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Symptomatic Diverticulosis Is Characterized By Loose Stools
Accepted Manuscript Symptomatic Diverticulosis Is Characterized By Loose Stools M. Ellionore Järbrink Sehgal, Anna Andreasson, Nicholas J. Talley, Lars Agréus, Jeong-Yeop Song, Peter T. Schmidt
PII: DOI: Reference:
S1542-3565(16)30318-4 10.1016/j.cgh.2016.06.014 YJCGH 54805
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 7 June 2016 Please cite this article as: Järbrink Sehgal ME, Andreasson A, Talley NJ, Agréus L, Song J-Y, Schmidt PT, Symptomatic Diverticulosis Is Characterized By Loose Stools, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.06.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Symptomatic Diverticulosis Is Characterized By Loose Stools
Authors: M. Ellionore Järbrink-Sehgal, Anna Andreasson, Nicholas J. Talley, Lars Agréus, Jeong-
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Yeop Song, Peter T Schmidt
Grant support: Magtarmförbundet, Bengt Ihre Stiftelsen, Stockholms County Council, Ersta Hospital, Astra Zeneca, Stockholm, Sweden
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Hospital 17176 Solna, Sweden. Email: [email protected]
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Correspondence: M. Ellionore Järbrink-Sehgal, M.D. Gastrocentrum A3:00, Karolinska University
Disclosures: None Author contributions:
M. Ellionore Järbrink-Sehgal, M.D.- Study hypothesis; analysis and interpretation of data; drafting
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of the manuscript; statistical analyses.
Anna Andreasson, Ph.D.- Study hypothesis; statistical analyses and critical revision of manuscript.
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Nicholas J. Talley, M.D., Ph.D.- Study idea, critical revision of manuscript.
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Lars Agréus, M.D., Ph.D.- Study idea, critical revision of manuscript. Jeong-Yeop Song, M.D. Ph.D.- Analysis and interpretation of data. Peter Thelin Schmidt, M.D., Ph.D.– Study idea, analysis and interpretation of data, critical revision of manuscript.
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ACCEPTED MANUSCRIPT SYMPTOMATIC DIVERTICULOSIS IS CHARACTERIZED BY LOOSE STOOLS
M. Ellionore Järbrink Sehgal(1, 2), Anna Andreasson(3, 4), Nicholas J. Talley(5), Lars Agréus(3),
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Jeong-Yeop Song(3, 6), Peter T Schmidt(1)
1. Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases Karolinska University Hospital, Stockholm, Sweden.
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2. Baylor College of Medicine, Department of Gastroenterology, Houston, TX, USA
3. Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska
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Institutet, Stockholm, Sweden.
4. Stress Research Institute, Stockholm University, Stockholm, Sweden.
5. Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia. 6. Division of Gastroenterology, Department of Internal Medicine, Leechuntek Hospital, Suwon,
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Korea.
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ACCEPTED MANUSCRIPT Abstract: Background & Aims: Symptomatic uncomplicated diverticular disease is considered to be a discreet clinical entity distinct from irritable bowel syndrome (IBS), but population-based data are unavailable. We aimed to investigate the prevalence and location of diverticulosis in the general
individuals with diverticulosis would report more constipation and IBS.
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population, and its association with colonic symptoms and mental health. We propose that
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Methods: We performed a population-based study of randomly select adults born in Sweden (18–70 years old, 57.2% women); 745 received a gastroenterology consultation, completed validated
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abdominal symptom and mental health questionnaires, and were examined by colonoscopy. Logistic regression was used to calculate the associations between diverticulosis and age, gender, gastrointestinal symptoms, anxiety, depression and self-rated health.
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Results: Among the 742 participants (54.6% women) 130 (17.5%) had diverticulosis. Age was the strongest predictor of diverticulosis (P<.001) and diverticulosis was rare in participants younger than 40 years (0.7%). All participants with diverticulosis had sigmoid involvement. Participants with
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diverticulosis were more likely to report loose stools (odds ratio [OR], 1.88; 95% CI, 1.20–2.96), urgency (OR, 1.64; 95% CI, 1.02–2.63), passing mucus (OR, 2.26; 95% CI, 1.08–4.72), and a high
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stool frequency (OR, 2.02; 95% CI, 1.11–3.65). Diverticulosis was associated with abdominal pain (OR, 2.10; 95% CI, 1.01–4.36; P=.047) and IBS-diarrhea (OR, 9.55; 95% CI, 1.08–84.08; P=.04) in participants older than 60 years. Presence of anxiety and depression and self-rated health were similar in participants with and without diverticulosis.
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ACCEPTED MANUSCRIPT Conclusion: The prevalence of diverticulosis is age dependent. Diverticulosis is associated with diarrhea in subjects across all age ranges. In subjects older than sixty, diverticulosis is associated with abdominal pain and diarrhea-predominant IBS.
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Symptomatic Uncomplicated Diverticular Disease (SUDD)
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KEY WORDS: Diverticulosis; colonoscopy; population-based; Irritable Bowel Syndrome (IBS),
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ACCEPTED MANUSCRIPT Introduction Colonic diverticular disease is a common and costly health problem, ranking as the fifth leading gastrointestinal (GI) disease in terms of health-care costs in Europe and North America.1 The prevalence of diverticulosis ranges from 5% to 45% by age 60 in Europe and North America.2
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However, the true prevalence of diverticulosis is uncertain, with current prevalence data mainly extracted from autopsy series, hospital admissions, radiological and endoscopic series among symptomatic subjects.3, 4, 5
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According to currently accepted definitions and terminology, “diverticulosis” is defined as the
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presence of colonic diverticula, which may or may not be symptomatic. While traditionally linked to constipation, it is controversial whether diverticulosis per se causes gastrointestinal symptoms and in particular if there is a link between diverticulosis and irritable bowel syndrome (IBS).6, 7, 8 “Diverticular disease” is defined as clinically significant and symptomatic diverticulosis, in which diverticulosis has escalated to an illness. Symptomatic uncomplicated diverticular disease (SUDD)
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refers to a separate clinical subtype of diverticular disease, in which there are persistent abdominal symptoms attributed to diverticula in the absence of macroscopically overt colitis or diverticulitis.9
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The definition of SUDD however is controversial in the literature. It has been defined as the presence of abdominal pain and change in bowel habits attributed to diverticula in the absence of alternate
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etiologies.10, 11, 12 Other authors have defined SUDD as abdominal pain or change in bowel habits in the presence of diverticulosis and absence of alternate etiologies13, while others have simply referred the presence of any symptoms in diverticular disease as symptomatic diverticular disease.14 In fact, SUDD may resemble IBS but does not fulfill the Rome criteria for diagnosis.14 Due to the alleged overlap between IBS and SUDD, several studies have addressed the symptom profiles in SUDD and IBS and one study has developed clinical criteria to differentiate these two.11, 12, 15 Purported differences characterizing SUDD include prolonged, less frequent, moderate to severe left lower abdominal pain (>24 hours) without relief by defecation and family history of a first degree relative
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ACCEPTED MANUSCRIPT with diverticular disease. The main differentiating study though included a select outpatient population, leaving it unclear how symptoms in the community are related to diverticulosis.11 Recently a possible causal link between diverticulitis and new onset IBS and mood disorder has been suggested.16 However, no population-based studies exist evaluating diverticulosis and mood
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disorders.
We performed a random population-based colonoscopy study to determine the prevalence of diverticulosis and the relation to gastrointestinal symptoms in the general population. We
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hypothesized that individuals with diverticulosis would report more constipation, IBS and mood
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disorders than those without. We also hypothesized that we would confirm the existence of a distinct subgroup with SUDD, defined as the presence of abdominal pain and change in bowel habits attributed to diverticula in the absence of alternate etiologies.
