Original article
Cohort study of corticosteroid use and risk of hospital admission for diverticular disease F. Hjern1 , M. W. Mahmood1 , M. Abraham-Nordling3 , A. Wolk2 and N. Håkansson2 1 Division of Surgery, Department of Clinical Sciences, Danderyd University Hospital, 2 Division of Nutritional Epidemiology, National Institute of Environmental Medicine, and 3 Institution of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden Correspondence to: Professor F. Hjern, Department of Surgery, Danderyd University Hospital, 182 88 Stockholm, Sweden (e-mail: [email protected])
Background: Medication has been suggested as a potential risk factor for diverticular disease. The objec-
tive of this study was to investigate the association between the intake of corticosteroids, indometacin or aspirin and diverticular disease. Method: This was a prospective population-based cohort study of middle-aged women in the Swedish Mammography Cohort. Use of corticosteroids (oral or inhaled), indometacin or aspirin in 1997 was determined from questionnaires. Cases of diverticular disease were identified from the Swedish national registers until the end of 2010. The relative risk (RR) of diverticular disease requiring hospital admission according to the use of medication was estimated using Cox proportional hazards models, adjusted for age, body mass index, physical activity, fibre intake, diabetes, hypertension, alcohol, smoking and education. Results: A total of 36 586 middle-aged women in the Swedish Mammography Cohort were included, of whom 674 (1⋅8 per cent) were hospitalized with diverticular disease at least once. Some 7⋅2 per cent of women reported intake of oral corticosteroids and 8⋅5 per cent use of inhaled corticosteroids. In multivariable analysis, women who reported oral corticosteroid intake had a 37 per cent (RR 1⋅37, 95 per cent c.i. 1⋅06 to 1⋅78; P = 0⋅012) increased risk of diverticular disease compared with those who reported no intake at all. Use of inhaled corticosteroids was associated with an even more pronounced increase in risk of 71 per cent (RR 1⋅71, 1⋅36 to 2⋅14; P < 0⋅001). There was a significant dose–response relationship, with the risk increasing with longer duration of inhaled corticosteroids (P for trend < 0⋅001). Use of indometacin (2⋅5 per cent of women) or aspirin (44⋅2 per cent) did not influence the risk. Conclusion: There was a significant relationship between corticosteroids (especially inhaled) and diverticular disease requiring hospital admission. Presented to the Annual Meeting of the European Society of Coloproctology, Vienna, Austria, September 2012; published in abstract form as Colorectal Dis 2012; 14(Suppl 2): 69–76 Paper accepted 29 September 2014 Published online 12 November 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9686
Introduction
Colonic diverticular disease is one of the most common gastrointestinal diseases. Inflammation is the most frequent manifestation, with perforation and peritonitis in the most severe cases1 – 3 . Painter and Burkitt4 suggested that a low content of dietary fibre is an important component in the development of the disease, which Aldoori and colleagues5 have confirmed. Low levels of physical activity, obesity and smoking are other risk factors that increase the incidence6 – 11 . Recent findings12,13 suggest that genetic factors may also contribute. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Medications can have an impact on the development of gastrointestinal disease; aspirin, for example, increases the risk of peptic ulcer disease. Oral corticosteroids have been reported to increase the risk of perforation in diverticular disease14 – 16 . Corticosteroids alter responses to inflammation and infection, and their chronic use reduces collagen turnover and may weaken the colon wall14,17 . Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin have also been associated with acute diverticulitis and diverticular bleeding owing to altered intestinal permeability caused by decreased prostaglandin synthesis15,18,19 . The aim of the present study was to BJS 2015; 102: 119–124
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Table 1
F. Hjern, M. W. Mahmood, M. Abraham-Nordling, A. Wolk and N. Håkansson
Baseline characteristics by intake of oral and inhaled corticosteroids in the Swedish Mammography Cohort, 1997 Oral corticosteroids
Total person-years Mean person-years Mean age (years) Current smoker (%) Mean intake of dietary fibre (g/day) Diabetes (%) Hypertension (%) Use of aspirin Use of indometacin Body mass index (kg/m2 ) Mean physical activity (min/day) Mean alcohol consumption (g/day) University-level education (%)
Inhaled corticosteroids
Non-use (n = 22 666)
Ever use (n = 2647)
Non-use (n = 26 314)
Ever use (n = 3099)
280 364 12⋅4 61⋅5 23⋅2 22⋅2 4⋅1 21⋅4 46⋅6 2⋅2 25⋅0 57⋅3 6⋅1 18⋅9
30 829 11⋅6 61⋅5 25⋅3 22⋅0 4⋅3 23⋅9 50⋅3 9⋅2 25⋅2 51⋅7 6⋅1 20⋅1
325 573 12⋅4 61⋅3 22⋅6 22⋅2 3⋅8 20⋅6 44⋅3 2⋅3 25⋅0 57⋅2 6⋅1 19⋅1
37 041 11⋅6 61⋅3 22⋅6 22⋅2 5⋅1 23⋅8 46⋅1 4⋅2 25⋅6 52⋅1 6⋅2 19⋅8
All mean values except age were standardized with respect to the age distribution in the study population.
determine whether the intake of oral/inhaled corticosteroids, indometacin or aspirin alters the risk of diverticular disease requiring hospital admission in a population-based prospective cohort.
