Coronary heart disease (CHD) is currently one of the most common causes of death in humans, and there has been a dramatic increase in the number of vascular interventional procedures and computer-enhanced scans requiring intravascular injection of iodine-based contrast media (ICM).[1-4] The World Health Organization (WHO) recommends a daily iodine intake of 150 μg for non-pregnant adults, while the amount of iodine in 100 mL of ICM (370 mgI/mL) can reach 37,000,000 μg. Iodine ions are concentrated in the kidneys and glands, and the thyroid gland is the only gland that can store and use iodine to synthesize thyroid hormones.
The short-term effects of ICM in euthyroid patients are transient and mild. To avoid the risk of thyroid crisis, patients with hyperthyroidism and hypothyroidism should undergo close monitoring of changes in thyroid function and receive necessary drug intervention after receiving ICM.[6,7]
To date, the long-term effects of supraphysiological iodine load on patients, especially patients with mild thyroid dysfunction (TD), have rarely been studied, and the corresponding guidelines are lacking. Total triiodothyronine (TT3) reduction is a special type of TD, and up to 28% of patients with CHD have TT3 reduction. However, the cause of TT3 reduction is unclear. It was thought to be due to the phenomenon of non-thyroidal illness syndrome, but affected patients have normal reverse triiodothyronine (rT3) levels in contrast to traditional low triiodothyronine (T3) syndrome, which casts doubt on the definition of traditional low T3 syndrome. Famine exposure in early life, universal salt iodination, and aging have been reported as possible causes of TT3 reduction.[10-13] Therefore, TT3 reduction was used in this study as a description of the phenomenon. The short-term effect of a single large dose of ICM in patients with T3 reduction has been shown in our previous study, but its long-term effects remain unclear.
The study protocol was designed to conform to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of Tianjin Chest Hospital (No. 2015-KT-SHL01). All patients provided written informed consent before enrollment.
Trial design and participants
This prospective cohort study was conducted at two sites in Tianjin Chest Hospital, China. The Tianjin Chest Hospital Cardiovascular Disease Center, Comprehensive Disease Center, and the Second Hospital of Tianjin Medical University Cardiovascular Disease Center were responsible for the scientific conduct of the study and independent analysis of the data.
Eligible patients were aged 20 years or older, presented with stable angina pectoris (SAP) with TT3 reduction (thyroid-stimulating hormone [TSH], rT3, and free thyroxine [FT4] levels in the normal range), and enrolled before percutaneous coronary surgery. The exclusion criteria were acute myocardial infarction, heart failure, cardiogenic shock, abnormal kidney function before surgery, major surgery within 90 days before enrollment, history of TD, use of iodine-containing drugs (eg, amiodarone), recent infection, tumors, physical or psychological trauma, and other critical illnesses. Patients who underwent major surgery, cardiogenic shock, use of iodine-containing drugs, severe infections, tumors, trauma, or other critical illnesses during the follow-up were excluded.
Venous blood was collected from the patients in the early morning before the surgery to determine TSH, total thyroxine (TT4), FT4, TT3, free triiodothyronine (FT3), rT3, thyroid peroxidase antibody (TPOAB), and thyroglobulin antibody (TGAB) levels and renal function. Iopromide (370 mgI/mL) was used uniformly as a non-ionic ICM in the coronary intervention.
Thyroid function (TSH, TT3, FT3, TT4, FT4, and rT3) and thyroid autoantibody levels (TPOAB and TGAB) were reviewed at 6 months and 1 year after surgery. Thyroid autoantibody levels and thyroid function were compared before and after surgery. Serum FT3, FT4, TT3, TT4, TSH, rT3, TPOAB, and TGAB levels were determined using electrochemical luminescence immunoassay performed with a Roche COBAS E602 automatic electrochemical luminescence analyzer, Roche kit, and calibrator (Roche Diagnostics GmbH, Mannheim, Germany). Serum urea nitrogen and creatinine levels were determined using an automatic biochemical analyzer.
The normal ranges were as follows: TT3, 1.30 to 3.10 nmol/L; FT3, 3.10 to 6.80 pmol/L; TT4, 66.00 to 181.00 nmol/L; FT4, 12.00 to 22.00 pmol/L; TSH, 0.27 to 4.20 μIU/mL, rT3, 0.20 to 0.64 ng/mL; TGAB, 0.00 to 115.00 IU/mL; and TPOAB, 0.00 to 34.00 IU/mL. Subclinical hyperthyroidism (SCHyper) is characterized by TSH reduction and normal FT4 and TT4 levels. Subclinical hypothyroidism (SCHypo) refers to elevated TSH levels and normal FT4 and TT4 levels. Hypothyroidism refers to increased TSH levels and decreased FT4 levels. The Klein Hyperthyroid Scale was used to assess whether patients with SCHyper required drug treatment.
