Abstract
Background:
The steep rise in thyroid cancer observed in recent decades has caused an increase in the population of long-term thyroid cancer survivors. Other than recurrences of cancer, the long-term health consequences of surviving thyroid cancer, particularly metabolic syndrome, have not yet been determined. The aim of this study was to estimate the risk of metabolic syndrome in thyroid cancer survivors.
Materials and Methods:
Population-based data from the Korean National Health and Nutrition Examination Survey (KNHANES) were used for the analysis. The data of KNHANES IV–VI from 2007–2014 were obtained. After excluding subjects who were under 19 years old, whose fasting interval was less than 8 hours, and whose data for predefined variables including metabolic syndrome components were incomplete, 34,347 subjects were analyzed. The incidence of metabolic syndrome and its components were evaluated in three groups: subjects with no history of thyroid cancer, subjects diagnosed with thyroid cancer within 3 years of the survey date, and subjects diagnosed more than 3 years before the survey date.
Results:
Thyroid cancer diagnoses were made within 3 years of the survey date for 95 subjects (group 1, short-term survivors) and more than 3 years earlier than the survey date for 60 subjects (group 2, long-term survivors). Metabolic syndrome was frequently observed with clinical significance (odds ratio [OR] 1.986 [95% confidence interval [CI] 1.0–3.70], p = 0.030) in short-term survivors compared with subjects with no thyroid cancer history. Risks for having high blood pressure and high fasting glucose were estimated to be higher in the short-term survivor group (OR 2.115 [CI 1.23–3.64], p = 0.006 and OR 1.792 [CI 1.03–3.11], p = 0.038, respectively). No significant associations were noticed in the long-term survivor group when compared with the group with no thyroid cancer history.
Conclusion:
Risks for metabolic syndrome, especially high blood pressure and high fasting glucose, were increased in short-term survivors of thyroid cancer but not in long-term survivors when compared with subjects with no history of thyroid cancer.
Introduction
R
The risk of metabolic syndrome (MetS) was evaluated in various types of cancer survivors (3). High incidences of metabolic deterioration or MetS were reported, especially among survivors who had malignancies (mostly hematologic malignancies) in childhood (4,5). In addition, prostate and breast cancer survivors who had had hormone-modifying therapies (6) had a high risk of MetS.
MetS, which is a well-known risk factor for cardiovascular disease (7,8), consists of five components: high blood pressure, high blood glucose and triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, and increased waist circumference. Because cancer survivors are at high risk for cardiovascular disease, which is the major cause of noncancer deaths in cancer survivors (9 –11), estimation of the actual risk of MetS, a condition that precedes cardiovascular disease, and its prevention will be very important in this population.
Because the incidence of thyroid cancer has increased sharply in the recent decade (12,13) and the survival rate is extremely high, a substantial number of thyroid cancer survivors are expected. Therefore, as for other cancer survivors, identification of long-term medical consequences that could commonly be developed in thyroid cancer survivors (other than cancer recurrences) will be of clinical importance. Considering the prominent high incidence of thyroid cancer (14) and high overall survival rate (15), the Korean population would be appropriate for evaluating the long-term health outcomes of thyroid cancer survivors.
Some studies (16 –18), except one (19), have reported weight gain in thyroid cancer patients after total thyroidectomy. Because an increase in weight or body mass index (BMI) could raise the risk of MetS, it is suspected that it may easily develop in thyroid cancer survivors. In addition, considering that MetS was related to increased risk of several cancers (20) and increased incidence of thyroid nodules (21), it would be also possible that risk of MetS had already been increased in thyroid cancer survivors before the diagnosis. However, it has not yet been determined whether thyroid cancer survivors have an increased risk of MetS.
The aim of the study was to identify the risk of MetS and its components in thyroid cancer survivors based on a nationwide cross-sectional survey of the Korean population.
Materials and Methods
Study population
We obtained data from the Korea National Health and Nutrition Examination Survey (KNHANES) IV–VI from the years 2007–2014 (n = 65973). KNHANES is a cross-sectional survey on the noninstitutionalized Korean population conducted by the Korean Ministry of Health and Welfare and the Korea Centers for Disease Control and Prevention. Detailed information about KNHANES is available at the KNHANES website (22). Briefly, the survey consists of health examinations, health interviews, and nutritional surveys to provide data for developing health policies and programs. To obtain a representation of the Korean population, a multi-stage clustered probability design was applied for selection of the sample subjects. Detailed Characteristics of KNHANES, which came from the complex sample design, for the statistical analysis were described in a previous study (23). Subjects under 19 years old (n = 15879), with fasting intervals less than 8 hours (n = 4755), with incomplete data for pre-defined variables including MetS components (n = 10992) were excluded from this study. Therefore, 34,347 subjects were analyzed in the study.