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Methods
Study approval was obtained from the local Ethics committee (No 394/01, Forskningskommitte Syd, Stockholm, Sweden) and written informed consent was obtained from all participants. This study was
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part of a larger study to survey colonic pathology and its association with gastrointestinal symptoms in a normal population.17 The logistics of the sampling procedure has been described in detail
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elsewhere (see supplementary documents).17 Study population
A random sample of 3556 individuals aged 18 to 70 years from two adjacent parishes in Stockholm, were mailed a validated questionnaire on troublesome gastrointestinal symptoms over the past three months (the Abdominal Symptom Questionnaire, ASQ).18, 19, 20 Of the 2293 questionnaire responders, 1244 out of 1673 reached by telephone were scheduled for a gastroenterologist consultation. At time of consultation additional questionnaires were completed including ASQ, the Rome II Modular
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ACCEPTED MANUSCRIPT questionnaire and the Hospital Anxiety Depression Scale (HADS). A total of 745 (426 women and 319 men) accepted to undergo a subsequent ileo-colonoscopy. Responders were similar to nonresponders as detailed elsewhere.17 Participation was not financially compensated.
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Procedures The colonoscopies were performed at Ersta hospital from June 2002 to October 2006 and followed Swedish clinical practice with biopsy sampling. Colonoscopy preparation included clear liquid diet
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and bowel cleansing with 45 ml Phosphoral taken orally twice within 4-hour interval. Seven
experienced endoscopists performed all procedures. Sedation and analgesics, given as needed,
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included inhaled nitric oxide, intravenous midazolam and/or alfentanyl. The endoscopists were aware of the study’s general aims and protocol but were blinded to participants’ past medical history and questionnaires results. Adverse events were recorded.
Diverticulosis
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Variables
IBS and IBS subtypes
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The presence and location of diverticulosis was recorded.
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Using the Rome II Modular questionnaire, IBS was defined as having abdominal pain or discomfort for at least 3 weeks (at least one day in each week) in the past 3 months with at least two out of three of the following: pain or discomfort improved or relieved after a bowel movement, onset of pain or discomfort associated with a change in the usual number of bowel movements, or onset of pain or discomfort associated with a change in stool consistency. IBS-Diarrhea (IBS-D) was defined as having IBS and reporting loose, mushy or watery stools but not hard or lumpy stools at least 25 % of the time for the last three months. IBS-Constipation (IBS-C) was defined as having IBS and reporting
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ACCEPTED MANUSCRIPT hard or lumpy stools but not loose, mushy or watery stools at least 25% of the time in the last 3 months.21
Gastrointestinal symptoms
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Symptoms from the Rome II Modular questionnaire were used and included abdominal pain or
discomfort (located anywhere in the abdomen for at least 3 weeks, at least one day in each week, in the past 3 months), mushy stools, high frequency defecation (more than three bowel movements a
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day), lumpy stools, low frequency defecation (one bowel movement less than every three days),
fecal incontinence.
Localization of abdominal pain or discomfort
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bloating, urgency, defecation straining, feeling of incomplete bowel movement, passing mucous and
The localization of abdominal pain/ discomfort was derived from the ASQ and was defined as
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presence of “troublesome“ abdominal pain/ discomfort in the preceding 3 months specified to epigastrium, periumbilical, suprapubic area, right quadrant, left quadrant or the whole abdomen.18, 19, 20
Left lower quadrant included the suprapubic area and left quadrant. All localizations were analyzed
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separately.
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Anxiety, depression and self-rated health Anxiety and depression was derived from the Hospital Anxiety and Depression Scale (HADS) and defined by an abnormal score of 8 or above respectively.22 Self-rated health was assessed with the question: “In general, would you say your health is: excellent, very good, good, fair or poor”.23
Laxatives and antibiotics
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ACCEPTED MANUSCRIPT Laxative and any antibiotic use 3 months prior were reported at the gastroenterology consultation interview and from electronic medical record using the ATC codes.
Inflammatory Bowel Disease (IBD) and Microscopic Colitis
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Past medical history of Crohn’s disease, ulcerative colitis or microscopic colitis was recorded in the questionnaires, during the gastroenterology consultation or at the time of colonoscopy. An expert pathologist reviewed all random biopsies from five segments (right colon, transverse, descending,
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sigmoid colon and rectum).
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Statistical methods
Logistic regression was used to analyze differences in background variables, IBS and gastrointestinal symptoms between participants with and without diverticulosis and the interaction between presence of diverticulosis and antibiotic use on gastrointestinal symptoms using an interaction term
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diverticulosis *use of antibiotics. All analyses were age and gender adjusted and performed using
was < 0.05.
Missing Data
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STATA (11.0. StataCorp Texas). Results were considered significant when the two-sided p value
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Missing data on presence (n=3) and localization (n=4) of diverticulosis left 742 and 738 participants, respectively, for analysis. A further 44 participants were missing data on gastrointestinal symptoms and 7 had no data on body mass index (BMI), leaving a total of 122 with and 577 participants without diverticulosis for analysis of gastrointestinal symptoms. In the analysis of localization of abdominal pain, report on pain localization was missing in 39, leaving 122 with and 581 participants without diverticulosis for the analysis. Data on antibiotic use was available in 737 participants but the ATC code was missing in 2 participants with and 17 participants without diverticulosis.
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ACCEPTED MANUSCRIPT Results Overview Colonoscopy participants were slightly older (mean age 51.7 years vs. 44.7 years, p<0.001), reported a higher rate of IBS (36.7% vs. 21.2%, p<0.001) and fewer participants were symptom free (31.9%
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vs. 45.1% p<0.001) than noncolonoscopy ASQ responders. There was no difference in gender or education between colonoscopy and noncolonoscopy participants.17 Among the 745 ileo-
colonoscopies, 702 (94%) were complete reaching the cecum and/or terminal ileum. In total, 422
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(57%) were women and 323 (43%) were men. Eleven participants had colitis (2 with Crohn’s
disease, 5 with ulcerative colitis and 4 with histology-evident microscopic colitis). No participant
Prevalence and localization of diverticulosis
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reported laxative use. No procedural adverse events occurred.
In total, 130 out of the 742 participants had diverticulosis (17.5%, 95%CI: 14.95- 20.4). All
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participants with diverticulosis had sigmoid involvement. Cecum, ascending colon, flexures with transverse colon and descending colon were involved in 3.2%, 4.0%, 13.6% and 12.7%, respectively. The prevalence of diverticulosis was similar in men (18.6%) and women (16.7%) but increased with
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age (p<0.001) and was low in participants younger than 40 years (0.7%) (Figure1). Consequently, the age differed significantly between those with and without diverticulosis (mean age=60, range 37-71
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years vs. mean age 51, range 19-70 years, respectively, p<0.001). BMI was not associated with diverticulosis (p=0.3). The study group characteristics are presented in Table I by age group and diverticulosis status excluding the participants with colitis.
Insert Table I here.
Diverticulosis and gastrointestinal symptoms, IBS and IBS subtypes
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ACCEPTED MANUSCRIPT Overall, participants older than 60 years reported less gastrointestinal symptoms than younger participants (Table I). Diverticulosis in all participants was associated with diarrhea-like symptoms, specifically mushy
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stools (OR: 1.88, 95%CI: 1.20-2.96, p=0.006), high frequency defecation (OR: 2.02, 95%CI: 1.113.65, p=0.02), urgency (OR: 1.64, 95%CI: 1.02-2.63, p=0.04) and passing mucus (OR: 2.26, 95%CI: 1.08-4.72, p=0.03). No significant differences were noted in other GI symptoms, IBS or IBS subtypes
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(data not shown).
When excluding colitis cases similar results were observed but there was a strong trend for
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abdominal pain (OR: 1.59, 95%CI: 0.98-2.59, p=0.06) and incomplete bowel movement (OR: 1.50, 95%CI: 0.96-2.37, p=0.08) (Table II). After additional exclusion of those with recent antibiotic exposure, diverticulosis was still associated with mushy stools (OR: 1.67, 95%CI: 1.01-2.76, p=0.04), passing mucus (OR: 2.39, 95%CI: 1.08-5.26, p=0.03) and the trend for abdominal pain (OR:
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1.69, 95%CI: 1.00-2.87, p=0.05) and feeling of incomplete evacuation (OR: 1.56, 95%CI: 0.95-2.54, p=0.08) remained (data not shown).
