==== Front Clin EpidemiolClin EpidemiolClinical EpidemiologyClinical Epidemiology1179-1349Dove Medical Press 10.2147/CLEP.S158869clep-10-907Original ResearchRisk of cancer in patients with thyroid disease and venous thromboembolism Christensen Diana H 1Veres Katalin 1Ording Anne G 1Jørgensen Jens Otto L 2Cannegieter Suzanne C 3Thomsen Reimar W 1Sørensen Henrik T 1 1 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, dhcr@clin.au.dk 2 Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark 3 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the NetherlandsCorrespondence: Diana H Christensen, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43–45, DK-8200, Aarhus N, Denmark, Tel +45 8 716 8248, Fax +45 8 716 7215, Email dhcr@clin.au.dk2018 02 8 2018 10 907 915 © 2018 Christensen et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective Risk of venous thromboembolism (VTE) is increased in patients with hypo/hyperthyroidism. It is unknown whether VTE may be a presenting symptom of occult cancer in these patients. Design Nationwide population-based cohort study based on Danish medical registry data. Methods We identified all patients diagnosed with VTE during 1978–2013 who had a previous or concurrent diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788). We followed them until a first-time cancer diagnosis, death, emigration, or study end, whichever came first. We calculated 1-year absolute cancer risk and standardized incidence ratios (SIRs) for cancer incidence in the study population compared with national cancer incidence in the general population. Results During the first year after a VTE diagnosis, the 1-year absolute cancer risk was 3.0% among patients with hypothyroidism and 3.9% among those with hyperthyroidism. During the first year of follow-up, SIRs for cancer in the study population compared with the general population were 1.96 (95% CI: 1.42–2.64) among patients with hypothyroidism and 2.67 (95% CI: 2.07–3.39) among those with hyperthyroidism. SIRs declined substantially after 1 year but remained increased during the remainder of the follow-up period (up to 36 years) (SIR for hypothyroidism=1.16 [95% CI: 0.97–1.39]; SIR for hyperthyroidism=1.26 [95% CI: 1.08–1.46]). Conclusion VTE may be a marker of underlying occult cancer in patients with hypothyroidism or hyperthyroidism. Keywords hyperthyroidismhypothyroidismvenous thromboembolismcancercohort study ==== Body Introduction Hyperthyroidism and hypothyroidism are common endocrine diseases, with estimated lifetime risks of 2%–5%.1,2 Hyperthyroidism is associated with biochemical changes consistent with vascular endothelial dysfunction and hypercoagulability – 2 of the 3 factors that comprise Virchow’s triad of pathophysiological factors in thrombosis development.3,4 Moreover, hyperthyroidism is associated with reduced fibrinolytic activity.3,4 Accordingly, several cohort and case–control studies have reported up to a 6-fold increased risk of venous thromboembolism (VTE) in patients with hyperthyroidism,5–10 with the increased VTE risk persisting for several years after diagnosis.5 The relation between hypothyroidism and coagulation disturbances is less clear. Some studies have noted bleeding tendencies and others have reported a hypercoagulable and hypofibrinolytic state.11 VTE risk in patients with hypothyroidism has been poorly investigated, with a single observational study reporting a 1.6-fold increased risk.12 VTE is a well-known and frequent cancer complication.13 Moreover, VTE occurrence may be the first sign of an as yet undiagnosed cancer.14–19 Previous studies have found a 2- to 4-fold increased 1-year risk of cancer among patients diagnosed with VTE compared with the general population.14–18 Initially, this was thought to be relevant only for primary or idiopathic VTE,19 that is, VTE occurring with no preceding risk factors, but increasing evidence suggests that occult cancer also may be a contributing cause in patients with secondary VTE.14 It is unknown whether VTE in patients with thyroid disease may be a marker of undiagnosed cancer. We, therefore, conducted this nationwide Danish population-based cohort study to compare cancer risk following VTE among patients with thyroid disease with that expected based on national cancer incidence. Materials and methods Setting and data sources The Danish social welfare system provides tax-funded health care to the entire Danish population, with all provided services registered in national health care databases. Accurate linkage of these databases is possible via the