Benign Thyroid Diseases and Risk of Thyroid Cancer: A Nationwide Cohort Study.
ABSTRACT: Context:Thyroid nodules, adenomas, and goiter have consistently been associated with thyroid cancer risk. Few studies have assessed whether thyroid dysfunction and thyroid autoimmunity influence this risk. Objective:To examine thyroid cancer risk after diagnoses of a wide range of benign thyroid conditions. Design:Hospital and cancer registry linkage cohort study for the years 1978 to 2013. Setting:Nationwide (Denmark). Participants:Patients diagnosed with hyperthyroidism (n = 85,169), hypothyroidism (n = 63,143), thyroiditis (n = 12,532), nontoxic nodular goiter (n = 65,782), simple goiter (n = 11,582), other/unspecified goiter (n = 21,953), or adenoma (n = 6,481) among 8,258,807 residents of Denmark during the study period. Main Outcome Measures:We computed standardized incidence ratios (SIRs) for differentiated thyroid cancer, excluding the first 12 months of follow-up after benign thyroid disease diagnosis. Results:SIRs were significantly elevated for all benign thyroid diseases apart from hypothyroidism. SIRs were higher for men than women and in the earlier follow-up periods. Elevated SIRs were observed for localized and regional/distant thyroid cancer. After excluding the first 10 years of follow-up, hyperthyroidism [n = 27 thyroid cancer cases; SIR = 2.00; 95% confidence interval (CI): 1.32 to 2.92], nontoxic nodular goiter (n = 83; SIR = 4.91; 95% CI: 3.91 to 6.09), simple goiter (n = 8; SIR = 4.33; 95% CI: 1.87 to 8.53), other/unspecified goiter (n = 20; SIR = 3.94; 95% CI: 2.40 to 6.08), and adenoma (n = 9; SIR = 6.02; 95% CI: 2.76 to 11.5) remained positively associated with thyroid cancer risk. Conclusions:We found an unexpected increased risk of differentiated thyroid cancer, including regional/distant disease, following diagnosis of hyperthyroidism and thyroiditis that could not be solely attributed to increased medical surveillance. Hypothyroidism was less clearly associated with thyroid cancer risk.
Project description:The association of thyroid disease and Ménière's disease would suggest that both are autoimmune diseases. This study aimed to investigate the relation of goiter, hypothyroidism, thyroiditis, hyperthyroidism, and autoimmune thyroiditis with Ménière's disease. The Korean National Health Insurance Service-Health Screening Cohort data from 2002 through 2015 were used. The 8183 adult patients with Ménière's disease were 1:4 matched with the 32,732 individuals of the control group for age, sex, income, and region of residence. The previous histories of thyroid disorders including goiter, hypothyroidism, thyroiditis, and hyperthyroidism were investigated using conditional logistic regression analyses. Subgroup analyses were conducted, including for age and sex. Smoking, alcohol consumption, obesity, Charlson Comorbidity Index, histories of benign paroxysmal vertigo, vestibular neuronitis, other peripheral vertigo, thyroid cancer, and levothyroxine medication were adjusted in the models. The histories of goiter (5.7% vs. 4.2%), hypothyroidism (4.7% vs. 3.6%), thyroiditis (2.1% vs. 1.6%), hyperthyroidism (3.6% vs. 2.5%), and autoimmune thyroiditis (0.99% vs. 0.67%) were higher in the Meniere's disease group than in the control group (all P?<?0.05). The histories of goiter, hypothyroidism, and hyperthyroidism were associated with Ménière's disease (adjusted odds ratio (OR)?=?1.19 [95% confidence interval (CI)?=?1.04-1.36] for goiter, 1.21 [95% CI 1.02-1.44] for hypothyroidism, and 1.27 [95% CI 1.09-1.49] for hyperthyroidism, each of P?<?0.05). In subgroup analyses, hypothyroidism was associated with Ménière's disease in?<?65-year-old women. Hyperthyroidism was related with Ménière's disease in women overall. Thyroid diseases of goiter, hypothyroidism, and hyperthyroidism were associated with Ménière's disease.