IBM SPSS 22 statistical software (IBM Corp, Armonk, NY, USA), was used for statistical analysis. Normally distributed data are expressed as the mean ± standard deviation, and count data are expressed as the adoption rate and composition ratio. The normality of the data distribution was examined using the Shapiro-Wilk test, and the Levene method was used to confirm the homogeneity of the variance. The Student–Newman–Keuls q test was used for pairwise comparisons. Analysis of variance was used for repeated measurements. The median (interquartile range) using a rank-sum test was used to evaluate non-normally distributed data. Statistical significance was set at P < 0.05.
A total of 154 patients with SAP and TT3 reduction were enrolled in this study between January 2017 and June 2018. A total of 154 patients completed the follow-up at 6 months and 149 at 1 year [Table 1]. The reasons for loss to follow-up were mostly logistical in nature and no losses were related to the study intervention. A sensitivity analysis was conducted for missing data. Post-hoc power analysis showed that a sample size of 154 patients yields a power of 99% for a moderate effect size of 0.5 at a significance level of 5% (two-sided). The average age of the 154 patients was 60.8 ± 9.9 years (range, 36.0–75.0 years). A total of 113 patients were men and 41 were women. Of the 154 patients, 41 had reduced FT3 levels. In total, 113 patients underwent percutaneous coronary intervention (PCI) and 41 underwent coronary angiography (CAG). The mean ICM dosage used in the surgery was 123.3 ± 47.1 mL (iodine load 45.6 ± 17.4 g, n = 154), with a minimum dosage of 40 mL (iodine load 14.8 g) and a maximum dosage of 220 mL (iodine load 81.4 g) for an individual patient [Supplementary file, https://links.lww.com/CM9/B297]. Except for rT3 a year after ICM exposure, all test data were not normally distributed.
Table 1 -
Baseline characteristics of patients (n
||60.8 ± 9.9
|Previous cerebrovascular accident
|Previous cardiovascular accident
|Amount of iopromide (370 mgI/mL) (mL)
||123.3 ± 47.1
|Amount of iodine administered (g)
||45.6 ± 17.4
| White blood cells (cells/μL)
||7.4 ± 1.8
| Hemoglobin (g/dL)
||13.1 ± 1.9
| Creatinine (μmol/L)
||75.1 ± 16.3
| Total cholesterol (mmol/L)
||4.6 ± 1.1
| Triglyceride (mmol/L)
||1.9 ± 0.9
Data are expressed as mean ± standard deviation or n (%). PCI: Percutaneous coronary intervention.
Changes in thyroid hormones
The levels of FT3, FT4, TT3, TT4, and TSH showed statistically significant changes 1 year after ICM exposure (P < 0.001). The rT3 level at 1 year was not significantly different from that before ICM exposure (P = 0.848) [Table 2]. Two patients (1.3%) had hypothyroidism and 11 patients (7.1%) had SCHypo 1 year after ICM exposure [Table 3]. SCHyper developed in 23 patients (14.9%) at 6 months and in 3 patients (1.9%) at 1 year after ICM exposure. The Klein Hyperthyroid Scale scores of all patients with SCHyper were <6 [Figure 1]. One female patient with myxedema caused by hypothyroidism was seen at 1 year, and her thyroid function returned to normal after 3 months’ treatment with daily oral levothyroxine sodium tablets at a dose gradually titrated to 125 μg and continued at that dose.
Table 2 -
Pre and postoperative changes in thyroid hormone and autoantibody levels (n
Data are expressed as median (interquartile range). Compared with the corresponding preoperative value (rank-sum test).
∗P < 0.001.
†P < 0.005. FT3: Free triiodothyronine; FT4: Free thyroxine; rT3: Reverse triiodothyronine; TGAB: Thyroglobulin antibody; TPOAB: Thyroid peroxidase antibody; TSH: Thyroid-stimulating hormone; TT3: Total triiodothyronine; TT4: Total thyroxine.
Table 3 -
Post-operative changes in patients with TD (n
= 154), n
∗All patients had elevated TGAB levels.
†17 of the 23 patients had elevated TGAB levels.
