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Family history, comorbidity, smoking and other risk factors in microscopic colitis: a case–control study

Wickbom, Anna; Nyhlin, Nils; Montgomery, Scott M.; Bohr, Johan; Tysk, Curt

European Journal of Gastroenterology & Hepatology: May 2017 - Volume 29 - Issue 5 - p 587–594
doi: 10.1097/MEG.0000000000000832
Original Articles: Inflammatory Bowel Diseases

Objectives Data on heredity, risk factors and comorbidity in microscopic colitis, encompassing collagenous colitis (CC) and lymphocytic colitis (LC), are limited.

Aim The aim was to carry out a case–control study of family history, childhood circumstances, educational level, marital status, smoking and comorbidity in microscopic colitis.

Methods A postal questionnaire was sent in 2008–2009 to microscopic colitis patients resident in Sweden and three population-based controls per patient, matched for age, sex and municipality.

Results Some 212 patients and 627 controls participated in the study. There was an association with a family history of microscopic colitis in both CC [odds ratio (OR): 10.3; 95% confidence interval (CI): 2.1–50.4, P=0.004] and LC (OR not estimated, P=0.008). Current smoking was associated with CC [OR: 4.7; 95% CI: 2.4–9.2, P<0.001) and LC (OR: 3.2; 95% CI: 1.6–6.7, P=0.002). The median age at diagnosis was around 10 years earlier in ever-smokers compared with never-smokers.

CC was associated with a history of ulcerative colitis (UC) (OR: 8.7, 95% CI: 2.2–33.7, P=0.002), thyroid disease (OR: 2.3; 95% CI: 1.1–4.5, P=0.02), coeliac disease (OR: 13.1; 95% CI: 2.7–62.7, P=0.001), rheumatic disease (OR 1.9; 95% CI: 1.0–3.5, P=0.042) and previous appendicectomy (OR: 2.2; 95% CI: 1.3–3.8, P=0.003), and LC with UC (OR: 6.8; 95% CI: 1.7–28.0, P=0.008), thyroid disease (OR: 2.4; 95% CI: 1.1–5.4, P=0.037) and coeliac disease (OR: 8.7; 95% CI: 2.8–26.7, P<0.001).

Conclusion Association with a family history of microscopic colitis indicates that familial factors may be important. The association with a history of UC should be studied further as it may present new insights into the pathogenesis of microscopic colitis and UC.

aSchool of Medical Sciences, Örebro University, Örebro

bThe Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

cDepartment of Epidemiology and Public Health, University College London, London, UK

Correspondence to Anna Wickbom, MD, Department of Medicine, Division of Gastroenterology, Örebro University Hospital, S-701 85 Örebro, Sweden Tel: +46 196 021 000; fax: +46 196 021 774; e-mail: anna.wickbom@regionorebrolan.se

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Received October 21, 2016

Accepted November 25, 2016

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Introduction

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.

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Patients and methods

Patients

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.

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Diagnostic criteria

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.

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Controls

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.

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Questionnaire

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.

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Statistics

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).

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Ethical considerations

The study was approved by the regional ethics committee in Uppsala, Sweden (2005/161).

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Results

Study population

Patients

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.

Fig. 1

Fig. 1

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Controls

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.

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Missing data

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.

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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).

Table 1

Table 1

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Tobacco use

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).

Table 2

Table 2

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.

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Association with autoimmune and other diseases

Collagenous colitis

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).

Table 3

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).

Table 4

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.

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Lymphocytic colitis

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.

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Discussion

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.

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Acknowledgements

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.

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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.

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Keywords:

inflammatory bowel diseases; microscopic colitis; risk factors; smoking

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