unique civil registration number (CPR number) assigned to each Danish resident at birth or upon emigration.20 The source population of the current cohort study consisted of the entire Danish population. During the 36-year study period (January 1, 1978 to November 30, 2013), the cumulative population included 8,096,820 persons. Cohort of patients with VTE and thyroid disease The Danish National Patient Registry (DNPR) contains information on all non-psychiatric inpatient admissions in Denmark since 1977. Hospital outpatient clinic visits and emergency room visits were added in 1995.21 Information recorded in the DNPR includes the CPR number, dates of admission and discharge, outpatient/emergency room visit dates, surgical procedures performed, and discharge diagnoses classified according to the International Classification of Diseases, Eighth Revision through 1993 and Tenth Revision (ICD-10) thereafter.21 We used the DNPR to identify all patients with a first-time VTE (deep venous thrombosis of the lower limb or pulmonary embolism) diagnosed during an inpatient admission or hospital outpatient clinic visit during the study period (N=156,387). Both primary and secondary discharge diagnoses were included. In Denmark, diagnoses of first-time VTE have a positive predictive value (PPV) higher than 80%.22 We excluded patients with VTEs diagnosed in the emergency room setting without a subsequent inpatient diagnosis, because of the low PPV (31%) of these diagnoses.23 We also excluded all VTE patients who had a cancer diagnosis recorded at any time before or during the hospital contact with VTE (N=32,778). We then restricted our study cohort to VTE patients with a diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788) recorded at any time before or during the hospital contact in which the VTE was diagnosed. Patients with ICD-10 codes for myxedema after treatment or thyrotoxicosis by overdose of thyroid hormone were excluded, because these patients could not clearly be assigned to either the hypo- or hyperthyroidism cohort. In the subgroup of VTE patients (N=226) who had both hypothyroidism and hyperthyroidism diagnoses recorded, the most recent pre-VTE thyroid disease diagnosis code determined membership in the hypothyroidism vs hyperthyroidism subcohort. This was done to ensure that subcohort membership reflected thyroid hormone levels closest in time to the VTE date. Cancer outcomes We obtained information on cancers from the Danish Cancer Registry, which has recorded all incident cancers in Denmark since 1943, with information on morphology, histology, and cancer stage at diagnosis.24 We used the same grouping of cancers as presented in the Annual Cancer Report published by the Danish National Board of Health. Covariates The inpatient and outpatient hospital history available in the DNPR provided information on classic VTE risk factors in the 90-day period prior to VTE diagnosis (surgery, fractures/trauma, and pregnancy), on obesity, and on diseases included in the Charlson Comorbidity Index (CCI).25,26 The CCI assigns 1–6 points to 19 disease categories according to their ability to predict short-term mortality. Based on total modified CCI scores (cancer excluded), we defined 3 categories of comorbidity burden: normal (0 points), moderate (1–2 points), and high (3 or more points). We obtained information on vital status from the Civil Registration System, which records data on death and migration with daily electronic updates.20 Relevant ICD codes and supporting information about grouping of cancers are provided in the online supplementary data (Table S1). Statistical analyses We followed patients from VTE diagnosis until a cancer diagnosis, death, emigration, or study end, whichever occurred first. The follow-up period was split into 0–1 year and 1+ years. The first year was further divided into 0–90 days and 91–365 days. We calculated 1-year absolute cancer risks for all cancers, treating death as a competing risk.27 We calculated the expected cancer rate among patients with hypo/hyperthyroidism and VTE, assuming the expected cancer risk in this population would be the same as in the general population. We multiplied the number of person-years of observation by the Danish national cancer incidence rates across gender, single-year age groups, and single-year periods of diagnosis year to achieve the expected number of incident cancers. We then calculated the standardized incidence ratio (SIR), that is, the ratio of the observed to the expected number of cancers. This served as a measure of the