Since microscopic colitis (MC) first was described during the 1970–1980s 1,2, knowledge has been steadily increasing on epidemiology, clinical characteristics and treatment. It is well established that collagenous colitis (CC) and lymphocytic colitis (LC) are two common disorders especially in elderly women, causing chronic watery diarrhoea, abdominal pain, weight loss and faecal incontinence 3–5.
The pathophysiology is not yet well understood, but is considered to be multifactorial involving a dysregulated immune response to luminal agents in predisposed individuals. Data on heredity are limited. Familial clustering of MC has been described 6–15, but it is uncertain whether these reflect random associations or shared familial traits. Associations with certain gene polymorphisms and human leukocyte antigen (HLA) haplotypes have been reported, but are poorly understood at present 16. Both CC and LC have been associated with the HLA-DQ2 haplotype, known to be of importance in autoimmune diseases such as coeliac disease, type 1 diabetes and thyroid disease 17,18, and there is an evident over-representation of such autoimmune disorders in MC 11,19–22. The occurrence of other comorbidity, however, is not well studied, except for lung cancer being reported more frequently in women with CC compared with controls 23. The relationship between MC and ulcerative colitis (UC) and Crohn’s disease is unknown. There are case reports reporting the development of MC in patients with an established diagnosis of UC or Crohn’s disease, or vice versa 24–33. Whether this merely represents a coincidence or shared pathophysiologic pathways is unknown.
Smoking and drug use are the best-documented environmental risk factors for MC. An increased risk for both CC and LC has consistently been reported in smokers 20,33–35. Furthermore, smokers develop the disease more than 10 years earlier than nonsmokers 35,36 and have more severe clinical symptoms 37.
There is, to our knowledge, no controlled study on the significance of background factors such as family history or childhood circumstances in MC. Our objective is to report a case–control study of various background factors such as family history, childhood circumstances, educational level, smoking and overall comorbidity in microscopic colitis, using a population-based, age-matched and sex-matched control group.
Patients and methods
All patients diagnosed with MC in our hospital from 1980 to 2008 have been registered retrospectively in a local research database. Their patient files were reviewed and clinical as well as histopathologic criteria for CC or LC had to be fulfilled to be included in the study.
The clinical criteria for MC were watery diarrhoea for more than 3 weeks’ duration and a macroscopically normal or almost normal colonic mucosa. The histopathologic criteria for CC were (i) a subepithelial collagen band of 10 µm or more in correctly oriented sections, (ii) epithelial damage with or without an increased number of intraepithelial lymphocytes and (iii) inflammation in the lamina propria with mainly lymphocytes. For LC, the histological criteria were as follows: (i) increased numbers of intraepithelial lymphocytes (>20/100 epithelial cells), (ii) epithelial damage and (iii) inflammation in the lamina propria with mainly lymphocytes and no increased collagen layer. The histopathological diagnosis of MC relied on an overall assessment of mucosal biopsies, where characteristic findings had to be present in at least two biopsies, supported by findings of chronic inflammation in additional biopsies and segments. All cases had been reviewed by one experienced pathologist with special interest in gastroenterology in previous epidemiological studies 38–40.
Statistics Sweden randomly identified a control group for this study consisting of three controls per patient matched for age, sex and residential municipality. The information on the controls was delivered anonymized.
A questionnaire containing questions on background factors such as family history, childhood circumstances, educational level, marital status, tobacco use and occurrence of other diseases was sent by post in 2008–2009 to 277 patients with MC within our primary catchment area and to 831 matched controls. The questionnaire included questions on the presence of inflammatory bowel disease, microscopic colitis or coeliac disease in first-degree relatives, childhood circumstances such as growing up on a farm, number of siblings and whether siblings were older or younger, educational degree, marital status, previous or current smoking habits, previous appendicectomy or cholecystectomy, a question on the occurrence of specified diseases (coeliac disease, thyroid disease, UC, Crohn’s disease, diabetes mellitus and rheumatic disease) that have been associated previously with microscopic colitis and an open question where the patient could report the occurrence of any other disease. Data on use of analgesics have been reported earlier 41. The questionnaire was developed by the authors and piloted on a few patients before finalizing the wording.