Project description:Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P?=?8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P?=?2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P?=?6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P?=?1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P?=?6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P?=?1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
Project description:To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors.Rates of self-reported thyroid dysfunction and thyroid cancer were determined among 3,579 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986, and compared with 3,846 siblings and population rates, respectively.The cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following leukemia diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively, both significantly increased compared with siblings. In multivariate analysis, survivors who received >or=20 Gy cranial radiotherapy plus any spinal radiotherapy had the highest risk of subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5) compared with those treated with chemotherapy alone. Craniospinal radiotherapy also was associated with an increased risk of subsequent hyperthyroidism (HR 6.1, 95% CI 1.1, 34.2) compared with chemotherapy alone, as well as an increased risk of subsequent thyroid cancers (SIR 30.3, 95% CI 14.5, 55.7) compared with population rates. In radiation dosimetry analysis, pituitary doses >or=20 Gy combined with thyroid doses >or=10 Gy were associated with hypothyroidism, whereas pituitary doses >or=20 Gy combined with thyroid doses >or=15 Gy were associated with hyperthyroidism.The risk of thyroid dysfunction and thyroid cancer was increased among childhood ALL survivors treated with craniospinal radiotherapy. In these individuals, long-term surveillance is warranted as no obvious plateau in risk was seen, even after 25 years of follow-up.
Project description:OBJECTIVE:The association between thyroid dysfunction and gastrointestinal cancer is unclear. DESIGN:We conducted a nationwide population-based cohort study to examine this potential association. METHODS:We used Danish medical registries to assemble a nationwide population-based cohort of patients diagnosed with hyperthyroid or hypothyroid disease from 1978 through 2013. We computed standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CI) as measures of the relative risk of each cancer, comparing patients with thyroid dysfunction with that expected in the general population. RESULTS:We included 163,972 patients, of which 92,783 had hyperthyroidism and 71,189 had hypothyroidism. In general, we found an increased risk of all gastrointestinal cancers within the first year after thyroid disease diagnosis. After more than five years of follow-up, patients with hyperthyroidism had a slightly increased risk of pancreatic and gallbladder and biliary tract cancer. Patients with hypothyroidism had a slightly increased risk of stomach, anal, liver, gallbladder and biliary tract, and pancreatic cancer after more than five years of follow-up, but the observed numbers of cancers were in general similar to the expected. CONCLUSIONS:The increased risks of all gastrointestinal cancers in the first year following hyper- or hypothyroidism diagnosis are likely due to detection bias. After more than five years of follow-up, there does not seem to be a consistent causal association between thyroid disease and gastrointestinal cancer.
Project description:Thyroid dysfunction after exposure to low or moderate doses of radioactive iodine-131 (131I) at a young age is a public health concern. However, quantitative data are sparse concerning 131I-related risk of these common diseases.Our goal was to assess the prevalence of thyroid dysfunction in association with 131I exposure during childhood (? 18 years) due to fallout from the Chernobyl accident.We conducted a cross-sectional analysis of hypothyroidism, hyperthyroidism, autoimmune thyroiditis (AIT), serum concentrations of thyroid-stimulating hormone (TSH), and autoantibodies to thyroperoxidase (ATPO) in relation to measurement-based 131I dose estimates in a Belarusian cohort of 10,827 individuals screened for various thyroid diseases.Mean age at exposure (± SD) was 8.2 ± 5.0 years. Mean (median) estimated 131I thyroid dose was 0.54 (0.23) Gy (range, 0.001-26.6 Gy). We found significant positive associations of 131I dose with hypothyroidism (mainly subclinical and antibody-negative) and serum TSH concentration. The excess odds ratio per 1 Gy for hypothyroidism was 0.34 (95% CI: 0.15, 0.62) and varied significantly by age at exposure and at examination, presence of goiter, and urban/rural residency. We found no evidence of positive associations with antibody-positive hypothyroidism, hyperthyroidism, AIT, or elevated ATPO.The association between 131I dose and hypothyroidism in the Belarusian cohort is consistent with that previously reported for a Ukrainian cohort and strengthens evidence of the effect of environmental 131I exposure during childhood on hypothyroidism, but not other thyroid outcomes.
