Abstract
Objectives
When exposed to iodine contrast medium (ICM), thyroid dysfunction may develop, due to excess amounts of iodide. The incidence of contrast-induced thyroid dysfunction has been difficult to interpret, because of the observational and retrospective designs of most previous studies. With the Swedish CArdioPulmonary bioImage Study (SCAPIS), where randomly selected individuals aged 50–65 years, underwent contrast-enhanced coronary CT angiography (CCTA), we were able to prospectively assess the incidence, magnitude and clinical impact of contrast-induced thyroid dysfunction.
Methods
In 422 individuals, thyroid hormone levels were analysed before and 4–12 weeks after CCTA. Thyroid-related patient-reported outcome questionnaires (ThyPRO) at the time of pre and post-CCTA blood samplings were provided by 368 of those individuals. Thyroid peroxidase antibodies (TPOab) were analysed and an ultrasound of the thyroid gland was performed to detect any thyroid nodules.
Results
There was a small statistically significant effect on thyroid hormone levels but no cases of overt hypo- or hyperthyroidism after ICM. Subclinical hypo- or hyperthyroidism or isolated low/high levels of free thyroxine (fT4) developed in 3.5% of the population with normal hormone levels pre-CCTA but without any increased thyroid-related symptoms compared to the remaining cohort. Elevated TPOab and being born outside Sweden were risk factors for developing subclinical hypothyroidism. The presence of thyroid nodules was not associated with ICM-induced thyroid dysfunction.
Conclusion
The results of this prospective study support the notion that in iodine-sufficient countries, ICM-associated thyroid dysfunction is rare, usually mild, self-limiting and oligo/asymptomatic in subjects aged 50–65 years.
Introduction
Injection of iodine contrast medium (ICM) may cause thyroid dysfunction due to free iodide in the solution (1). Normally, excess amounts of iodide in healthy persons result in transient inhibition of thyroid hormone production by autoregulation, known as the Wolff–Chaikoff effect. Some individuals are unable to escape from the Wolff–Chaikoff effect and may develop hypothyroidism. In others, especially individuals living in iodine-deficient regions or with multinodular goitre, failure of the protective Wolff–Chaikoff mechanism may lead to hyperthyroidism (Jod–Basedow phenomenon) and even, rarely, thyrotoxic crisis (2, 3, 4). The maximum upper limit allowed for free iodide in ICM, according to United States Pharmacopeia, is 0.02% of the total amount of bound iodine, while up to 0.15% may be released in the body within a week after injection (5, 6, 7). Thus, an exposure of 30 g bound iodine, a normal dose of intravenous ICM at computed tomography (100 mL 300 mg I/mL), may result in up to 45,000 µg free iodide, to be compared with the recommended daily intake of 150 μg for adults (8).
Reported frequencies of ICM-induced thyroid dysfunction range from 0.05% to 22% (9, 10, 11, 12). The risk of developing thyroid dysfunction, especially hyperthyroidism, after ICM exposure, is lower in iodine-sufficient countries such as Sweden (13, 14), but we need to be aware of these adverse effects, as they become more common with the increasing use of ICM in elderly patients and in immigrants from potentially iodine-deficient areas. In the past 20 years, the use of ICM has increased by more than 200% in Sweden (15). This widespread use of ICM, and the wide variation in frequency of ICM-induced thyroid effects, call for prospective, controlled studies. If we can better identify patients at risk of ICM-induced thyroid dysfunction prior to ICM-enhanced procedures, we can assess the risks and, if needed, choose proper prophylaxis or other imaging options. In this prospective study of individuals randomly selected from the general population to undergo coronary computed tomography angiography (CCTA), we aimed to determine the incidence, degree and clinical importance of ICM-induced thyroid dysfunction, and its related risk factors, including the presence of thyroid peroxidase antibodies (TPOabs) and thyroid nodules.
Materials and methods
Participants
The study was approved by the Regional Research Ethics Committee in Gothenburg (26 April 2017: reference number 277-17 and 04 December 2017: reference number T1036-17) and the amendment was approved by the Swedish Ethical Review Authority on 15 November 2019 (2019-05515). The study was performed according to the Declaration of Helsinki. Participants were informed orally and in writing and signed an informed consent form.
Study participants were enrolled from the Swedish CArdioPulmonary bioImage Study (SCAPIS), a large prospective multicentre study on biomarkers for cardiovascular and pulmonary disease (16). SCAPIS participants (50–65 years of age) were randomly selected from the population registry in Sweden. The Gothenburg SCAPIS cohort consisted of 6,256 individuals (52% of those invited) with inclusion between 2013 and 2017 (17). There were no exclusion criteria, except the inability to understand Swedish.
The SCAPIS study protocol consisted of, among other examinations, CCTA and carotid ultrasound (16). Based on the serum creatinine data from SCAPIS, the glomerular filtration rate was estimated (eGFR) and those with eGFR >50 mL/min were offered CCTA with intravenous injection of iohexol. In the Gothenburg SCAPIS cohort, 661 individuals (11%) did not receive ICM, due to eGFR <50 mL/min, contraindications to ICM or if they chose not to receive ICM. Individuals on levothyroxine were given ICM, while ICM was contraindicated in individuals with known untreated hyperthyroidism (as per clinical routine). No prophylaxis regarding hyperthyroidism was administered. For the present study with thyroid hormone measurements pre and post CCTA, we utilized the last part of the Gothenburg SCAPIS cohort with the inclusion of May–December 2017. Participants were consecutively included based on available time slots for CCTA and the availability of staff for handling the blood samples. In total, 598 individuals had pre-CCTA blood samples taken.