relative risk of cancer in patients with thyroid disease and VTE. We calculated 95% CIs under the assumption that the observed number of cancers in a specific category followed a Poisson distribution.28 Exact 95% CIs were used when the observed number of cancers was <10; otherwise, Byar’s approximation was used.28 Assuming that cancers detected during the first year following VTE also were present at the time of VTE diagnosis, we calculated the reciprocal of the excess risk ([observed number of cancers/follow-up time] − [expected number of cancers/follow-up time]) for the first year of follow-up, in order to determine the number needed to examine at time of VTE to detect 1 excess cancer.29 As well, 95% CIs were calculated as the reciprocal of the CIs for the excess risk estimate.30 In subgroup analyses, the results were stratified according to age at VTE diagnosis, calendar-year period of VTE diagnosis (1978–1993 and 1994–2013), gender, comorbidity burden, obesity, and presence/absence of classic VTE risk factors. In this study, we excluded all VTEs preceded by a cancer diagnosis. However, there may have been some delay in recording the cancer diagnosis. In addition, VTEs could have been detected coincidentally during diagnostic workup in patients suspected to have cancer. In order to examine the potential impact of including such VTEs in the analysis, the 90-day follow-up period was divided into 0–30 days and 31–90 days in sensitivity analyses. We also repeated all analyses after excluding cancers detected within the first 30 days. Moreover, we repeated all analyses excluding the 226 patients recorded as having both hypothyroidism and hyperthyroidism. Pharmacological or – for hyperthyroidism – surgical treatment may change hormone status to euthyroid. Therefore, we also conducted a sensitivity analysis in which we restricted the cohort to patients with a maximum 2-year interval between their first hypo/hyperthyroid disease diagnosis and their first VTE diagnosis in order to increase the likelihood that our study population reflects patients with ongoing thyroid disease. Statistical analyses were conducted using the SAS statistical software package, version 9.4 (SAS Institute, Cary, NC, USA). This study did not involve any patient contact or any intervention. Thus, approval from the Danish Scientific Ethical Committee and patient consent were not required. The study was approved by the Danish Data Protection Agency (record number 1-16-02-1-08). Results Descriptive data We identified 1481 patients with hypothyroidism (86% female, median age: 75 years) and 1788 patients with hyperthyroidism (83% female, median age: 74 years) with a first-time VTE diagnosis (Table 1). Median time from first thyroid disease diagnosis to VTE diagnosis was 4.1 years (interquartile range [IQR]=0.6–10.0 years). The hypothyroidism subcohort was followed for a median of 2.5 years (IQR=0.4–6.1 years) and the hyperthyroidism subcohort was followed for a median of 2.6 years (IQR=0.3–6.6 years). In both subcohorts, 24%–25% of patients had classic risk factors and ≥78% of patients were diagnosed with VTE in the second half of the study period (1994–2013). Hospital-coded obesity was relatively uncommon (6%–11%) and was most prevalent among patients with hypothyroidism. Hospital-diagnosed comorbidity, defined as CCI points ≥1, was observed in 65% of patients with hypothyroidism and in 56% of those with hyperthyroidism. Cancer data During follow-up, 164 cancers were diagnosed among patients with hypothyroidism and 239 among those with hyperthyroidism. In the hypothyroidism subcohort, the 1-year absolute cancer risk was 3.0%, corresponding to a 1-year cancer SIR of 1.96 (95% CI: 1.42–2.64). In the hyperthyroidism subcohort, the 1-year absolute cancer risk was 3.9%, corresponding to a 1-year cancer SIR of 2.67 (95% CI: 2.07–3.39). Cancers were diagnosed most often within the first 90 days after a VTE diagnosis. In the hypothyroidism subcohort, the 90-day cancer SIR was 2.36 (95% CI: 1.29–3.96), the 91–365 days SIR was 1.81 (95% CI: 1.21–2.60), and the SIR during 1+ years of follow-up was 1.16 (95% CI: 0.97–1.39). A similar pattern was observed for the hyperthyroidism subcohort. However, the cancer risk within the first 90 days was even higher and the risk remained modestly increased beyond 1 year of follow-up. The 0–90 day cancer SIR was 5.32 (95% CI: 3.75–7.33), the 91–365 day cancer SIR was 1.68 (95% CI: 1.14–2.38), and the cancer SIR during 1+ years of follow-up was 1.26 (95% CI: 1.08–1.46; Tables 2 and 3). The number of patients needed