Smoking- and alcohol habits in relation to the clinical picture of women with microscopic colitis compared to controls

Women who had been treated for MC at any outpatient clinic of the Departments of Gastroenterology in the district of Skåne, between 2002 and 2010, were identified by search for the ICD-10 classification of the two forms CC and LC (K52.8) in outpatient records, as well as in the local register at the Department of Pathology, Skåne University Hospital, Malmö. About one-third of the total numbers of patients identified were excluded due to age over 73 years, as they had many other concomitant diseases and drug therapies. Of the patients recognized, only the 240 patients (median age 63 years, range 22–73 years) who had the diagnoses verified by colonic biopsy, and were under 73 years of age, were invited to participate in the present study. Altogether, 159 (median age 63 years, range 22–73 years) of the 240 patients invited accepted and were recruited to the study, but one patient was excluded due to another IBD diagnosis a few weeks after the inclusion, leaving 158 patients (66). Of these, 133 (55) also agreed to provide blood samples. These patients represent the majority of female cases of diagnosed MC in the southernmost districts of Sweden under the age of 73 years.

Both MC and IBS are more frequent in women than in men, and the quality of life and the perception of symptoms differ between the genders [1, 14]. For this reason we chose to include only women in the study.

Between March and June 2011, invitations, including information about the study and the same questionnaire as sent to controls about marital status, education, employment, smoking habits, wine consumption, physical activity, medical conditions, and medication was dispatched by post to all 240 women identified as having MC. In addition, also questionnaires about gastrointestinal symptoms, psychological well-being and Rome III criteria were sent by post to the women with MC. The data collection concerned the status for the patients at the time of follow-up and inclusion in the study, and not the status at the time of diagnosis. They were invited to visit the outpatient clinics of the Departments of Gastroenterology, Skåne University Hospital, Malmö or at the Central Hospital in Kristianstad, to provide blood samples. A reminding letter was sent a month after the invitation letter to those who had not answered. Questionnaires were completed 1–3 weeks before the blood samples were collected. Medical records were scrutinized, and age, gastrointestinal symptoms, examinations, and treatments were recorded. Their diagnosis, either CC or LC, was registered. Patients were divided into two groups based on their clinical presentation of their MC. One group included patients with at least two episodes of watery diarrhea; and/or their dependence on long-term treatment of corticosteroids to maintain remission; and/or two pathological intestinal mucosa biopsies (MC1, n = 78). These criteria are in line with those suggested for diagnosing IBD [19]. The other group included patients who had had only one episode of severe diarrhea (diarrhea that rendered examination by colonoscopy), or had had a normal biopsy after the initial pathological intestinal biopsy, in combination with a clinical remission (MC2, n = 53). Patients with concomitant celiac disease (9 patients) or an acute gastroenteritis shortly prior to the diagnostic colonoscopy (4 patients) were excluded as they had an obvious organic explanation for the intestinal inflammation, and were considered to be suffering from secondary MC [3, 4]. The patients were also divided into two groups depending on whether concomitant IBS-like symptoms were present or not. Patients were compared to controls from the MDSC study.

The data were analyzed using the statistical software package SPSS for Windows^© (Release 20.0; IBM, NY, USA). The patients were significantly older, with a wider age range than the controls. Therefore, the 12 patients younger and the two patients older than the controls were excluded, as were patients with celiac disease and gastroenteritis (13 patients), leaving 131 of the original 158 patients for the statistical calculations comparing patients with controls. Thus, both controls and patients were within the same age range 45–73 years. First, the distribution of continuous variables (age, disease duration, body mass index (BMI), days of wine drinking/month, and minutes of physical activity/week) was tested using an one-sample Kolmogorov-Smirnov test. All distributions differed significantly (p < 0.05) from a normal distribution, and therefore the factors studied were categorized and the values were given as median (interquartile range). There was no difference between CC and LC in any patient characteristics (data not shown), in accordance with a previous systematic review [22]. For this reason, all calculations were performed irrespective of the diagnosis, CC or LC. Differences between groups were calculated by the 2-tailed Mann–Whitney U -test. Correlations were performed by the Spearman rank correlation test. Fisher’s exact test was used for categorical variables. The Kruskal-Wallis test was used to calculate differences in VAS-IBS between subgroups of smoking- and alcohol habits, and was the only calculation including all 158 patients. A p-value < 0.05 was considered statistically significant.