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Older versus younger participants
In participants older than 60 years, diverticulosis was associated with abdominal pain (OR: 2.10,
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95%CI: 1.01-4.37, p=0.047), IBS-D (OR: 9.55, 95%CI: 1.08-84.08, p=0.04) and diarrhea symptoms. Specifically, mushy stools (OR: 3.33, 95%CI: 1.69-6.58, p<0.001), high frequency stools (OR: 5.11, 95%CI: 1.85-14.16, p=0.002) and incomplete bowel movements (OR: 1.99, 95%CI: 1.03-3.87, p=0.04) were all associated with diverticulosis in this older age group. No significant differences were noted in other GI symptoms or IBS-C. Similar findings were observed when excluding participants with colitis. The symptom associations remained for abdominal pain (OR: 2.46, 95%CI: 1.09-5.55, p=0.03), urgency (OR: 2.61, 95%CI: 1.19-5.71, p=0.02) and mushy stools (OR: 2.49, 95%CI: 1.16-5.32, p=0.02) when those exposed to antibiotics were excluded.
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ACCEPTED MANUSCRIPT No association between diverticulosis and GI symptoms, IBS or IBS subtypes, were noted in those sixty or younger.
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Diverticulosis and anxiety, depression and self-rated health There was no difference in anxiety, depression or self-rated health between participants with and
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without diverticulosis regardless of age group, colitis or antibiotic exposure. (Table II).
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Insert Table II here.
Diverticulosis and localization of abdominal pain/ discomfort
ASQ derived troublesome abdominal pain/ discomfort was reported by 55 of 122 participants with diverticulosis (45.1%) and by 286 of 581 participants without (49.2%). Presence of abdominal pain/
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discomfort was similar between the two groups but a trend for a left lower quadrant localization of the abdominal pain/discomfort among all participants with diverticulosis was observed (OR: 1.83; 95%CI: 0.92-3.64, p=0.09). When age was stratified, left lower quadrant localization of reported
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abdominal pain/ discomfort was significantly associated with diverticulosis in participants older than
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age 60 years (OR: 6.78, 95%CI: 1.80-25.56, p=0.005).
Diverticulosis and use of antibiotics Overall, recent antibiotic exposure was present in 70 out of 610 (11.5%) in the non-diverticulosis group and 21 out of 127 (16.5%) in the diverticulosis group. The main antibiotic indications were urinary tract and upper respiratory infections. None had diverticulitis as the indication for antibiotic use. Regardless of diverticulosis status, antibiotic exposure was significantly higher in those older
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ACCEPTED MANUSCRIPT than sixty than in those age sixty or below (14.1% (95%CI: 13.8-14.4) vs. 11.5% (95%CI: 11.4-11.6) p<0.001).
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Interaction between diverticulosis and recent antibiotic use on GI symptoms Participants with diverticulosis and recent antibiotic use reported more GI symptoms than those with diverticulosis without recent antibiotic use, or participants without diverticulosis with recent
antibiotic use, as shown by a positive interaction effect between the presence of diverticulosis and
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mushy stools, high frequency stools and urgency.
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recent antibiotic use (See Figure 2). The GI symptoms associated with the positive interaction were
Discussion
In this large population-based cohort, we describe the true prevalence of diverticulosis in a community. As expected there was a significant association between increasing age and
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diverticulosis.2, 3, 5, 7, 24 More importantly, we present new information on diverticulosis and its association with diarrhea-like symptoms in subjects across all age ranges, and with abdominal pain
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and diarrhea-predominant IBS in those older than sixty years. Unlike the traditionally accepted theory, we found no association between diverticulosis and constipation. Laxative use, microscopic
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colitis or IBD did not account for the association between diverticulosis and diarrhea-like symptoms. Non-population-based studies have shown variable results associating constipation, abdominal pain and IBS to colonic diverticulosis.6, 12, 25 Two population-based non-colonoscopy studies and a recent colonoscopy study have shown a link between diverticulosis and diarrhea-predominant IBS, which further supports the evidence in our study. 7, 8, 26 We found that the symptom associations, abdominal pain and diarrhea-predominant IBS, were only present in those older than sixty with diverticulosis. The IBS prevalence in our study (14.7%) is comparable to the IBS prevalence in the Swedish community (6-18%).27, 28 While the odds ratio was nearly 10 fold suggesting a strong association, the
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ACCEPTED MANUSCRIPT link between diverticulosis and diarrhea-predominant IBS should be viewed with caution given the wide confidence intervals and larger studies are needed to confirm this link. The biological mechanisms by which diarrhea-like symptoms may occur in diverticulosis are unknown but several possible explanatory pathophysiological mechanisms exist. First, colonic
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diverticulosis is more prevalent in the older population, where age-related changes in the function of smooth muscle or neurons are possible but this alone seems unlikely to account for diarrhea.29, 30 Alternatively, chronic low-grade inflammation may play a role by influencing the function of
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epithelial cells, smooth muscle and enteric nerves leading to changes in motility and sensation.31 Recent studies suggest that inflammation and enteric neuromuscular pathology plays a role in the
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early pathogenesis of diverticulosis and its symptoms.32
We speculate that alterations in the intestinal microbiota may play a role in the symptomatic diverticulosis. In our study, 21 out of 127 participants with diverticulosis reported recent antibiotic use. We found participants with diverticulosis and a history of recent antibiotic use to have a
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significant 4 to 7 fold increased likelihood of urgency, increased stool frequency and looser stools. The well-known major mechanisms of antibiotic-associated diarrhea involve disturbance of gut
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microbiota and the direct gastrointestinal irritation of antibiotics on the mucous membranes.33 Interestingly, this was not observed in participants without diverticulosis despite recent antibiotic use.
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Although no cause-or-effect relationship can be established, it raises the question whether patients with diverticulosis are perhaps more sensitive to gut microbiome disturbances.
Another important finding in our study is the lack of association between diverticulosis and mood disorders. Mood disorders have been associated with diverticulitis.16 We found participants with diverticulosis to have good self-rated health and no association between diverticulosis and anxiety or depression was observed. We used the validated HADS (Hospital Anxiety Depression Scale) questionnaire to assess depression and anxiety. Although not the gold standard for screening
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ACCEPTED MANUSCRIPT depression and anxiety, it has been validated to assess prevalence and symptom severity in the general population.22 It is still conceivable that acute inflammation is the key trigger for developing mood disorder and not diverticulosis per se as our study population had no diverticulitis history, but
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prospective studies are needed to confirm this association.
Lastly, sub-analysis of ASQ derived data suggests that in older participants (above 60) with
diverticulosis, abdominal pain/ discomfort localizes to the left lower quadrant. Although purported to
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association and no other specific pain symptoms were identified.
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be a feature of SUDD12, the wide confidence intervals warrant larger studies to confirm this
Our study has several strengths. First, it is a random population-based study with participants from the general population, unbiased by those seeking medical attention for secondary gain, minimizing selection bias and improving the generalizability of our results. Secondly, it has a high participation
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rate and a wide age range. Third, our diagnostic method for identification of diverticulosis was colonoscopy performed by experienced endoscopists. This has been a major limitation in prior studies.2, 3, 4, 7, 8, 12, 16 Moreover, an expert gastrointestinal pathologist reviewed the histology
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excluding microscopic colitis as a confounder. Lastly, we excluded individuals born abroad, in total 11 % of the two parishes total inhabitants, minimizing results biased by differences in genetics and
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foreign microbiota.
Some limitations of our study need to be recognized though. Firstly, this is a cross-sectional study. Hence, no causal inference between diverticulosis and diarrheal symptoms can be established. Secondly, our study population were more symptomatic than nonparticipants, urban, slightly better educated than average and included only Swedish born participants, potentially affecting lifestyle factors, diet and exercise. Any symptom bias however was more prominent among younger
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ACCEPTED MANUSCRIPT participants and significant in the youngest age group only. As diverticulosis was found only in participants over 40 years of age any symptom bias is likely to play less of a role in the present study. Thirdly, the Rome II criteria were used for IBS diagnosis. However, although we applied the Rome II criteria for IBS, the three primary symptom criteria in Rome III are very similar.34 The lack of stool
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diary and data on duration of pain are also possible limitations. Lastly, the underrepresentation of younger participants, especially men, likely explains the lower diverticulosis prevalence in this age
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group in comparison to prior studies with a reported prevalence of 1-2%.6
In conclusion, in this population-based colonoscopy study the prevalence of diverticulosis increases
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with age and diverticulosis is associated with diarrhea symptoms across all age ranges. In those older than sixty, diverticulosis is associated with abdominal pain and diarrhea-predominant IBS. We found no evidence linking diverticulosis to constipation or mood disorders. The link between diverticulosis and diarrhea, abdominal pain and diarrhea-predominant IBS should direct future age specific studies
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aimed at finding tailored therapeutic strategies, and importantly increase our awareness of
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symptomatic diverticulosis in patients older than sixty years.
