|Year : 2019 | Volume
| Issue : 2 | Page : 74-80
Association between aortic aneurysm and ulcerative colitis: A nationwide taiwanese retrospective cohort study
Chih-Jen Yang1, Chi-Hsiang Chung2, Sy-Jou Chen3, Wen-I Liao1, Yi-Da Tsai1, Jen-Chun Wang4, Wu-Chien Chien5
1 Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center; School of Public Health, National Defense Medical Center; Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
3 Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center; College of Public Health and Nutrition, Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan
4 Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
5 Department of Medical Research, Tri-Service General Hospital; School of Public Health, National Defense Medical Center, Taipei, Taiwan
|Date of Submission||10-Jul-2018|
|Date of Decision||20-Aug-2018|
|Date of Acceptance||17-Sep-2018|
|Date of Web Publication||28-Mar-2019|
Dr. Jen-Chun Wang
Department of Emergency Medicine, National Defense Medical Center, Tri-Service General Hospital, No. 325, Sec. 2, Cheng-Kung Road, Neihu Dist., Taipei 11490
Dr. Wu-Chien Chien
Department of Medical Research, National Defense Medical Center, Tri-Service General Hospital, 7115R, No. 325, Sec. 2, Cheng-Kung Road, Neihu Dist., Taipei 11490
Source of Support: None, Conflict of Interest: None
Background: Ulcerative colitis (UC) is an immune-mediated inflammatory disease that is associated with an increased incidence of cardiovascular events. Several inflammatory mechanisms associated with the pathogenesis of UC are involved in the initiation and progression of aortic aneurysms (AAs). We aimed to evaluate whether patients with UC have an increased risk of AA. Methods: We conducted a retrospective cohort study using data extracted from Taiwan's National Health Insurance Research Database. All medical conditions for each case and control subject were categorized using the International Classification of Diseases, 9th Revision. Hazard ratios and 95% confidence intervals for associations between UC and AA were estimated using the Cox regression adjusted for comorbidities. Results: Our analyses included 7256 UC patients and propensity score-matched controls. Compared to the controls, UC patients exhibited a significantly increased risk of developing an AA (adjusted odds ratio = 3.154, P < 0.001). Conclusion: UC patients have an increased risk of developing an AA, and healthcare professionals should be aware of this risk when treating UC patients. Aortic surveillance may be required for UC patients.
Keywords: Ulcerative colitis, aortic aneurysm, inflammatory bowel disease
|How to cite this article:|
Yang CJ, Chung CH, Chen SJ, Liao WI, Tsai YD, Wang JC, Chien WC. Association between aortic aneurysm and ulcerative colitis: A nationwide taiwanese retrospective cohort study. J Med Sci 2019;39:74-80
|How to cite this URL:|
Yang CJ, Chung CH, Chen SJ, Liao WI, Tsai YD, Wang JC, Chien WC. Association between aortic aneurysm and ulcerative colitis: A nationwide taiwanese retrospective cohort study. J Med Sci [serial online] 2019 [cited 2021 Jan 24];39:74-80. Available from: https://www.jmedscindmc.com/text.asp?2019/39/2/74/243817
| Introduction|| |
Ulcerative colitis (UC) is a chronic, nonspecific inflammatory disease of the colonic mucosa with an unclear etiology. Pathologically, UC is characterized by ulceration in the mucosal and submucosal areas, and degradation of the extracellular matrix is one of the major events that occur during this process. The incidence rates of UC worldwide vary between 0.5 and 24.5 per 100,000 inhabitants. Between 2000 and 2010, the overall incidence rates of UC were 0.208 and 0.838 per 100,000 person-years in Taiwan. UC can affect patients at any age; however, its onset typically follows a bimodal pattern with one peak at 15–25 years and a smaller peak at 55–65 years. UC is slightly more common in women than in men. Aortic aneurysms (AAs) are often diagnosed accidentally. Enlarged aneurysms can result in rupture and are a common cause of sudden death. The incidence of AA ranges from six cases per 100,000 persons to 9.1 per 100,000 among women and 16.3 per 100,000 among men annually based on studies performed in England and Sweden., Among the Asian population, the average annual incidence of AA is 5.6 per 100,000 persons in Taiwan, and the prevalence is 19.9 per 100,000 persons, with a predominance noted among men 50–54 years of age (27.3 per 100,000 persons per year).