‡23 of the 29 patients had elevated TGAB levels. SCHyper: Subclinical hyperthyroidism; SCHypo: Subclinical hypothyroidism; TGAB: Thyroglobulin antibody; TD: Thyroid dysfunction.
Changes in thyroid hormone antibodies
TGAB was elevated in 41 of 154 patients before ICM exposure (median 252.50, range 122.10–480.10 IU/mL), 11 of whom also had elevated TPOAB levels (median 83.20, range 36.10–226.30 IU/mL). None of the patients with normal TGAB levels had elevated TPOAB levels. One year after ICM exposure, 2 patients (4.9%, n = 41) with elevated TGAB levels had hypothyroidism, 11 patients (26.8%, n = 41) had SCHypo, and 3 patients (7.3%) had SCHyper [Table 3]. The mean TGAB level was decreased at 6 months after ICM exposure (P < 0.001) but increased at 1 year (P = 0.002) [Table 2].
Changes in low-dose ICM group
There were 41 patients with an ICM dosage <100 mL (low-dose ICM group, CAG group). Specifically, 40 to 80 mL (61.46 ± 12.76 mL, n = 41) was used for each person. Forty patients completed follow-up at 1 year. At 1 year, the levels of TT3, TT4, and TGAB showed no statistically significant difference compared to those before ICM exposure (P > 0.05), whereas the TPOAB level was lower than that before ICM exposure (P = 0.006) [Table 4].
Table 4 -
Pre and post-operative changes in thyroid hormone and autoantibody levels in the low-dose group (n
= 41) M(Q).
Compared with the corresponding preoperative value (rank-sum test).
∗P < 0.001.
†P < 0.05. FT3: Free triiodothyronine; FT4: Free thyroxine; M(Q): Median (interquartile range); rT3: Reverse triiodothyronine; TGAB: Thyroglobulin antibody; TPOAB: Thyroid peroxidase antibody; TSH: Thyroid-stimulating hormone; TT3: Total triiodothyronine; TT4: Total thyroxine.
Changes in high-dose ICM group
There were 113 patients with an ICM dosage ≥100 mL (high-dose ICM group, PCI group). Specifically, 100 to 220 mL (145.66 ± 32.59 mL, n = 113) was used for each person. A total of 109 patients completed follow-up at 1 year. TT3, TT4, FT3, FT4, and TSH levels were higher than those before ICM exposure (P < 0.001). The level of TGAB at 6 months was lower than that before ICM exposure (P < 0.001) but higher at 1 year than that before exposure (P = 0.023) [Table 5].
Table 5 -
Pre and post-operative changes in thyroid hormone and autoantibody levels in the high-dose group (n
Data are expressed as median (interquartile range). Compared with the corresponding preoperative value (rank-sum test).
∗P < 0.001.
†P < 0.05. FT3: Free triiodothyronine; FT4: Free thyroxine; rT3: Reverse triiodothyronine; TGAB: Thyroglobulin antibody; TPOAB: Thyroid peroxidase antibody; TSH: Thyroid-stimulating hormone; TT3: Total triiodothyronine; TT4: Total thyroxine.
The main findings of this study are as follows: (1) female patients with pre-operative thyroid antibody elevation with TT3 reduction are at risk of severe hypothyroidism with myxedema at 1 year; (2) 1 year after ICM exposure, the risk of transient SCHypo tended to increase while the risk of transient SCHyper tended to decrease; (3) no patient developed hyperthyroidism 1 year after ICM exposure; (4) the effect of ICM on thyroid function was dose-related, and 75.5% of cases of post-operative TD occurred in the high-dose group; (5) the mean level of TGAB was decreased at the 6 months but increased at 1 year after ICM exposure.
A previous study showed that 28% of patients with CHD had serum TT3 reduction.[8,14] In this study, we found that 14.6% of patients with SAP in China had a TT3 reduction. Patients with acute myocardial infarction, heart failure, complicated infection, physical or psychological trauma, and critical illness might have low TT3 due to stress and were thus excluded. Patients with TT3 reduction with SAP only were enrolled in this study to avoid potential interference from stress. The rT3 level was normal before ICM exposure and showed no statistically significant change at 1 year after surgery from that before ICM exposure.