The answers to the questions on all other diseases were categorized according to the chapters in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), and the diseases that have been associated with MC earlier were analysed separately as well.
Differences between patients and controls were determined using logistic regression, and presented as odds ratios (OR) with a 95% confidence interval (CI), as well as P-values, where a P-value less than 0.05 was considered statistically significant. The matching factors were age, sex and residential municipality. The odds ratios were calculated adjusted for age and sex. The reason for not using conditional logistic regression was that we would lose cases and controls in pairs where either was missing. When variables with n less than 6 were present in any cell, significance was corrected using Fisher’s exact test. When comparing the median age at diagnosis in smokers and nonsmokers, an independent-samples Mann–Whitney U-test was used. The statistical analysis was carried out using IBM SPSS Statistics 22 for Windows (SPSS Inc., Chicago, Illinois, USA).
The study was approved by the regional ethics committee in Uppsala, Sweden (2005/161).
The demographic data on the patients are shown in Fig. 1. The questionnaire was completed by 226/277 (82%) patients. Fourteen of these cases did not fulfil the diagnostic criteria for MC and were excluded. In seven cases, the diagnosis changed during follow-up, six of them from LC to CC and one from CC to LC. The most recent diagnosis was registered. A total of 115 CC patients (97 women) were enrolled in this study, with a median age of 66 (27–91) years, and 97 LC patients (79 women) with a median age of 64 (33–94) years. The patients who did not respond to the questionnaire (n=51) were older [CC 77 (34–95) years, LC 75 (31–92) years], but did not differ in sex distribution from the participating patients.
Overall, 627/828 (76%) of the controls answered the questionnaire (Statistics Sweden had selected three more controls who died before the questionnaire was sent) (Fig. 1). There were no statistically significant differences in demographic data between the patient and the control groups. There were no reports of an MC diagnosis in the control group.
Missing data were generally few per question; in the CC patient group, between 0 and 5%, in the CC control group between 0 and 4%, in the LC patient group between 0 and 4% and in the LC control group, it varied between 0 and 4% missing items.
Family history, childhood circumstances, educational level and marital status
Patients with CC reported having a first-degree relative with MC more often than controls (OR: 10.3; 95% CI: 2.1–50.4, P=0.004). The LC patients reported significantly more a first-degree relative with MC, inflammatory bowel diseases (IBD) or coeliac disease than their controls, but the numbers are small (Table 1). After adjustment for the presence of coeliac disease in cases/controls, who had reported first-degree relatives with coeliac disease, the association with LC disappeared (OR: 2.1; 95% CI: 0.6–7.7, P=0.28). Patients with microscopic colitis did not differ from their controls in the aspects of growing up on a farm, number of siblings and birth order, educational level or marital status (Table 1).
Smoking influenced the risk of MC (Table 2). In both CC and LC, there was an association with smoking, with 28% current smokers in the CC population compared with 13% in the control group (OR: 4.7; 95% CI: 2.4–9.2, P<0.001), and in the LC group, 26% current smokers compared with 12% in the control group (OR: 3.2; 95% CI: 1.6–6.7, P=0.002).
We have no data on the temporal relationship between age at diagnosis and time of quitting smoking. Therefore, we included ex-smokers and current smokers in the group of ever-smokers. Ever-smokers with MC were diagnosed earlier than the never-smokers. In CC, the median age at diagnosis was 58 [interquartile range (IQR): 48–65] years in ever-smokers compared with 70 (IQR: 56–82) years in the never smoking group, P=0.001. In LC, the median age at diagnosis was 55 (IQR: 47–66) years in ever-smokers and in the never smoking group 64 (IQR: 53–73) years, P=0.031.
