Endocrinol Metab.  2021 Aug;36(4):790-799. 10.3803/EnM.2021.1034.

Association between Iodine Intake, Thyroid Function, and Papillary Thyroid Cancer: A Case-Control Study

• Kim K
• Cho SW
• Park YJ
• Lee KE
• Lee DW
• Park SK

• KMID: 2519667
• DOI: http://doi.org/10.3803/EnM.2021.1034

Abstract

Background
This study aimed to assess the effects of iodine intake, thyroid function, and their combined effect on the risk of papillary thyroid cancer (PTC) and papillary thyroid microcarcinoma (PTMC).
Methods
A case-control study was conducted including 500 community-based controls who had undergone a health check-up, and 446 overall PTC cases (209 PTC and 237 PTMC) from the Thyroid Cancer Longitudinal Study. Urinary iodine concentration (UIC), was used as an indicator of iodine intake, and serum for thyroid function. The risk of PTC and PTMC was estimated using unconditional logistic regression.
Results
Excessive iodine intake (UIC ≥220 μg/gCr) was associated with both PTC (odds ratio [OR], 18.13 95% confidence interval [CI], 8.87 to 37.04) and PTMC (OR, 8.02; 95% CI, 4.64 to 13.87), compared to adequate iodine intake (UIC, 85 to 219 μg/gCr). Free thyroxine (T4) levels ≥1.25 ng/dL were associated with PTC (OR, 1.97; 95% CI, 1.36 to 2.87) and PTMC (OR, 2.98; 95% CI, 2.01 to 4.41), compared to free T4 levels of 0.7 to 1.24 ng/dL. Individuals with excessive iodine intake and high free T4 levels had a greatly increased OR of PTC (OR, 43.48; 95% CI, 12.63 to 149.62), and PTMC (OR, 26.96; 95% CI, 10.26 to 70.89), compared to individuals with adequate iodine intake and low free T4 levels.
Conclusion
Excessive iodine intake using creatinine-adjusted UIC and high free T4 levels may have a synergistic effect on PTC and PTMC. Considering both iodine intake and thyroid function is important to assess PTC and PTMC risk.

Keyword

Thyroid cancer, papillary; Papillary thyroid microcarcinoma; Iodine; Thyroid function tests

Figure

• 

  Fig. 1 Area under the curve of receiver operating characteristic (AUC-ROC) between models based on (A) papillary thyroid cancer (PTC) and (B) papillary thyroid microcarcinoma (PTMC) according to creatinine-adjusted urinary iodine concentration (UIC). Model 1 consists of UIC; Model 2 consists of model 1+thyroid stimulating hormone, and free thyroxine level; Model 3 consists of model 2+sex, age, education level, family history of cancer, past history of thyroid disease, dyslipidemia, and total energy intake.

Reference

1. International Agency for Research on Cancer. World Health Organization. GLOBOCAN 2020: Global Cancer Observatory, Cancer Today [Internet]. Lyon: International Agency for Research on Cancer;2021. [cited 2021 Jul 14]. Available from: http://gco.iarc.fr/today .

2. Park S, Oh CM, Cho H, Lee JY, Jung KW, Jun JK, et al. Association between screening and the thyroid cancer “epidemic” in South Korea: evidence from a nationwide study. BMJ. 2016; 355:i5745.

3. Liu Y, Su L, Xiao H. Review of factors related to the thyroid cancer epidemic. Int J Endocrinol. 2017; 2017:5308635.

4. Chung HR. Iodine and thyroid function. Ann Pediatr Endocrinol Metab. 2014; 19:8–12.

5. Sun X, Shan Z, Teng W. Effects of increased iodine intake on thyroid disorders. Endocrinol Metab (Seoul). 2014; 29:240–7.

6. Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol. 2015; 3:286–95.

7. Dong W, Zhang H, Zhang P, Li X, He L, Wang Z, et al. The changing incidence of thyroid carcinoma in Shenyang, China before and after universal salt iodization. Med Sci Monit. 2013; 19:49–53.

8. Blomberg M, Feldt-Rasmussen U, Andersen KK, Kjaer SK. Thyroid cancer in Denmark 1943–2008, before and after iodine supplementation. Int J Cancer. 2012; 131:2360–6.

