The relationship between iodine deficiency and thyroid dysfunction and disease has been well-established for nearly a century, resulting in strong efforts to ensure sufficient iodine for populations around the world.
Interestingly, over the past few decades, incidence rates for thyroid cancers have reportedly been increasing dramatically, sparking research into the association of iodine excess and thyroid disease. In this article, we focus on the relationship between iodine and thyroid disorders, the updated clinical risk classification of thyroid cancer stages, and the possible impact of these changes on the insurance industry.
Iodine is a micronutrient necessary for human development and health. It is required for the synthesis of thyroxine (T4) and triiodothyronine (T3), two thyroid hormones that play key roles in human metabolic functions and processes. It is derived mainly from diet, and is dependent on concentrations in soil and water as well as supplementation. Excess iodine is primarily eliminated in urine.
Until about 100 years ago, lack of dietary iodine played a major role in the prevalence of goiter (enlarged and malfunctioning thyroid gland) and certain types of neurocognitive impairment. These conditions are today rarely seen in the developed world, but are still evident in certain areas of China, India, Central Asia, and Central Africa.
Iodine’s role in curing and preventing thyroid disease has long been recognized, but it was not until the early 20th century that public health steps began to be taken to ensure improved population access. Iodized salt and iodine tablets were first introduced into Canada, Switzerland, and the U.S. shortly after the First World War (early 1920s).
In 1990, the United Nations World Summit for Children set forth the goal of eliminating iodine deficiency worldwide, resulting in the issuance in 1993 of recommended standards for universal salt iodization by the World Health Organization (WHO) and the United Nations International Children’s Emergency Fund (UNICEF). The standard recommended that “All food- grade salt, used in household and food processing, should be fortified with iodine as a safe and effective strategy for the prevention and control of iodine deficiency disorders in populations living in stable and emergency settings.”
Today, universal salt iodization (USI) has been implemented in more than 120 countries,2 and approximately 86% of the world’s population currently has at least some access to iodized salt.
The benefits of correcting iodine deficiency are remarkable: Goiter, if caused by an iodine deficiency, is directly treatable using iodine. In addition, some systematic reviews have shown that providing iodized salt to populations has brought both a significant reduction in the risk of low intelligence (defined as IQ <70), and an almost 10-point overall increase in population IQ among iodine-deficient children.3, 4
Unfortunately, however, iodine deficiency disorder is still a major global public health problem today. As of 2012, an estimated 2.2 billion people worldwide were known to be living in iodine-deficient areas.
Is excess intake a risk for thyroid cancer?
Interestingly, the relationship between iodine intake and thyroid disorders tends to be u-shaped, in that both deficiency and excess can cause thyroid dysfunction.
According to recommended dietary iodine standards from WHO, UNICEF, and the International Council for Control of IDD (ICCIDD), a normal range of urinary iodine concentration (UIC) is 100 to 199μg/L. A UIC level of <100μg/L indicates an iodine deficiency, a level of between 200 and 299μg/L is above normal, and ≥300μg/L indicates excess iodine.
At the 1927 International Conference on Goiter, eminent German pathologist Carl Wegelin predicted the incidence of thyroid cancer and endemic goiter would disappear due to iodized salt over the next 30 to 40 years. His prediction, insofar as goiter is concerned, has for the most part come true. As for cancer, however, the story is quite different.
The prevalence of anaplastic thyroid cancer (ATC), also known as undifferentiated thyroid cancer (UTC), decreased in many countries with the introduction of iodized salt. However, incidence of differentiated thyroid cancers such as papillary thyroid cancer (PTC) increased, particularly since the 1980s. PTC is now the fastest-growing cancer, especially among women, in high-income countries such as the U.S., South Korea, and several European countries including the United Kingdom and Switzerland.
The reason for this increase is unclear, although many researchers point to the growth in rates of imaging studies of the neck due to mandated screening programs in some countries. Small thyroid nodules are frequently discovered during imaging exams before they become apparent on physical exams. This has led to some belief among investigators that thyroid cancer is being over-diagnosed.
In March 2014, in an effort to slow the explosive growth in thyroid cancer cases diagnosed in South Korea, a group of South Korean physicians formed “The Coalition of Doctors to Prevent Over-diagnosis of Thyroid Cancer.” Ultrasonography screenings of healthy people was called into question. Since then, insurance claims data suggest a 30% reduction in the incidence of thyroid cancer in South Korea.5
Still, whether the huge increase in thyroid cancer incidence was solely the result of over-detection or attributable to known or new risk factors causing a real change in the incidence is still up for debate.
Some researchers have suggested that higher iodine intakes are contributing to the increase in PTC, while others disagree.
Recent research from countries with high incidence of thyroid cancer has pointed out the association between excessive iodine exposure and increasing thyroid cancer risk.
In South Korea, for example, a meta-review of 16 studies determined that the odds ratio (OR) for the overall effect size between high iodine intake and PTC risk was 1.418 (95% confidence interval 1.054 – 1.909). Seven other studies conducted in high-iodinated regions showed a positive association between iodine intake and PTC (95% CI 1.389 – 3.483).6 Similarly, median UIC levels were significantly higher in the PTC group (786.0μg/l) than in the control group (112.0μg/l; p < 0.001).7
Studies from China have pointed out a temporal association between the country’s introduction of mandatory universal salt iodization in 1996 and a subsequent increase in PTC incidence.8 Most cases are papillary thyroid microcarcinoma (PTMC) with a maximum tumor diameter (MTD) < 1 cm. Medullary thyroid carcinoma (MTC) and follicular thyroid carcinoma (FTC), however, decreased.9
Several studies also found that thyroid cancer incidence in East China was highest while that in Middle China was the lowest. In addition, incidence was higher in urban than in rural areas. The highest urban incidence was in Dalian, and rural incidence in the Fujian province’s Changle district.10 In addition, in 2010, Zhejiang, a coastal province south of Shanghai, had thyroid cancer incidence of 10.74/100,000, much higher China’s nationwide incidence (3.23/100,000).9 Although the above-mentioned coastal areas do not belong to regions noted for iodine deficiency, they are still supplied with iodized salt.