Study parameters
All measurements and questionnaires were obtained by trained personnel. Detailed anthropometric measurement methods were carried out as in previous studies (24,25). Waist circumference, height, and weight were included in the analysis. Blood pressure was also measured by trained technicians using a Baumanometer mercury sphygmomanometer (WA Baum, Copiague, NY), and all the subjects were seated at least 5 minutes before the measurements were taken. Body mass indices (BMIs) and waist:height ratios (WHRs) were derived from weight, height, and waist values. BMI was categorized as underweight (<18.5), normal weight (≥18.5, <23), overweight (≥23, <25), and obese (≥25). WHR was divided into two groups with a cutoff of 0.5.
Detailed health questionnaires are provided on the KNHANES website. Briefly, weight variation was defined as weight gain or loss within a recent year at the time of the survey. Self-payment of cancer screening was decided based on self-reporting. Subjects with history of cancer types other than thyroid were defined as someone who had an accompanying other cancer. For the evaluation of socioeconomic status, income, and educational status were determined. Income status was categorized into quartiles. Educational status was classified into four groups according to the final academic achievement: elementary school or less, middle school graduate, high school graduate, or university graduate or higher. The strength and frequency of physical activity were considered in the estimations of physical activity. Positive physical activity included strenuous physical activity for more than 20 minutes per day at least 3 days per week, moderate physical activity for more than 30 minutes per day at least 5 days per week, or walking for more than 30 minutes 5 days per week. Four categories of drinking habits were defined: nondrinking, once per month, less than five times per month, and more than twice per week. The subjects were defined as nonsmokers, current smokers or former smokers.
For biochemical measurements, blood sampling was carried out after at least 8 hours of fasting. Details of the biochemical measurement methods have been described in previous studies (26). The following biochemical parameters were used to define the presence of MetS: fasting glucose, HDL cholesterol, and triglycerides.
Definition of MetS and thyroid cancer
MetS was defined according to the American Heart Association/National Heart, Lung, and Blood Institute criteria, except for waist circumference (7). Waist circumference criteria for Asian populations were used in the study (≥90 cm in men and ≥80 cm in women) (27). Subjects who had three or more of the following components were defined as having MetS: fasting plasma glucose ≥100 mg/dL (or taking glucose-lowering medication), blood pressure ≥130/85 mm Hg (or taking blood pressure-lowering medication), triglycerides ≥150 mg/dL, HDL-C <40 mg/dL in men or <50 mg/dL in women, or waist circumference ≥90 cm (35 in) in men and ≥80 cm (32 in) in women. For comparison, each component was dichotomized into “yes” or “no” with respect to whether it met criteria for a metabolic syndrome component or not.
In this study, subjects with thyroid cancer were categorized into two groups based on previous observational studies and consideration of the recommended treatment and monitoring strategies suggested by several thyroid associations (28,29). Previous reports (17,18) showed that weight gain or increased BMI was relatively prominent within 3 years of a thyroidectomy. In addition, intermediate- to high-risk thyroid cancer patients usually undergo radioactive iodine (RAI) therapy with a high likelihood of follow-up of an iodine whole body scan (WBS) within 6 to 12 months of the RAI therapy. If no abnormal findings are found, RAI therapy and WBS can be carried out within 3 years of the surgery. Because both RAI therapy and WBS require dietary measures to control iodine intake and result in hypothyroidism in cases of thyroxine (T4) withdrawal for thyrotropin (TSH) stimulation, there is a high probability of changes in weight and even blood pressure. Therefore, we divided the subjects with thyroid cancer into two groups: group 1 subjects had been diagnosed within 3 years of the survey date, and group 2 subjects had been diagnosed more than 3 years prior to the survey date.