Association with autoimmune and other diseases
Patients with CC reported significantly more digestive diseases other than CC, diseases of the skin and subcutaneous tissue and diseases from the musculoskeletal system and connective tissue than the control group (Table 3).
There was an association with the occurrence of inflammatory or autoimmune diseases in CC; 47% of CC patients reported one or more concomitant diseases compared with 29% of the controls (OR: 2.4; 95% CI: 1.5–3.9, P<0.001) (Table 4).
CC was associated with thyroid disease, which 17% of the patients reported compared with 9% in the control group (OR: 2.3; 95% CI: 1.1–4.5, P=0.02) (Table 4). There was no association with diabetes mellitus (Table 4).
CC was associated with a history of both UC (OR: 8.7; 95% CI: 2.2–33.7, P=0.002)) and coeliac disease (OR: 13.1; 95% CI: 2.7–62.7, P=0.001), but not of Crohn’s disease (Table 4). Thirty-six percent of the CC patients reported diseases from the musculoskeletal system and connective tissue compared with 16% in the control group (OR: 3.2; 95% CI: 1.9–5.5, P<0.001) (Table 3). When restricting the analysis to inflammatory rheumatic disorders (inflammatory polyarthropathies, systemic connective tissue disorders and inflammatory spondylopathies), the difference remained (OR: 1.9; 95% CI: 1.0–3.5, P=0.042) (Table 4).
An association with skin diseases was observed in CC, but the figures are small; 5% of the CC patients reported skin disease as did 1% in the control group (OR: 6.0; 95% CI: 1.4–26.0, P=0.018) (Table 3). The analysis includes various skin disorders; thus, the association is uncertain.
Previous appendicectomy was associated with CC (OR: 2.2; 95% CI: 1.3–3.8, P=0.003), whereas no association was found with past cholecystectomy (OR: 0.8; 95% CI: 0.4–1.6, P=0.589) (Table 1). The overall risk of malignancy was not different from controls.
Patients with LC reported significantly more digestive diseases and diseases of the nervous system than controls (Table 3). Thirty-one percent of the LC patients had gastrointestinal disorders other than LC compared with 11% in the control group (OR: 4.0; 95% CI: 2.1–7.6, P<0.001) (Table 3).
There was an association with several concomitant inflammatory or autoimmune disorders and LC, yielding an overall adjusted OR of 2.5 (95% CI: 1.4–4.3, P=0.001) (Table 4).
LC was associated with thyroid disease, which was reported by 14% of the LC patients and 7% of the controls (OR: 2.4; 95% CI: 1.1–5.4, P=0.037), but not with diabetes mellitus. There were associations with a history of UC, which was reported by 7% of the LC patients and 1% of the controls (OR: 6.8; 95% CI: 1.7–28.0, P=0.008), of coeliac disease, which 15% of the patients and 2% of the controls reported (OR: 8.7; 95% CI: 2.8–26.7, P<0.001), but not of Crohn’s disease (OR: 2.8; 95% CI: 0.4–18.1, P=0.279) (Table 4).
There was an association with diseases of the nervous system that was reported by 7% of the LC patients compared with 2% of the controls (OR: 4.1; 95% CI: 1.2–14.2, P=0.029), but the association disappeared when the significance was corrected using Fisher’s exact test (P=0.051) (Table 3). There was no association with past appendicectomy (OR: 0.7; 95% CI: 0.4–1.2, P=0.218) or cholecystectomy (OR: 1.5; 95% CI: 0.8–2.9, P=0.256) in LC (Table 1). The overall risk of malignancy was not different from that of the controls.