Methods
Ethical approval was granted by the Regional Ethical Review Board at Karolinska Institute (Stockholm, Sweden). The study is reported according to the criteria set out in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist20 .
Assessment of medication intake Information on the use of oral corticosteroids was based on the question: ‘Have you used oral corticosteroids (yes/no)?’. If ‘yes’, the subject was ask to specify the level of exposure: ‘How many episodes?’. Information on the use of inhaled corticosteroids was based on the question: ‘Have you used inhaled corticosteroids?’. If ‘yes, presently’, the subject answered the question: ‘For how many years?’. Information on the use of aspirin and indometacin was based on the question: ‘Have you used this drug (yes/no)?’. If ‘yes’, further questions were: ‘How many pills/week and for how many years?’.
Follow-up and ascertainment of hospital admission Swedish Mammography Cohort The Swedish Mammography Cohort is a population-based prospective cohort of 66 651 women from central Sweden recruited between 1987 and 1990. Details of the cohort have been described previously21 . All women born during the years 1914–1948 were invited by mail to participate in a mammography screening programme, and to complete a questionnaire regarding diet, weight, height, parity and educational level. Answers were obtained from 73⋅8 per cent. In 1997, a follow-up questionnaire was sent to women who were still alive and living within the study area. This questionnaire included additional questions concerning diet, smoking status, alcohol use, use of vitamin supplements, physical activity, medication, hypertension and diabetes. The 1997 questionnaire was used as baseline for the present analysis (Table 1). © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
All women in the cohort with diverticular disease were identified through linkage of individual records to the National Patient Register and the Swedish Death Register. Dichotomized outcome variables (at least once/never) were obtained. The National Patient Register covers more than 99 per cent of all hospital discharges in Sweden and has been shown to be valid for most diagnoses22 . Outcome variables were defined in accordance with the World Health Organization ICD-10; diverticular disease was defined by a primary diagnosis of K572 (diverticular disease of the large bowel with abscess and/or perforation), K573 (diverticular disease of the large bowel without abscess and/or perforation), K574 (diverticular disease of the small and large bowel with abscess and/or perforation), K575 (diverticular disease of the small and large bowel without abscess and/or perforation), K578 (diverticular disease of the bowel, with perforation and/or abscess) and K579 (diverticular disease of the bowel, without www.bjs.co.uk
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perforation and/or abscess). Using restricted coding, diverticular disease with perforation and/or abscess was identified by a primary diagnosis of K572, K574 and K578. Incident cases of symptomatic diverticular disease in the cohort between 15 September 1997 and 31 December 2010 were identified. Data on cause and date of death were ascertained from the Swedish Death Registry and the Swedish Population Registry.
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Original SMC cohort recruited 1987–1990 Women born 1914–1948 Previous cancer excluded n = 61 433 Dead or moved out of study area n = 5403 Extended questionnaire 1997 (baseline in present study) n = 56 030
Statistical analysis Each woman contributed follow-up time from entry into the cohort to the date of a diverticular disease diagnosis, date of death from any cause or 31 December 2010, whichever occurred first. The risk of diverticular disease was examined in relation to the intake of corticosteroids (inhaled or oral), indometacin or aspirin. Regarding factors for which adjustment was made in the multivariable model, an extra level for missing values for each specific variable was used so that an individual would not be excluded from the analyses. After confirming that proportional hazards assumptions were satisfied (by means of Kaplan–Meier curves), relative risks (RRs) with 95 per cent c.i. were estimated by means of Cox proportional hazards regression using the PHREG procedure in SAS® version 9.1 (SAS Institute, Cary, North Carolina, USA)23 . Multivariable analyses were adjusted for age (5-year age groups), intake of dietary fibre (g/day divided into quartiles), diabetes (yes/no), hypertension (yes/no), body mass index (BMI), physical activity, alcohol, smoking and educational level. All P values are two-sided. P < 0⋅050 was considered statistically significant for all analyses. Results
