Association between urinary iodine concentration and the risk of papillary thyroid cancer by gender and age: A case-control study

Abstract

Previous studies on dietary iodine intake and the risk of papillary thyroid cancer(PTC) have demonstrated inconsistent results. We aimed to evaluate the association between the urinary iodine concentration(UIC), a surrogate biomarker for dietary iodine intake, and the risk of thyroid cancer stratified by gender and age in an iodine-sufficient area. A hospital-based case-control study was conducted in Seoul, South Korea. A total of 492 cases of newly diagnosed PTC and 595 controls were included. Compared with the lowest quartile of creatine-adjusted UIC(< 159.3 µg/gCr), the highest quartile(≥ 1037.3 µg/gCr) showed an increased risk of PTC(odds ratio[OR] = 1.49, 95% confidence interval[CI]: 1.04–2.13), especially in those who were < 45 years old(p_trend = 0.01) than in those who were ≥ 45 years old(p_trend = 0.48). For those who were < 45 years old, the positive association between creatinine-adjusted UIC and the risk of PTC was observed in both men (q4 vs. q1, OR = 4.27, 95% CI: 1.14–18.08) and women (OR = 1.97, 95% CI: 1.04–3.78). For those who were ≥ 45 years old, no association was found in any gender. Creatinine-adjusted UIC was positively associated with the risk of PTC especially in those who were younger than 45-years for both men and women.

Introduction

The incidence of thyroid cancer has been increasing in several countries, and the age-standardized rate(ASR) of thyroid cancer worldwide in 2020 was estimated to be 6.6 per 100,000 people¹. In South Korea, thyroid cancer cases accounted for 12% of the total number of cancer cases for both genders combined in 2019, ranking first among the incidence rates of different types of cancer². The incidence rate was 90.0 per 100,000 in women and 29.3 per 100,000 in men. Age specific thyroid cancer incidence rate peaked at the age range of 40–44 and decreased with a shape of parabola for both women and men in South Korea.

The rapid increase in the incidence of thyroid cancer can be attributed to the development of high-resolution ultrasound technology, resulting in an increase in the rate of microcarcinoma diagnosis through ultrasound-induced fine-needle aspiration cell examination³. The increase has mostly been accounted for by an overdiagnosis of subclinical lesions⁴. Papillary thyroid cancer (PTC) is increasing in a steeper pattern than are other histological shapes, especially for micropapillary cancer with a tumor size of less than 1cm^5,6. The proportion of PTC in all types of thyroid cancer in South Korea increased from 79.7% in 1995 to 95.7% in 2018^7,8. Some could argue that higher opportunities to get thyroid ultrasound screening, as it was frequently included in health examination program, might account for the high incidence. However, even in the 15–19 year-old age group, who rarely undergo thyroid cancer screening, thyroid cancer was the most common type of cancer in both male and female population in South Korea². Therefore, the steep increase in incidence of thyroid cancer in South Korea cannot be fully accounted for by overdiagnosis or excessive health screening, and factors associated with the real risk increase should be investigated.

Iodine-rich diet is another factor that could account for the high incidence of thyroid cancer in South Korea. The usual Korean diet is very rich in iodine. Also, it is customary to eat seaweed soup on birthdays, and women in postpartum period eat seaweed soup almost every day for months. Both deficient^9–11 and excess^12,13 intake of iodine showed association with increased risk of thyroid cancer in human populations, with mixed results depending on the ethnicities and dietary iodine levels. A study on multi-ethnic women living in the San Francisco Bay in the United States reported that high iodine intake may lower the risk of thyroid cancer⁹. However, in Japanese women with a high iodine intake, those who consumed seaweed daily had an approximately 1.86-times-higher risk of thyroid cancer than those who consumed seaweed less than twice a week¹².