to examine in order to detect 1 excess cancer within the first year following VTE was 52 (95% CI: 32–142) in the hypothyroidism subcohort and 30 (95% CI: 22–49) in the hyperthyroidism subcohort. Subgroup analyses In the hypothyroidism subcohort, the 1-year cancer SIR was higher among patients who were younger and had a lower comorbidity burden. In contrast, the SIR showed only minor changes after stratification by gender, hospital-diagnosed obesity, calendar-year period, and presence/absence of classic VTE risk factors (Table 2). In the hyperthyroidism subcohort, 1-year cancer SIRs varied modestly by age, comorbidity burden, gender, and calendar-year period (Table 3). In the hypothyroidism subcohort, a 3-fold or greater increase was observed within the first year of follow-up for cancers of the ovary and for non-Hodgkin malignant lymphoma. In the hyperthyroidism subcohort, corresponding increases were observed for cancers of the large intestine, pancreas, uterine cervix, uterus, ovary, prostate, and urinary bladder, as well as for non-specified cancers and metastases (Tables S2 and S3). Sensitivity analyses Within 30 days following the VTE diagnosis date, 8 cancers were diagnosed in the hypothyroidism subcohort and 27 in the hyperthyroidism subcohort. The 30-day SIRs were 3.91 (95% CI: 1.69–7.70) and 11.10 (95% CI: 7.32–16.16), respectively, in the 2 subcohorts (Tables S4 and S5). Excluding these cancers, the 1-year SIR decreased to 1.76 (95% CI: 1.23–2.45) in the hypothyroidism subcohort and to 1.78 (95% CI: 1.28–2.42) in the hyperthyroidism subcohort. (Tables S6 and S7). Excluding the 226 patients with both hypo- and hyperthyroid diagnosis did not change the results (data not shown). Restricting the cohort to patients with a maximum interval of 2 years from hypo/hyperthyroid diagnosis to VTE diagnosis had no significant effect on the results for the hypothyroidism subcohort (Tables S8–S10). For the hyperthyroidism subcohort, the SIRs, in general, increased, except for the 91–365 days period; 0–90 days SIR: 8.27 (95% CI: 4.90–13.08), 91–365 days SIR: 1.36 (95% CI: 0.59–2.68), 1-year SIR: 3.22 (95% CI: 2.11–4.72), and SIR during 1+ years of follow-up: 1.54 (95% CI: 1.22–1.91; Tables S11–S13). However, precision was reduced in these sensitivity analyses. Discussion In this large population-based cohort study, we evaluated the association between VTE occurrence and subsequent cancer diagnoses in patients with hypo/hyperthyroidism. We found an absolute cancer risk of 3.0%–3.9% in the first year following VTE and a relative cancer risk of 2.0–2.7 compared with the general population. The relative risk of cancer declined after the first year of follow-up, suggesting that development of a VTE can be regarded as a potential early manifestation of an underlying malignancy among patients with hypo/hyperthyroid disease. Our study adds to the literature on VTE and cancer by clarifying the association for patients with hypo/hyperthyroidism, in whom thyroid disease itself may cause coagulation disturbances and increase VTE risk, independent of underlying cancer. Similar to previous studies in the general population, we observed the highest increase in cancer risk immediately after VTE diagnosis, followed by a decline.14,16–18 One-year SIRs in our study were consistent with the 2- to 4-fold increased cancer risk observed in studies of VTE in the general population.14–18 The persistent but modest increase in cancer risk beyond 1 year of follow-up also has been observed for VTE patients in general14,16–18 and may be explained by common shared lifestyle risk factors for VTE and cancer, such as smoking, obesity, or hormone replacement therapy, or by premalignant changes that promote thrombosis.17 Another possible explanation for our results is the putative oncogenic effects of thyroid hormones.31 Awareness of the association between VTE and cancer may lead to heightened diagnostic efforts. This is suggested by the higher SIRs observed in the later calendar-year period. However, a period of increased cancer risk then would have been followed by a compensatory deficit,17 which was not observed. This implies that detection bias does not explain our results. The number of patients needed to examine to detect 1 excess cancer within the first year after VTE was only 30 in the hyperthyroidism subcohort and 52 in the hypothyroidism subcohort. However, the clinical utility of extensive screening for cancer in VTE patients depends on the ability to detect the cancer using these methods, as well as on the prognostic impact