This is, to our knowledge, the first population-based, case–control study of family history, childhood circumstances, education and marital status in MC. We found an association with a family history for MC in patients with CC and LC, even though the number of persons with first-degree relatives with MC was small. Our data support earlier case reports on family clustering in MC and underscore that those reports were not merely chance findings 6–15. A total of 16 families have been reported with two or more first-degree relatives affected by CC or LC; two sisters were affected in 10 of these reports, and in 6/10 families, both siblings had CC. In an uncontrolled study on LC by Olesen et al. 42, 7% of the patients reported a first-degree relative with UC or Crohn’s disease, 1% reported a first-degree relative with CC and 2% reported a first-degree relative with coeliac disease. These findings are in line with the results in our study. As opposed to UC and Crohn’s disease, the knowledge on genetics is limited in MC. Data from genome-wide association studies in UC and Crohn’s disease have advanced during the last 10 years and about 200 genetic loci have been reported associated with UC or Crohn’s disease 43,44. Genetic data are sparse in MC. Studies published so far have reported gene polymorphisms in the interleukin-6, matrix metalloproteinase and serotonin reuptake transporter genes and HLA-DQ-haplotypes that could be associated with MC 16. More genetic studies are required and an increased knowledge of genetics may also provide further insight into the biological mechanisms of MC as shown in UC and Crohn’s disease 45.
There have been several reports of patients with UC or Crohn’s disease who develop MC or vice versa 24–33. This may indicate that the diseases are related and may share common pathophysiologic pathways. Alternatively, a random association of two fairly common disorders occurring in the same individual cannot be ruled out. To date, there have been no controlled data on this topic. Here, we report an increased frequency of patients with CC or LC reporting a history of UC, which, to our knowledge, has not been shown earlier. The numbers are small, but compared with controls, there was a several-fold increased odds ratio, which was not found for Crohn’s disease. This is an interesting finding that deserves further study.
We found no association with childhood environment as has been shown in UC and Crohn’s disease 46. In that study, growing up on a livestock farm in the first 5 years in life was associated with a lower risk of IBD, but only in patients born after 1952, and it was speculated that lower microbial diversity in the 1950s and later might explain this finding. In our study, the majority of the patients were born before 1952, perhaps explaining why place of upbringing was not of importance for development of MC in this study.
A recently published study on risk factors in MC found no association with educational level 47, in contrast to others who reported an association with higher educational degree 48. We found no association in this respect in either CC or LC.
Our study confirms previously published data on smoking 20,33–36 that smokers have a 3–4-fold increased risk for both CC and LC, and have an earlier onset of disease: around 10 years earlier than nonsmokers. There are insufficient and conflicting data on the effect of smoking on the clinical course. Fernandez-Bañares et al. 36 reported no effect of smoking on clinical symptoms at diagnosis or clinical remission rate, whereas Münch et al. 37 found more severe symptoms and lower remission rates in smokers.
There is an inverse association between appendicectomy at young age because of appendicitis and UC 49,50. In a Danish cohort study, individuals with a first-degree relative diagnosed with appendicitis before the age of 20 years had a reduced risk of UC, especially when there was a family predisposition for UC, suggesting that genetic or environmental factors, rather than the appendicitis itself, play a role in this association 51. In contrast, previous appendicectomy has been associated with an increased risk of developing Crohn’s disease, most likely because of diagnostic bias 52,53. In MC, previous controlled studies by Laing et al. 54 and Fernández-Bañares et al. 20 did not find an association with appendicectomy. In this study, there was an association with appendicectomy in CC, where a significantly larger proportion of the CC patients had undergone an appendicectomy compared with the control group. We have no data on the diagnostic accuracy of actual appendicitis or on the temporal relationship between appendicectomy and CC, which make this association somewhat obscure. No association with past appendicectomy was found in LC.
Bile acid malabsorption has been reported in 27–44% of patients with CC and in 9–60% of patients with LC 55–57. As bile acid malabsorption and diarrhoea may occur after a cholecystectomy, studies have been carried out to analyse a possible association with MC 20,54. In these studies, previous cholecystectomy was not associated with MC. Our data are in accordance with previous studies and no association between previous cholecystectomy and MC was found here.