Pre-CCTA blood sampling
At the time of the CCTA procedure, an intravenous blood sample was obtained from participants before receiving ICM for analysis of thyroid-stimulating hormone (S-TSH), free thyroxine (S-fT4), free triiodothyronine (S-fT3), and thyroid peroxidase antibodies (S-TPOab).
Contrast medium administration
All participants received intravenous injections of iohexol 325 mg I/kg (Omnipaque 350 mg I/mL, GE Healthcare AB), applying a minimum/maximum dosing weight of 50/80 kg for women and 50/90 kg for men. The mean and median doses injected were 27.9 and 28.7 grams iodine, respectively.
Post-CCTA blood sampling
Participants were asked to provide post-CCTA blood samples (S-TSH, S-fT4, S-fT3) 6–8 weeks after the CCTA procedure. Instructions stated that all blood samples should be sent to the Department of Clinical Chemistry at Sahlgrenska University Hospital (SU) for analysis. Individuals with abnormal hormone levels were discussed with an endocrinologist (HFN) and, when indicated, contacted for additional follow-up.
Post-CCTA blood samples were obtained in 448 of the 598 (75%) individuals within 11–270 days after CCTA. Follow-up samples were taken as recommended, i.e. within 6–8 weeks, in 296 individuals and in 422 participants within 4–12 weeks. This wider time range is likely to reflect any clinically important changes in thyroid function (1, 4). Therefore, the latter cohort (n = 422, 230 women) was used for the final analysis (Fig. 1). Individual characteristics are presented in Table 1 and the country of origin for those born outside Sweden is presented in Fig. 2.
Flow chart of study population. Number of individuals with obtained thyroid hormone samples at CCTA, and number of participants with available follow-up samples (26 individuals with follow-up samples excluded due to samples obtained outside the 4–12 weeks time frame after CCTA).
Citation: European Thyroid Journal 13, 6; 10.1530/ETJ-24-0244
Answers from SCAPIS Core Questionnaire, concerning the question ‘Were you born in Sweden? Yes/No’ and if no, stated country of origin. Diagram showing the region of origin for the 68/422 individuals who were born outside Sweden.
Citation: European Thyroid Journal 13, 6; 10.1530/ETJ-24-0244
Baseline characteristics of the study cohort and the remaining Gothenburg SCAPIS cohort. No difference between the study cohort and the remaining Gothenburg SCAPIS cohort with regard to sex, age or smoking. Contrast medium dose was significantly lower in the study cohort, but the difference was small and likely of no clinical importance. No available information regarding participants’ possible history of thyroid disease. P < 0.05 indicates a statistically significant difference.
| Study cohort | Remaining Gothenburg SCAPIS cohort | P | Standard difference* | |
|---|---|---|---|---|
| n | 422 | 5842 | ||
| Females (%) | 54.7 | 52.1 | 0.313 | |
| Age (years) | ||||
| Mean ± s.d. | 57.8 ± 4.2 | 57.4 ± 4.3 | 0.063 | 0.095 |
| Median (25th/97.5th percentiles) | 58.0 (50.6/64.8) | 57.4 (50.6/64.9) | 0.061 | |
| Smokers or ex-smokers (%) | 49.5 | 53.6 | 0.11 | |
| Born outside Sweden (%) | 16.1 | N/A | ||
| Contrast medium dose (grams iodine) | ||||
| Mean ± s.d. | 27.9 ± 3.6 | 28.4 ± 3.9 | 0.010 | 0.14 |
| Median (25th/97.5th percentiles) | 28.7 (21.1/32.9) | 29.1 (21.0/32.9) | 0.006 |
*For continuous variables.
Questionnaires
Study participants were asked to fill out the short version of the Thyroid-related Patient-Reported Outome questionnaire (ThyPRO) (18), concerning thyroid-related symptoms before and after the CCTA, at the time of the two blood sampling procedures. It consists of 13 items (scales) related to goitre symptoms (Table 2A and B, questionnaire shown in Supplementary material, see section on supplementary materials given at the end of this article). Scores before and after CCTA were compared.
Thyroid hormone level differences in the 14/399 (3.5%) individuals with normal baseline thyroid hormone levels and onset of thyroid dysfunction after ICM exposure.
| Median difference | Range | |
|---|---|---|
| TSH (mIU/L) | 1.15 | −0.80 to 3.10 |
| fT4 (pmol/L) | −0.5 | −4.0 to 8.0 |
| fT3 (pmol/L) | −0.25 | −1.10 to 1.30 |
Biochemical methods
FT4, fT3, TSH and TPOab were continuously analysed with electrochemiluminescence immunoassay (ECLIA) at the Department of Clinical Chemistry at SU, Gothenburg, Sweden, using a Roche Elecsys® ECL (Roche Diagnostics International AG). Reference intervals were: fT4 12–22 pmol/L, fT3 3.1–6.8 pmol/L, TSH 0.30–4.2 mIU/L, and TPO ab <34 U/mL. For the 33 (7.8%) individuals with post-CCTA samples analysed at Unilabs (Advia Centaur system, Västra Götaland region, Sweden), the reference intervals were fT4 10–22 pmol/L, fT3 3.3–6.0 pmol/L, and TSH 0.4–4.0 mIU/L. One individual (with normal thyroid hormone levels pre and post-CCTA) had a follow-up at a third laboratory (Region Halland, Sweden).