Statistical analysis
Sample weights provided by KNHANES were applied in all the analyses. Data were expressed as numbers with weighted percentages, means ± standard error, and odds ratios (ORs) with 95% confidence intervals. Due to complex sample design, a sample weight, which was assigned to each sample person after calculating the base weight, adjusting for nonresponse, and poststratification adjustment to match previous population census control totals was considered for the analysis of data. Detailed characteristics of KNHANES for the statistical analysis are available in a previous study (23). The Rao-Scott chi-squared test was performed for comparison of baseline characteristics. Odds ratios and confidence interval values for detection of MetS, and each of its components were calculated using logistic regression analysis in three groups according to the status of thyroid cancer. After adjustment for possible confounding factors such as age, sex, self-payment of cancer screening, ORs were also calculated. All the analyses were performed using SAS version 9.4 software (SAS Institute Inc., Cary, NC).
Results
Baseline characteristics
Among 34,347 subjects, 155 thyroid cancer cases were observed. Diagnoses of thyroid cancer were made within 3 years of the survey date for 95 subjects (group 1, short-term survivors) and more than 3 years prior to the survey date for 60 subjects (group 2, long-term survivors). Groups 1 and 2 were predominantly female. Self-payment of cancer screening was more frequent in group 1. Subjects in both groups generally showed healthy habits in terms of drinking and smoking. In contrast, no significance difference was found in physical activity between groups 1 and 2 (p = 0.129). In addition, recent weight changes within a year were not different. The detailed characteristics are shown in Table 1.
Data are presented as mean ± standard deviation, n (weighted %).
Statistics were carried out using Rao-Scott Chi-square test.
p-Value of significant differences between ‘No’ vs. ‘within’ (*), ‘No’ vs. ‘exceeds’ (†), and ‘within’ vs. ‘exceeds’ (‡), by multiple comparisons using Bonferroni method.
Weight variation was defined as weight gain or loss within a year at the time of the survey.
For comparison, each component was dichotomized into “yes” or “no” whether it met criteria for metabolic syndrome component or not.
BMI, body mass index; HDL, high-density lipoprotein.
An increased risk of MetS was observed in subjects who were diagnosed with thyroid cancer in the past 3 years (Table 2). Statistical significance was observed when adjusted for the possible confounding factors of age, sex, self-payment of screening, weight variation, WHR, physical activity, drinking and smoking. In contrast, no increased risk of MetS was observed in group 2 subjects compared with subjects with no thyroid cancer history.
Data are presented as odds ratio (OR) [95% confidence interval (CI)].
Statistics were carried out using logistic regression adjusted for age, sex, BMI, educational status, self-pay of cancer screening, weight variation, waist:height ratio, physical activity, drinking, and smoking.
In the multiple logistic regression analysis of each component of MetS, the ORs for the presence of high blood pressure and glucose intolerance were 2.108 and 1.848, respectively, and only statistically significant in group 1 (i.e., subjects who were diagnosed as thyroid cancer within 3 years) (Table 3). Risks for MetS components were not found in group 2.
Data are presented OR [CI].
Statistics were carried out using logistic regression adjusted for age, sex, BMI, educational status, self-pay of cancer screening, weight variation, waist:height ratio, physical activity, drinking, and smoking.
Discussion
In this study, long-term thyroid cancer survivors diagnosed more than 3 years prior to the survey were not at a higher risk of developing MetS than were subjects without thyroid cancer. In contrast, short-term thyroid cancer survivors, whose cancer history was 3 years or less, had a high risk of high blood pressure and impaired glucose homeostasis.
Early detection and advances in cancer treatment have increased the number of cancer survivors. In particular, a steep rise in the population of thyroid cancer survivors is expected due to recent increases in thyroid cancer detection and favorable prognoses. Nevertheless, the long-term health consequences of having survived thyroid cancer have yet to be well defined.
Several types of cancer survivors have often shown unfavorable long-term health consequences. In particular, long-term health consequences related to cancer treatment modalities have been well evaluated for prostate, breast, and hematologic malignancies. Androgen deprivation therapy in prostate cancer patients has been related to a high risk of MetS in survivors (30). Insulin resistance and hyperglycemia have been observed in both long-term (31) and short-term androgen deprivation therapy for prostate cancer patients (32). Several hormone-modifying tools for breast cancer, such as tamoxifen, aromatase inhibitors, and bilateral oophorectomy, have been reported to have different metabolic effects. Favorable metabolic effects after use of tamoxifen have been observed in several studies (33 –35). In contrast, aromatase inhibitor therapy and bilateral oophorectomy have shown unfavorable metabolic effects (36,37). In addition, late adverse metabolic effects of cancer treatment were reported in many studies of hematologic malignancy survivors (38,39) and adult survivors of childhood cancer (40).