We confirm previous reports that MC patients more often than controls have concomitant inflammatory or autoimmune diseases 42,58–60. An increased association with coeliac disease, found in both CC and LC, is consistent with previous data 11,19,61,62. Associated thyroid disease has received limited attention in MC and was reported in 9–21% of patients in previous uncontrolled series 42,58–60,62. Reports from studies with control populations are divergent; an increased prevalence was observed in the reports by Kao et al. 19 and Williams et al. 22, but not by Koskela et al. 11. We found an association with thyroid disorder in both CC and LC, which was reported by 17 and 14% of the patients, yielding ORs of 2.3 and 2.4, respectively, compared with the controls.
In line with previous studies 11,19,58,63,64, musculoskeletal disorders were reported more often in CC patients compared with controls, and when analysing rheumatic disorders separately, there was an association with CC, but not with LC. This is consistent with our previous study of the same patient cohort 41, where we reported that more than 50% of CC patients suffered from pain in joints or muscles compared with about 35% of the controls. In the same study, we reported an increased use of analgesics, such as paracetamol and weak opioids, but not NSAIDs, in patients with CC, but not in those with LC compared with the controls.
The strengths of this study are the absence of referral bias as all included patients with MC were living in our catchment area and therefore likely representative for the studied disorders. The control group is large, with three controls per case, and were randomly selected, population based and matched for age, sex and residential area. The response rates among cases and controls are high, reducing the risk of differential bias.
The main limitation of this study is that we could not verify reported concomitant diseases either in the cases or in the controls. There is a risk of surveillance bias as it is more likely that patients will be investigated for other diseases because of their symptoms than controls, possibly contributing at least to some extent towards the associations found. Similarly, patients with gastrointestinal disease will probably be more likely to remember their relatives’ gastrointestinal diseases. Because of small numbers, CIs of ORs are wide in some analyses.
In conclusion, this case–control study shows that MC is associated with a family history of MC, indicating that familial factors may play a role in the pathogenesis of MC. We confirm earlier reports that smoking is a risk factor in MC. Interestingly, both CC and LC were associated with a history of UC. These associations should be studied further and may also argue for considering MC as a part of the spectrum of IBD.
This work was supported by the Örebro University Hospital Research Foundation (Nyckelfonden), the Swedish Society of Medicine, the Bengt Ihre Foundation, (grant numbers 22100-2009, 98031-2010, 176271-2011) and the Örebro County Research Committee.
Conflicts of interest
Curt Tysk has served as a speaker for Dr Falk Pharma, Tillotts Pharma, Ferring, MSD and AstraZeneca. Johan Bohr has served as speaker for Dr Falk Pharma and Tillotts Pharma. For the remaining authors there are no conflicts of interest.
1. Lindstrom CG. ‘Collagenous colitis’ with watery diarrhoea – a new entity? Pathol Eur 1976; 11:87–89.
2. Lazenby AJ, Yardley JH, Giardiello FM, Jessurun J, Bayless TM. Lymphocytic (‘microscopic’) colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol 1989; 20:18–28.
3. Pardi DS, Kelly CP. Microscopic colitis
. Gastroenterology 2011; 140:1155–1165.
4. Münch A, Aust D, Bohr J, Bonderup O, Fernández Bañares F, Hjortswang H, et al. Microscopic colitis
: current status, present and future challenges: statements of the European Microscopic Colitis
Group. J Crohns Colitis 2012; 6:932–945.
5. Bohr J, Wickbom A, Hegedus A, Nyhlin N, Hultgren Hörnquist E, Tysk C. Diagnosis and management of microscopic colitis
: current perspectives. Clin Exp Gastroenterol 2014; 7:273–284.
6. Abdo AA, Zetler PJ, Halparin LS. Familial microscopic colitis
. Can J Gastroenterol 2001; 15:341–343.