Thyroid dysfunction definitions
Subclinical and overt thyroid dysfunction is defined as biochemically independent of clinical symptoms (19):
-
Overt hypothyroidism: TSH above and fT4 and/or fT3 below reference ranges
-
Subclinical hypothyroidism: TSH above reference range and fT4 and fT3 normal
-
Isolated hypothyroxinemia: TSH normal and fT4 and/or fT3 below reference ranges
-
Overt hyperthyroidism: TSH below and fT4 and/or fT3 above reference ranges
-
Subclinical hyperthyroidism: TSH below reference range and fT4 and fT3 normal
-
Isolated hyperthyroxinemia: TSH normal and fT4 and/or fT3 above reference range
Thyroid ultrasonography
Ultrasonography was performed at the time of inclusion by a certified ultrasonographer, using a Siemens Acuson S2000 ultrasound scanner with a 9L4 linear transducer (Siemens Healthineers). For this study, the SCAPIS carotid ultrasound examination protocol was extended to also include an 8 MHz transverse scan sequence over both thyroid lobes to assess the presence of thyroid nodules. These cine loops were reviewed continuously by one of the authors (JC) during the period of inclusion. Thyroid lesions were measured and characterized according to the Thyroid Imaging Reporting and Data System (TIRADS) (20). Purely cystic nodules were not considered relevant nodules because of their inability to function as autonomous nodules (21). Lesions <5 mm were not included due to their small size and the limited ability to characterize these adequately and differentiate them from cysts. Participants with nodules in need of further follow-up based on size and image characteristics according to TIRADS were referred to clinical thyroid ultrasound with fine needle aspiration.
Endpoints
The primary endpoint of this study was the frequency and magnitude of early thyroid dysfunction 4–12 weeks after ICM exposure. Secondary endpoints included tests of associations between ICM-induced thyroid dysfunction and related risk factors (thyroid nodules, TPOab and demographic data) and if ICM-induced thyroid dysfunction affected the participants’ QoL.
Clinical follow-up
Participants with subclinical hyperthyroidism or isolated increase of fT4 were referred to the endocrinology department at SU for evaluation. Individuals with subclinical hypothyroidism were referred to their primary healthcare unit for follow-up. The central chemistry laboratory database of SU was checked in 2020 (i.e. 2–3 years after inclusion in the study) for all 598 participants in order to identify cases of thyroid dysfunction possibly missed during the study period.
Statistical analysis
For comparisons between groups, the chi-square test or Fisher’s exact test was used for proportions and the Students paired t test was used for continuous variables of normal distribution and ANOVA for comparison between groups. For data without normal distribution, the Wilcoxon signed rank test and McNemar’s test were used for paired analysis and the Mann–Whitney U test for independent samples. All significance tests were two-sided and P-values below 0.05 were considered statistically significant. Relative risk was calculated for risk assessments.
Results
Thyroid hormone levels before and after ICM administration (group level)
Of the 422 participants (mean age: 57.8 ± 4.2 years, 231 women) with post-CCTA blood samples 4–12 weeks after the CCTA, 388 (92%) had their follow-up samples analysed at SU. Median TSH increased significantly by 0.10 mIU/L (2.5th/97.5th percentiles: −1.24/2.09, P = 0.003), fT4 had a median change of 0.00 pmol/L (2.5th/97.5th percentiles: −3.0/3.11, P = 0.157) and fT3 median increased 0.10 pmol/L (2.5th/97.5th percentiles: −3.1/1.15, P = 0.172).
Incidence of thyroid hormone dysfunction (individual level)
Pre-CCTA, 399/422 (95%) had normal thyroid hormone levels while 23 had abnormal levels (TSH or fT4). Post-CCTA the corresponding number was 27. For the type of thyroid dysfunction and results from additional follow-up, see Fig. 3. Most individuals with abnormal thyroid hormone levels pre-CCTA, especially those with subclinical hyperthyroidism, had remaining thyroid dysfunction 4–12 weeks after ICM exposure as well as at additional follow-up (Supplementary Table).
Flow chart of normal/abnormal thyroid hormone levels of study cohort (n = 422) before and after iodine contrast medium exposure and, when indicated, at additional follow-up. High fT4, isolated hyperthyroxinemia; Low fT4, isolated hypothyroxinemia; Subclin Hyper, subclinical hyperthyroidism; Subclin Hypo, subclinical hypothyroidism.
Citation: European Thyroid Journal 13, 6; 10.1530/ETJ-24-0244
Of the 399 individuals with normal hormone levels pre-CCTA, 14 (3.5%) developed thyroid dysfunction. Twelve of them had both pre- and post-CCTA blood samples analysed at SU. Differences in hormone levels are shown in Table 2.
Of the 14 individuals with onset of thyroid dysfunction after ICM exposure, seven had normalized hormone levels at additional follow-up (Fig. 3). Four individuals had such small deviations that no additional sampling was indicated according to an endocrinologist (HFN), one had missing data and two showed persistent thyroid dysfunction (subclinical hypothyroidism).
Clinical impact
Of the 422 individuals, 368 (87%) responded to the ThyPRO questionnaire before and after CCTA. As shown in Table 3A, in 11/13 categories concerning thyroid-related symptoms there were no statistically significant differences after ICM exposure. Regarding eye symptoms, the difference was statistically significant (P = 0.001) but small, with a mean score decrease of 2.0 units (mean score: 13.62/100 before and 11.61/100 after ICM exposure). A similar small statistically significant decrease was observed for hyperthyroid symptoms with a mean decrease of 0.98 units (mean score: 13.82/100 before and 11.35/100 after ICM).
ThyPRO questionnaire response before and after ICM was available for 10/14 individuals with onset of thyroid dysfunction. No statistically significant changes in ThyPRO scores were observed after CCTA, but all 13 categories were not assessed for these 10 individuals due to missing data as shown in Table 3B. In six categories, there was no median difference in symptom scores and in 12/13 categories the median difference was less than 10 units (cognitive problems were less pronounced post-CCTA, median score 8.3/100 compared to 20.8/100 before CCTA). When comparing these 14 individuals with the onset of thyroid dysfunction and their differences in ThyPRO results with the remaining study cohort, there was no statistically significant difference in any of the 13 ThyPRO categories.