One of the reasons for the inconsistencies in the association between dietary iodine intake and the risk of thyroid cancer was the difficulty in the accurate assessment of the dietary iodine intake due to the incomplete food composition table for iodine and large variation of iodine content by food sources. Since over 90% of dietary iodine absorbed in our body was excreted through urine within 1 to 2 days, urinary iodine concentration(UIC) has been used as the standard means to assess the population iodine status¹⁴. UIC is a less desirable biomarker to assess iodine status in individual level because it reflects only the recent diet, not the long-term usual diet. However, when accurate dietary iodine assessment is unavailable, UIC could be a good surrogate biomarker for iodine intake.

There are several studies that have investigated the association between the UIC and thyroid diseases^17,18 and thyroid cancer^19–21, but to our knowledge, well-designed epidemiologic studies on the association between the UIC and risk of thyroid cancer are sparse.

Therefore, we conducted a hospital-based case-control study to investigate the association between UIC, a surrogate biomarker for iodine intake, and risk of thyroid cancer in South Korea, where iodine intake is sufficient. Secondary purpose of this study was to investigate possible interaction by gender and age because Korean women have additional exposure to high dietary iodine at postpartum period, and the age-specific incidence curve changes its slope after 45 years of age.

Materials And Methods

Study population

This study included outpatient clinic patients of the Thyroid Center at Samsung Medical Center(SMC), Seoul, South Korea from November 2011 to June 2016. Research team doctors actively recruited eligible case and control patients. The Division of Endocrinology and Metabolism and Department of Surgery were congregated together at the Thyroid Center, and the research interviewers waited on-site every day and conducted the comprehensive risk factor survey whenever patients were recruited.

The case group included patients aged 20-80, newly diagnosed with pathologically confirmed PTC, with or without follicular variant, who did not have any history of cancer. Those who were found not to have cancer according to the pathologic report after the surgery were excluded. Further excluding those who did not finish the interview (n = 17) and those who were younger than 20 years-old (n = 2), a total of 1,172 cancer patients completed the interview. Of those, we included in this study 492 cancer patients who actually consented to donate urine samples. There was no significant difference in basic characteristics between urine donors and non-donors in case group, except for the proportion of men(21.7% among donors, 27.2% among non-donors, p = 0.039) and the proportion of cases with history of benign thyroid diseases(21.2% among donors, 34.8% among non-donors, p < 0.001). The control group included patients aged 20-80 with benign thyroid diseases, such as thyroid nodules, cysts, hyperplasia, hypothyroidism, hyperparathyroidism, etc. or self-induced thyroid screening, who did not have any history of cancer. As healthy as possible patients were selected as controls and many of the controls had no plans for long term follow-up. When a control patient was diagnosed with PTC later in time during the study period, he/she was switched to the case group. After excluding those who did not finish the interview (n = 29) and those who were younger than 20 years-old (n=2), a total of 1,171 control patients completed the interview. Of those, we included in this study 595 controls who actually consented to donate urine samples. There was no significant difference in basic characteristics between urine donors and non-donors in control group, except the proportion of controls with history of benign thyroid diseases(34.3% among donors, 44.0% among non-donors, p = 0.001). (Figure 1). 

Data collection

Research interviewers explained the purpose and contents of the survey to the patients, obtained written consent, and conducted interviews using a structured questionnaire on various risk factors including life-style, medical history, radiation, and diet. For the cancer case group, the interview was conducted before surgery. Weight and height were measured in shoeless state using an automatic height and weight machine. After the interview was completed, participants were led to the Diabetes Education Center to measure body composition using InBody3.0(BioSpace). Ten ml whole blood and 12 ml spot urine samples were collected in accordance with the next diagnostic test schedule in the SMC’s central lab. Fasting time before sample collection was 4 hours for afternoon appointments to 12 hours for morning appointments. Collected samples were stored at -20°C on-site and then delivered every day to the Seegene central lab, the collaborating commercial lab for our research group, and then aliquoted and stored at -70°C.

Questionnaires were doubly entered into the database by two interviewers independently, and the data was compared using a Statistical Analysis System (SAS) ver.9.4. When the program picked out inconsistencies in the data, we went back to the original questionnaire and made necessary corrections to minimize the input errors.