7. Barta Z, Zold E, Nagy A, Zeher M, Csipo I. Celiac disease and microscopic colitis
: a report of 4 cases. World J Gastroenterol 2011; 17:2150–2154.
8. Freeman HJ. Familial occurrence of lymphocytic colitis. Can J Gastroenterol 2001; 15:757–760.
9. Jarnerot G, Hertervig E, Granno C, Thorhallsson E, Eriksson S, Tysk C, et al. Familial occurrence of microscopic colitis
: a report on five families. Scand J Gastroenterol 2001; 36:959–962.
10. Kong SC, Keogh S, Carter MJ, Lobo AJ, Sanders DS. Familial occurrence of microscopic colitis
: an opportunity to study the relationship between microscopic colitis
and coeliac disease? Scand J Gastroenterol 2002; 37:1344–1345.
11. Koskela RM, Niemela SE, Karttunen TJ, Lehtola JK. Clinical characteristics of collagenous and lymphocytic colitis. Scand J Gastroenterol 2004; 39:837–845.
12. Phull PS, Vijayan B, Bisset WM, Murray GI. Familial collagenous colitis involving a 6-year old child. J Crohns Colitis 2012; 6:606–609.
13. Thomson A, Kaye G. Further report of familial occurrence of collagenous colitis. Scand J Gastroenterol 2002; 37:1116.
14. van Tilburg AJ, Lam HG, Seldenrijk CA, Stel HV, Blok P, Dekker W, et al. Familial occurrence of collagenous colitis. A report of two families. J Clin Gastroenterol 1990; 12:279–285.
15. Vernier G, Cocq P, Baron P, Paquet PY, Colombel JF. [Familial occurrence of collagenous colitis]. Gastroenterol Clin Biol 2005; 29:474–476.
16. Pisani LF, Tontini GE, Vecchi M, Pastorelli L. Microscopic colitis
: what do we know about pathogenesis? Inflamm Bowel Dis 2016; 22:450–458.
17. Fernández-Bañares F, Esteve M, Farré C, Salas A, Alsina M, Casalots J, et al. Predisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis
. Eur J Gastroenterol Hepatol 2005; 17:1333–1338.
18. Westerlind H, Mellander MR, Bresso F, Munch A, Bonfiglio F, Assadi G, et al. Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis. Gut 2015. [Epub ahead of print].
19. Kao KT, Pedraza BA, McClune AC, Rios DA, Mao YQ, Zuch RH, et al. Microscopic colitis
: a large retrospective analysis from a health maintenance organization experience. World J Gastroenterol 2009; 15:3122–3127.
20. Fernández-Bañares F, de Sousa MR, Salas A, Beltrán B, Piqueras M, Iglesias E, et al. Epidemiological risk factors
in microscopic colitis
: a prospective case–control study. Inflamm Bowel Dis 2013; 19:411–417.
21. Guagnozzi D, Lucendo AJ, Angueira T, Gonzalez-Castillo S, Tenias JM. Drug consumption and additional risk factors
associated with microscopic colitis
: case–control study. Rev Esp Enferm Dig 2015; 107:347–353.
22. Williams JJ, Kaplan GG, Makhija S, Urbanski SJ, Dupre M, Panaccione R, et al. Microscopic colitis
-defining incidence rates and risk factors
: a population-based study. Clin Gastroenterol Hepatol 2008; 6:35–40.
23. Chan JL, Tersmette AC, Offerhaus GJ, Gruber SB, Bayless TM, Giardiello FM. Cancer risk in collagenous colitis. Inflamm Bowel Dis 1999; 5:40–43.
24. Freeman HJ, Berean KW, Nimmo M. Evolution of collagenous colitis into severe and extensive ulcerative colitis. Can J Gastroenterol 2007; 21:315–318.