Previous studies have demonstrated that AA is more prevalent in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) than in the general population. Several studies have suggested that UC is associated with an increased incidence of cardiovascular events, including arterial stiffening, atherosclerosis, and ischemic heart disease due to systemic inflammation, which leads to oxidative stress and phenotypic changes in smooth muscle cells.,,
We hypothesized that UC patients may have an increased risk of AA due to UC-related cardiovascular risks and shared molecular mechanisms. AA has been reported to be a rare complication of UC., However, the association between UC and AA has not been thoroughly evaluated in large-scale studies. Therefore, we aimed to determine whether UC patients exhibit an increased risk of AA using a national healthcare insurance claim database.
| Methods|| |
The national health insurance program was launched in Taiwan in 1995, and 97% of medical providers and more than 99% of the entire population (approximately 23 million beneficiaries) are included in it. The national health insurance research database (NHIRD) is used for national population-based retrospective cohort studies. A subgroup database of the NHIRD, the longitudinal health insurance database (LHID), which provides information on medical service utilization using a randomly selected sample of one million people receiving benefits (representing approximately 5% of Taiwan's population), was used to study the association between AA and UC. The accuracy of the diagnoses in the NHIRD, particularly the diagnoses of major diseases (e.g. acute coronary syndrome and stroke), has previously been confirmed., The LHID consists of “deidentified” secondary data. International classification of diseases, 9th revision, clinical modification (ICD-9-CM) diagnostic and procedure codes (up to five each), genders, ages, patient identification numbers, dates of admission and discharge, and outcomes are coded. In addition, information regarding the medical institutions that served the patients was obtained. We used encoded personal identification to prevent ethical violations related to individual information. Our study followed the Declaration of Helsinki and other relevant guidelines. The Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, permitted this study (TSGH IRB No. 2-105-05-082).
This study had a retrospective, matched cohort design. Using the LHID, we selected adult patients aged ≥20 years who were newly diagnosed with UC (ICD-9-CM 710.2) and who were followed up between 2000 and 2013. We excluded patients who were diagnosed with AA (ICD-9-CM 441.0-441.9), Turner syndrome (ICD-9-CM 758.6), aortic coarctation (ICD-9-CM 747.10), a bicuspid aortic valve (ICD-9-CM 746.4), Marfan syndrome (ICD-9-CM 759.82), and Ehlers–Danlos syndrome (ICD-9-CM 756.83). Patients were monitored for <6 months. The date of UC diagnosis was used as the index date. Control candidate sampling comparisons were selected from individuals in the LHID with no history of UC. The patient and control cohorts were selected by 1:1 matching according to the following baseline variables: age; sex; comorbidities including hypertension (ICD-9-CM 401-405), diabetes mellitus (DM) (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272.0-272.4), Behcet's disease (ICD-9-CM 136.1), giant cell arteritis (ICD-9-CM 446.5), RA and other inflammatory polyarthropathies (ICD-9-CM 714), relapsing polychondritis (ICD-9-CM 733.99), and Takayasu's arteritis (ICD-9-CM 446.7); chronic obstructive pulmonary disease (COPD) (ICD-9-CM 490-496); and medication history including use of a β-blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, diuretic, steroid, or other immunosuppressant drug. The index dates for control patients were the same as the corresponding dates for patients with AA. The study outcome was a diagnosis of an AA during the 14-year follow-up period. AAs were identified using ICD-9 codes. The end point of the follow-up period was December 31, 2013, the time at which an AA event occurred, or when the patient died.