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ACCEPTED MANUSCRIPT Table I. Study group characteristics by diverticulosis status and age groups excluding participants with colitis. Background variables
Ages 60 years or less
Ages over 60 years
Div -
Total
Div +
Div -
Total
Number (N)
50
465
515
79
137
216
Age Mean (sd)
53(5.5)
45.0(10.5)
45.8(10.4)
65.7(2.8)
65.7(2.9)
65.7(2.9)
Women N (%)
29(58.0)
268(57.6)
297(57.7)
42(53.2)
79(57.7)
121(56.0)
Body mass index (BMI) Mean (sd)
25.2(3.7)
24.4(4.0)
24.5(4.0)
26.1(3.9)
25.6(3.8)
25.8(3.8)
IBS and GI symptoms % (95%CI)
Div +
Div -
Total
Div +
Div -
Total
Number (N)
50
441
491
72
127
199
Irritable bowel syndrome (IBS)
16.0
17.0
16.9
12.5
5.5
8.0
(5.5-26.5)
(13.5-20.5)
(13.6-20.2)
(4.7-20.3)
(1.5-9.5)
(4.3-11.9)
2.0
5.2
4.9
6.9**
0
2.5
(2.0-6.0)
(3.1-7.3)
(3.0-6.8)
(0.9-13.0)
2.0
2.9
2.9
2.8
3.1
3.0
(1.4-4.5)
(1.4-4.3)
(-0.1-6.7)
(0.1-6.2)
(0.6-5.4)
33.6
33.4
25 *
13.4
17.6
(29.1-38.0)
(29.2-37.6)
(14.8-35.2)
(7.4-19.4)
(12.322.9)
(-2.0-6.0) Abdominal pain/ discomfort
32.0
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(18.6-45.4)
High frequency defecation
Low frequency defecation Bloating
(0.3-4.2)
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34.0
33.8
33.8
37.5 ***
14.2
22.6
(20.4-47.6)
(29.4-38.2)
(29.6-38.0)
(26.0-49.0)
(8.0-20.3)
(16.828.5)
14.0
15.2
15.1
19.4***
3.9
9.5
(4.0-24.0)
(11.8-28.6)
(11.9-18.2)
(10.1-28.2)
(0.5-7.4)
(5.4-13.7)
30.0
25.9
26.3
26.4
22.0
23.6
(16.8-43.2)
(21.7-30.0)
(22.4-30.2)
(16.0-36.8)
(14.7-29.4)
(17.729.6)
6.0
10.2
9.8
9.7
5.5
7.0
(-0.8-12.8)
(7.4-13.0)
(7.1-12.4)
(2.7-16.7)
(1.5-9.5)
(3.4-10.2)
30.0
35.4
34.8
19.4
18.9
19.1
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Mushy stools
Lumpy stools
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IBS-Constipation
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IBS-Diarrhea
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Div +
(13.6-
17
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(30.6-39.1)
(10.1-28.8)
(12.0-25.8)
24.6)
26.0
28.3
28.1
33.3**
14.2
21.1
(13.4-38.6)
(24.1-32.6)
(24.1-32.1)
(22.2-44.5)
(8.0-20.3)
(15.426.8)
34.0
32.0
32.2
29.2
19.7
23.1
(20.4-47.6)
(27.6-36.3)
(28.0-36.3)
(18.4-39.9)
(12.7-26.7)
(17.229.0)
38.0
37.0
37.1
31.9*
18.9
23.6
(24.1-51.9)
(32.4-41.5)
(32.8-41.4)
(20.9-43.0)
(12.0-25.8)
(17.729.6)
14.0
9.3
9.8
8.3
3.9
5.5
(4.0-24.0)
(6.6-12.0)
(7.1-12.4)
(1.8-14.9)
(0.5-7.4)
(2.3-8.7)
8.0(0.2-15.8)
6.6(4.3-8.9)
6.7(4.5-8.9)
13.9(5.7-221)
13.9(7.4-19.4)
13.6(8.818.4)
Number (N)
50
465
HADS- A % (95%CI)
24.0(11.7-36.3)
HADS- D % (95%CI)
6.0(-0.8-12.8)
Self-rated health (N)
50
Excellent %
10.0
Very good %
36.0
Good %
40.0
Fair % Poor %
Feeling of incomplete bowel movement
Passing mucous
Fecal incontinence Anxiety, depression and self-rated health
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Defecation straining
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Urgency
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(16.8-43.2)
79
137
216
24.3(20.428.2)
24.3(20.228.0)
17.7(9.1-26.3)
16.8(10.523.1)
17.1(12.1 -22.2)
13.3(10.216.4)
12.6(9.7-15.5)
11.4(4.2-18.6)
9.5(4.5-14.5)
10.2(6.114.3)
443
493
72
127
199
11.5
11.3
16.7
14.2
15.1
38.6
38.3
40.3
31.5
34.7
33.2
33.9
26.4
38.6
34.2
14
14.9
14.8
16.7
14.2
15.1
0
1.8
1.6
2.8
0
1.0
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EP
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515
Div (+)= Diverticulosis, Div (-) =No diverticulosis, HADS –Hospital Anxiety (A) and Depression (D) Scale *p< .05 **p< .01 ***p< .001
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ACCEPTED MANUSCRIPT Table II. Differences in background variables and presence of gastrointestinal symptoms between participants with and without diverticulosis calculated with logistic regression analysis
95% CI
Age
1.10***1
1.08-1.13
Women
0.902
0.60-1.36
BMI
1.03
0.98-1.08
IBS
1.65
0.88-3.09
IBS-D
2.06
0.73-5.78
IBS-C
0.91
0.23-3.53
Abdominal pain/discomfort
1.59
Mushy stools
1.94**
High frequency defecation
2.14*
Lumpy stools
1.41
Low frequency defecation
1.00
0.47-2.16
Bloating
1.04
0.63-1.72
Urgency
1.67*
1.04-2.68
0.98-2.59
1.23-3.06
1.17-3.89
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0.86-2.30
1. 36
0.85-2.16
Feeling of incomplete bowel movement
1.50
0.96-2.37
Passing mucous
2.26*
1.08-4.73
Fecal incontinence
1.03
0.53-2.03
Anxiety
1.02
0.96-1.08
Depression
0.95
0.88-1.03
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Defecation straining
1
Gender adjusted
2
Age adjusted
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OR
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Background variables
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and presented as odds ratios (OR) and 95% confidence intervals (95%CI).
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0.93
0.74-1.16
BMI- body mass index; IBS – irritable bowel syndrome; D- diarrhea; C- constipation; *p< .05 **p< .01
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***p< .001
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Figure legends:
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Figure 1: Prevalence of diverticulosis per age group presented as % and 95%CI.
Figure 2. Adjusted OR with 95% CI for each gastrointestinal symptom evaluating the interaction of antibiotics and diverticulosis in all four different groups. The reference group is ” No Antibiotics, No Diverticulosis ” with OR: 1.00. The other groups are ”Recent Antibiotics, Positive Diverticulosis”;
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“Recent Antibiotics, No Diverticulosis” and “No Antibiotics, Positive Diverticulosis”.
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ACCEPTED MANUSCRIPT References:
1 Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500-1511.
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2 Painter NS, Burkitt DP. Diverticular disease of the colon: a deficiency disease of western civilization. Br Med J 1971;2:450–454.
3 Hughes LE. Postmortem survey of diverticular disease of the colon. Gut 1960;10:336
population of Oxford area. Br Med J 1967;23;3(5568):762-763.
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4 Manuosos ON, Truelove SC, Lumsden K, et al. Prevalence of colonic diverticulosis in general
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5 Delveux M. Diverticular disease of the colon in Europe: epidemiology, impact on citizen health and prevention. Aliment Pharmacol Ther 2003;18:71-74.