After excluding patients with an erroneous national registration number or a previous diagnosis of cancer, the Swedish Mammography Cohort comprised 61 433 women at baseline in 1987–1990. In all, 39 277 (70⋅0 per cent) of 56 030 women living in the study area completed the follow-up questionnaire in 1997; 219 were too sick to fill in the questionnaire, 548 declined to answer and 16 036 did not respond (Fig. 1). Patients with inflammatory bowel disease or previous diverticular disease were excluded, leaving a final study cohort of 36 586 women at the start of follow-up. During follow-up, 674 patients (1⋅8 per cent of the women in the cohort) required hospital admission at least once owing to symptomatic diverticular disease. Based on restricted coding, 112 (0⋅3 per cent of the total) had perforation and/or an abscess. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Non-responders n = 16 803
Responders (70·0%) n = 39 227 Excluded n = 2641 Erroneous registration number n = 249 IBD n = 210 Cancer n = 1717 Previous diverticular disease n = 465 Final cohort n = 36 586 Fig. 1
Study flow chart. IBD, inflammatory bowel disease
Corticosteroids Some 7⋅2 per cent of women reported intake of oral corticosteroids at least once. In multivariable analysis, these women had a 37 per cent (RR 1⋅37, 95 per cent c.i. 1⋅06 to 1⋅78; P = 0⋅012) increased risk of disease compared with those who had never used corticosteroids (Table 2). To examine the association between the amount of exposure to corticosteroids, the data were stratified by number of episodes (1–6, 7 or more); the association was found to be weak (Table 3). Some 8⋅5 per cent of women in the cohort reported the use of inhaled corticosteroids and these patients had a significantly increased risk of disease (RR 1⋅71, 1⋅36 to 2⋅14; P < 0⋅001) (Table 2). To examine the association between duration of exposure to inhaled corticosteroids, the data were stratified by duration of medication intake (less than 10, 11–20 and 21 or more years). There was a significant dose–response relationship, with the risk increasing with duration of inhaled corticosteroid intake (P for trend < 0⋅001) (Table 3). Some 112 women had perforation and/or abscess, of whom ten had used oral steroids and 13 inhaled steroids. Oral and inhaled steroid intake was associated with a slightly, but not significantly, increased risk: RR 1⋅13 (95 www.bjs.co.uk
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F. Hjern, M. W. Mahmood, M. Abraham-Nordling, A. Wolk and N. Håkansson
Age-adjusted and multivariable relative risks for symptomatic diverticular disease in the Swedish Mammography Cohort, 1997–2010, by intake of inhaled and oral corticosteroids
Table 2
Relative risk
Oral corticosteroids No Yes Unknown Inhaled corticosteroids No Yes Unknown
No. in cohort
No. with diverticular disease
Age-adjusted
Multivariable*
22 666 2647 11 273
409 67 198
1⋅00 (reference) 1⋅42 (1⋅09, 1⋅84)
1⋅00 (reference) 1⋅37 (1⋅06, 1⋅78)
26 314 3099 7173
444 91 139
1⋅00 (reference) 1⋅79 (1⋅43, 2⋅25)
1⋅00 (reference) 1⋅71 (1⋅36, 2⋅14)
Values in parentheses are 95 per cent confidence intervals. *Cox proportional hazards regression analyses adjusted for age, intake of dietary fibre, body mass index, diagnosis of diabetes and hypertension, use of aspirin and indometacin, alcohol consumption, smoking status, physical activity and educational level.
Age-adjusted and multivariable relative risks of hospital admission for diverticular disease in the Swedish Mammography Cohort, 1997–2010, in relation to level of exposure to oral and inhaled corticosteroids
Table 3
Relative risk Corticosteroid use Oral intake (episodes) None 1–6 ≥7 Inhaled intake (years) None 1–10 11–20 ≥ 21
No. in cohort
No. with diverticular disease
Age-adjusted
Multivariable*
22 666 1651 237
409 37 6
1⋅00 (reference) 1⋅25 (0⋅89, 1⋅75) 1⋅47 (0⋅66, 3⋅28)
1⋅00 (reference) 1⋅19 (0⋅85, 1⋅66) 1⋅40 (0⋅62, 3⋅14)
26 314 1785 271 87
444 44 9 8
1⋅00 (reference) 1⋅51 (1⋅11, 2⋅05) 2⋅06 (1⋅06, 3⋅98) 6⋅09 (3⋅02, 12⋅29)
1⋅00 (reference) 1⋅44 (1⋅06, 1⋅97)† 1⋅95 (1⋅01, 3⋅77)† 6⋅07 (3⋅00, 12⋅3)†
Values in parentheses are 95 per cent confidence intervals. *Multivariable Cox proportional hazards regression analyses adjusted for age, intake of dietary fibre, body mass index, diagnosis of diabetes and hypertension, use of aspirin and indometacin, alcohol consumption, smoking status, physical activity and educational level. †P for trend < 0⋅001.
per cent c.i. 0⋅58 to 2⋅21) and RR 1⋅47 (0⋅81 to 2⋅65) respectively.