Body mass index (BMI) was calculated by dividing the measured weight(kg) by the square of the height(m²). Smoking status was divided into nonsmokers, past smokers, and current smokers after asking if they had smoked more than 20 packs of cigarettes. The daily intake of alcohol was calculated based on the frequency and amount of alcohol intake over 1 year and the types of alcohol consumed, such as makgeolli(Korean rice wine), wine, soju, beer, and spirits. Supplement intake combined the intake frequencies of multivitamins, vitamin C, vitamin E, vitamin D, calcium, omega 3, and red ginseng. Physical activity was classified as yes or no according to whether regular exercise enough to sweat on the body was performed. Education level was classified elementary school or less, middle school diploma, high school diploma, or college degree or higher. Family history of cancer included cancer in parents and children, and history of thyroid disease included thyroid nodules and benign tumors, hypothyroidism, hyperthyroidism, goiter, and other thyroid diseases.

UIC was measured from a spot urine sample by inductively coupled plasma-mass spectrometry (ICP-MS, Perkin Elmer, ICPMSD, Waltham, MA, USA), and creatinine level was measured by Jaffe(C702, Roche, Mannheim, Germany), and the iodine/creatinine level ratio(μg/gCr) was used as the creatinine-adjusted UIC to minimize diurnal and day to day variation ²². Still, as mentioned before, UIC had limitations in reflecting long-term usual dietary iodine intake in individual level. Therefore, rather than using absolute cut-off points, such as 100μg/L for deficiency, we used the quartiles of the creatinine-adjusted UIC in the controls (<159.3 μg/gCr, 159.3–394.3 μg/gCr, 394.3–1037.3 μg/gCr, and ≥1037.3 μg/gCr) to categorize the participants into four groups. 

Statistical analyses

Categorical variables were expressed as the frequency and percentage, and the chi-square test was used to compare the characteristics of the participants between case group and control group. Continuous variables were presented as the mean and standard deviation(SD), and t-test was performed to compare the continuous variables between the two groups.

Age, sex, educational level, physical activity, supplement intake, BMI, daily alcohol intake, smoking status, family history of cancer, and history of thyroid disease were adjusted for as confounding variables. Odds ratios(ORs) and 95% confidence intervals(CIs) of the risk of thyroid cancer were calculated for participants exposed to the higher creatinine-adjusted UICs(μg/gCr) compared with those exposed to the lowest creatinine-adjusted UIC using unconditional logistic regression. To evaluate possible interaction by gender and age, stratified analyses were also performed. P for interaction was calculated by adding product interaction term to the model, and results were presented under the tables. All analyses were conducted using R, version 3.6.3, and a two-tailed p value of <0.05 was defined as significant.

This study was approved by the institutional review board of Samsung Medical Center (IRB No. 2011-11-025, 2011-11-076). Informed consent was obtained from all subjects and their legal guardians. All methods were performed in accordance with the relevant guidelines and regulations.

Results

The general characteristics of the participants in the case and control groups are summarized in Table 1. Men consisted of 19.9% of the participants. The average age of the participants in the case group was younger (46.5 years) than that of the case group (49.7 years, p < 0.001). The daily intake of alcohol in those in the case group was lower than that of those in the control group, whereas the rate of physical activity and supplement intake were higher, but the differences were not significant. Higher proportion of people had past history of benign thyroid diseases in control group than in case group (p < 0.001). The median value of UIC in the case group was 472.0 μg/gCr, and that in the control group was 353.1 μg/gCr.

Table 2 exhibits the association between the risk of PTC and quartiles of creatinine-adjusted UIC after adjusting for the confounders. The highest quartile of creatinine-adjusted UIC(≥1037.3 μg/gCr) exhibited a 1.49-times-higher risk of thyroid cancer than the lowest quartile of creatinine-adjusted UIC group(<159.3 μg/gCr).

The results of the stratified analysis by gender are presented in Table 3. In women, the highest quartile of creatinine-adjusted UIC group exhibited a significantly higher risk of thyroid cancer than the lowest quartile of creatine-adjusted UIC group(OR = 1.56, 95% CI: 1.04–22.34). There was no significant association between creatinine-adjusted UIC and the risk of thyroid cancer in men (p for trend = 0.3795). Furthermore, there was no significant interaction observed (p = 0.7071).