6 Parks TG. Natural history of diverticular disease of the colon. Clin Gastroenterol 1975;4:53-69. 7 Jung HK, Choung RS, Locke III GR, et al. Diarrhea predominant irritable bowel syndrome is
661.
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associated with diverticular disease: a population based study. Am J Gastroenterol 2010;105(3):652-
8 Yamada E, Inamori M, Uchida E, et al. Association between the location of diverticular disease and
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the irritable bowel syndrome: a multicenter study in Japan. Am J Gastroenterol 2014;109:1900-1905.
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9 Elisei W, Tursi A. Recent advances in the treatment of colonic diverticular disease and prevention of acute diverticulitis. Ann of Gastroenterol 2016;29(1):24-32. 10 Kohler L, Sauerland S, Neugebauer E. Diagnosis and treatment of diverticular disease: results of a consensus development conference. The Scientific Committee of the European Association for Endoscopic Surgery. Surg Endosc 1999;13:430–436. 11 Annibale B, Lahner E, Maconi G. Clinical features of symptomatic uncomplicated diverticular disease: a multicenter Italian survey. Int J Colorectal Dis 2012:27:1151-1159.
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ACCEPTED MANUSCRIPT 12 Tursi A, Elisei W, Picchio M, et al. Moderate to severe and prolonged left lower abdominal pain is the best symptom characterizing symptomatic uncomplicated diverticular disease of the colon: a comparison with fecal calprotectin in clinical setting. J Clin Gastroenterol 2015;49:218-221.
clinical insights. Am J Gastroenterol 2012;107:1486-1493.
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13 Strate LL, Modi R, Cohen E. Diverticular disease as a chronic illness: evolving epidemiologic and
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14 Spiller RC. Is it diverticular disease or is it irritable bowel syndrome? Dig Dis 2012;30:64-69. 15 Cuomo R, Barbara G, Andreozzi P, et al. Symptom pattern can distinguish diverticular disease
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from irritable bowel syndrome. Eur J Clin Invest 2013; 43 (11): 1147-1155.
16 Cohen E, Fuller G, Bolus R, et al. Increased risk for irritable bowel syndrome after acute diverticulitis. Clin Gastroenterol Hepatol 2013;11:1614-1619.
17 Kjellström L, Molinder H, Agréus L, et al. A randomly selected population sample undergoing
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colonoscopy: prevalence of the irritable bowel syndrome and the impact of selection forces. Eur J Gastroenterolog and Hepatol 2014;26(3):268-275.
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18 Agréus L. The abdominal symptom study.An epidemiological survey of gastrointestinal and other abdominal symptoms in the adult population of Östhammar, Sweden. Thesis. Uppsala University,
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Uppsala, Sweden 1993.
19 Agréus L, Svärdsudd K, Nyrén O, et al. Reproducibility and validity of a postal questionnaire. The abdominal symptom study. Scand J Prim Health Care 1993;11:252-262. 20 Agréus L, Svärdsudd K, Nyrén O, et al. Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time. Gastroenterology 1995;109:671-680. 21 Drossman DA. Rome II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus, 2nd edition. McLean, VA: Degnon Associates, 2000.
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ACCEPTED MANUSCRIPT 22 Bjelland I, Dahl A, Tangen HT, et al. The validity of the hospital anxiety and depression scale- an updated literature review. J of Psychosom Res 2002;52:69–77. 23 DeSalvo KB, Bloser N, et al. Mortality prediction with a single general self-rated health question.
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A meta-analysis. J Gen Intern Med 2006;21(3):267-275. 24 Stollman NH, Raskin JB. Ad hoc practice parameters committee of the American College of
Gastroenterology. Diagnosis and management of diverticular disease of the colon in adults. Am J
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Gastroenterol 1999;94:3110-3121.
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25 Zollinger RW. The prognosis in diverticulitis of the colon. Arch Surg 1968;97:418-422. 26 Simpson J, Neal R, Scholefield JH, et al. Patterns of pain in diverticular disease. Eur J Gastroenterol Hepatol 2003;15:1005-1010.
27 Kay L. Prevalence, incidence and prognosis of gastrointestinal symptoms in a random sample of
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an elderly population. Age Ageing 1994;23:146–149.
28 Österberg E, Blomquist L, Krakau I, et al. A population study on irritable bowel syndrome and
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mental health. Scand J Gastroent 2000; 264- 267.
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29 Szurswewski JH, Holt PR, Schuster M, et al. Proceedings of a workshop entitled neuromuscular function and dysfunction of the gastrointestinal tract in aging. Dig Dis Sci 1989;34:1135-1146. 30 Smiths GJ, Lefebvre RA. Influence of age on cholinergic and inhibitory nonadrenergic noncholinergic responses in the rat ileum. Eur J Pharmacol 1996;303:79-86. 31 Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 1996;111:1683-1699. 32 Böttner M, Wedel T. Abnormalities of neuromuscular anatomy in diverticular disease. Dig Dis 2012; 30:19–23.
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ACCEPTED MANUSCRIPT 33 Högenauer C, Hammer HF, Krejs GJ, et al. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis 1998;27(4):702-710. 34 Drossman DA. The functional gastrointestinal disorders and the Rome III process.
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Gastroenterology 2006;130:1377-1390.
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SUPPORTING TABLES
1.10***1 1.102 1.03 1.55 1.85 1.22 1.69
1.07-1.13 0.71 -1.71 0.97-1.09 0.77-3.12 0.53-5.78 0.30-4.92 1.00-2.87
1.67* 1.5
1.01-2.76 0.76-3.09
1.36 1.09
0.80-2.32 0.49-2.44
1.21 1.33 1. 38 1.56
0.70-2.07 0.78-2.26 0.83-2.28 0.95-2.54
2.39* 0.89 1.00 0.93 0.89
1.08-5.26 0.41-1.91 0.94-1.07 0.85-1.01 0.70-1.13
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1 2
Gender adjusted Age adjusted
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95% CI
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Background variables Age Women BMI IBS IBS-D IBS-C Abdominal pain or discomfort Mushy stools High frequency defecation Lumpy stools Low frequency defecation Bloating Urgency Defecation straining Feeling of incomplete bowel movement Passing mucous Fecal incontinence Anxiety Depression Self-rated health
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OR
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Table III. Differences in age, gender and prevalence of symptom reports between participants with and without diverticulosis excluding all with colitis and antibiotic exposure. Age and gender adjusted logistic analysis.
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BMI- body mass index; IBS – irritable bowel syndrome; Ddiarrhea; C- constipation; *p<.05 **p<.01 ***p<.001
Table IV. Recent antibiotic exposure by diverticulosis status and age groups excluding participants with IBD and microscopic colitis.
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DIV (-) Age group Age group >60 <60 77 464 14(18.2) 52(11.2) 63(81.8) 412(88.8)
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EP
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N (%) Antibiotics No Antibiotics
DIV (+) Age group <60 49 7 (14.3) 42(85.7)
Age group >60 136 16 (11.8) 120 (88.2)
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PII: DOI: Reference:
S1542-3565(16)30318-4 10.1016/j.cgh.2016.06.014 YJCGH 54805
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 7 June 2016 Please cite this article as: Järbrink Sehgal ME, Andreasson A, Talley NJ, Agréus L, Song J-Y, Schmidt PT, Symptomatic Diverticulosis Is Characterized By Loose Stools, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.06.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Symptomatic Diverticulosis Is Characterized By Loose Stools
Authors: M. Ellionore Järbrink-Sehgal, Anna Andreasson, Nicholas J. Talley, Lars Agréus, Jeong-
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Yeop Song, Peter T Schmidt
Grant support: Magtarmförbundet, Bengt Ihre Stiftelsen, Stockholms County Council, Ersta Hospital, Astra Zeneca, Stockholm, Sweden
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Hospital 17176 Solna, Sweden. Email: [email protected]
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Correspondence: M. Ellionore Järbrink-Sehgal, M.D. Gastrocentrum A3:00, Karolinska University
Disclosures: None Author contributions:
M. Ellionore Järbrink-Sehgal, M.D.- Study hypothesis; analysis and interpretation of data; drafting
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of the manuscript; statistical analyses.