All data analyses were conducted using SPSS software version 22 (SPSS Inc., Chicago, IL, USA). Chi-square and t-tests were used to evaluate the distributions of categorical and continuous variables, respectively. The primary goal of the study was to determine whether UC patients exhibit an increased risk of developing an AA. The association between the outcomes (prognoses) and clinical characteristics was investigated using the Cox regression. The results are presented as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). A two-tailed P < 0.05 was considered to indicate the statistical significance.
| Results|| |
A flow diagram of our patient enrollment scheme is depicted in [Figure 1]. A total of 7256 patients diagnosed with UC were identified in the NHIRD, which contains a total of 989,753 individuals. An additional 7256 age-matched, gender-matched, comorbidity-matched, and medication-matched patients were designated controls. As shown in [Table 1], no significant differences in gender; age; comorbidities including DM, hypertension, hyperlipidemia, cancer, congestive heart failure, RA, SLE, chronic kidney disease, and COPD; or medication use were noted between the two groups after matching. [Table 2] presents the incidences of AA during the 10-year follow-up period. At the end of the follow-up period, UC patients exhibited a significantly increased incidence of AA (0.76% vs. 0.58%, P = 0.045). Patients with UC exhibited a significantly increased cumulative risk of developing an AA in subsequent years compared to patients without UC [log-rank test <0.001, [Figure 2]. Regarding the Cox regression analysis, independent of the effects of gender, age, comorbidities and medication use, and patients with UC also exhibited a significantly increased risk of developing an AA compared to patients without UC [adjusted HR = 3.154, 95% CI = 2.073–4.798, P < 0.001, [Table 3] and [Supplemental Table 1].
|Table 2: Incidences of aortic aneurysm and dissection and other characteristics during the 10-year follow-up period|
Click here to view
|Figure 2: Kaplan–Meier curve of the cumulative risk of aortic aneurysm due to ulcerative colitis|
Click here to view
|Table 3: Factors of aortic aneurysm and dissection by using conditional Cox logistic regression|
Click here to view
| Discussion|| |
Our cohort study revealed the novel finding that UC is associated with an increased incidence of AA development compared to a control cohort. After adjusting for comorbidities and medications used, we found that the HR for subsequent AAs among UC patients was 3.154 times that of the control subjects.
Patients with rheumatologic diseases have an increased risk of cardiovascular disease. Therefore, the regular follow-up care for cardiovascular disease has been suggested for these patients. Although the prevalence of traditional cardiovascular risk factors, including hypertension, DM, hyperlipidemia, and obesity, is lower in UC patients than in the general population, UC patients have an increased risk of venous thromboembolism, arterial stiffness, coronary artery disease, and stroke.
The pathophysiological association between UC and AA remains unclear. Several molecular mechanisms, including inflammatory cytokines (interleukin [IL]-1 and tumor necrosis factor [TNF]-α) and matrix metalloproteinase (MMP) activation, are associated with the pathogenesis of UC., These molecular mechanisms also actively participate in the initiation and progression of AAs. Systemic inflammation in UC patients elevates levels of inflammatory cytokines, such as TNF-α and IL-1, which might trigger phenotypic changes in vascular smooth muscle cells and further lead to the expression of osteoblast markers, resulting in medial calcification, and reduced vessel elasticity. Calcification and bony metaplasia are common pathological findings for AAs. Many studies have revealed aberrantly increased expression of MMPs in intestinal biopsy tissue from patients with active UC including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13.,, MMP-9 is among the most abundantly expressed MMPs in the bowel mucosa of active UC patients, and it correlates with disease activity. However, MMPs are responsible for vessel-wall remodeling, and MMP-2 and MMP-9 play an important role in the degradation of elastin and collagen in the aortic wall in AA. Defects in intestinal epithelial barrier function are a characteristic feature of UC that can facilitate the translocation of endotoxins and bacterial lipopolysaccharides produced by intestinal microflora into the circulatory system, and the resulting activation of inflammatory responses can lead to atherosclerosis. Gut microbiota has been recognized as one of the essential factors for the development of IBD. Gut microbiota and intestinal epithelial barrier function are altered in patients with IBD. However, many gut microbes have been identified within atherosclerotic arteries and nonatherosclerotic AAs, which implie that the gut microbiota might contribute to the inflammatory response that leads to aneurysm formation.