25. Chandratre S, Bramble MG, Cooke WM, Jones RA. Simultaneous occurrence of collagenous colitis and Crohn’s disease. Digestion 1987; 36:55–60.
26. O’Beirne JP, Ireland A. Progression of collagenous colitis to Crohn’s disease. Eur J Gastroenterol Hepatol 2005; 17:573–575.
27. Haque M, Florin T. Progression of ulcerative colitis to collagenous colitis: chance, evolution or association? Inflamm Bowel Dis 2007; 13:1321.
28. Pokorny CS, Kneale KL, Henderson CJ. Progression of collagenous colitis to ulcerative colitis. J Clin Gastroenterol 2001; 32:435–438.
29. Giardiello FM, Jackson FW, Lazenby AJ. Metachronous occurrence of collagenous colitis and ulcerative colitis. Gut 1991; 32:447–449.
30. Aqel B, Bishop M, Krishna M, Cangemi J. Collagenous colitis evolving into ulcerative colitis: a case report and review of the literature. Dig Dis Sci 2003; 48:2323–2327.
31. Goldstein NS, Gyorfi T. Focal lymphocytic colitis and collagenous colitis: patterns of Crohn’s colitis? Am J Surg Pathol 1999; 23:1075–1081.
32. Mellander MR, Ekbom A, Hultcrantz R, Lofberg R, Ost A, Bjork J. Microscopic colitis
: a descriptive clinical cohort study of 795 patients with collagenous and lymphocytic colitis. Scand J Gastroenterol 2016; 51:556–562.
33. Thorn M, Sjoberg D, Ekbom A, Holmstrom T, Larsson M, Nielsen AL, et al. Microscopic colitis
in Uppsala health region, a population-based prospective study 2005–2009. Scand J Gastroenterol 2013; 48:825–830.
34. Yen EF, Pokhrel B, Du H, Nwe S, Bianchi L, Witt B, et al. Current and past cigarette smoking
significantly increase risk for microscopic colitis
. Inflamm Bowel Dis 2012; 18:1835–1841.
35. Vigren L, Sjoberg K, Benoni C, Tysk C, Bohr J, Kilander A, et al. Is smoking
a risk factor for collagenous colitis? Scand J Gastroenterol 2011; 46:1334–1339.
36. Fernández-Bañares F, de Sousa MR, Salas A, Beltrán B, Piqueras M, Iglesias E, et al. Impact of current smoking
on the clinical course of microscopic colitis
. Inflamm Bowel Dis 2013; 19:1470–1476.
37. Münch A, Tysk C, Bohr J, Madisch A, Bonderup OK, Mohrbacher R, et al. Smoking
status influences clinical outcome in collagenous colitis. J Crohns Colitis 2016; 10:449–454.
38. Bohr J, Tysk C, Eriksson S, Jarnerot G. Collagenous colitis in Orebro, Sweden, an epidemiological study 1984–1993. Gut 1995; 37:394–397.
39. Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Microscopic colitis
: a common diarrhoeal disease. An epidemiological study in Orebro, Sweden, 1993–1998. Gut 2004; 53:346–350.
40. Wickbom A, Bohr J, Eriksson S, Udumyan R, Nyhlin N, Tysk C. Stable incidence of collagenous colitis and lymphocytic colitis in Orebro, Sweden, 1999–2008: a continuous epidemiologic study. Inflamm Bowel Dis 2013; 19:2387–2393.
41. Nyhlin N, Wickbom A, Montgomery SM, Tysk C, Bohr J. Long-term prognosis of clinical symptoms and health-related quality of life in microscopic colitis
: a case–control study. Aliment Pharmacol Ther 2014; 39:963–972.
42. Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients. Gut 2004; 53:536–541.
43. Rivas MA, Graham D, Sulem P, Stevens C, Desch AN, Goyette P, et al. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun 2016; 7:12342.
44. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015; 47:979–986.
45. de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun 2015; 64:91–100.