ThyPRO questionnaire results for the entire cohort (A) respectively individuals with onset of thyroid dysfunction (B) after iodine contrast media (ICM) exposure. Responses are scored 0 = not at all, 1 = a little, 2 = some, 3 = quite a bit, 4 = very much/completely, and all response values (0–4) in a scale are added and linearly transformed to provide a total score of 0–100 given that at least two questions per item were answered. 368/422 (87%) of the entire cohort in 3A and 10/14 individuals in 3B provided questionnaires before and after contrast media. A significance level of 0.05 rendering statistically significant change for two categories (eye symptoms and hyperthyroid symptoms) for the entire cohort. No statistically significant changes in reported symptoms after contrast media exposure were found among individuals with the onset of thyroid dysfunction.
| Before ICM exposure | 4–12 weeks after ICM exposure | P | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Mean | s.d. | Min | Max | Percentiles | n | Mean | s.d. | Min | Max | Percentiles | ||||||
| 25th | 50th* | 75th | 25th | 50th* | 75th | ||||||||||||
| A: Entire cohort | |||||||||||||||||
| Goitre symptoms | 365 | 3.74 | 10.12 | 0.00 | 91.67 | 0.00 | 0.00 | 0.00 | 364 | 4.03 | 11.14 | 0.00 | 83.33 | 0.00 | 0.00 | 0.00 | 0.788 |
| Hyperthyroid symptoms | 365 | 12.33 | 13.82 | 0.00 | 81.25 | 0.00 | 6.25 | 18.75 | 365 | 11.35 | 15.23 | 0.00 | 81.25 | 0.00 | 6.25 | 18.75 | 0.049 |
| Hypothyroid symptoms | 365 | 12.14 | 14.67 | 0.00 | 93.75 | 0.00 | 6.25 | 18.75 | 365 | 10.89 | 14.36 | 0.00 | 75.00 | 0.00 | 6.25 | 18.75 | 0.053 |
| Eye symptoms | 365 | 13.61 | 17.90 | 0.00 | 91.67 | 0.00 | 8.33 | 20.83 | 364 | 11.62 | 17.58 | 0.00 | 91.67 | 0.00 | 0.00 | 16.67 | 0.001 |
| Tiredness | 366 | 35.97 | 19.39 | 0.00 | 100.00 | 25.00 | 33.33 | 50.00 | 365 | 35.90 | 21.46 | 0.00 | 100.00 | 16.67 | 33.33 | 50.00 | 0.932 |
| Cognitive problems | 365 | 15.87 | 19.34 | 0.00 | 100.00 | 0.00 | 8.33 | 25.00 | 365 | 15.87 | 20.91 | 0.00 | 100.00 | 0.00 | 8.33 | 25.00 | 0.670 |
| Anxiety | 366 | 18.12 | 21.70 | 0.00 | 100.00 | 0.00 | 8.33 | 25.00 | 366 | 16.83 | 21.90 | 0.00 | 100.00 | 0.00 | 8.33 | 25.00 | 0.077 |
| Depressivity | 366 | 24.58 | 17.19 | 0.00 | 91.67 | 8.33 | 16.67 | 33.33 | 366 | 25.46 | 18.08 | 0.00 | 100.00 | 14.58 | 16.67 | 33.33 | 0.306 |
| Emotional susceptibility | 365 | 25.82 | 19.35 | 0.00 | 100.00 | 8.33 | 25.00 | 41.67 | 368 | 25.88 | 21.35 | 0.00 | 100.00 | 8.33 | 16.67 | 41.67 | 0.623 |
| Social impairment | 73 | 6.39 | 11.66 | 0.00 | 50.00 | 0.00 | 0.00 | 8.33 | 71 | 6.81 | 13.90 | 0.00 | 58.33 | 0.00 | 0.00 | 8.33 | 0.877 |
| Impaired daylife | 74 | 7.55 | 13.87 | 0.00 | 66.67 | 0.00 | 0.00 | 8.33 | 71 | 7.98 | 14.33 | 0.00 | 50.00 | 0.00 | 0.00 | 8.33 | 0.093 |
| Cosmetic complaints | 72 | 5.79 | 14.98 | 0.00 | 75.00 | 0.00 | 0.00 | 0.00 | 69 | 5.80 | 15.81 | 0.00 | 91.67 | 0.00 | 0.00 | 0.00 | 0.389 |
| Negative impact | 71 | 8.45 | 19.34 | 0.00 | 75.00 | 0.00 | 0.00 | 0.00 | 69 | 8.33 | 19.01 | 0.00 | 75.00 | 0.00 | 0.00 | 0.00 | 0.599 |
| B: With thyroid dysfunction | |||||||||||||||||
| Goitre symptoms | 9 | 3.70 | 6.05 | 0.00 | 16.67 | 0.00 | 0.00 | 8.33 | 9 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.16 |
| Hyperthyroid symptoms | 9 | 17.36 | 10.72 | 0.00 | 31.25 | 9.38 | 18.75 | 28.13 | 9 | 12.50 | 12.88 | 0.00 | 37.50 | 0.00 | 12.50 | 21.88 | 0.71 |
| Hypothyroid symptoms | 9 | 18.06 | 9.60 | 6.25 | 31.25 | 9.38 | 18.75 | 28.13 | 9 | 12.50 | 8.27 | 0.00 | 25.00 | 6.25 | 12.50 | 18.75 | 0.74 |
| Eye symptoms | 9 | 13.89 | 16.67 | 0.00 | 33.33 | 0.00 | 0.00 | 33.33 | 9 | 6.48 | 6.94 | 0.00 | 16.67 | 0.00 | 8.33 | 12.50 | 0.457 |
| Tiredness | 10 | 44.17 | 22.24 | 8.33 | 91.67 | 31.25 | 45.83 | 52.08 | 9 | 37.96 | 14.50 | 16.67 | 58.33 | 25.00 | 41.67 | 50.00 | 0.595 |
| Cognitive problems | 10 | 23.33 | 19.95 | 0.00 | 58.33 | 6.25 | 20.83 | 41.67 | 9 | 24.07 | 27.46 | 0.00 | 66.67 | 0.00 | 8.33 | 50.00 | 1 |
| Anxiety | 10 | 26.67 | 24.78 | 0.00 | 66.67 | 0.00 | 25.00 | 50.00 | 10 | 24.17 | 24.36 | 0.00 | 66.67 | 0.00 | 20.83 | 45.83 | 0.618 |