of earlier cancer detection. These topics were not investigated in this study. Cancers preceded by VTE have a higher stage at diagnosis and a worse prognosis compared with other cancers.32 Previous studies have not provided strong evidence that extensive screening to detect occult cancer after VTE improves patient prognosis.33–36 Moreover, extensive screening for cancer may be associated with physical and psychological discomfort.37 Still, detection of an underlying cancer may have implications for VTE management, including treatment of the VTE.38 We, thus, concur that patients with hypo/hyperthyroidism and VTE undergo diagnostic workup for cancer to the same extent as non-thyroid patients diagnosed with VTE. The validity of our results depends on several factors. Major study strengths are its nationwide population-based design and completeness of patient follow-up, which reduced the risk of selection bias. As the DNPR covers all hospital contacts in Denmark, the study was not affected by selective inclusion of specific hospitals, health insurance systems, or age groups. As well, the validity of data on VTE,22 thyroid disease,39 cancer,40 and comorbidities41 is high. Study limitations include the potential for protopathic bias, that is, cancer diagnostic activities leading to a VTE diagnosis. Moreover, in some cases, the registration of a cancer diagnosis might be delayed compared with a concomitant VTE diagnosis. However, in our study, an increased cancer risk was still observed after excluding cancers detected within 30 days post-VTE. Our cancer site-specific results should be interpreted with caution since analysis of the high-risk cancer sites were based on small numbers of cancers, limiting statistical precision. We lacked drug utilization data and could, therefore, not stratify our cancer analyses of thyroid disease patients by use of VTE-associated drugs. Finally, we lacked biochemical data and thus, could not evaluate the association between VTE and cancer stratified by thyroid hormone levels. This may be relevant since some studies have indicated that coagulation disturbances in patients with thyroid disease become more marked with increasing deviation of thyroid hormone levels from the normal range.6,8 However, restricting our cohort to patients with a more recent thyroid disease diagnosis did not change the results for the hypothyroidism subcohort. For the hyperthyroidism subcohort, the SIRs increased rather than decreased, as would be expected if the hormone disturbances caused more VTEs. Conclusion In conclusion, VTE is a multicausal disease and our findings suggest that among patients with hypothyroidism or hyperthyroidism, VTE also may be a marker of underlying cancer, consistent with observations in the general population. Thus, our results support that patients with hypo/hyperthyroidism and VTE undergo diagnostic workup for cancer to the same extent as non-thyroid patients diagnosed with VTE. Acknowledgments This work was supported by the Danish Cancer Society (grant number R73-A4284-13-S17) and the Program for Clinical Research Infrastructure established by the Lundbeck Foundation and the Novo Nordisk Foundation. Author contributions All authors are responsible for the study design. KV performed the analyses. DHC wrote the initial draft. All authors participated in discussing and interpreting the results. All authors critically revised the manuscript for intellectual content and approved the final version before submission. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work. Disclosure The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of these studies had any relation to the present study. The salary of Diana Christensen is paid by the International Diabetic Neuropathy Consortium (IDNC) research programme, which is supported by a Novo Nordisk Foundation Challenge Programme grant ([Grant number NNF14OC0011633)]. The authors report no other conflicts of interest in this work. Table 1 Characteristics of patients with thyroid disease and a VTE, Denmark, 1978–2013 Hypothyroidism Hyperthyroidism N (%) N (%) Total 1481 (100) 1788 (100) Female 1278 (86) 1480 (83) Median age at VTE diagnosis (IQR), years 75 (65–82) 74 (64–82) Age at VTE diagnosis  <60 years 259 (17) 326 (18)  60–74 years 488 (33) 598 (33)  75+ years 734 (50) 864 (48) Comorbidity burdena  Normal 516 (35) 789 (44)  Medium 673 (45) 762 (43)  High 292 (20) 237 (13) Charlson Comorbidity Index conditions  Myocardial infarction 167 (11) 158 (9)  Congestive heart failure 247 (17) 281 (16)  Peripheral vascular disease 145 (10) 172 (10)  Cerebrovascular disease 251 (17) 275 (15)  Dementia 56 (4) 46 (3)  Chronic pulmonary disease 302 (20) 312 (17)  Connective tissue disease 192 (13) 124 (7)  Gastrointestional ulcer 139 (9) 132 (7)  Mild liver disease 39 (3) 19 (1)  Diabetes 202 (14) 182 (10)  Hemiplegia 8 (1) 7 (0.4)  Moderate-to-severe renal disease 100 (7) 65 (4)  Diabetes with end-organ disease 103 (7) 84 (5)  Moderate-to-severe liver disease 7 (1) 3 (0.2)  AIDS 0 (0) 0 (0) Year of VTE diagnosis  1978–1993 318 (21) 397 (22)  1994–2011 1,163 (79) 1,391 (78) Obesity 163 (11) 108 (6) Provoking factorsb  Classic provoking factors, overall 371 (25) 424 (24)  Surgery 293 (20) 341 (19)  Trauma/fracture 136 (9) 171 (10)  Pregnancy 5 (0.3) 4 (0.2) Notes: a Three categories of comorbidity burden based on the Charlson Comorbidity Index; normal=0 points, moderate=1–2 points, and high=3 or more points. Cancer was excluded from the comorbidity index. b Within the 3 months prior to a VTE diagnosis. Abbreviations: IQR, interquartile range; VTE, venous thromboembolism; AIDS, acquired immune deficiency syndrome. Table 2 Absolute 1-year cancer risk and standardized incidence ratios of cancer in patients with VTE and hypothyroidism (N=1481) by follow-up interval, Denmark, 1978–2013 Absolute risk 0–90 days 91–365 days 0–1 year 1+ year 1 year AR (%) (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) Hypothyroidism 3.00 (2.20–3.97) 14/5.9 2.36 (1.29–3.96) 29/16.0 1.81 (1.21–2.60) 43/21.9 1.96 (1.42–2.64) 121/104.0 1.16 (0.97–1.39) Female – 12/4.9 2.46 (1.27–4.29) 25/13.2 1.90 (1.23–2.80) 37/18.1 2.05 (1.44–2.82) 100/88.7 1.13 (0.92–1.37) Male – 2/1.0 1.93 (0.23–6.95) 4/2.8 1.41 (0.38–3.61) 6/3.9 1.55 (0.57–3.38) 21/15.4 1.37 (0.85–2.09) Age at VTE diagnosis <60 years – 0 – 6/1.2 5.17 (1.90–11.28) 6/1.6 3.85 (1.41–8.40) 25/18.8 1.33 (0.86–1.96) Age at VTE diagnosis 60–74 years – 9/1.9 4.72 (2.16–8.96) 9/5.3 1.68 (0.77–3.20) 18/7.3 2.48 (1.47–3.92) 51/46.9 1.09 (0.81–1.43) Age at VTE diagnosis ≥75 years – 5/3.6 1.38 (0.45–3.22) 14/9.5 1.47 (0.81–2.47) 19/13.1 1.45 (0.87–2.26) 45/38.3 1.18 (0.86–1.57) Comorbidity burden,a normal – 5/1.9 2.57 (0.83–5.99) 11/5.6 1.98 (0.98–3.54) 16/7.5 2.13 (1.22–3.46) 50/52.8 0.95 (0.70–1.25) Comorbidity burden, moderate – 8/2.8 2.91 (1.25–5.72) 12/7.4 1.63 (0.84–2.84) 20/10.1 1.97 (1.20–3.05) 58/40.7 1.42 (1.08–1.84) Comorbidity burden, high – 1/1.2 0.81 (0.02–4.53) 6/3.1 1.96 (0.72–4.28) 7/4.3 1.63 (0.66–3.37) 13/10.5 1.24 (0.66–2.11) Obesity − – 12/5.3 2.26 (1.17–3.96) 26/14.3 1.82 (1.19–2.67) 38/19.6 1.94 (1.37–2.66) 111/93.8 1.18 (0.97–1.42) Obesity + – 2/0.7 3.19 (0.39–11.52) 3/1.7 1.74 (0.36–5.09) 5/2.3 2.13 (0.69–4.97) 10/10.2 0.98 (0.47–1.80) Year of VTE diagnosis 1978–1993 – 1/0.8 1.29 (0.03–7.20) 6/2.2 2.75 (1.01–6.00) 7/2.9 2.37 (0.95–4.88) 33/28.4 1.16 (0.80–1.63) Year of VTE diagnosis 1994–2013 – 13/5.2 2.52 (1.34–4.31) 23/13.8 1.66 (1.05–2.50) 36/19.0 1.90 (1.33–2.63) 88/75.6 1.16 (0.93–1.43) Classic provoking factors,b overall − – 13/4.5 2.88 (1.53–4.93) 25/12.1 2.07 (1.34–3.05) 38/16.6 2.29 (1.62–3.14) 96/78.9 1.22 (0.99–1.49) Classic provoking factors, overall + – 1/1.4 0.70 (0.02–3.92) 4/3.9 1.02 (0.28–2.62) 5/5.3 0.94 (0.30–2.19) 25/2.1 1.00 (0.64–1.47)  Recent pregnancy − – 14/5.9 2.37 (1.29–3.97) 29/16.0 1.81 (1.21–2.61) 43/21.9 1.96 (1.42–2.64) 121/103.2 1.17 (0.97–1.40)  Recent pregnancy + – 0 – 0 – 0 – 0 –  Recent fracture/trauma − – 14/5.4 2.62 (1.43–4.39) 28/14.5 1.94 (1.29–2.80) 42/19.8 2.12 (1.53–2.87) 114/96.9 1.18 (0.97–1.41)  Recent fracture/trauma + – 0 – 1/1.6 0.64 (0.02–3.58) 1/2.1 0.47 (0.01–2.62) 7/7.2 0.98 (0.39–2.01)  Recent surgery − – 13/4.8 2.70 (1.44–4.62) 25/12.9 1.93 (1.25–2.85) 38/17.7 2.14 (1.52–2.94) 101/83.3 1.21 (0.99–1.47)  Recent surgery + – 1/1.1 0.89 (0.02–4.98) 4/3.1 1.30 (0.35–3.33) 5/2.4 1.19 (0.39–2.78) 20/20.7 0.96 (0.59–1.49) Notes: a Three categories of comorbidity burden based on the Charlson Comorbidity Index; normal=0 points, moderate=1–2 points, and high=3 or more points. Cancer was excluded from the comorbidity index. b Within the 3 months prior to a venous thromboembolism diagnosis. Abbreviations: AR, absolute risk; O/E, observed number/expected number; SIR, standardized incidence ratio; VTE, venous thromboembolism. Table 3 Absolute one-year cancer risk and standardized incidence ratios of cancer in patients with VTE and hyperthyroidism (N=1788), by follow-up interval, Denmark, 1978–2013 Absolute risk 0–90 days 91–365 days 0–1 year 1+ year 1-year AR (%) (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) Hyperthyroidism 3.87 (3.04–4.85) 