Anna Andreasson, Ph.D.- Study hypothesis; statistical analyses and critical revision of manuscript.
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Nicholas J. Talley, M.D., Ph.D.- Study idea, critical revision of manuscript.
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Lars Agréus, M.D., Ph.D.- Study idea, critical revision of manuscript. Jeong-Yeop Song, M.D. Ph.D.- Analysis and interpretation of data. Peter Thelin Schmidt, M.D., Ph.D.– Study idea, analysis and interpretation of data, critical revision of manuscript.
1
ACCEPTED MANUSCRIPT SYMPTOMATIC DIVERTICULOSIS IS CHARACTERIZED BY LOOSE STOOLS
M. Ellionore Järbrink Sehgal(1, 2), Anna Andreasson(3, 4), Nicholas J. Talley(5), Lars Agréus(3),
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Jeong-Yeop Song(3, 6), Peter T Schmidt(1)
1. Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases Karolinska University Hospital, Stockholm, Sweden.
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2. Baylor College of Medicine, Department of Gastroenterology, Houston, TX, USA
3. Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska
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Institutet, Stockholm, Sweden.
4. Stress Research Institute, Stockholm University, Stockholm, Sweden.
5. Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia. 6. Division of Gastroenterology, Department of Internal Medicine, Leechuntek Hospital, Suwon,
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Korea.
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ACCEPTED MANUSCRIPT Abstract: Background & Aims: Symptomatic uncomplicated diverticular disease is considered to be a discreet clinical entity distinct from irritable bowel syndrome (IBS), but population-based data are unavailable. We aimed to investigate the prevalence and location of diverticulosis in the general
individuals with diverticulosis would report more constipation and IBS.
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population, and its association with colonic symptoms and mental health. We propose that
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Methods: We performed a population-based study of randomly select adults born in Sweden (18–70 years old, 57.2% women); 745 received a gastroenterology consultation, completed validated
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abdominal symptom and mental health questionnaires, and were examined by colonoscopy. Logistic regression was used to calculate the associations between diverticulosis and age, gender, gastrointestinal symptoms, anxiety, depression and self-rated health.
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Results: Among the 742 participants (54.6% women) 130 (17.5%) had diverticulosis. Age was the strongest predictor of diverticulosis (P<.001) and diverticulosis was rare in participants younger than 40 years (0.7%). All participants with diverticulosis had sigmoid involvement. Participants with
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diverticulosis were more likely to report loose stools (odds ratio [OR], 1.88; 95% CI, 1.20–2.96), urgency (OR, 1.64; 95% CI, 1.02–2.63), passing mucus (OR, 2.26; 95% CI, 1.08–4.72), and a high
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stool frequency (OR, 2.02; 95% CI, 1.11–3.65). Diverticulosis was associated with abdominal pain (OR, 2.10; 95% CI, 1.01–4.36; P=.047) and IBS-diarrhea (OR, 9.55; 95% CI, 1.08–84.08; P=.04) in participants older than 60 years. Presence of anxiety and depression and self-rated health were similar in participants with and without diverticulosis.
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ACCEPTED MANUSCRIPT Conclusion: The prevalence of diverticulosis is age dependent. Diverticulosis is associated with diarrhea in subjects across all age ranges. In subjects older than sixty, diverticulosis is associated with abdominal pain and diarrhea-predominant IBS.
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Symptomatic Uncomplicated Diverticular Disease (SUDD)
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KEY WORDS: Diverticulosis; colonoscopy; population-based; Irritable Bowel Syndrome (IBS),
4
ACCEPTED MANUSCRIPT Introduction Colonic diverticular disease is a common and costly health problem, ranking as the fifth leading gastrointestinal (GI) disease in terms of health-care costs in Europe and North America.1 The prevalence of diverticulosis ranges from 5% to 45% by age 60 in Europe and North America.2
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However, the true prevalence of diverticulosis is uncertain, with current prevalence data mainly extracted from autopsy series, hospital admissions, radiological and endoscopic series among symptomatic subjects.3, 4, 5
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According to currently accepted definitions and terminology, “diverticulosis” is defined as the
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presence of colonic diverticula, which may or may not be symptomatic. While traditionally linked to constipation, it is controversial whether diverticulosis per se causes gastrointestinal symptoms and in particular if there is a link between diverticulosis and irritable bowel syndrome (IBS).6, 7, 8 “Diverticular disease” is defined as clinically significant and symptomatic diverticulosis, in which diverticulosis has escalated to an illness. Symptomatic uncomplicated diverticular disease (SUDD)
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refers to a separate clinical subtype of diverticular disease, in which there are persistent abdominal symptoms attributed to diverticula in the absence of macroscopically overt colitis or diverticulitis.9
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The definition of SUDD however is controversial in the literature. It has been defined as the presence of abdominal pain and change in bowel habits attributed to diverticula in the absence of alternate
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etiologies.10, 11, 12 Other authors have defined SUDD as abdominal pain or change in bowel habits in the presence of diverticulosis and absence of alternate etiologies13, while others have simply referred the presence of any symptoms in diverticular disease as symptomatic diverticular disease.14 In fact, SUDD may resemble IBS but does not fulfill the Rome criteria for diagnosis.14 Due to the alleged overlap between IBS and SUDD, several studies have addressed the symptom profiles in SUDD and IBS and one study has developed clinical criteria to differentiate these two.11, 12, 15 Purported differences characterizing SUDD include prolonged, less frequent, moderate to severe left lower abdominal pain (>24 hours) without relief by defecation and family history of a first degree relative
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ACCEPTED MANUSCRIPT with diverticular disease. The main differentiating study though included a select outpatient population, leaving it unclear how symptoms in the community are related to diverticulosis.11 Recently a possible causal link between diverticulitis and new onset IBS and mood disorder has been suggested.16 However, no population-based studies exist evaluating diverticulosis and mood
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disorders.
We performed a random population-based colonoscopy study to determine the prevalence of diverticulosis and the relation to gastrointestinal symptoms in the general population. We
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hypothesized that individuals with diverticulosis would report more constipation, IBS and mood
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disorders than those without. We also hypothesized that we would confirm the existence of a distinct subgroup with SUDD, defined as the presence of abdominal pain and change in bowel habits attributed to diverticula in the absence of alternate etiologies.
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Methods
Study approval was obtained from the local Ethics committee (No 394/01, Forskningskommitte Syd, Stockholm, Sweden) and written informed consent was obtained from all participants. This study was
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part of a larger study to survey colonic pathology and its association with gastrointestinal symptoms in a normal population.17 The logistics of the sampling procedure has been described in detail
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elsewhere (see supplementary documents).17 Study population
A random sample of 3556 individuals aged 18 to 70 years from two adjacent parishes in Stockholm, were mailed a validated questionnaire on troublesome gastrointestinal symptoms over the past three months (the Abdominal Symptom Questionnaire, ASQ).18, 19, 20 Of the 2293 questionnaire responders, 1244 out of 1673 reached by telephone were scheduled for a gastroenterologist consultation. At time of consultation additional questionnaires were completed including ASQ, the Rome II Modular
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ACCEPTED MANUSCRIPT questionnaire and the Hospital Anxiety Depression Scale (HADS). A total of 745 (426 women and 319 men) accepted to undergo a subsequent ileo-colonoscopy. Responders were similar to nonresponders as detailed elsewhere.17 Participation was not financially compensated.
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Procedures The colonoscopies were performed at Ersta hospital from June 2002 to October 2006 and followed Swedish clinical practice with biopsy sampling. Colonoscopy preparation included clear liquid diet
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and bowel cleansing with 45 ml Phosphoral taken orally twice within 4-hour interval. Seven
experienced endoscopists performed all procedures. Sedation and analgesics, given as needed,
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included inhaled nitric oxide, intravenous midazolam and/or alfentanyl. The endoscopists were aware of the study’s general aims and protocol but were blinded to participants’ past medical history and questionnaires results. Adverse events were recorded.
Diverticulosis
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Variables
IBS and IBS subtypes
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The presence and location of diverticulosis was recorded.