| Depressivity | 10 | 33.33 | 23.90 | 0.00 | 66.67 | 14.58 | 33.33 | 52.08 | 10 | 34.17 | 20.95 | 0.00 | 58.33 | 14.58 | 37.50 | 52.08 | 0.888 |
| Emotional susceptibility | 10 | 32.50 | 23.06 | 0.00 | 66.67 | 8.33 | 37.50 | 52.08 | 10 | 35.83 | 28.07 | 0.00 | 83.33 | 6.25 | 37.50 | 54.17 | 0.551 |
| Social impairment | 3 | 16.67 | 28.87 | 0.00 | 50.00 | 0.00 | 0.00 | 50.00 | 4 | 4.17 | 8.33 | 0.00 | 16.67 | 0.00 | 0.00 | 12.50 | 0.317 |
| Impaired daylife | 3 | 13.89 | 17.35 | 0.00 | 33.33 | 0.00 | 8.33 | 33.33 | 4 | 10.42 | 10.49 | 0.00 | 25.00 | 2.08 | 8.33 | 20.83 | 1 |
| Cosmetic complaints | 3 | 8.33 | 8.33 | 0.00 | 16.67 | 0.00 | 8.33 | 16.67 | 4 | 8.33 | 9.62 | 0.00 | 16.67 | 0.00 | 8.33 | 16.67 | 0.317 |
| Negative impact | 3 | 8.33 | 14.43 | 0.00 | 25.00 | 0.00 | 0.00 | 25.00 | 4 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.317 |
*median values.
Country of birth and elevated TPOab
Of the 14 individuals with the onset of thyroid dysfunction after CCTA, seven (50%) were born outside Sweden. The relative risk of developing subclinical hypothyroidism after normal pre-CCTA thyroid hormone levels was 36 times higher for those being born outside Sweden compared to native Swedes (Fig. 4A). Of those seven individuals born outside Sweden, six had elevated TPOab. The only case of subclinical hypothyroidism after ICM exposure among participants born in Sweden also had elevated TPOab. The relative risk of developing subclinical hypothyroidism was 37 times higher for those with elevated TPOab compared to those with normal levels (Fig. 4B). Of all the 422 individuals, 7.6% had elevated TPOab, 5.2% among men and 12.7% among women. There was a statistically significant association between being born outside Sweden and having elevated TPOab (P = 0.01), the relative risk was 3.4 times higher for those born outside Sweden compared to native Swedes (Fig. 4C).
(A) Increased risk for individuals born outside Sweden to develop subclinical hypothyroidism after ICM exposure, P < 0.001. (B) Elevated thyroid peroxidase antibodies (TPOab) as a risk factor for developing subclinical hypothyroidism after ICM exposure, P < 0.001. (C) Higher frequency of elevated thyroid peroxidase antibodies (TPOab) among individuals born outside Sweden compared to native Swedes, P = 0.001. Fisher’s exact test used to determine statistically significant association. Subjects in A and B had normal thyroid hormone levels before ICM exposure.
Citation: European Thyroid Journal 13, 6; 10.1530/ETJ-24-0244
Thyroid nodules and thyroid function post-CCTA
Of the 422 individuals, thyroid ultrasonography was obtained in 329. Solid or partly solid thyroid nodules 5–9 mm and >10 mm in diameter were seen in 133 (40.4%) and 54 (16.4%) individuals, respectively. There was no association between the presence of thyroid nodules and subclinical hyperthyroidism or isolated high fT4 at follow-up. Also, there was no significant correlation between the presence of nodules and fT4 or TSH changes (Table 4).
Number of thyroid nodules in relationship to hyperthyroidism and fT4 and TSH changes pre- compared to post-iodine contrast medium exposure. Thyroid nodules with cut-off limits of 5 mm and 10 mm. Fisher’s exact test was used to determine a statistically significant association, significance level set at P = 0.05.
| Thyroid nodules ≥ 5 mm | Thyroid nodules ≥ 10 mm | |||||
|---|---|---|---|---|---|---|
| None | Present | P | None | Present | P | |
| SCH or isolated high fT4 post-CCTA | 3/196 (1.5%) | 1/133 (0.8%) | 0.650 | 3/275 (1.1%) | 1/54 (1.9%) | 0.514 |
| fT4 change pmol/L, (95% CI) | 0.087 (−0.144, 0.319) | 0.095 (−0.174, 0.364) | 0.051 (0.135, 0.237) | 0.292 (−0.206, 0.790) | ||
| TSH change mIU/L, (95% CI) | 0.113 (−0.009, 0.235) | 0.186 (0.069, 0.303) | 0.120 (0.023, 0.218) | 0.252 (0.077, 0.427) | ||
SCH, subclinical hyperthyroidism.
Long-term follow-up
The search for post-CCTA thyroid dysfunction in the original study population (n = 598) in the database of the Department of Clinical Chemistry at SU 2 years after CCTA showed no cases of missed severe thyroid dysfunction after CCTA.