When we stratified the analysis into those who were <45 years old and those who were ≥45 years old, the association between the creatinine-adjusted UIC and the risk of thyroid cancer appeared in those aged younger than 45 years (q4 vs. q1, OR = 2.22, 95% CI: 1.27–3.94), but not in those aged 45 or older (q4 vs. q1, OR = 1.15, 95% CI: 0.72–1.83), however the interaction was not significant (p_interaction = 0.11) (Table 4). When we stratified the analysis further by sex, for those who were aged younger than 45 years, creatinine-adjusted UIC was associated with the risk of thyroid cancer in both men (q4 vs. q1, OR = 4.27, 95% CI: 1.14–18.08) and women (q4 vs. q1, OR = 1.97, 95% CI: 1.04–3.78). 

For sensitivity analysis, we changed the age limit for stratification from age 45 to age 50. The result was similar; the association between the creatinine-adjusted UIC and the risk of PTC appeared in those aged younger than 50 years (q4 vs. q1, OR = 1.97, 95% CI: 1.23–3.16), but not in those aged 50 or older (q4 vs. q1, OR = 0.96, 95% CI: 0.56–1.66, p_interaction =0.07). In further stratification by gender, the association weakened in men (q4 vs. q1, OR=2.42, 95% CI: 0.85–7.17) but persisted in women (q4 vs. q1, OR = 1.93, 95% CI: 1.13–3.33) for those aged younger than 50 years. Using creatinine-unadjusted UIC did not change the result. Compared to those with the lowest quartile of the UIC (<138.1 μg/L), those with the highest quartile of the UIC (>936.4 μg/L) had 1.54 (95% CI: 1.05–2.26) times more risk of PTC.

Discussion

In this study, we observed the association between the urinary iodine concentration (UIC) and PTC risk in younger (< 45 years old) men and women in South Korea, a country well known for her excessive iodine intake and high thyroid cancer incidence. We used the age stratification criteria as 45-years-old because the age specific incidence rate of thyroid cancer in South Korea peaked at age 40–44 and subsequently decreased for both men and women. It is interesting that our result supports for the increasing period of age-related incidence curve.

Urinary iodine excretion is the most widely used biomarker of recent iodine intake, as more than 90% of iodine consumed as food is excreted in urine after being metabolized^23,24. A 24-h urine test is the gold-standard method, but it has a risk of selection bias due to low compliance²⁵. We used a single spot urine test in this study. The spot urine test is easier and has an advantage of being able to test many more participants than the 24-h urine test, but it is highly affected by the urine volume, diurnal iodine changes^22,25, or even by season¹⁴. To minimize these variations, the iodine/creatinine ratio was used as the urinary iodine level measure in this study. Still, spot urine test cannot replace 24-h urine test^26,27. Reduced accuracy due to single spot urine would introduce non-differential misclassification and the magnitude of true association might be underestimated.

Since UIC is greatly affected by recent diet, single UIC may not be a suitable marker for a patient’s long-term dietary iodine intake, especially when the patient has changed his/her diet recently. We collected the spot urine on the day of next outpatient visit, that is, pre-operational visit for cancer patients and routine follow-up visit for control patients. No dietary guideline was given to cases and controls at the time of urine collection. All participants were on their usual diet, and it is unlikely that either cases or controls would have changed their iodine intake differentially from their comparison group. Daily fluctuation of dietary iodine intake would also be similar between cases and controls.