Project description:The prevalence of hyperthyroidism and hypothyroidism is 0.5-4% in iodine-replete communities, but it is 5-10 times higher in women than in men. Those conditions are associated with a broad range of metabolic disorders and cardiovascular diseases. Biological evidence of a role of thyroid hormones in carcinogenesis also exists. However, the association between thyroid dysfunction and cardiovascular disease or cancer mortality risk remains controversial. In a large cohort of women, the associations of hyperthyroidism and hypothyroidism with cause-specific mortality were evaluated after nearly 30 years of follow-up.The prospective study included 75,076 women aged 20-89 years who were certified as radiologic technologists in the United States in 1926-1982, completed baseline questionnaires in 1983-1998 from which medical history was ascertained, and reported no malignant disease or benign thyroid disease except thyroid dysfunction. A passive follow-up of this cohort was performed through the Social Security Administration database and the National Death Index-Plus. Cause-specific mortality risks were compared according to self-reported thyroid status, with proportional hazards models adjusted for baseline year and age, race/ethnicity, body mass index, family history of breast cancer, and life-style and reproductive factors.During a median follow-up of 28 years, 2609 cancer, 1789 cardiovascular or cerebrovascular, and 2442 other non-cancer deaths were recorded. Women with hyperthyroidism had an elevated risk of breast cancer mortality after 60 years of age (hazard ratio [HR]?=?2.04 [confidence interval (CI) 1.16-3.60], 13 cases in hyperthyroid women) compared to women without thyroid disease. Hypothyroid women had increased mortality risks for diabetes mellitus (HR?=?1.58 [CI 1.03-2.41], 27 cases in hypothyroid women), cardiovascular disease (HR?=?1.20 [CI 1.01-1.42], 179 cases), and cerebrovascular disease (HR?=?1.45 [CI 1.01-2.08], 35 cases, when restricting the follow-up to ?10 years after baseline). Other causes of death were not associated with hyperthyroidism or hypothyroidism, though there was a suggestion of an elevated risk of ovarian cancer mortality in hyperthyroid women based on very few cases.The excess mortality risks observed in a large, prospective 30-year follow-up of patients with thyroid dysfunction require confirmation, and, if replicated, further investigation will be needed because of the clinical implications.
Project description:BACKGROUND:Despite the biological link between thyroid hormones and breast cancer cell proliferation shown in experimental studies, little is known about the association between hyperthyroidism and breast cancer, as well as its association with the most common mammographic and genetic risk predictors for breast cancer. METHODS:This study estimates the incidence rate ratios (IRRs) of breast cancer among women diagnosed with hyperthyroidism, compared to those who are not, using two cohorts: a Swedish national cohort of the general female population (n?=?3,793,492, 2002-2011) and the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, n?=?69,598, 2002-2017). We used logistic regression to estimate the odds ratios (ORs) of hyperthyroidism according to the mammographic and genetic risk predictors for breast cancer. RESULTS:An increased risk of breast cancer was observed in patients in the national cohort with hyperthyroidism (IRR?=?1.23, 95% CI?=?1.12-1.36), particularly for toxic nodular goiter (IRR?=?1.38, 95% CI?=?1.16-1.63). Hyperthyroidism was associated with higher body mass index, early age at first birth, and lower breastfeeding duration. Higher mammographic density was observed in women with toxic nodular goiter, compared to women without hyperthyroidism. Additionally, among genotyped women without breast cancer in the KARMA cohort (N?=?11,991), hyperthyroidism was associated with a high polygenic risk score (PRS) for breast cancer overall (OR?=?1.98, 95% CI?=?1.09-3.60) and for estrogen receptor-positive specific PRS (OR?=?1.90, 95% CI?=?1.04-3.43). CONCLUSION:Hyperthyroidism is associated with an increased risk of breast cancer, particularly for patients with toxic nodular goiter. The association could be explained by higher mammographic density among these women, as well as pleiotropic genetic variants determining shared hormonal/endocrine factors leading to the pathology of both diseases.
Project description:Female breast cancer patients have an increased risk of developing subsequent malignant diseases, but this issue is rarely discussed in regards to male breast cancer patients. Thus, we conducted a national survey that included 100,915 female and 578 male breast cancer patients to investigate the risk of second primary malignancy (SPM). During a follow-up period that included 529,782 person-years, 3,153 cases of SPM developed. Compared with the general population, the standardized incidence ratio (SIR) of SPM in breast cancer patients was 1.51 [95% confidence interval (CI): 1.46-1.56]. The observed risk was significantly higher in male patients (SIR 2.17, 95% CI 1.70-2.73) and in patients whose age at breast cancer diagnosis was 40 years or younger (SIR 3.39, 95% CI 2.80-4.07), comparing to age-matched general population. Compared with the overall female population, the SIRs of female breast cancer patients with uterine (SIR: 2.66, 95% CI: 2.37-2.98), thyroid (SIR: 2.30, 95% CI: 2.02-2.62), and bone and soft tissue (SIR: 2.16, 95% CI: 1.56-2.91) cancers were significantly increased. Male breast cancer patients also displayed significantly higher SIRs for thyroid (SIR: 13.2, 95% CI: 1.60-47.69), skin (SIR: 8.24, 95% CI: 3.02-17.94) and head and neck (SIR: 4.41, 95% CI: 2.35-7.54) cancers. Among breast cancer patients, risk factors significantly associated with SPM included male gender, older age, chemotherapy treatment and comorbidity with liver cirrhosis. From our analysis, we concluded that the risk of SPM was significantly higher for both male and female breast cancer patients compared with the general population, suggesting that more intensive surveillance may be needed, especially in high-risk patients.