46. Timm S, Svanes C, Janson C, Sigsgaard T, Johannessen A, Gislason T, et al. Place of upbringing in early childhood as related to inflammatory bowel diseases
in adulthood: a population-based cohort study in Northern Europe. Eur J Epidemiol 2014; 29:429–437.
47. Larsson JK, Sonestedt E, Ohlsson B, Manjer J, Sjoberg K. The association between the intake of specific dietary components and lifestyle factors and microscopic colitis
. Eur J Clin Nutr 2016; 70:1309–1317.
48. Sonnenberg A, Turner KO, Genta RM. Differences in the socio-economic distribution of inflammatory bowel disease and microscopic colitis
. Colorectal Dis 2016. [Epub ahead of print].
49. Frisch M, Pedersen BV, Andersson RE. Appendicitis, mesenteric lymphadenitis, and subsequent risk of ulcerative colitis: cohort studies in Sweden and Denmark. BMJ 2009; 338:b716.
50. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N Engl J Med 2001; 344:808–814.
51. Nyboe Andersen N, Gortz S, Frisch M, Jess T. Reduced risk of UC in families affected by appendicitis: a Danish national cohort study. Gut 2016. [Epub ahead of print].
52. Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn’s disease after an appendectomy: a population-based cohort study in Sweden and Denmark. Gut 2007; 56:1387–1392.
53. Kaplan GG, Jackson T, Sands BE, Frisch M, Andersson RE, Korzenik J. The risk of developing Crohn’s disease after an appendectomy: a meta-analysis. Am J Gastroenterol 2008; 103:2925–2931.
54. Laing AW, Pardi DS, Loftus EV Jr, Smyrk TC, Kammer PP, Tremaine WJ, et al. Microscopic colitis
is not associated with cholecystectomy or appendectomy. Inflamm Bowel Dis 2006; 12:708–711.
55. Ung KA, Gillberg R, Kilander A, Abrahamsson H. Role of bile acids and bile acid binding agents in patients with collagenous colitis. Gut 2000; 46:170–175.
56. Ung KA, Kilander A, Willen R, Abrahamsson H. Role of bile acids in lymphocytic colitis. Hepatogastroenterology 2002; 49:432–437.
57. Fernandez-Bañares F, Esteve M, Salas A, Forné TM, Espinos JC, Martín-Comin J, et al. Bile acid malabsorption in microscopic colitis
and in previously unexplained functional chronic diarrhea. Dig Dis Sci 2001; 46:2231–2238.
58. Bjornbak C, Engel PJ, Nielsen PL, Munck LK. Microscopic colitis
: clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther 2011; 34:1225–1234.
59. Bohr J, Tysk C, Eriksson S, Abrahamsson H, Jarnerot G. Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients. Gut 1996; 39:846–851.
60. Pardi DS, Ramnath VR, Loftus EV Jr, Tremaine WJ, Sandborn WJ. Lymphocytic colitis: clinical features, treatment, and outcomes. Am J Gastroenterol 2002; 97:2829–2833.
61. Stewart M, Andrews CN, Urbanski S, Beck PL, Storr M. The association of coeliac disease and microscopic colitis
: a large population-based study. Aliment Pharmacol Ther 2011; 33:1340–1349.
62. Vigren L, Tysk C, Strom M, Kilander AF, Hjortswang H, Bohr J, et al. Celiac disease and other autoimmune diseases in patients with collagenous colitis. Scand J Gastroenterol 2013; 48:944–950.
63. Baert F, Wouters K, D’Haens G, Hoang P, Naegels S, D’Heygere F, et al. Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis. Gut 1999; 45:375–381.
64. Fernández-Bañares F, Salas A, Esteve M, Espinós J, Forné M, Viver JM. Collagenous and lymphocytic colitis. evaluation of clinical and histological features, response to treatment, and long-term follow-up. Am J Gastroenterol 2003; 98:340–347.