Discussion
In this cohort of randomly selected individuals aged 50–65 years exposed to ICM at CCTA, a small, but statistically significant increase in TSH levels was found 4–12 weeks later. Eight individuals developed subclinical hypothyroidism and one developed subclinical hyperthyroidism, but no cases of overt hypo- or hyper-thyroidism were noted. Although not covered in the definitions of overt or subclinical hypo- or hyper-thyroidism, we also registered isolated hypothyroxinemia and hyperthyroxinemia as thyroid dysfunction as this has been associated with altered physical functional status (22). Our results in the present Swedish cohort suggest that clinically significant effects of ICM on thyroid function are rare, and mild thyroid hormone level effects are seen in only a minority of cases, not yielding any significant clinical symptoms.
Previous studies have shown varying degrees of ICM effects on thyroid hormone levels, possibly due to varying patient selection criteria and underlying variations in dietary iodine intake (23, 24). The limited frequency of post-ICM thyroid dysfunction in our study may reflect that Sweden is considered an iodine-sufficient country (25). Guidelines from the European Thyroid Association (ETA) stated in 2021 that new onset thyroid dysfunction after ICM is most often mild and self-limited without a need for specific treatment (13). Iodine sufficiency or an increase in iodine levels is associated with more autoimmune hypothyroidism (26). Positive TPOab is a marker of chronic autoimmune thyroiditis, which sometimes causes hypothyroidism. Elevated TPOab was associated with a higher risk of developing thyroid dysfunction after ICM exposure, which indicates difficulty in escaping from the Wolff–Chaikoff effect (27). Elevated TPOab was also more common among individuals born outside Sweden than in those born in Sweden. Even a small increase in iodine levels in a population can affect thyroid dysfunction epidemiology (28) and can lead to an increased frequency of autoimmune thyroid diseases. There is no reliable data on hypothyroidism in Sweden, but for Graves’ disease (autoimmune diffuse hyperthyroidism) immigration has been made responsible for an increasing number of cases in Southern Sweden (14).
The frequency of TPOab increases with age and in our target population of randomly selected individuals aged 50–65 years, the frequency was comparable to what has been reported from neighbouring countries (29). The frequency of thyroid nodules also increases with age but surprisingly, we found no association between the presence of thyroid nodules and thyroid dysfunction after ICM. Since we had no cases of overt hyperthyroidism in our cohort after ICM exposure, we cannot fully dismiss such an association, which has been previously described in the literature (23), perhaps due to sample size. We can however state that given the frequency of prevalent thyroid nodules (16% and 40% for those ≥10 and 5–9 mm, respectively), in an iodine-sufficient country like Sweden, this is not a major risk factor for developing ICM-induced thyroid dysfunction, and there was no association between presence of thyroid nodules and pre-CCTA versus post-CCTA fT4 or TSH changes.
As there were no cases of overt hypo- or hyper-thyroidism, the thyroid-related risks of ICM exposure seem low for a randomly selected Swedish cohort, consistent with a meta-analysis from 2021 showing an extremely low incidence of overt hyperthyroidism after ICM exposure (0.1%) (30). Although randomly selected, one could argue that participants in the SCAPIS may not be fully representative of the general population, as recruitment to SCAPIS was higher in socio-economically more favourable parts of the uptake area (31). Also, the SCAPIS population does not fully represent a patient cohort requiring ICM in a medical situation. ICM was not given to individuals with eGFR below 50 mL/min and participants could decline ICM injection if they so chose. Elimination half-time increases in patients with decreased renal function which may increase the amount of free iodide released from the ICM molecule in the body. In the literature, an association between renal dysfunction and thyroid dysfunction, and vice versa, has been described (13, 32). ICM may potentially affect renal function, but this seems unlikely in our study where only individuals with e-GFR of at least 50 mL/min were included. Furthermore, no clinically significant effect of ICM was found in an analysis of renal function before and after ICM in an earlier cohort of the SCAPIS population, with identical inclusion criteria in a similar setting, using the same ICM and dosing as in the present study (33). The SCAPIS population was reported as representative of an age-matched Swedish background population with only minimal bias concerning cardiac atherosclerosis (34). However, patients requiring ICM in a clinical situation may also have other or additional risk factors, e.g. heart failure, and thus less tolerance for thyroid dysfunction compared to this randomly selected cohort. There was no documentation in SCAPIS concerning background thyroid disease, but as per clinical routine, participants were asked about risk factors before ICM administration, including questions on thyroid disease. Individuals on levothyroxine were given ICM, while ICM was contraindicated in individuals with known untreated hyperthyroidism. Lack of further detailed information regarding the participants’ medications and possible thyroid disease history is a limitation of our study. Another limitation, as in most other studies, was the lack of information on individual dietary iodine intake. Also, the US cine loops did not allow for the calculation of thyroid volume, another risk factor for ICM-induced hyperthyroidism (35). On the other hand, the prospective and controlled design of the study, the correlation with ultrasonographic thyroid nodules, TPOab, evaluation of clinical symptoms before and after ICM administration and the high compliance with a 75% participation rate at post-CCTA blood sampling (and among those, 87% participation with ThyPRO questionnaires before and after ICM exposure) are among the strengths of our study.
In conclusion, after ICM exposure there was a small increase in the number of patients with thyroid hormone levels outside the reference intervals compared to before ICM exposure, but the difference was not statistically significant. The small variations in thyroid hormone levels did not cause any significant clinical symptoms according to ThyPRO questionnaires. Individuals with elevated TPOab and those born outside Sweden had a higher risk of developing subclinical hypothyroidism after ICM exposure. In contradiction to previous studies (23), our study did not show an increased risk of ICM-induced thyroid dysfunction in individuals with thyroid nodules. The results of this prospective study support the notion that in iodine-sufficient countries, ICM-associated thyroid dysfunction is rare, usually mild, self-limiting and oligo/asymptomatic in subjects aged 50–65 years. Our results support the ETA and ESUR guidelines (13) suggesting that baseline thyroid function testing prior to intravenous ICM is not recommended in adults without known risk factors for thyroid disease.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ETJ-24-0244.