37/7.0 5.32 (3.75–7.33) 31/18.5 1.68 (1.14–2.38) 68/25.5 2.67 (2.07–3.39) 171/135.6 1.26 (1.08–1.46) Female – 27/5.5 4.91 (3.24–7.15) 22/14.6 1.51 (0.94–2.28) 49/20.1 2.44 (1.80–3.22) 141/104.3 1.35 (1.14–1.59) Male – 10/1.5 6.85 (3.28–12.60) 9/3.9 2.31 (1.06–4.39) 19/5.4 3.55 (2.14–5.54) 30/31.3 0.96 (0.65–1.37) Age at VTE diagnosis <60 years – 2/0.5 3.99 (0.48–14.41) 2/1.5 1.33 (0.16–4.79) 4/2.0 1.99 (0.54–5.10) 38/26.9 1.42 (1.00–1.94) Age at VTE diagnosis 60–74 years – 16/2.3 6.92 (3.95–11.24) 13/6.5 1.99 (1.06–3.40) 29/8.9 3.27 (2.19–4.70) 78/63.4 1.23 (0.97–1.54) Age at VTE diagnosis ≥75 years – 19/4.1 4.59 (2.76–7.16) 16/10.4 1.53 (0.88–2.49) 35/14.6 2.40 (1.67–3.34) 55/45.4 1.21 (0.91–1.58) Comorbidity burden,a normal – 15/2.8 5.30 (2.96–8.74) 12/8.0 1.50 (0.77–2.61) 27/10.9 2.49 (1.64–3.62) 109/85.7 1.27 (1.04–1.53) Comorbidity burden, moderate – 16/3.0 5.27 (3.01–8.56) 19/7.8 2.44 (1.47–3.80) 35/10.8 3.23 (2.25–4.49) 51/42.2 1.24 (0.92–1.63) Comorbidity burden, high – 6/1.1 5.52 (2.03–12.04) 0 – 6/3.8 1.59 (0.59–3.48) 11/8.7 1.26 (0.63–2.25) Obesity − – 35/6.5 5.35 (3.73–7.44) 28/17.4 1.61 (1.07–2.33) 63/23.9 2.63 (2.02–3.37) 162/130.0 1.25 (1.06–1.45) Obesity + – 2/0.4 4.86 (0.59–17.53) 3/1.1 2.68 (0.55–7.83) 5/1.5 3.27 (1.06–7.61) 9/5.7 1.58 (0.72–3.00) Year of VTE diagnosis 1978–1993 – 1/0.9 1.07 (0.03–5.97) 5/2.6 1.95 (0.63–4.53) 6/3.5 1.71 (0.63–3.73) 41/36.4 1.13 (0.81–1.53) Year of VTE diagnosis 1994–2013 – 36/6.0 5.98 (4.19–8.28) 26/15.9 1.63 (1.07–2.39) 62/22.0 2.82 (2.17–3.62) 130/99.3 1.31 (1.09–1.56) Classic provoking factors,b overall − – 29/5.4 5.36 (3.59–7.70) 27/14.3 1.89 (1.25–2.75) 56/19.7 2.85 (2.15–3.70) 128/102.0 1.26 (1.05–1.49) Classic provoking factors, overall + – 8/1.5 5.17 (2.23–10.19) 4/4.2 0.95 (0.26–2.42) 12/5.8 2.08 (1.07–3.63) 43/33.7 1.28 (0.92–1.72)  Recent pregnancy − – 37/7.0 5.32 (3.75–7.34) 31/18.5 1.68 (1.14–2.38) 68/25.4 2.67 (2.08–3.39) 171/135.5 1.26 (1.08–1.47)  Recent pregnancy + – 0 – 0 – 0 – 0 –  Recent fracture/trauma − – 33/6.3 5.25 (3.61–7.37) 29/16.7 1.74 (1.16–2.50) 62/23.0 2.70 (2.07–3.46) 157/123.0 1.28 (1.08–1.49)  Recent fracture/trauma + – 4/0.7 6.01 (1.63–15.38) 2/1.8 1.10 (0.13–3.98) 6/2.5 2.42 (0.89–5.28) 14/12.7 1.10 (0.60–1.85)  Recent surgery − – 30/5.7 5.23 (3.53–7.47) 27/15.2 1.78 (1.17–2.58) 57/20.9 2.72 (2.06–3.53) 135/108.8 1.24 (1.04–1.47)  Recent surgery + – 7/1.2 5.74 (2.30–11.83) 4/3.3 1.21 (0.33–3.10) 11/4.5 2.43 (1.21–4.36) 36/26.8 1.34 (0.94–1.86) Notes: a Three categories of comorbidity burden based on the Charlson Comorbidity Index; normal=0 points, moderate=1–2 points, and high=3 or more points. Cancer is excluded from the comorbidity index. b Within the 3 months prior to a VTE diagnosis. Abbreviations: AR, absolute risk; O/E, observed number/expected number; SIR, standardized incidence ratio; VTE, venous thromboembolism. ==== Refs References 1 Carle A Laurberg P Pedersen IB Epidemiology of subtypes of hypothyroidism in Denmark Eur J Endocrinol 2006 154 1 21 28 16381987 2 Cooper DS Hyperthyroidism Lancet 2003 362 9382 459 468 12927435 3 Erem C Ersoz HO Karti SS Blood coagulation and fibrinolysis in patients with hyperthyroidism J Endocrinol Invest 2002 25 4 345 350 12030606 4 Stuijver DJ van Zaane B Romualdi E Brandjes DP Gerdes VE Squizzato A The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors: a systematic review and meta-analysis Thromb Haemost 2012 108 6 1077 1088 23014708 5 Dekkers OM Erzsebet Horvath-Puho E Cannegieter SC Vandenbroucke J Sorensen HT Jorgensen JO Acute cardiovascular events and all-cause mortality in patients with hyperthyroidism: population-based cohort study Eur J Endocrinol 2017 176 1 1 9 27697972 6 Debeij J Dekkers OM Asvold BO Increased levels of free thyroxine and risk of venous thrombosis in a large population-based prospective study J Thromb Haemost 2012 10 8 1539 1546 22703181 7 Kootte RS Stuijver DJ Dekkers OM The incidence of venous thromboembolism in patients with overt hyperthyroidism: a retrospective multicentre cohort study Thromb Haemost 2012 107 3 417 422 22234657 8 van Zaane B Squizzato A Huijgen R Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: a case-control study Blood 2010 115 22 4344 4349 20308594 9 Franchini M Lippi G Targher G Hyperthyroidism and venous thrombosis: a casual or causal association? A systematic literature review Clin Appl Thromb Hemost 2011 17 4 387 392 20308227 10 Lin HC Yang LY Kang JH Increased risk of pulmonary embolism among patients with hyperthyroidism: a 5-year follow-up study J Thromb Haemost 2010 8 10 2176 2181 20738759 11 