Indometacin and aspirin Use of indometacin (2⋅5 per cent of women) or aspirin (44⋅2 per cent) did not influence the risk of diverticular disease: RR 1⋅06 (95 per cent 0⋅66 to 1⋅70) and 1⋅05 (0⋅89 to 1⋅48) respectively. Discussion
This population-based prospective cohort study has demonstrated that the intake of steroids, both inhaled and oral, increases the risk of admission to hospital with diverticular disease. Possible explanations for the stronger association of inhaled compared with oral corticosteroids in this study may relate to duration of exposure or to associations with chronic pulmonary disease and collagen degeneration. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Previous studies have found an association between oral corticosteroids and diverticular disease. Humes and colleagues14 identified a cohort with matched controls from a British general practice research database. Some 20 per cent of these patients with diverticular disease were current users of oral corticosteroids, compared with 10 per cent of controls. In a retrospective analysis of patients admitted for diverticular disease, Morris and co-workers17 noted a 6–8-fold increase among patients who had used corticosteroids. Other smaller series15,16 have reported similar findings. Inhaled corticosteroids have been used in the treatment of asthma and chronic obstructive pulmonary disease for more than 20 years. They are generally preferred over systemic steroids to improve control of local disease and possibly reduce systemic adverse effects. However, systemic dose-dependent side-effects of inhaled corticosteroids are well known. They appear to affect the gastrointestinal tract, increasing the risk of side-effects at this location24 . The use of a spacer device, however, www.bjs.co.uk
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seemed to decrease these events. In addition, intranasal administration, which had not yet been introduced in 1997 when the exposure data in the present study were collected, may possibly further reduce gastrointestinal events25,26 . According to recent findings, glucocorticoid-induced tumour necrosis factor receptor and matrix metalloproteinase 9 within inflammatory cells may be a potential molecular link between immunosuppression induced by steroid intake and complicated sigmoid diverticulitis27 . Intake of indometacin or aspirin was not a risk factor for symptomatic diverticular disease in the present study. Aspirin and NSAIDs have previously been shown to increase diverticular bleeding28 . As ICD-10 does not provide a specific code for diverticular bleeding, these events are most likely coded under a combination of diagnostic codes, and were therefore not captured here because the primary diagnostic codes for diverticular disease (K572, K573, K574, K575, K578 and K579) were used as the main outcome measure. The strengths of the present study are the population-based design, high response rate, independent prospective data ascertainment, homogeneous classification of exposures and outcomes, and complete follow-up through national registers. There are weaknesses too. Some misclassification of medication use was inevitable, as it was assessed by means of a self-administered questionnaire. Potential confounders, such as diet, smoking, BMI, educational level and physical activity, were included in the multivariable analysis, but there is a possibility that unmeasured or residual confounders may have biased the study findings. Unfortunately, the questionnaire did not collect information on indication for which the medication was administered. Furthermore, the classification of disease might have been flawed. The final diagnosis was made by a clinician and stated in the discharge summary, then reported subsequently to the National Patient Register. In the present study, women with mild symptoms were likely to have been missed, as only those with symptomatic disease requiring hospital care were included. Finally, the variability between different corticosteroid drugs regarding potency, device and administration technique could affect drug absorption, and subsequently have affected the results. Acknowledgements
This study was supported by grants from the Karolinska Institute, the Ruth and Richard Julins Foundation, and the Swedish Research Council/Maintenance. None of the funders had any influence on the conduct of the study. Disclosure: The authors declare no conflict of interest. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
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References 1 Feingold D, Steele SR, Lee S, Kaiser A, Boushey R, Buie WD et al. Practice parameters for the treatment of sigmoid diverticulitis. Dis Colon Rectum 2014; 57: 284–294. 2 McDermott FD, Collins D, Heeney A, Winter DC. Minimally invasive and surgical management strategies tailored to the severity of acute diverticulitis. Br J Surg 2014; 101: e90–e99. 3 Strate LL, Modi R, Cohen E, Spiegel BM. Diverticular disease as a chronic illness: evolving epidemiologic and clinical insights. Am J Gastroenterol 2012; 107: 1486–1493. 4 Painter NS, Burkitt DP. Diverticular disease of the colon: a deficiency disease of Western civilization. Br Med J 1971; 2: 450–454. 5 Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Trichopoulos DV, Willett WC. A prospective study of diet and the risk of symptomatic diverticular disease in men. Am J Clin Nutr 1994; 60: 757–764. 6 Strate LL, Erichsen R, Baron JA, Mortensen J, Pedersen JK, Riis AH et al. Heritability and familial aggregation of diverticular disease: a population-based study of twins and siblings. Gastroenterology 2013; 144: 736–742.e1. 7 Strate LL, Liu YL, Aldoori WH, Syngal S, Giovannucci EL. Obesity increases the risks of diverticulitis and diverticular bleeding. Gastroenterology 2009; 136: 115–122.e1. 8 Hjern F, Wolk A, Håkansson N. Smoking and the risk of diverticular disease in women. Br J Surg 2011; 98: 997–1002. 9 Hjern F, Wolk A, Håkansson N. Obesity, physical inactivity, and colonic diverticular disease requiring hospitalization in women: a prospective cohort study. Am J Gastroenterol 2012; 107: 296–302. 10 Aldoori WH, Giovannucci EL, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA et al. Prospective study of physical activity and the risk of symptomatic diverticular disease in men. Gut 1995; 36: 276–282. 11 Templeton AW, Strate LL. Updates in diverticular disease. Curr Gastroenterol Rep 2013; 15: 339. 12 Strate LL, Erichsen R, Baron JA, Mortensen J, Pedersen JK, Riis AH et al. Heritability and familial aggregation of diverticular disease: a population-based study of twins and siblings. Gastroenterology 2013; 144: 736–742.e1. 13 Granlund J, Svensson T, Olen O, Hjern F, Pedersen NL, Magnusson PK et al. The genetic influence on diverticular disease – a twin study. Aliment Pharmacol Ther 2012; 35: 1103–1107. 14 Humes DJ, Fleming KM, Spiller RC, West J. Concurrent drug use and the risk of perforated colonic diverticular disease: a population-based case–control study. Gut 2011; 60: 219–224. 15 Piekarek K, Israelsson LA. Perforated colonic diverticular disease: the importance of NSAIDs, opioids, corticosteroids, and calcium channel blockers. Int J Colorectal Dis 2008; 23: 1193–1197.