Corticosteroids may be used to treat symptoms of UC. Prolonged or high-dose corticosteroid treatment likely causes disintegration of connective tissue of the media and possibly primary aortic wall involvement and/or vascular damage in patients with autoimmune disorders, which can result in AA enlargement., In this study, UC patients and control subjects were matched for steroid use. Therefore, the effect of corticosteroids was controlled.
The main strength of our study is its population-based database design. We accounted for several aneurysm-related confounding factors. Although we adjusted the results extensively using the multivariate logistic regression models, there were several limitations and unmeasured confounders in our study. First, Asia is traditionally considered an area with a relatively low incidence of IBD, ranging from 0.54 to 3.44 per 100,000 individuals with a UC predilection in Asia. Nevertheless, the incidence of UC is rapidly increasing as a Westernized lifestyle becomes more popular. Second, the NHIRD registry cannot provide detailed information on laboratory results, family histories, and health-related lifestyle factors, such as tobacco use, that can increase the risk of AA. These were potential confounding factors in this study. In this study, we considered the COPD incidence as a proxy variable for tobacco use to eliminate its potential confounding effect. Third, most AAs are asymptomatic unless they dissect or rupture and are therefore diagnosed incidentally when the abdomen is imaged for other indications. Abdominal pain is one of the most common problems for people with UC. Patients with UC are more likely to undergo abdominal imaging than are patients without UC, facilitating incidental identification of AAs but possible inducing selection bias. Although our study identified an association between UC and AA, the cohort study design did not enable determination of a cause-effect relationship. Further prospective follow-up studies, mechanistic studies, and animal experiments should be performed.
| Conclusion|| |
UC patients have an increased risk of developing an AA, and healthcare professionals should be aware of this risk when treating UC patients. AA is a silent disease; however, it is life-threatening when the aneurysm ruptures. To reduce the incidence of AA rupture, the early detection of AAs in UC patients should be improved. Developing AA prevention strategies might be helpful in limiting the incidence of AA in selected high-risk groups.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al.
Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42.
Kuo CJ, Yu KH, See LC, Chiu CT, Su MY, Hsu CM, et al.
The trend of inflammatory bowel diseases in Taiwan: A population-based study. Dig Dis Sci 2015;60:2454-62.
Mavragani CP, Moutsopoulos HM. The geoepidemiology of Sjögren's syndrome. Autoimmun Rev 2010;9:A305-10.
Howard DP, Banerjee A, Fairhead JF, Perkins J, Silver LE, Rothwell PM, et al.
Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the oxford vascular study. Circulation 2013;127:2031-7.
Olsson C, Thelin S, Ståhle E, Ekbom A, Granath F. Thoracic aortic aneurysm and dissection: Increasing prevalence and improved outcomes reported in a nationwide population-based study of more than 14,000 cases from 1987 to 2002. Circulation 2006;114:2611-8.
Yeh TY, Chen CY, Huang JW, Chiu CC, Lai WT, Huang YB. Epidemiology and medication utilization pattern of aortic dissection in Taiwan: A population-based study. Medicine (Baltimore) 2015;94:e1522.
Shovman O, Tiosano S, Comaneshter D, Cohen AD, Amital H, Sherf M. Aortic aneurysm associated with rheumatoid arthritis: A population-based cross-sectional study. Clin Rheumatol 2016;35:2657-61.
Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol 2011;106:741-7.
Bernstein CN, Wajda A, Blanchard JF. The incidence of arterial thromboembolic diseases in inflammatory bowel disease: A population-based study. Clin Gastroenterol Hepatol 2008;6:41-5.
Rungoe C, Basit S, Ranthe MF, Wohlfahrt J, Langholz E, Jess T. Risk of ischaemic heart disease in patients with inflammatory bowel disease: A nationwide Danish cohort study. Gut 2013;62:689-94.
Karakurt C, Koçak G, Selimoǧlu A, Ozen M. Aortic aneurysm: A rare complication of ulcerative colitis. Anadolu Kardiyol Derg 2007;7:461-2.
Kashima K, Kawasaki D, Yotsumoto G, Hatake S, Yamashita E, Nagayoshi S, et al.