The daily iodine intake dose recommended by the WHO for healthy adults is 150 μg, and the maximum daily iodine intake for Chinese adults is 800 μg. Iopromide 370, as a non-ionic second-generation ICM, has been widely used worldwide. In general, 100 mL iopromide 370 contains 37,000,000 μg of iodine, which is bound by a covalent bond to a benzene ring with a dissociation rate of 10,000:1. When iodine ions are absorbed by the thyroid, the bound iodine atoms continue to dissociate to maintain equilibrium. In addition to using iodine to synthesize thyroxine, the thyroid gland also stores iodine. Therefore, we should focus on whether a large dose of ICM will have long-term adverse effects on the thyroid gland.
Iodine is a basic element involved in the synthesis of thyroid hormones. The self-regulatory mechanism of the thyroid gland and regulation of the hypothalamic–pituitary–thyroid axis play an important role in maintaining normal thyroid function during changes in serum iodine levels. Both high and low serum iodine levels can cause changes in thyroid morphology and function and lead to thyroid disease. There is an epidemiological U-shaped curve between iodine level and the incidence of thyroid disease. Pharmacological doses of iodine can inhibit the organization of iodine over a period of hours to days, thereby reducing hormone biosynthesis, hydrolysis of thyroglobulin, and secretion of thyroid hormones, an effect known as the Wolff–Chaikoff effect. After the acute phase, thyroid function returns to normal and is no longer affected by continued excess iodine exposure, a phenomenon known as the escape from the acute Wolff–Chaikoff effect.
In our previous study, transient hypothyroidism occurred at 1 day and 1 month after ICM exposure, especially in patients in the high-dose ICM group, which could be ascribed to an excessive Wolff–Chaikoff effect. In this study, severe hypothyroidism occurred at 1 year after ICM exposure because of a failure to escape the acute Wolff–Chaikoff effect. Female patients with pre-operative thyroid antibody elevation and TT3 reduction are at risk of severe hypothyroidism at 1 year, which should be taken seriously. SCHyper developed in 23 (14.9%) patients at 6 months and in only 3 (1.9%) patients at 1 year after ICM exposure, which was attributed to an insufficient Wolff–Chaikoff effect, as these patients had normal TSH levels 1 day after ICM exposure. All SCHyper patients had a Klein Hyperthyroid Scale score of <6 and <3 when <150 mL of intra-operative ICM was used.
The presence of thyroid autoantibodies (TPOAB and TGAB) has been regarded as a hallmark of autoimmune thyroid disease for decades. More recently, a study conducted in China reported a stable prevalence of thyroid antibody positivity in the population after two decades of a universal salt iodination program. This study also found an inverse relationship between iodine intake and thyroid antibodies, suggesting that urinary iodine concentration (UIC) between 100 and 300 μg/L is optimal and safe for thyroid autoimmunity. UIC was also inversely associated with thyroglobulin antibodies. Available data from long-term population surveys show that a long-term higher than adequate population iodine intake could induce thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis.
Our results showed that thyroid antibody levels at 6 months were lower than those before ICM exposure (P < 0.001), suggesting that autoimmune thyroiditis may be inhibited within 6 months after a single large dose of ICM. Rebound thyroid antibody levels were seen at 1 year and were more pronounced in the high-dose group, suggesting that the rebound was related to the amount of contrast agent used.
Compared with the prevalence of the disease, the small sample size was a limitation of this study, and future expansion of the sample size is helpful for further analysis. The patients enrolled in this study were from coastal areas, and their responses to ICM exposure did not represent the response characteristics of those in inland areas. The follow-up period of only a year was another limitation of this study. More than 1 year after ICM exposure, it remains to be seen whether the adverse effects on the thyroid are more significant.
2021 European Thyroid Association Guidelines for the Management of Iodine-Based Contrast Media-Induced Thyroid Dysfunction suggest the measurement of baseline serum TSH in high-risk patients for ICM-induced TD, especially in older adults and patients at risk of cardiovascular disease. At present, the prevalence and clinical significance of ICM-induced TD are incompletely characterized. This study showed that female patients with preoperative thyroid antibody elevation and T3 reduction are at risk of severe hypothyroidism with myxedema at 1 year. Therefore, follow-up of this population 9 to 12 months after ICM exposure is warranted.
A single large dose of ICM exposure in patients with SAP and TT3 reduction may increase the risk of transient subclinical TD and hypothyroidism in a year. Female patients with preoperative thyroid antibody elevation and T3 reduction were at risk of severe hypothyroidism with myxedema at 1 year.
This work was supported by grants from the Hospital Level Project of Tianjin Chest Hospital in 2018 (No. 2018XKC08) and funded by the Tianjin Key Medical Discipline (Specialty) Construction Project.
Conflicts of interest
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