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Using the Rome II Modular questionnaire, IBS was defined as having abdominal pain or discomfort for at least 3 weeks (at least one day in each week) in the past 3 months with at least two out of three of the following: pain or discomfort improved or relieved after a bowel movement, onset of pain or discomfort associated with a change in the usual number of bowel movements, or onset of pain or discomfort associated with a change in stool consistency. IBS-Diarrhea (IBS-D) was defined as having IBS and reporting loose, mushy or watery stools but not hard or lumpy stools at least 25 % of the time for the last three months. IBS-Constipation (IBS-C) was defined as having IBS and reporting
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ACCEPTED MANUSCRIPT hard or lumpy stools but not loose, mushy or watery stools at least 25% of the time in the last 3 months.21
Gastrointestinal symptoms
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Symptoms from the Rome II Modular questionnaire were used and included abdominal pain or
discomfort (located anywhere in the abdomen for at least 3 weeks, at least one day in each week, in the past 3 months), mushy stools, high frequency defecation (more than three bowel movements a
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day), lumpy stools, low frequency defecation (one bowel movement less than every three days),
fecal incontinence.
Localization of abdominal pain or discomfort
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bloating, urgency, defecation straining, feeling of incomplete bowel movement, passing mucous and
The localization of abdominal pain/ discomfort was derived from the ASQ and was defined as
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presence of “troublesome“ abdominal pain/ discomfort in the preceding 3 months specified to epigastrium, periumbilical, suprapubic area, right quadrant, left quadrant or the whole abdomen.18, 19, 20
Left lower quadrant included the suprapubic area and left quadrant. All localizations were analyzed
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separately.
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Anxiety, depression and self-rated health Anxiety and depression was derived from the Hospital Anxiety and Depression Scale (HADS) and defined by an abnormal score of 8 or above respectively.22 Self-rated health was assessed with the question: “In general, would you say your health is: excellent, very good, good, fair or poor”.23
Laxatives and antibiotics
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ACCEPTED MANUSCRIPT Laxative and any antibiotic use 3 months prior were reported at the gastroenterology consultation interview and from electronic medical record using the ATC codes.
Inflammatory Bowel Disease (IBD) and Microscopic Colitis
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Past medical history of Crohn’s disease, ulcerative colitis or microscopic colitis was recorded in the questionnaires, during the gastroenterology consultation or at the time of colonoscopy. An expert pathologist reviewed all random biopsies from five segments (right colon, transverse, descending,
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sigmoid colon and rectum).
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Statistical methods
Logistic regression was used to analyze differences in background variables, IBS and gastrointestinal symptoms between participants with and without diverticulosis and the interaction between presence of diverticulosis and antibiotic use on gastrointestinal symptoms using an interaction term
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diverticulosis *use of antibiotics. All analyses were age and gender adjusted and performed using
was < 0.05.
Missing Data
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STATA (11.0. StataCorp Texas). Results were considered significant when the two-sided p value
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Missing data on presence (n=3) and localization (n=4) of diverticulosis left 742 and 738 participants, respectively, for analysis. A further 44 participants were missing data on gastrointestinal symptoms and 7 had no data on body mass index (BMI), leaving a total of 122 with and 577 participants without diverticulosis for analysis of gastrointestinal symptoms. In the analysis of localization of abdominal pain, report on pain localization was missing in 39, leaving 122 with and 581 participants without diverticulosis for the analysis. Data on antibiotic use was available in 737 participants but the ATC code was missing in 2 participants with and 17 participants without diverticulosis.
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ACCEPTED MANUSCRIPT Results Overview Colonoscopy participants were slightly older (mean age 51.7 years vs. 44.7 years, p<0.001), reported a higher rate of IBS (36.7% vs. 21.2%, p<0.001) and fewer participants were symptom free (31.9%
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vs. 45.1% p<0.001) than noncolonoscopy ASQ responders. There was no difference in gender or education between colonoscopy and noncolonoscopy participants.17 Among the 745 ileo-
colonoscopies, 702 (94%) were complete reaching the cecum and/or terminal ileum. In total, 422
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(57%) were women and 323 (43%) were men. Eleven participants had colitis (2 with Crohn’s
disease, 5 with ulcerative colitis and 4 with histology-evident microscopic colitis). No participant
Prevalence and localization of diverticulosis
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reported laxative use. No procedural adverse events occurred.
In total, 130 out of the 742 participants had diverticulosis (17.5%, 95%CI: 14.95- 20.4). All
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participants with diverticulosis had sigmoid involvement. Cecum, ascending colon, flexures with transverse colon and descending colon were involved in 3.2%, 4.0%, 13.6% and 12.7%, respectively. The prevalence of diverticulosis was similar in men (18.6%) and women (16.7%) but increased with
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age (p<0.001) and was low in participants younger than 40 years (0.7%) (Figure1). Consequently, the age differed significantly between those with and without diverticulosis (mean age=60, range 37-71
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years vs. mean age 51, range 19-70 years, respectively, p<0.001). BMI was not associated with diverticulosis (p=0.3). The study group characteristics are presented in Table I by age group and diverticulosis status excluding the participants with colitis.
Insert Table I here.
Diverticulosis and gastrointestinal symptoms, IBS and IBS subtypes
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ACCEPTED MANUSCRIPT Overall, participants older than 60 years reported less gastrointestinal symptoms than younger participants (Table I). Diverticulosis in all participants was associated with diarrhea-like symptoms, specifically mushy
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stools (OR: 1.88, 95%CI: 1.20-2.96, p=0.006), high frequency defecation (OR: 2.02, 95%CI: 1.113.65, p=0.02), urgency (OR: 1.64, 95%CI: 1.02-2.63, p=0.04) and passing mucus (OR: 2.26, 95%CI: 1.08-4.72, p=0.03). No significant differences were noted in other GI symptoms, IBS or IBS subtypes
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(data not shown).
When excluding colitis cases similar results were observed but there was a strong trend for
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abdominal pain (OR: 1.59, 95%CI: 0.98-2.59, p=0.06) and incomplete bowel movement (OR: 1.50, 95%CI: 0.96-2.37, p=0.08) (Table II). After additional exclusion of those with recent antibiotic exposure, diverticulosis was still associated with mushy stools (OR: 1.67, 95%CI: 1.01-2.76, p=0.04), passing mucus (OR: 2.39, 95%CI: 1.08-5.26, p=0.03) and the trend for abdominal pain (OR:
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1.69, 95%CI: 1.00-2.87, p=0.05) and feeling of incomplete evacuation (OR: 1.56, 95%CI: 0.95-2.54, p=0.08) remained (data not shown).
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Older versus younger participants
In participants older than 60 years, diverticulosis was associated with abdominal pain (OR: 2.10,
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95%CI: 1.01-4.37, p=0.047), IBS-D (OR: 9.55, 95%CI: 1.08-84.08, p=0.04) and diarrhea symptoms. Specifically, mushy stools (OR: 3.33, 95%CI: 1.69-6.58, p<0.001), high frequency stools (OR: 5.11, 95%CI: 1.85-14.16, p=0.002) and incomplete bowel movements (OR: 1.99, 95%CI: 1.03-3.87, p=0.04) were all associated with diverticulosis in this older age group. No significant differences were noted in other GI symptoms or IBS-C. Similar findings were observed when excluding participants with colitis. The symptom associations remained for abdominal pain (OR: 2.46, 95%CI: 1.09-5.55, p=0.03), urgency (OR: 2.61, 95%CI: 1.19-5.71, p=0.02) and mushy stools (OR: 2.49, 95%CI: 1.16-5.32, p=0.02) when those exposed to antibiotics were excluded.
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ACCEPTED MANUSCRIPT No association between diverticulosis and GI symptoms, IBS or IBS subtypes, were noted in those sixty or younger.
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Diverticulosis and anxiety, depression and self-rated health There was no difference in anxiety, depression or self-rated health between participants with and
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without diverticulosis regardless of age group, colitis or antibiotic exposure. (Table II).
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Insert Table II here.
Diverticulosis and localization of abdominal pain/ discomfort
ASQ derived troublesome abdominal pain/ discomfort was reported by 55 of 122 participants with diverticulosis (45.1%) and by 286 of 581 participants without (49.2%). Presence of abdominal pain/
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discomfort was similar between the two groups but a trend for a left lower quadrant localization of the abdominal pain/discomfort among all participants with diverticulosis was observed (OR: 1.83; 95%CI: 0.92-3.64, p=0.09). When age was stratified, left lower quadrant localization of reported
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abdominal pain/ discomfort was significantly associated with diverticulosis in participants older than
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age 60 years (OR: 6.78, 95%CI: 1.80-25.56, p=0.005).