Age was divided into 5-year intervals. The cohort was divided into quartiles of the number of days of drinking wine/month and the average number of exercising minutes per week during the year. Smoking was divided into three categories: subjects who had never smoked, subjects who had stopped smoking, and current smokers, including both regular and occasional smokers at the time of inclusion in the study. Subjects who denied intake of beer, wine, and liquor during the previous month before completion of the questionnaire were defined as having no alcohol intake. All subjects were then divided into four groups: subjects not using tobacco and alcohol, subjects only drinking alcohol, subjects only smoking, and subjects both smoking and drinking alcohol. Employment was divided into three categories: employed, retired or others, where others included housewives, students and unemployed. Education was divided into having a university education or not. There were missing values in days of drinking wine/month, smoking- and alcohol habits, physical activity, and level of education, which were labeled each as a specific category. The first category was used as reference. Factors intended for study (independent variables), namely, smoking habits and smoking- and alcohol habits, were initially examined using an unconditional logistic regression to calculate odds ratios with 95 confidence intervals (OR with 95 CI). Analyses of smoking habits were then performed adjusted for age at baseline, physical activity, days of drinking wine/month, level of education, and type of employment, as these characteristics had > 5 percentage difference between controls and patients, except in the case of MC2, where level of education did not differ between patients and controls. Smoking- and alcohol habits were adjusted for age, physical activity, level of education, and employment, except for MC2, where no adjustment for level of education was performed. Calculations were first performed on the whole patient group compared to controls, and then separately for patients with primary, persistent MC (MC1), transient MC (MC2), patients with IBS-like symptoms in addition to MC, and patients without IBS vs. controls (dependent variables).

In total, 131 women (median age 63 (59–67) years) with MC were included in the statistical calculations, CC was diagnosed in 82 patients (62.6) and LC in 49 patients (37.4) (Table 1). The IBS criteria were fulfilled in 43 patients (52.4) with CC, and in 25 patients (51.0) with LC. The duration of the disease, at the time of inclusion in the study and data collection, was 7 [3‐14] years. Measurements of hemoglobin (Hb) in blood and C-reactive protein (CRP) in plasma were in the majority of patients within reference values. Besides MC and IBS, 36 suffered from hypertension, 24 from rheumatoid arthritis, and 17 from asthma or bronchitis. The most common drug treatments at the time of inclusion in the study were corticosteroids (32.1), proton pump inhibitors (26.0), antidepressant drugs of the type selective serotonin reuptake inhibitors (21.4), angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists (18.3), statins (17.6), thyroid hormones (17.6), and beta-blockers (16.0). Patients with drug treatments at inclusion were older than patients without treatment, (64.92 (60.00–68.34) years and 62.07 (55.55–64.24) years, respectively, p = 0.012).

Of the patients, 91.7 were born in Sweden, compared with 90.2 of the controls. More patients than controls had a university degree (p = 0.001). As the patients were older than the controls, more patients were retired (p < 0.001) (Table 1). There was no difference between MC1 and MC2 regarding concomitant IBS-like symptoms (Table 2). The group of patients who only smoked, with no intake of alcohol, had the lowest values (most symptoms) on all VAS-IBS scales, but reached statistical significance only on the scales bloating and flatulence (p = 0.011) and the gastrointestinal symptoms’ influence on daily life (p = 0.012).

Of the patients, 27.5 had never smoked, in contrast to 42.3 of the controls. The prevalence of current smokers was 35.9 of the MC patients and 27.8 of the controls, whereas the prevalence of women who had stopped smoking was 36.6 of the patients compared with 29.9 of the controls. Of the 48 patients who had stopped smoking, 20 patients had done so during the observation period 2002–2010. In the MC patients, 16.0 used no tobacco or alcohol, 46.6 used alcohol, 13.0 were current smokers, and 20.6 used both tobacco and alcohol (3.8 missing values). The values for the controls are shown in Table 1. There was an association of increased risk for both former and current smokers to develop MC, calculated on the whole group (OR = 1.88, 95 CI = 1.04–3.39 and OR = 2.71, 95 CI = 1.50–4.91, respectively). When calculated with respect to both smoking- and alcohol habits, only the group of smoking without concomitant alcohol intake was associated with an increased risk to develop MC (OR = 2.80, 95 CI = 1.19–6.63). There was no association between smoking habits and the number of days of wine drinking/month in patients (Table 3).

There were only few patients and controls drinking beer and stronger alcoholic beverages, albeit with many missing values. Therefore, only the parameter of “number of days of drinking wine/month” was used in the adjustments. The majority of patients drank 1–2 glasses a day when drinking. Those who drank beer and stronger alcoholic beverages were those who drank wine most days in the month (data not shown).

There was no statistically significant difference between MC1- and MC2 patients regarding smoking habits (p = 0.128), days of drinking wine/month (p = 0.711) or smoking- and alcohol habits (p = 0.160) (Table 1). Although fewer patients in the MC2 group had a university degree and more were unemployed compared to MC1 patients, these differences were not statistically significant (p = 0.277 and p = 0.344, respectively). In the MC1 group, current smoking was the only risk factor for developing MC, whereas in the MC2 group, past smoking was associated with an increased risk of developing the disease (Table 4).

There were more smokers in the IBS group than in the non-IBS group (p = 0.021). The number of days drinking wine/month did not differ between groups (p = 0.508), but the smoking- and alcohol habits differed, with more patients who neither smoked nor drank alcohol in the non-IBS group (p = 0.019) (Table 1). Patients with and without IBS-like symptoms had the same level of education (p = 1.000) and employment (p = 0.588) (Table 1). Smoking was associated with an increased risk to develop MC with IBS-like symptoms, whereas in the group of MC patients who were free of symptoms of IBS, this association was not seen (Table 5).