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16 Weiner HL, Rezai AR, Cooper PR. Sigmoid diverticular perforation in neurosurgical patients receiving high-dose corticosteroids. Neurosurgery 1993; 33: 40–43. 17 Morris CR, Harvey IM, Stebbings WS, Speakman CT, Kennedy HJ, Hart AR. Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease. Br J Surg 2003; 90: 1267–1272. 18 Laine L, Smith R, Min K, Chen C, Dubois RW. Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2006; 24: 751–767. 19 Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Family Med 1998; 7: 255–260. 20 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007; 335: 806–808. 21 Holmberg L, Ohlander EM, Byers T, Zack M, Wolk A, Bergström R et al. Diet and breast cancer risk. Results from a population-based, case–control study in Sweden. Arch Int Med 1994; 154: 1805–1811. 22 Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim
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Cohort study of corticosteroid use and risk of hospital admission for diverticular disease F. Hjern1 , M. W. Mahmood1 , M. Abraham-Nordling3 , A. Wolk2 and N. Håkansson2 1 Division of Surgery, Department of Clinical Sciences, Danderyd University Hospital, 2 Division of Nutritional Epidemiology, National Institute of Environmental Medicine, and 3 Institution of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden Correspondence to: Professor F. Hjern, Department of Surgery, Danderyd University Hospital, 182 88 Stockholm, Sweden (e-mail: [email protected])
Background: Medication has been suggested as a potential risk factor for diverticular disease. The objec-
tive of this study was to investigate the association between the intake of corticosteroids, indometacin or aspirin and diverticular disease. Method: This was a prospective population-based cohort study of middle-aged women in the Swedish Mammography Cohort. Use of corticosteroids (oral or inhaled), indometacin or aspirin in 1997 was determined from questionnaires. Cases of diverticular disease were identified from the Swedish national registers until the end of 2010. The relative risk (RR) of diverticular disease requiring hospital admission according to the use of medication was estimated using Cox proportional hazards models, adjusted for age, body mass index, physical activity, fibre intake, diabetes, hypertension, alcohol, smoking and education. Results: A total of 36 586 middle-aged women in the Swedish Mammography Cohort were included, of whom 674 (1⋅8 per cent) were hospitalized with diverticular disease at least once. Some 7⋅2 per cent of women reported intake of oral corticosteroids and 8⋅5 per cent use of inhaled corticosteroids. In multivariable analysis, women who reported oral corticosteroid intake had a 37 per cent (RR 1⋅37, 95 per cent c.i. 1⋅06 to 1⋅78; P = 0⋅012) increased risk of diverticular disease compared with those who reported no intake at all. Use of inhaled corticosteroids was associated with an even more pronounced increase in risk of 71 per cent (RR 1⋅71, 1⋅36 to 2⋅14; P < 0⋅001). There was a significant dose–response relationship, with the risk increasing with longer duration of inhaled corticosteroids (P for trend < 0⋅001). Use of indometacin (2⋅5 per cent of women) or aspirin (44⋅2 per cent) did not influence the risk. Conclusion: There was a significant relationship between corticosteroids (especially inhaled) and diverticular disease requiring hospital admission. Presented to the Annual Meeting of the European Society of Coloproctology, Vienna, Austria, September 2012; published in abstract form as Colorectal Dis 2012; 14(Suppl 2): 69–76 Paper accepted 29 September 2014 Published online 12 November 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9686
Introduction
Colonic diverticular disease is one of the most common gastrointestinal diseases. Inflammation is the most frequent manifestation, with perforation and peritonitis in the most severe cases1 – 3 . Painter and Burkitt4 suggested that a low content of dietary fibre is an important component in the development of the disease, which Aldoori and colleagues5 have confirmed. Low levels of physical activity, obesity and smoking are other risk factors that increase the incidence6 – 11 . Recent findings12,13 suggest that genetic factors may also contribute. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Medications can have an impact on the development of gastrointestinal disease; aspirin, for example, increases the risk of peptic ulcer disease. Oral corticosteroids have been reported to increase the risk of perforation in diverticular disease14 – 16 . Corticosteroids alter responses to inflammation and infection, and their chronic use reduces collagen turnover and may weaken the colon wall14,17 . Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin have also been associated with acute diverticulitis and diverticular bleeding owing to altered intestinal permeability caused by decreased prostaglandin synthesis15,18,19 . The aim of the present study was to BJS 2015; 102: 119–124