As mentioned earlier, the relationship of iodine intake to thyroid disease is u-shaped due to the fact that both deficient and excessive intake can impair thyroid function. Iodized salt program should be monitored carefully to provide adequate iodine but also avoid excess intakes.
Risk classification update11
In October 2016, against the backdrop of fast-increasing PTC (especially PTMC) incidence, the American Joint Committee on Cancer (AJCC) published its 8th edition of the AJCC/TNM cancer staging system.
In the new staging system, thyroid cancers range from stage I to stage IV, with higher stages indicating greater spread. The system, which stages thyroid cancers in accordance with the size of the tumor (T), the spread to nearby lymph nodes (N), and the spread, or metastasis to distant sites, is one of the most important tools for underwriting and claims assessment.
The two main differences in the new staging system are:
- The age cutoff for stage I thyroid cancers has been raised from 45 to 55
- The definition of T3 disease has removed regional lymph node metastases and microscopic extrathyroidal extension
In other words, the new staging guidelines move a significant number of higher-stage thyroid cancer patients to lower stages. A significant number of patients between ages 45 and 54 with low lymph node spread and no metastasis (N1, M0) will automatically be downstaged to stage I, and older patients will be downstaged to either stage I (≥ 55 years old, minor extrathyroidal extension, N0, M0) or stage II (≥ 55 years old, N1, M0). In addition, all patients with differentiated thyroid cancer (≤ 4 cm) confined to the thyroid will be classified as stage I. The prior edition had classified smaller tumors (≤ 2 cm) as stage I and larger tumors (2 cm - 4 cm) as stage II.
Based on this new edition, many substandard or postponed cases will be issued at standard, and many thyroid cancer cases that were earlier defined as stage T2 and T3 are now to be classified as stage T1 and excluded from cancer claims but transferred into early-stage cancer group. This may impact underwriting manuals, CI definitions, and pricing bases.
Increased use of ultrasound screening over the past few decades has greatly increased detection of thyroid cancer, especially papillary and early-stage tumors, resulting in a large increase in incidence of thyroid cancer. Not all of the increase in incidence, however, can be explained by overdiagnosis. Other risk factors, including radiation exposure, iodine intake, obesity, diabetes, estrogen supplementation, reproductive factors, and Hashimoto’s thyroiditis, can be considered possible causes.
The u-shaped curve describing the relationship between iodine intake and thyroid disorders reflects the fact that both deficient and excessive iodine intake can impair thyroid gland function. Thus, iodized salt programs should be carefully monitored to provide adequate but not excess iodine intake.
As for the most updated AJCC-8 thyroid cancer staging guidelines, underwriting, claims, pricing and product development departments of insurance companies need to pay close attention and make timely adjustments in their risk management.
World Health Organization. Guideline: Fortification of food-grade salt with iodine for the prevention and control of iodine deficiency disorders. 2014. http://www.who.int/nutrition/publications/guidelines/ fortification_foodgrade_saltwithiodine/en/
Andersson M, et al. Global iodine status in 2011 and trends over the past decade. The Journal of Nutrition. 2012 Apr;142(4): 744-50. https://www.ncbi.nlm.nih. gov/pubmed/22378324
Aburto N, et al. Effect and safety of salt iodization to prevent iodine deficiency disorders: a systematic review with meta-analyses. World Health Organization. 2014. http://apps.who.int/iris/bitstream/ handle/10665/148175/9789241508285_eng.pdf;jsess ionid=FDECD232981284CD6C66F4739FC5B1E9?sequence=1
Bougma K, et al. Iodine and mental development of children 5 years old and under: a systematic review and meta-analysis. Nutrients. 2013 Apr 22; 5(4), 1384-416. https://www.ncbi.nlm.nih.gov/ pubmed/23609774
Ahn HS, Welch HG. South Korea’s Thyroid-Cancer “Epidemic” – Turning the Tide. The New England Journal of Medicine. 2015 Dec 10; 373(24):2389-90. https://www.nejm.org/doi/10.1056/NEJMc1507622
Lee JH, et al. Relationship between iodine levels and papillary thyroid carcinoma: A systematic review and meta-analysis. Head Neck. 2017 Aug; 39(8): 1711-18. https://www.ncbi.nlm.nih.gov/pubmed/28513893
Lee JH, et al. Case-Control Study of Papillary Thyroid Carcinoma on Urinary and Dietary Iodine Status in South Korea. World J Surgery. 2018 May; 42(5): 1424-31. https://www.ncbi.nlm.nih.gov/ pubmed/29067516
Dong W, et al. The changing incidence of thyroid carcinoma in Shenyang, China before and after universal salt iodization. Medical Science Monitor. 2013 Jan 14; 19: 49-53. https://www.ncbi.nlm.nih.gov/ pubmed/23314590
Du L, et al. Thyroid cancer: trends in incidence, mortality and clinical-pathological patterns in Zhejiang Province, Southeast China. BMC Cancer. 2018; 18: 291. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5856225/
Dong F, et al. Distribution and risk factors of thyroid cancer in China. China Oncology. 2016; 26(1): 47-52. http://wprim.whocc.org.cn/admin/article/articleDetail? WPRIMID=491863&articleId=491863&locale=en_US
American Joint Committee on Cancer. AJCC Cancer Staging Manual, Eighth Edition. 2018. www.cancerstaging.org
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