Previous studies examining relationship between UIC and PTC compared the median values of UIC between the PTC and control group, and reported no significant differences^19,20. However, a retrospective clinical study conducted in Korea showed U-shaped association between UIC and the risk of thyroid cancer²¹. Recently, Kim et al. (2021) reported with 446 hospital-based PTC cases and 500 community-based controls that those with creatinine-adjusted UIC ≥ 220 µg/gCr had 18.13 times (95% CI: 8.87–37.04) higher risk of PTC than those with UIC, 85 to 219 µg/gCr. The OR of the risk of papillary thyroid microcarcinoma for the same level of UIC was 8.02 (95% CI: 4.64–13.87)¹⁶. The positive association was in line with our study, although the magnitude of their association was much larger than that of our study. There are several possible explanations for that. First, the distribution of creatinine-adjusted UIC among case group and control group are different from our study. The proportion of UIC > 300 µg/L among case group was 93.3% in Kim et al.’s while 59.1% in ours, and the proportion of UIC > 300 µg/L among control group was 43.4% in Kim et al.’s while 55.0% in ours. Much wider difference existed in Kim et al.’s study. According to the Korean National Health and Nutrition Examination Survey 2013–2015, the national median of UIC was 293.9 µg/L²⁷. The control group in our study had slightly higher median (353.1 µg/L), probably because we included patients with benign thyroid diseases in our control group and their iodine intake could be higher than normal people. This could also lead the association towards the null and underestimation of the OR. Secondly, in Kim et al’s study, the authors recruited cases and controls from different source population during unknown period for controls. In this case, comparability issues can arise that could lead to bias of the association.

There are several strengths in our study. Case and control participants were recruited from one institution under the same protocol simultaneously. Therefore, comparability was secured. Also, interviewers were well trained for the whole survey procedure, biospecimen were handled under tightly controlled protocol, and measurement for biomarkers were done as one batch so that no experiment bias would affect the result.

There are several limitations in this study. First, samples were limited to a single institution, possibly compromising the representativeness of the data. However, the chance of selection bias was substantially reduced by recruiting control patients from the same department in the same hospital because the cases and controls had similar catchment area. Healthy controls from the health screening center in the same hospital would have induced more selection bias because their catchment area was very different from the case population. Second, as mentioned before, the source population of the control group is people with benign thyroid diseases. If UIC were also associated with control diseases, the UIC level of case and control group would have been similar each other leading the ORs toward the null. Thirdly, there is a limitation in estimating the normal intake of iodine because a spot urine test was used. However, the limitation is non-differential between case and control groups leading the ORs toward the null. Therefore, the true association between creatinine-adjusted UIC and the risk of PTC might be greater than that observed in our study.

Conclusions

Creatinine-adjusted UIC had positive association with the risk of PTC especially among those who were younger than 45 years for both men and women. The fact that South Korea is a country with iodine-rich diet and has a unique parabolic age-related incidence curve matches well with the linear relationship between UIC and the risk of PTC among younger age group. Further studies on long term iodine intake and the risk of PTC especially among younger population and male population are warranted.

Declarations

Acknowledgments

No. 

Authorship Contribution Statement

YH: writing-original draft(lead); formal analysis(lead).

HK.O: data acquisition(equal); methodology(equal).

J.H.C: conceptualization(equal); methodology(equal). 

S.W.K: conceptualization(equal); methodology(equal). 

JH.K: conceptualization(equal); methodology(equal). 

J.S.K: conceptualization(equal); methodology(equal). 

MH.S: conceptualization and design of the study (lead); data acquisition (lead); methodology(lead); writing-review and editing^,

Author Disclosure Statement

All the authors have no conflicts of interests to disclose. 

Funding Statement

This study was supported by grants from the Korean Foundation for Cancer Research and Samsung Medical Center. 

Data Availability

The data sets used and analysed during the current study available from the corresponding author on reasonable request..

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Tables

Table 1. Characteristics of the case group with papillary thyroid cancer diagnosed in 2011-2016, and control group with thyroid disease other than thyroid cancer at Samsung Medical Center(SMC).

Table 2. Logistic regression analysis for the risk of PTC and quartiles of creatinine-adjusted UIC after adjusting for the confounders

Table 3. Logistic regression analysis for the risk of PTC and quartiles of creatinine-adjusted UIC by gender after adjusting for the confounders

Table 4. Logistic regression analysis for the risk of PTC and quartiles of creatinine-adjusted UIC by gender and age after adjusting for the confounders