal thyroid function. Moreover, the lack of hypothyroidism observed after ICM administration also may be attributable to the insufficient duration of our study’s follow-up period. A long-term follow-up study reported cases of severe hypothyroidism occurring 1 year after ICM exposure because of the failure to escape from the acute Wolff-Chaikoff effect [27]. Therefore, it is crucial for us to continue monitoring and following up with these patients in the future to fully assess the long-term effects of ICM. Considering that autoimmune thyroiditis may also cause subclinical hypothyroidism [39], we also measured TPOAb and TgAb after ICM exposure and found that there was no difference of the TPOAb and TgAb levels. Moreover, Jarvis et al. found that no patients who tested negative for thyroid antibodies developed new-onset hypothyroidism [16], suggesting that ICM does not affect thyroid autoimmunity in the short term. This may be one of the reasons for no difference in the incidence of subclinical hypothyroidism after ICM exposure.
Previous studies on the effects of ICM exposure on the thyroid did not pay much attention to iodine clearance or the iodine dosage. Here, we conducted a correlation analysis between the peak UIC we measured, CA dose, and thyroid function to deeply investigate the underlying relationships between them. Interestingly, we found a weak negative correlation between the CA dose and TPOAb only at 1 month after the ICM infusion, while there was no relationship with other thyroid indicators. As for urinary iodine, similar to reports by Padovani et al. and Ho et al. at 1 week after the ICM infusion, the UIC reached a peak (median UIC level was 2001 µg/mL) and gradually decreased to near the baseline over the next 4 weeks [40,41]. The UIC levels reflected the metabolic clearance of iodine in the body. This result indicates that ICM accumulates in the body during the first week but was mostly cleared within 4 weeks. This finding has clinical implications as it provides guidance on the timing of thyroid scans and radioactive iodine therapy in patients who have recently received ICM. Consistent with the results of Sun et al. the present study did not find a relationship between the peak UIC we measured and thyroid dysfunction [42]. However, a weak positive correlation between the peak UIC we measured and FT4 was detected.
Subsequently, 3-month follow-ups were conducted for patients who developed thyroid dysfunction within 1 month after ICM exposure. We found that most of these patients returned to euthyroidism after iodine loading, suggesting that the impact of ICM exposure on thyroid function was transient and that most patients could recover spontaneously. However, for patients with baseline thyroid abnormalities such as Hashimoto’s thyroiditis or isolated elevation of thyroid antibodies, their abnormalities did not recover within 3 months after ICM exposure, which may be related to underlying autoimmune disease. The presence of TPO antibodies, a marker of thyroid autoimmunity, may indicate a predisposition to iodine-induced thyroid dysfunction. Similar to our findings, Si et al. observed through long-term follow-up that patients with pre-operative thyroid antibody elevation were at a risk of severe hypothyroidism with myxoedema at 1 year [27]. And another prospective study found patients with preoperative thyroid antibody elevation were more likely to have subclinical thyroid dysfunction after ICM exposure [30]. Fortunately, none of patients in our study required drug intervention temporarily, we will continue to monitor their thyroid function.
Limitations
There were still some limitations in this study that must be addressed. Our results only indicated the underlying relationship between ICM exposure with normal thyroid function. Patients with subclinical thyroid dysfunction were not included in our study, yet this population may be more susceptible to the effects of ICM. Therefore, future studies will additionally recruit patients with different demographic characteristics, particularly this clinically relevant group to better support our results and expand our conclusion. Additionally, we only investigated patients who received a single dose of ICM. The effect of ICM exposure for multiple times in a short period on thyroid function still has not been well elucidated. Therefore, further study is needed. Furthermore, the limited number of patients included restricts our ability to independently assess the effects of different types of iodine contrast agents, meaning we are unable to conduct subgroup analyses based on the type of iodine contrast agent.
Conclusions
ICM exposure has an impact on the short-term changes in thyroid function. Patients with thyroid nodules had a significantly increased risk of subclinical hyperthyroidism at 1 month after iodine contrast imaging. The effect was transient, and most patients could self-recover without any intervention. Based on the aforementioned data, we recommend that thyroid function tests be performed within 1 months after ICM exposure in patients with thyroid nodules.
Supplementary Material
Acknowledgement
We thank all those who contributed to this manuscript.
Funding Statement
There is no support funding.
Ethic declaration
We confirm your study adheres to the Declaration of Helsinki.
Informed consent
All participants agreed to participate in the project and signed an informed consent form.
Participation
This study recruited patients who planned to receive intravenous ICM at Sun Yat-sen Memorial Hospital affiliated with Sun Yat-sen University and Huizhou People’s Hospital from January 2022 to October 2022. This study was approved by the Ethics Committee of the Faculty of Sun Yat-sen Memorial Hospital affiliated with Sun Yat-sen University (Reference number: SYSEC-KY-KS-2022-002).
Disclosure statement
We declare there is no any conflict of interest and without used any AI technique.
Data availability statement
The data that support the findings of this study are available from the corresponding author, Meng Ren, upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, Meng Ren, upon reasonable request.