Franchini M Hemostatic changes in thyroid diseases: haemostasis and thrombosis Hematology 2006 11 3 203 208 17325963 12 Danescu LG Badshah A Danescu SC Venous thromboembolism in patients hospitalized with thyroid dysfunction Clin Appl Thromb Hemost 2009 15 6 676 680 19671566 13 Goldhaber SZ Bounameaux H Pulmonary embolism and deep vein thrombosis Lancet 2012 379 9828 1835 1846 22494827 14 Sorensen HT Svaerke C Farkas DK Superficial and deep venous thrombosis, pulmonary embolism and subsequent risk of cancer Eur J Cancer 2012 48 4 586 593 22129887 15 Iodice S Gandini S Lohr M Lowenfels AB Maisonneuve P Venous thromboembolic events and organ-specific occult cancers: a review and meta-analysis J Thromb Haemost 2008 6 5 781 788 18284604 16 Murchison JT Wylie L Stockton DL Excess risk of cancer in patients with primary venous thromboembolism: a national, population-based cohort study Br J Cancer 2004 91 1 92 95 15226761 17 Baron JA Gridley G Weiderpass E Nyren O Linet M Venous thromboembolism and cancer Lancet 1998 351 9109 1077 1080 9660575 18 Sorensen HT Mellemkjaer L Steffensen FH Olsen JH Nielsen GL The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism N Engl J Med 1998 338 17 1169 1173 9554856 19 Prandoni P Lensing AW Buller HR Deep-vein thrombosis and the incidence of subsequent symptomatic cancer N Engl J Med 1992 327 16 1128 1133 1528208 20 Schmidt M Pedersen L Sorensen HT The Danish Civil Registration System as a tool in epidemiology Eur J Epidemiol 2014 29 8 541 549 24965263 21 Lynge E Sandegaard JL Rebolj M The Danish National Patient Register Scand J Public Health 2011 39 7 Suppl 30 33 21775347 22 Sundboll J Adelborg K Munch T Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study BMJ Open 2016 6 11 e012832 23 Severinsen MT Kristensen SR Overvad K Dethlefsen C Tjonneland A Johnsen SP Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution J Clin Epidemiol 2010 63 2 223 228 19595569 24 Gjerstorff ML The Danish Cancer Registry Scand J Public Health 2011 39 7 Suppl 42 45 21775350 25 Charlson ME Pompei P Ales KL MacKenzie CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation J Chronic Dis 1987 40 5 373 383 3558716 26 Ording AG Sorensen HT Concepts of comorbidities, multiple morbidities, complications, and their clinical epidemiologic analogs Clin Epidemiol 2013 5 199 203 23861599 27 Kim HT Cumulative incidence in competing risks data and competing risks regression analysis Clin Cancer Res 2007 13 2 Pt 1 559 565 17255278 28 Breslow NE Day NE Statistical methods in cancer research. Volume II – The design and analysis of cohort studies IARC Sci Publ 1987 82 69 72 29 Kirkwood B Sterne J Standardization Goodgame F Medical Statistics 2nd ed Oxford Blackwell Publishing 2003 263 271 30 Altman DG Confidence intervals for the number needed to treat BMJ 1998 317 7168 1309 1312 9804726 31 Hellevik AI Asvold BO Bjoro T Romundstad PR Nilsen TI Vatten LJ Thyroid function and cancer risk: a prospective population study Cancer Epidemiol Biomarkers Prev 2009 18 2 570 574 19155436 32 Sorensen HT Mellemkjaer L Olsen JH Baron JA Prognosis of cancers associated with venous thromboembolism N Engl J Med 2000 343 25 1846 1850 11117976 33 Piccioli A Lensing AW Prins MH SOMIT Investigators Group Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial J Thromb Haemost 2004 2 6 884 889 15140122 34 Van Doormaal FF Terpstra W Van Der Griend R Is extensive screening for cancer in idiopathic venous thromboembolism warranted? J Thromb Haemost 2011 9 1 79 84 20946181 35 Robertson L Yeoh SE Stansby G Agarwal R Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in patients with unprovoked VTE Cochrane Database Syst Rev 2015 3 CD010837 36 Carrier M Lazo-Langner A Shivakumar S SOME Investigators Screening for occult cancer in unprovoked venous thromboembolism N Engl J Med 2015 373 8 697 704 26095467 37 Prins MH Lensing AW Hirsh J Idiopathic deep venous thrombosis. Is a search for malignant disease justified? Arch Intern Med 1994 154 12 1310 1312 8002682 38 Shaboodien R Stansby G Hunt BJ Agarwal R Unprovoked venous thromboembolism: assess for cancer Lancet Oncol 2012 13 10 973 974 23026822 39 Vestergaard P Mosekilde L Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients Thyroid 2002 12 5 411 419 12097203 40 Storm HH Michelsen EV Clemmensen IH Pihl J The Danish Cancer Registry-history, content, quality and use Dan Med Bull 1997 44 5 535 539 9408738 41 Thygesen SK Christiansen CF Christensen S Lash TL Sorensen HT The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients BMC Med Res Methodol 2011 11 83 21619668