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Table 1
F. Hjern, M. W. Mahmood, M. Abraham-Nordling, A. Wolk and N. Håkansson
Baseline characteristics by intake of oral and inhaled corticosteroids in the Swedish Mammography Cohort, 1997 Oral corticosteroids
Total person-years Mean person-years Mean age (years) Current smoker (%) Mean intake of dietary fibre (g/day) Diabetes (%) Hypertension (%) Use of aspirin Use of indometacin Body mass index (kg/m2 ) Mean physical activity (min/day) Mean alcohol consumption (g/day) University-level education (%)
Inhaled corticosteroids
Non-use (n = 22 666)
Ever use (n = 2647)
Non-use (n = 26 314)
Ever use (n = 3099)
280 364 12⋅4 61⋅5 23⋅2 22⋅2 4⋅1 21⋅4 46⋅6 2⋅2 25⋅0 57⋅3 6⋅1 18⋅9
30 829 11⋅6 61⋅5 25⋅3 22⋅0 4⋅3 23⋅9 50⋅3 9⋅2 25⋅2 51⋅7 6⋅1 20⋅1
325 573 12⋅4 61⋅3 22⋅6 22⋅2 3⋅8 20⋅6 44⋅3 2⋅3 25⋅0 57⋅2 6⋅1 19⋅1
37 041 11⋅6 61⋅3 22⋅6 22⋅2 5⋅1 23⋅8 46⋅1 4⋅2 25⋅6 52⋅1 6⋅2 19⋅8
All mean values except age were standardized with respect to the age distribution in the study population.
determine whether the intake of oral/inhaled corticosteroids, indometacin or aspirin alters the risk of diverticular disease requiring hospital admission in a population-based prospective cohort.
Methods
Ethical approval was granted by the Regional Ethical Review Board at Karolinska Institute (Stockholm, Sweden). The study is reported according to the criteria set out in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist20 .
Assessment of medication intake Information on the use of oral corticosteroids was based on the question: ‘Have you used oral corticosteroids (yes/no)?’. If ‘yes’, the subject was ask to specify the level of exposure: ‘How many episodes?’. Information on the use of inhaled corticosteroids was based on the question: ‘Have you used inhaled corticosteroids?’. If ‘yes, presently’, the subject answered the question: ‘For how many years?’. Information on the use of aspirin and indometacin was based on the question: ‘Have you used this drug (yes/no)?’. If ‘yes’, further questions were: ‘How many pills/week and for how many years?’.
Follow-up and ascertainment of hospital admission Swedish Mammography Cohort The Swedish Mammography Cohort is a population-based prospective cohort of 66 651 women from central Sweden recruited between 1987 and 1990. Details of the cohort have been described previously21 . All women born during the years 1914–1948 were invited by mail to participate in a mammography screening programme, and to complete a questionnaire regarding diet, weight, height, parity and educational level. Answers were obtained from 73⋅8 per cent. In 1997, a follow-up questionnaire was sent to women who were still alive and living within the study area. This questionnaire included additional questions concerning diet, smoking status, alcohol use, use of vitamin supplements, physical activity, medication, hypertension and diabetes. The 1997 questionnaire was used as baseline for the present analysis (Table 1). © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
All women in the cohort with diverticular disease were identified through linkage of individual records to the National Patient Register and the Swedish Death Register. Dichotomized outcome variables (at least once/never) were obtained. The National Patient Register covers more than 99 per cent of all hospital discharges in Sweden and has been shown to be valid for most diagnoses22 . Outcome variables were defined in accordance with the World Health Organization ICD-10; diverticular disease was defined by a primary diagnosis of K572 (diverticular disease of the large bowel with abscess and/or perforation), K573 (diverticular disease of the large bowel without abscess and/or perforation), K574 (diverticular disease of the small and large bowel with abscess and/or perforation), K575 (diverticular disease of the small and large bowel without abscess and/or perforation), K578 (diverticular disease of the bowel, with perforation and/or abscess) and K579 (diverticular disease of the bowel, without www.bjs.co.uk
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perforation and/or abscess). Using restricted coding, diverticular disease with perforation and/or abscess was identified by a primary diagnosis of K572, K574 and K578. Incident cases of symptomatic diverticular disease in the cohort between 15 September 1997 and 31 December 2010 were identified. Data on cause and date of death were ascertained from the Swedish Death Registry and the Swedish Population Registry.