Declaration of interest
The authors declare no relationships with any companies, whose products or services may be related to the subject matter of the article.
Funding
This study has received funding by grants from the Västra Götaland Region and grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement. Additional support was received from the Sahlgrenska University Hospital. The main funding body of the Swedish CArdioPulmonary bioImage Study (SCAPIS) is the Swedish Heart-Lung Foundation. SCAPIS is also funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council and VINNOVA (Sweden’s Innovation Agency), the University of Gothenburg and Sahlgrenska University Hospital, Karolinska Institutet and Stockholm county council, Linköping University and University Hospital, Lund University and Skåne University Hospital, Umeå University and University Hospital, and Uppsala University and University Hospital.
References
- 1↑
Rhee CM, Bhan I, Alexander EK, & Brunelli SM. Association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism. Archives of Internal Medicine 2012 172 153–159. (https://doi.org/10.1001/archinternmed.2011.677)
- 2↑
Gartner W, & Weissel M. Do iodine-containing contrast media induce clinically relevant changes in thyroid function parameters of euthyroid patients within the first week? Thyroid 2004 14 521–524. (https://doi.org/10.1089/1050725041517075)
- 3↑
Jarvis C. A low incidence of iodine-induced hyperthyroidism following administration of iodinated contrast in an iodine-deficient region. Clinical Endocrinology 2015 0 1–6.
- 4↑
Conn JJ, Sebastian MJ, Deam D, Tam M, & Martin FIR. A prospective study of the effect of nonionic contrast media on thyroid function. Thyroid 1996 6 107–110. (https://doi.org/10.1089/thy.1996.6.107)
- 5↑
Rendl J, & Saller B. Schilddrüse und Röntgenkontrastmittel: pathophysiologie, Häufigkeit und Prophylaxe der jodinduzierten Hyperthyreose. Dt Ärztebl 2001 98 A402–A406.
- 6↑
United_States_Pharmacopeial_Convention. Iohexol Injection. USP-NF Standard Updates. 2011. (www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/iohexolinjection.pdf) Accessed 25 October 2024.
- 7↑
Hudzik B, & Zubelewicz-Szkodzińska B. Radiocontrast-induced thyroid dysfunction: is it common and what should we do about it? Clinical Endocrinology 2014 80 322–327. (https://doi.org/10.1111/cen.12376)
- 8↑
Nordic_Council_of_Ministers. Nordic Nutrition Recommendations 2012: Integrating Nutrition and Physical Activity. 2014. (pub.norden.org/nord2023-003/nord2023-003.pdf) Accessed 25 October 2024.
- 9↑
Hintze G, Blombach O, Fink H, Burkhardt U, & Kobberling J. Risk of iodine-induced thyrotoxicosis after coronary angiography: an investigation in 788 unselected subjects. European Journal of Endocrinology 1999 140 264–267. (https://doi.org/10.1530/eje.0.1400264)
- 10↑
Lee SY, Chang DLF, He X, Pearce EN, Braverman LE, & Leung AM. Urinary iodine excretion and serum thyroid function in adults after iodinated contrast administration. Thyroid 2015 25 471–477. (https://doi.org/10.1089/thy.2015.0024)
- 11↑
Kornelius E, Chiou JY, Yang YS, Peng CH, Lai YR, & Huang CN. Iodinated contrast media increased the risk of thyroid dysfunction: a 6-year retrospective cohort study. Journal of Clinical Endocrinology and Metabolism 2015 100 3372–3379. (https://doi.org/10.1210/JC.2015-2329)
- 12↑
Inoue K, Guo R, Lee ML, Ebrahimi R, Neverova NV, Currier JW, Bashir MT, & Leung AM. Iodinated contrast administration and risks of thyroid dysfunction: a retrospective cohort analysis of the U.S. Veterans Health Administration System. Thyroid 2023 33 230–238. (https://doi.org/10.1089/thy.2022.0393)
- 13↑
Bednarczuk T, Brix TH, Schima W, Zettinig G, & Kahaly GJ. 2021 European Thyroid Association guidelines for the management of iodine-based contrast media-induced thyroid dysfunction. European Thyroid Journal 2021 10 269–284. (https://doi.org/10.1159/000517175)
- 14↑
Lantz M, Abraham-Nordling M, Svensson J, Wallin G, & Hallengren B. Immigration and the incidence of Graves’ thyrotoxicosis, thyrotoxic multinodular goiter and solitary toxic adenoma. European Journal of Endocrinology 2009 160 201–206. (https://doi.org/10.1530/EJE-08-0548)
- 16↑
Bergström G, Berglund G, Blomberg A, Brandberg J, Engström G, Engvall J, Eriksson M, de Faire U, Flinck A, Hansson MG, et al.The Swedish cardiopulmonary BioImage Study: objectives and design. Journal of Internal Medicine 2015 278 645–659. (https://doi.org/10.1111/joim.12384)
- 17↑
Bonander C, Nilsson A, Björk J, Blomberg A, Engström G, Jernberg T, Sundström J, Östgren CJ, Bergström G, & Strömberg U. The value of combining individual and small area sociodemographic data for assessing and handling selective participation in cohort studies: evidence from the Swedish cardiopulmonary BioImage Study. PLoS One 2022 17 e0265088. (https://doi.org/10.1371/journal.pone.0265088)
- 18↑