9. Bosetti C, Negri E, Kolonel L, Ron E, Franceschi S, Preston-Martin S, et al. A pooled analysis of case-control studies of thyroid cancer. VII. Cruciferous and other vegetables (International). Cancer Causes Control. 2002; 13:765–75.

10. Cao LZ, Peng XD, Xie JP, Yang FH, Wen HL, Li S. The relationship between iodine intake and the risk of thyroid cancer: a meta-analysis. Medicine (Baltimore). 2017; 96:e6734.

11. Zimmermann MB, Galetti V. Iodine intake as a risk factor for thyroid cancer: a comprehensive review of animal and human studies. Thyroid Res. 2015; 8:8.

12. Arija V, Abellana R, Ribot B, Ramon JM. Biases and adjustments in nutritional assessments from dietary questionnaires. Nutr Hosp. 2015; 31(Suppl 3):113–8.

13. Teas J, Pino S, Critchley A, Braverman LE. Variability of iodine content in common commercially available edible seaweeds. Thyroid. 2004; 14:836–41.

14. Cho YA, Kong SY, Shin A, Lee J, Lee EK, Lee YJ, et al. Biomarkers of thyroid function and autoimmunity for predicting high-risk groups of thyroid cancer: a nested case-control study. BMC Cancer. 2014; 14:873.

15. Lee KE, Park YJ, Cho B, Hwang Y, Choi JY, Kim SJ, et al. Protocol of a thyroid cancer longitudinal study (T-CALOS): a prospective, clinical and epidemiological study in Korea. BMJ Open. 2015; 5:e007234.

16. Ahn J, Lee JH, Lee J, Baek JY, Song E, Oh HS, et al. Association between urinary sodium levels and iodine status in Korea. Korean J Intern Med. 2020; 35:392–9.

17. WHO/UNICEF/ICCIDD Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers. 3rd ed. [Internet]. Geneva: World Health Organization;2007. [cited 2021 Jul 14]. Available from: http://whqlibdoc.who.int/publications/2007/9789241595827_eng.pdf .

18. Munley PH, Bains DS, Bloem WD, Busby RM. Post-traumatic stress disorder and the MMPI-2. J Trauma Stress. 1995; 8:171–8.

19. Dasgupta PK, Liu Y, Dyke JV. Iodine nutrition: iodine content of iodized salt in the United States. Environ Sci Technol. 2008; 42:1315–23.

20. Seoul National University Hospital Clinical Trial Center. SNUH Clinical Lab. Reference Ranges [Internet]. Seoul: Seoul National University Hospital;2020. [cited 2021 Jul 14]. Available from: http://ctc.bri.snuh.org/researcher/researcherdown/_/notice/7714/download.do?resId=20618 .

21. Chung JH. Update on thyroid hormone levels and thyroid dysfunction in the Korean population based on data from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015). Endocrinol Metab (Seoul). 2020; 35:7–13.

22. Kipnis V, Midthune D, Freedman L, Bingham S, Day NE, Riboli E, et al. Bias in dietary-report instruments and its implications for nutritional epidemiology. Public Health Nutr. 2002; 5:915–23.

23. Kipnis V, Subar AF, Midthune D, Freedman LS, Ballard-Barbash R, Troiano RP, et al. Structure of dietary measurement error: results of the OPEN biomarker study. Am J Epidemiol. 2003; 158:14–21.

24. Vejbjerg P, Knudsen N, Perrild H, Laurberg P, Andersen S, Rasmussen LB, et al. Estimation of iodine intake from various urinary iodine measurements in population studies. Thyroid. 2009; 19:1281–6.

25. Hou D, Xu H, Li P, Liu J, Qian Z. Potential role of iodine excess in papillary thyroid cancer and benign thyroid tumor: a case-control study. Asia Pac J Clin Nutr. 2020; 29:603–8.

26. Lee JH, Song RY, Yi JW, Yu HW, Kwon H, Kim SJ, et al. Case-control study of papillary thyroid carcinoma on urinary and dietary iodine status in South Korea. World J Surg. 2018; 42:1424–31.

27. Yan AR, Zhang X, Shen H, Zhou X, Li R, Yuan Z. Urinary iodine is increased in papillary thyroid carcinoma but is not altered by regional population iodine intake status: a meta-analysis and implications. Endocr J. 2019; 66:497–514.