Considering the recommended guidelines for thyroid cancer treatment (28,29), several factors could affect the risk of development of MetS or derangement in long-term thyroid cancer survivors. First, thyroid hormone replacement could influence metabolism. Supplementation with exogenous T4 has been shown to increase resting metabolism, which may induce weight reduction in the long term (41 –43). Additionally, elevation of TSH levels without overt hypothyroidism was reported to be associated with MetS (44 –46). In clinical practice, relatively high doses of thyroid hormone replacement to suppress TSH levels to below the limit of normal values could be maintained for several years in patients who have a high risk of recurrence compared with the common dose of thyroid hormone administered for autoimmune hypothyroidism. Although the risk of recurrence is low to intermediate, clinicians should try to prevent a rise in TSH levels above normal values, which could promote the growth of remaining malignant cells. Therefore, we could assume that most of the thyroid cancer survivors, whose thyroid functions would be normal or at subclinical hyperthyroidism status rather than exhibiting subclinical or overt hypothyroidism, may avoid metabolic derangement related to increased TSH levels after surgery (or even without surgery). However, in a recent study, long-term T4 replacement and suppressive therapy did not have significant effects on energy metabolism (47). Also, subclinical hyperthyroidism was reported to be associated with insulin resistance (48) Thus, the effect of T4 replacement in thyroid cancer survivors are not conclusive at this point. Second, performance of RAI therapy or WBS surveillance could cause metabolic changes in thyroid cancer survivors, specifically in short-term survivors. TSH stimulation is required for the preparation for RAI or WBS. Although the recent introduction of recombinant human TSH helps to prevent overt hypothyroidism during TSH stimulation (49,50), thyroid hormone withdrawal as preparation for TSH stimulation has been the standard method for several decades and is still applied in many cases. Overt hypothyroidism causes many metabolic derangements, including increased blood pressure, especially diastolic pressure; elevation of cholesterol; and liver dysfunction (51). Although the resumption of T4 replacement would reverse most of the symptoms and metabolic derangement (52), weight gain was prominent in patients who had experienced overt hypothyroidism (18). Because weight gain could be related to a high incidence of hypertension and MetS, long-term survivors were suspected to have an increased risk of MetS or its components. However, in this study, an increased risk of high blood pressure and impaired glucose tolerance was only noted among the short-term survivors. Previously, associations of increased TSH with high blood pressure (53) and impaired glucose homeostasis (54) have been reported. Although no data for RAI therapy or WBS were provided for the population, short-term survivors may have had a high probability of experiencing recent TSH stimulation. Initial therapy and surveillance may increase the short-term risks of MetS or its components. Additionally, previously reported associations of metabolic syndrome with risk of several cancers (20) and thyroid nodules (21), which would suggest that subjects with thyroid cancers were at risk of MetS before the diagnosis of cancers, could also have an influence on the development of MetS in thyroid cancer survivors. However, as shown in long-term survivors, an increased risk of metabolic derangement does not last for many years.
Health behaviors were reported to change in a positive way in studies of cancer survivors (55,56). In our study, although healthier drinking and smoking habits were found in both long-term and short-term thyroid cancer survivors, it was impossible to evaluate behavioral changes before and after cancer treatment due to the lack of data in the survey. The female predominance of thyroid cancer may explain the smaller population of drinkers and smokers among cancer survivors than in the noncancer population. In Korea, the amounts of alcohol consumed and the proportion of smokers are lower among women than men (22,57). Therefore, the existence of significant health behavior changes among thyroid cancer survivors could not be determined in our study.
Because the study utilized cross-sectional data, inferred conclusions could not be the definite causal relationship between metabolic derangement and management of thyroid cancer. In addition, because detailed information about individual treatments was not obtained in the survey, general principles of thyroid cancer management were applied to explain the phenomena found in this study. Finally, as the diagnosis of thyroid cancer was based on questionnaires, not on medical records, underestimation of thyroid cancer cases could occur. Nevertheless, this is the first study to evaluate the risk of MetS in thyroid cancer survivors from nationwide population data.
In conclusion, long-term survivors of thyroid cancer did not have a high risk of MetS compared with the general population. More precautions should be taken to avoid increased blood pressure and impaired glucose homeostasis in short-term thyroid cancer survivors.
Footnotes
Acknowledgments
The statistical consultation was supported by a Korea Health Technology R&D Project grant through the Korea Health Industry Development Institute (KHIDI), which is funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1062).
Author Disclosure Statement
No competing financial interests exist.