Watt T, Bjorner JB, Groenvold M, Cramon P, Winther KH, Hegedüs L, Bonnema SJ, Rasmussen ÅK, Ware JE, & Feldt-Rasmussen U. Development of a short version of the thyroid-related patient-reported outcome ThyPRO. Thyroid 2015 25 1069–1079. (https://doi.org/10.1089/thy.2015.0209)
- 19↑
Cooper DS, & Biondi B. Subclinical thyroid disease. Lancet 2012 379 1142–1154. (https://doi.org/10.1016/S0140-6736(11)60276-6)
- 20↑
Shin JH, Baek JH, Chung J, Ha EJ, Kim JH, Lee YH, Lim HK, Moon WJ, Na DG, Park JS, et al.Ultrasonography diagnosis and imaging-based management of thyroid nodules: revised Korean society of thyroid radiology consensus statement and recommendations. Korean Journal of Radiology 2016 17 370–395. (https://doi.org/10.3348/kjr.2016.17.3.370)
- 21↑
Baser H, Topaloglu O, Bilginer MC, Ulusoy S, Kılıcarslan A, Ozdemir E, Ersoy R, & Cakir B. Are cytologic and histopathologic features of hot thyroid nodules different from cold thyroid nodules? Diagnostic Cytopathology 2019 47 898–903. (https://doi.org/10.1002/dc.24251)
- 22↑
van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, & Lamberts SWJ. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. Journal of Clinical Endocrinology and Metabolism 2005 90 6403–6409. (https://doi.org/10.1210/jc.2005-0872)
- 23↑
van der Molen AJ, Thomsen HS, Morcos SK & Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Effect of iodin ated contrast media on thyroid function in adults. European Radiology 2004 14 902–907. (https://doi.org/10.1007/s00330-004-2238-z)
- 24↑
Sohn SY, Inoue K, Bashir MT, Currier JW, Neverova NV, Ebrahimi R, Rhee CM, Lee ML, & Leung AM. Thyroid dysfunction risk after iodinated contrast media administration: a prospective longitudinal cohort analysis. Journal of Clinical Endocrinology and Metabolism 2024. (https://doi.org/10.1210/clinem/dgae304)
- 25↑
Andersson M, Berg G, Eggertsen R, Filipsson H, Gramatkovski E, Hansson M, Hulthén L, Milakovic M, & Nyström E. Adequate iodine nutrition in Sweden: a cross-sectional national study of urinary iodine concentration in school-age children. European Journal of Clinical Nutrition 2009 63 828–834. (https://doi.org/10.1038/ejcn.2008.46)
- 26↑
Laurberg P, Cerqueira C, Ovesen L, Rasmussen LB, Perrild H, Andersen S, Pedersen IB, & Carlé A. Iodine intake as a determinant of thyroid disorders in populations. Best Practice and Research. Clinical Endocrinology and Metabolism 2010 24 13–27. (https://doi.org/10.1016/j.beem.2009.08.013)
- 27↑
Lee SY, Rhee CM, Leung AM, Braverman LE, Brent GA, & Pearce EN. A review: radiographic iodinated contrast media-induced thyroid dysfunction. Journal of Clinical Endocrinology and Metabolism 2015 100 376–383. (https://doi.org/10.1210/jc.2014-3292)
- 28↑
Cerqueira C, Knudsen N, Ovesen L, Laurberg P, Perrild H, Rasmussen LB, & Jørgensen T. Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt? European Journal of Epidemiology 2011 26 629–635. (https://doi.org/10.1007/s10654-011-9590-5)
- 29↑
Bjoro T, Holmen J, Krüger O, Midthjell K, Hunstad K, Schreiner T, Sandnes L, & Brochmann H. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The health study of Nord-Trondelag (HUNT). European Journal of Endocrinology 2000 143 639–647. (https://doi.org/10.1530/eje.0.1430639)
- 30↑
Bervini S, Trelle S, Kopp P, Stettler C, & Trepp R. Prevalence of iodine-induced hyperthyroidism after administration of iodinated contrast during radiographic procedures: a systematic review and meta-analysis of the literature. Thyroid 2021 31 1020–1029. (https://doi.org/10.1089/thy.2020.0459)
- 31↑
Björk J, Strömberg U, Rosengren A, Toren K, Fagerberg B, Grimby-Ekman A, & Bergström GML. Predicting participation in the population-based Swedish cardiopulmonary bio-image study (SCAPIS) using register data. Scandinavian Journal of Public Health 2017 45(17_suppl) 45–49. (https://doi.org/10.1177/1403494817702326)
- 32↑
You AS, Kalantar-Zadeh K, Brent GA, Narasaki Y, Daza A, Sim JJ, Kovesdy CP, Nguyen DV, & Rhee CM. Impact of thyroid status on incident kidney dysfunction and chronic kidney disease progression in a nationally representative cohort. Mayo Clinic Proceedings 2024 99 39–56. (https://doi.org/10.1016/j.mayocp.2023.08.028)
- 33↑
Carlqvist J, Nyman U, Sterner G, Brandberg J, Fagman E, & Hellström M. Minimal risk of contrast-induced kidney injury in a randomly selected cohort with mildly reduced GFR. European Radiology 2021 31 3248–3257. (https://doi.org/10.1007/s00330-020-07429-w)
- 34↑
Bergström G, Persson M, Adiels M, Björnson E, Bonander C, Ahlström H, Alfredsson J, Angerås O, Berglund G, Blomberg A, et al.Prevalence of subclinical coronary artery atherosclerosis in the general population. Circulation 2021 144 916–929. (https://doi.org/10.1161/CIRCULATIONAHA.121.055340)
- 35↑
Pelewicz K, Wolny R, Bednarczuk T, & Miśkiewicz P. Prevention of iodinated contrast media-induced hyperthyroidism in patients with euthyroid goiter. European Thyroid Journal 2021 10 306–313. (https://doi.org/10.1159/000515126)