Rapid progression of aortic regurgitation with thoracic aortic aneurysm due to Takayasu arteritis associated with ulcerative colitis. Intern Med 2010;49:1007-11.
Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the national health insurance research database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011;20:236-42.
Mao CT, Tsai ML, Wang CY, Wen MS, Hsieh IC, Hung MJ, et al.
Outcomes and characteristics of patients undergoing percutaneous angioplasty followed by below-knee or above-knee amputation for peripheral artery disease. PLoS One 2014;9:e111130.
Prasad M, Hermann J, Gabriel SE, Weyand CM, Mulvagh S, Mankad R, et al.
Cardiorheumatology: Cardiac involvement in systemic rheumatic disease. Nat Rev Cardiol 2015;12:168-76.
Nguyen GC, Bernstein CN, Bitton A, Chan AK, Griffiths AM, Leontiadis GI, et al.
Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology 2014;146:835-48.e6.
Zanoli L, Rastelli S, Inserra G, Lentini P, Valvo E, Calcagno E, et al.
Increased arterial stiffness in inflammatory bowel diseases is dependent upon inflammation and reduced by immunomodulatory drugs. Atherosclerosis 2014;234:346-51.
Keller JJ, Wang J, Huang YL, Chou CC, Wang LH, Hsu JL, et al.
Increased risk of stroke among patients with ulcerative colitis: A population-based matched cohort study. Int J Colorectal Dis 2014;29:805-12.
Fonseca-Camarillo G, Yamamoto-Furusho JK. Immunoregulatory pathways involved in inflammatory bowel disease. Inflamm Bowel Dis 2015;21:2188-93.
O'Shea NR, Smith AM. Matrix metalloproteases role in bowel inflammation and inflammatory bowel disease: An up to date review. Inflamm Bowel Dis 2014;20:2379-93.
Floege J, Ketteler M. Vascular calcification in patients with end-stage renal disease. Nephrol Dial Transplant 2004;19 Suppl 5:V59-66.
von Lampe B, Barthel B, Coupland SE, Riecken EO, Rosewicz S. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 2000;47:63-73.
Jimbo K, Ohtsuka Y, Kojima Y, Hosoi K, Ohbayashi N, Ikuse T, et al.
Increased expression of CXCR3 axis components and matrix metalloproteinase in pediatric inflammatory bowel disease patients. Pediatr Int 2014;56:873-83.
Vaalamo M, Karjalainen-Lindsberg ML, Puolakkainen P, Kere J, Saarialho-Kere U. Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am J Pathol 1998;152:1005-14.
Dale MA, Suh MK, Zhao S, Meisinger T, Gu L, Swier VJ, et al.
Background differences in baseline and stimulated MMP levels influence abdominal aortic aneurysm susceptibility. Atherosclerosis 2015;243:621-9.
Wiesner P, Choi SH, Almazan F, Benner C, Huang W, Diehl CJ, et al.
Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: Possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia. Circ Res 2010;107:56-65.
Sheehan D, Moran C, Shanahan F. The microbiota in inflammatory bowel disease. J Gastroenterol 2015;50:495-507.
Marques da Silva R, Lingaas PS, Geiran O, Tronstad L, Olsen I. Multiple bacteria in aortic aneurysms. J Vasc Surg 2003;38:1384-9.
Amălinei C, Căruntu ID, Giuşcă SE, Bălan RA. Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol 2010;51:215-28.
Sholter DE, Armstrong PW. Adverse effects of corticosteroids on the cardiovascular system. Can J Cardiol 2000;16:505-11.
Ng SC, Tang W, Ching JY, Wong M, Chow CM, Hui AJ, et al.
Incidence and phenotype of inflammatory bowel disease based on results from the Asia-Pacific Crohn's and colitis epidemiology study. Gastroenterology 2013;145:158-65.e2.
Yu TM, Chuang YW, Yu MC, Chen CH, Yang CK, Huang ST, et al
. Risk of cancer in patients with polycystic kidney disease: A propensity-score matched analysis of a nationwide, population-based cohort study. Lancet Oncol 2016;17:1419-25.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]