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Original SMC cohort recruited 1987–1990 Women born 1914–1948 Previous cancer excluded n = 61 433 Dead or moved out of study area n = 5403 Extended questionnaire 1997 (baseline in present study) n = 56 030
Statistical analysis Each woman contributed follow-up time from entry into the cohort to the date of a diverticular disease diagnosis, date of death from any cause or 31 December 2010, whichever occurred first. The risk of diverticular disease was examined in relation to the intake of corticosteroids (inhaled or oral), indometacin or aspirin. Regarding factors for which adjustment was made in the multivariable model, an extra level for missing values for each specific variable was used so that an individual would not be excluded from the analyses. After confirming that proportional hazards assumptions were satisfied (by means of Kaplan–Meier curves), relative risks (RRs) with 95 per cent c.i. were estimated by means of Cox proportional hazards regression using the PHREG procedure in SAS® version 9.1 (SAS Institute, Cary, North Carolina, USA)23 . Multivariable analyses were adjusted for age (5-year age groups), intake of dietary fibre (g/day divided into quartiles), diabetes (yes/no), hypertension (yes/no), body mass index (BMI), physical activity, alcohol, smoking and educational level. All P values are two-sided. P < 0⋅050 was considered statistically significant for all analyses. Results
After excluding patients with an erroneous national registration number or a previous diagnosis of cancer, the Swedish Mammography Cohort comprised 61 433 women at baseline in 1987–1990. In all, 39 277 (70⋅0 per cent) of 56 030 women living in the study area completed the follow-up questionnaire in 1997; 219 were too sick to fill in the questionnaire, 548 declined to answer and 16 036 did not respond (Fig. 1). Patients with inflammatory bowel disease or previous diverticular disease were excluded, leaving a final study cohort of 36 586 women at the start of follow-up. During follow-up, 674 patients (1⋅8 per cent of the women in the cohort) required hospital admission at least once owing to symptomatic diverticular disease. Based on restricted coding, 112 (0⋅3 per cent of the total) had perforation and/or an abscess. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Non-responders n = 16 803
Responders (70·0%) n = 39 227 Excluded n = 2641 Erroneous registration number n = 249 IBD n = 210 Cancer n = 1717 Previous diverticular disease n = 465 Final cohort n = 36 586 Fig. 1
Study flow chart. IBD, inflammatory bowel disease
Corticosteroids Some 7⋅2 per cent of women reported intake of oral corticosteroids at least once. In multivariable analysis, these women had a 37 per cent (RR 1⋅37, 95 per cent c.i. 1⋅06 to 1⋅78; P = 0⋅012) increased risk of disease compared with those who had never used corticosteroids (Table 2). To examine the association between the amount of exposure to corticosteroids, the data were stratified by number of episodes (1–6, 7 or more); the association was found to be weak (Table 3). Some 8⋅5 per cent of women in the cohort reported the use of inhaled corticosteroids and these patients had a significantly increased risk of disease (RR 1⋅71, 1⋅36 to 2⋅14; P < 0⋅001) (Table 2). To examine the association between duration of exposure to inhaled corticosteroids, the data were stratified by duration of medication intake (less than 10, 11–20 and 21 or more years). There was a significant dose–response relationship, with the risk increasing with duration of inhaled corticosteroid intake (P for trend < 0⋅001) (Table 3). Some 112 women had perforation and/or abscess, of whom ten had used oral steroids and 13 inhaled steroids. Oral and inhaled steroid intake was associated with a slightly, but not significantly, increased risk: RR 1⋅13 (95 www.bjs.co.uk
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F. Hjern, M. W. Mahmood, M. Abraham-Nordling, A. Wolk and N. Håkansson
Age-adjusted and multivariable relative risks for symptomatic diverticular disease in the Swedish Mammography Cohort, 1997–2010, by intake of inhaled and oral corticosteroids
Table 2
Relative risk
Oral corticosteroids No Yes Unknown Inhaled corticosteroids No Yes Unknown
No. in cohort
No. with diverticular disease
Age-adjusted
Multivariable*
22 666 2647 11 273
409 67 198
1⋅00 (reference) 1⋅42 (1⋅09, 1⋅84)
1⋅00 (reference) 1⋅37 (1⋅06, 1⋅78)
26 314 3099 7173
444 91 139
1⋅00 (reference) 1⋅79 (1⋅43, 2⋅25)
1⋅00 (reference) 1⋅71 (1⋅36, 2⋅14)
Values in parentheses are 95 per cent confidence intervals. *Cox proportional hazards regression analyses adjusted for age, intake of dietary fibre, body mass index, diagnosis of diabetes and hypertension, use of aspirin and indometacin, alcohol consumption, smoking status, physical activity and educational level.