Project description:Importance:Thyroid hormones have been shown to affect several important pathways in cancer development, including colorectal cancer (CRC). Clinical studies examining the association between thyroid disorders and colorectal cancer have conflicting results and have predominantly involved white populations. Objective:To determine if a diagnosis of hyperthyroidism or hypothyroidism is associated with the risk of developing colorectal cancer in an East Asian population. Design, Setting, and Participants:This nationwide population-based case-control study was conducted from April 27, 2018, to November 8, 2018, using the Taiwanese National Health Insurance Research Database. Participants were adults (n?=?139?426) either with a new diagnosis (between 2008 and 2013) of primary colorectal cancer without a history of cancer, or without cancer. Cases and controls were matched 1:1 by age, sex, and index date. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of colorectal cancer (or the same index date in controls) was then determined. Main Outcomes and Measures:Risk differences in developing colorectal cancer among patients with a medical history of hyperthyroidism or hypothyroidism. Results:A total of 139?426 patients were included in the study, and 69?713 individuals made up each case and control group, which were both predominantly male (39 872 [57.2%]). The mean (SD) age for those with CRC was 65.8 (13.7) years and for those without CRC was 66.0 (13.6) years. Both hyperthyroidism (adjusted odds ratio [aOR], 0.77; 95% CI, 0.69-0.86; P?<?.001) and hypothyroidism (aOR, 0.78; 95% CI, 0.65-0.94; P?=?.008) were associated with a decreased risk of being diagnosed with colorectal cancer. An inverse association of rectal cancer was found among patients aged 50 years or older with a history of hypothyroidism despite treatment (aOR, 0.54; 95% CI, 0.39-0.74; P?<?.001). A history of hyperthyroidism in all age groups was associated with a lower risk of colon cancer (aOR, 0.74; 95% CI, 0.64-0.85; P?<?.001), with a stronger association seen among those younger than 50 years (aOR, 0.55; 95% CI, 0.36-0.85; P?=?.007). Conclusions and Relevance:In this study, hypothyroidism appeared to be associated with a lower risk of rectal cancer, whereas hyperthyroidism appeared to be associated with a lower risk of colon cancer. Because of this, biochemical in vivo research and epidemiologic studies appear to be needed to further clarify the nature of these associations.
Project description:OBJECTIVES: To examine the risk of atrial fibrillation in relation to the whole spectrum of thyroid function in a large cohort of patients. DESIGN: Population based cohort study of general practice patients identified by linkage of nationwide registries at the individual level. SETTING: Primary care patients in the city of Copenhagen. SUBJECTS: Registry data for 586,460 adults who had their thyroid function evaluated for the first time by their general practitioner during 2000-10 and who were without previously recorded thyroid disease or atrial fibrillation. MAIN OUTCOME MEASURE: Poisson regression models used to estimate risk of atrial fibrillation by thyroid function. RESULTS: Of the 586,460 individuals in the study population (mean (SD) age 50.2 (16.9) years, 39% men), 562,461 (96.0%) were euthyroid, 1670 (0.3%) had overt hypothyroidism, 12,087 (2.0%) had subclinical hypothyroidism, 3966 (0.7%) had overt hyperthyroidism, and 6276 (1.0%) had subclinical hyperthyroidism. Compared with the euthyroid individuals, the risk of atrial fibrillation increased with decreasing levels of thyroid stimulating hormone (TSH) from high normal euthyroidism (incidence rate ratio 1.12 (95% CI 1.03 to 1.21)) to subclinical hyperthyroidism with reduced TSH (1.16 (0.99 to 1.36)) and subclinical hyperthyroidism with supressed TSH (1.41 (1.25 to 1.59)). Both overt and subclinical hypothyroidism were associated with a lower risk of atrial fibrillation. CONCLUSION: The risk of atrial fibrillation was closely associated with thyroid activity, with a low risk in overt hypothyroidism, high risk in hyperthyroidism, and a TSH level dependent association with risk of atrial fibrillation across the spectrum of subclinical thyroid disease.