28. Zhao H, Li H, Huang T. High urinary iodine, thyroid autoantibodies, and thyroid-stimulating hormone for papillary thyroid cancer risk. Biol Trace Elem Res. 2018; 184:317–24.

29. Kim HJ, Kim NK, Park HK, Byun DW, Suh K, Yoo MH, et al. Strong association of relatively low and extremely excessive iodine intakes with thyroid cancer in an iodine-replete area. Eur J Nutr. 2017; 56:965–71.

30. Xiu C, He Q, Zhao HJ, Yuan ZN, Guo LH, Wang FQ, et al. Strong correlation of abnormal serum and urinary iodine levels with papillary thyroid cancer: a case-control study. Biomed Environ Sci. 2020; 33:62–7.

31. Huang F, Cong W, Xiao J, Zhou Y, Gong M, Sun J, et al. Association between excessive chronic iodine exposure and the occurrence of papillary thyroid carcinoma. Oncol Lett. 2020; 20:189.

32. Zhao H, Li H, Huang T. High iodine intake and central lymph node metastasis risk of papillary thyroid cancer. J Trace Elem Med Biol. 2019; 53:16–21.

33. Kim HJ, Park HK, Byun DW, Suh K, Yoo MH, Min YK, et al. Iodine intake as a risk factor for BRAF mutations in papillary thyroid cancer patients from an iodine-replete area. Eur J Nutr. 2018; 57:809–15.

34. Guan H, Ji M, Bao R, Yu H, Wang Y, Hou P, et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab. 2009; 94:1612–7.

35. Wu X, Lun Y, Jiang H, Gang Q, Xin S, Duan Z, et al. Coexistence of thyroglobulin antibodies and thyroid peroxidase antibodies correlates with elevated thyroid-stimulating hormone level and advanced tumor stage of papillary thyroid cancer. Endocrine. 2014; 46:554–60.

36. Lin HY, Tang HY, Shih A, Keating T, Cao G, Davis PJ, et al. Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic. Steroids. 2007; 72:180–7.

37. McLeod DS. Thyrotropin in the development and management of differentiated thyroid cancer. Endocrinol Metab Clin North Am. 2014; 43:367–83.

38. Lavado-Autric R, Calvo RM, de Mena RM, de Escobar GM, Obregon MJ. Deiodinase activities in thyroids and tissues of iodine-deficient female rats. Endocrinology. 2013; 154:529–36.

39. Li N, Jiang Y, Shan Z, Teng W. Prolonged high iodine intake is associated with inhibition of type 2 deiodinase activity in pituitary and elevation of serum thyrotropin levels. Br J Nutr. 2012; 107:674–82.

40. Ko YM, Kwon YS, Park YK. An iodine database establishment and iodine intake in Korean adults: based on the 1998~2014 Korea National Health and Nutrition Examination Survey. J Nutr Health. 2017; 50:624–44.

41. Lipsitz SR, Fitzmaurice GM, Regenbogen SE, Sinha D, Ibrahim JG, Gawande AA. Bias correction for the proportional odds logistic regression model with application to a study of surgical complications. J R Stat Soc Ser C Appl Stat. 2013; 62:233–50.

42. Walker DA, Smith TJ. Logistic regression under sparse data conditions. J Mod Appl Stat Methods. 2019; 18:eP3372.

43. Kuo CL, Duan Y, Grady J. Unconditional or conditional logistic regression model for age-matched case-control data? Front Public Health. 2018; 6:57.

44. Caldwell KL, Maxwell CB, Makhmudov A, Pino S, Braverman LE, Jones RL, et al. Use of inductively coupled plasma mass spectrometry to measure urinary iodine in NHANES 2000: comparison with previous method. Clin Chem. 2003; 49(6 Pt 1):1019–21.

45. Knudsen N, Christiansen E, Brandt-Christensen M, Nygaard B, Perrild H. Age- and sex-adjusted iodine/creatinine ratio. A new standard in epidemiological surveys? Evaluation of three different estimates of iodine excretion based on casual urine samples and comparison to 24 h values. Eur J Clin Nutr. 2000; 54:361–3.

46. Kim HK, Lee SY, Lee JI, Jang HW, Kim SK, Chung HS, et al. Usefulness of iodine/creatinine ratio from spot-urine samples to evaluate the effectiveness of low-iodine diet preparation for radioiodine therapy. Clin Endocrinol (Oxf). 2010; 73:114–8.