Age-adjusted and multivariable relative risks of hospital admission for diverticular disease in the Swedish Mammography Cohort, 1997–2010, in relation to level of exposure to oral and inhaled corticosteroids
Table 3
Relative risk Corticosteroid use Oral intake (episodes) None 1–6 ≥7 Inhaled intake (years) None 1–10 11–20 ≥ 21
No. in cohort
No. with diverticular disease
Age-adjusted
Multivariable*
22 666 1651 237
409 37 6
1⋅00 (reference) 1⋅25 (0⋅89, 1⋅75) 1⋅47 (0⋅66, 3⋅28)
1⋅00 (reference) 1⋅19 (0⋅85, 1⋅66) 1⋅40 (0⋅62, 3⋅14)
26 314 1785 271 87
444 44 9 8
1⋅00 (reference) 1⋅51 (1⋅11, 2⋅05) 2⋅06 (1⋅06, 3⋅98) 6⋅09 (3⋅02, 12⋅29)
1⋅00 (reference) 1⋅44 (1⋅06, 1⋅97)† 1⋅95 (1⋅01, 3⋅77)† 6⋅07 (3⋅00, 12⋅3)†
Values in parentheses are 95 per cent confidence intervals. *Multivariable Cox proportional hazards regression analyses adjusted for age, intake of dietary fibre, body mass index, diagnosis of diabetes and hypertension, use of aspirin and indometacin, alcohol consumption, smoking status, physical activity and educational level. †P for trend < 0⋅001.
per cent c.i. 0⋅58 to 2⋅21) and RR 1⋅47 (0⋅81 to 2⋅65) respectively.
Indometacin and aspirin Use of indometacin (2⋅5 per cent of women) or aspirin (44⋅2 per cent) did not influence the risk of diverticular disease: RR 1⋅06 (95 per cent 0⋅66 to 1⋅70) and 1⋅05 (0⋅89 to 1⋅48) respectively. Discussion
This population-based prospective cohort study has demonstrated that the intake of steroids, both inhaled and oral, increases the risk of admission to hospital with diverticular disease. Possible explanations for the stronger association of inhaled compared with oral corticosteroids in this study may relate to duration of exposure or to associations with chronic pulmonary disease and collagen degeneration. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Previous studies have found an association between oral corticosteroids and diverticular disease. Humes and colleagues14 identified a cohort with matched controls from a British general practice research database. Some 20 per cent of these patients with diverticular disease were current users of oral corticosteroids, compared with 10 per cent of controls. In a retrospective analysis of patients admitted for diverticular disease, Morris and co-workers17 noted a 6–8-fold increase among patients who had used corticosteroids. Other smaller series15,16 have reported similar findings. Inhaled corticosteroids have been used in the treatment of asthma and chronic obstructive pulmonary disease for more than 20 years. They are generally preferred over systemic steroids to improve control of local disease and possibly reduce systemic adverse effects. However, systemic dose-dependent side-effects of inhaled corticosteroids are well known. They appear to affect the gastrointestinal tract, increasing the risk of side-effects at this location24 . The use of a spacer device, however, www.bjs.co.uk
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seemed to decrease these events. In addition, intranasal administration, which had not yet been introduced in 1997 when the exposure data in the present study were collected, may possibly further reduce gastrointestinal events25,26 . According to recent findings, glucocorticoid-induced tumour necrosis factor receptor and matrix metalloproteinase 9 within inflammatory cells may be a potential molecular link between immunosuppression induced by steroid intake and complicated sigmoid diverticulitis27 . Intake of indometacin or aspirin was not a risk factor for symptomatic diverticular disease in the present study. Aspirin and NSAIDs have previously been shown to increase diverticular bleeding28 . As ICD-10 does not provide a specific code for diverticular bleeding, these events are most likely coded under a combination of diagnostic codes, and were therefore not captured here because the primary diagnostic codes for diverticular disease (K572, K573, K574, K575, K578 and K579) were used as the main outcome measure. The strengths of the present study are the population-based design, high response rate, independent prospective data ascertainment, homogeneous classification of exposures and outcomes, and complete follow-up through national registers. There are weaknesses too. Some misclassification of medication use was inevitable, as it was assessed by means of a self-administered questionnaire. Potential confounders, such as diet, smoking, BMI, educational level and physical activity, were included in the multivariable analysis, but there is a possibility that unmeasured or residual confounders may have biased the study findings. Unfortunately, the questionnaire did not collect information on indication for which the medication was administered. Furthermore, the classification of disease might have been flawed. The final diagnosis was made by a clinician and stated in the discharge summary, then reported subsequently to the National Patient Register. In the present study, women with mild symptoms were likely to have been missed, as only those with symptomatic disease requiring hospital care were included. Finally, the variability between different corticosteroid drugs regarding potency, device and administration technique could affect drug absorption, and subsequently have affected the results. Acknowledgements
This study was supported by grants from the Karolinska Institute, the Ruth and Richard Julins Foundation, and the Swedish Research Council/Maintenance. None of the funders had any influence on the conduct of the study. Disclosure: The authors declare no conflict of interest. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
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