Diverticulosis and use of antibiotics Overall, recent antibiotic exposure was present in 70 out of 610 (11.5%) in the non-diverticulosis group and 21 out of 127 (16.5%) in the diverticulosis group. The main antibiotic indications were urinary tract and upper respiratory infections. None had diverticulitis as the indication for antibiotic use. Regardless of diverticulosis status, antibiotic exposure was significantly higher in those older
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ACCEPTED MANUSCRIPT than sixty than in those age sixty or below (14.1% (95%CI: 13.8-14.4) vs. 11.5% (95%CI: 11.4-11.6) p<0.001).
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Interaction between diverticulosis and recent antibiotic use on GI symptoms Participants with diverticulosis and recent antibiotic use reported more GI symptoms than those with diverticulosis without recent antibiotic use, or participants without diverticulosis with recent
antibiotic use, as shown by a positive interaction effect between the presence of diverticulosis and
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mushy stools, high frequency stools and urgency.
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recent antibiotic use (See Figure 2). The GI symptoms associated with the positive interaction were
Discussion
In this large population-based cohort, we describe the true prevalence of diverticulosis in a community. As expected there was a significant association between increasing age and
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diverticulosis.2, 3, 5, 7, 24 More importantly, we present new information on diverticulosis and its association with diarrhea-like symptoms in subjects across all age ranges, and with abdominal pain
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and diarrhea-predominant IBS in those older than sixty years. Unlike the traditionally accepted theory, we found no association between diverticulosis and constipation. Laxative use, microscopic
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colitis or IBD did not account for the association between diverticulosis and diarrhea-like symptoms. Non-population-based studies have shown variable results associating constipation, abdominal pain and IBS to colonic diverticulosis.6, 12, 25 Two population-based non-colonoscopy studies and a recent colonoscopy study have shown a link between diverticulosis and diarrhea-predominant IBS, which further supports the evidence in our study. 7, 8, 26 We found that the symptom associations, abdominal pain and diarrhea-predominant IBS, were only present in those older than sixty with diverticulosis. The IBS prevalence in our study (14.7%) is comparable to the IBS prevalence in the Swedish community (6-18%).27, 28 While the odds ratio was nearly 10 fold suggesting a strong association, the
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ACCEPTED MANUSCRIPT link between diverticulosis and diarrhea-predominant IBS should be viewed with caution given the wide confidence intervals and larger studies are needed to confirm this link. The biological mechanisms by which diarrhea-like symptoms may occur in diverticulosis are unknown but several possible explanatory pathophysiological mechanisms exist. First, colonic
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diverticulosis is more prevalent in the older population, where age-related changes in the function of smooth muscle or neurons are possible but this alone seems unlikely to account for diarrhea.29, 30 Alternatively, chronic low-grade inflammation may play a role by influencing the function of
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epithelial cells, smooth muscle and enteric nerves leading to changes in motility and sensation.31 Recent studies suggest that inflammation and enteric neuromuscular pathology plays a role in the
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early pathogenesis of diverticulosis and its symptoms.32
We speculate that alterations in the intestinal microbiota may play a role in the symptomatic diverticulosis. In our study, 21 out of 127 participants with diverticulosis reported recent antibiotic use. We found participants with diverticulosis and a history of recent antibiotic use to have a
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significant 4 to 7 fold increased likelihood of urgency, increased stool frequency and looser stools. The well-known major mechanisms of antibiotic-associated diarrhea involve disturbance of gut
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microbiota and the direct gastrointestinal irritation of antibiotics on the mucous membranes.33 Interestingly, this was not observed in participants without diverticulosis despite recent antibiotic use.
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Although no cause-or-effect relationship can be established, it raises the question whether patients with diverticulosis are perhaps more sensitive to gut microbiome disturbances.
Another important finding in our study is the lack of association between diverticulosis and mood disorders. Mood disorders have been associated with diverticulitis.16 We found participants with diverticulosis to have good self-rated health and no association between diverticulosis and anxiety or depression was observed. We used the validated HADS (Hospital Anxiety Depression Scale) questionnaire to assess depression and anxiety. Although not the gold standard for screening
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ACCEPTED MANUSCRIPT depression and anxiety, it has been validated to assess prevalence and symptom severity in the general population.22 It is still conceivable that acute inflammation is the key trigger for developing mood disorder and not diverticulosis per se as our study population had no diverticulitis history, but
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prospective studies are needed to confirm this association.
Lastly, sub-analysis of ASQ derived data suggests that in older participants (above 60) with
diverticulosis, abdominal pain/ discomfort localizes to the left lower quadrant. Although purported to
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association and no other specific pain symptoms were identified.
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be a feature of SUDD12, the wide confidence intervals warrant larger studies to confirm this
Our study has several strengths. First, it is a random population-based study with participants from the general population, unbiased by those seeking medical attention for secondary gain, minimizing selection bias and improving the generalizability of our results. Secondly, it has a high participation
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rate and a wide age range. Third, our diagnostic method for identification of diverticulosis was colonoscopy performed by experienced endoscopists. This has been a major limitation in prior studies.2, 3, 4, 7, 8, 12, 16 Moreover, an expert gastrointestinal pathologist reviewed the histology
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excluding microscopic colitis as a confounder. Lastly, we excluded individuals born abroad, in total 11 % of the two parishes total inhabitants, minimizing results biased by differences in genetics and
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foreign microbiota.
Some limitations of our study need to be recognized though. Firstly, this is a cross-sectional study. Hence, no causal inference between diverticulosis and diarrheal symptoms can be established. Secondly, our study population were more symptomatic than nonparticipants, urban, slightly better educated than average and included only Swedish born participants, potentially affecting lifestyle factors, diet and exercise. Any symptom bias however was more prominent among younger
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ACCEPTED MANUSCRIPT participants and significant in the youngest age group only. As diverticulosis was found only in participants over 40 years of age any symptom bias is likely to play less of a role in the present study. Thirdly, the Rome II criteria were used for IBS diagnosis. However, although we applied the Rome II criteria for IBS, the three primary symptom criteria in Rome III are very similar.34 The lack of stool
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diary and data on duration of pain are also possible limitations. Lastly, the underrepresentation of younger participants, especially men, likely explains the lower diverticulosis prevalence in this age
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group in comparison to prior studies with a reported prevalence of 1-2%.6
In conclusion, in this population-based colonoscopy study the prevalence of diverticulosis increases
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with age and diverticulosis is associated with diarrhea symptoms across all age ranges. In those older than sixty, diverticulosis is associated with abdominal pain and diarrhea-predominant IBS. We found no evidence linking diverticulosis to constipation or mood disorders. The link between diverticulosis and diarrhea, abdominal pain and diarrhea-predominant IBS should direct future age specific studies
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aimed at finding tailored therapeutic strategies, and importantly increase our awareness of
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symptomatic diverticulosis in patients older than sixty years.
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ACCEPTED MANUSCRIPT Table I. Study group characteristics by diverticulosis status and age groups excluding participants with colitis. Background variables
Ages 60 years or less
Ages over 60 years
Div -
Total
Div +
Div -
Total
Number (N)
50
465
515
79
137
216
Age Mean (sd)
53(5.5)
45.0(10.5)
45.8(10.4)
65.7(2.8)
65.7(2.9)
65.7(2.9)
Women N (%)
29(58.0)
268(57.6)
297(57.7)
42(53.2)
79(57.7)
121(56.0)
Body mass index (BMI) Mean (sd)
25.2(3.7)
24.4(4.0)
24.5(4.0)
26.1(3.9)
25.6(3.8)
25.8(3.8)
IBS and GI symptoms % (95%CI)
Div +
Div -
Total
Div +
Div -
Total
Number (N)
50
441
491
72
127
199
Irritable bowel syndrome (IBS)
16.0
17.0
16.9
12.5
5.5
8.0
(5.5-26.5)
(13.5-20.5)
(13.6-20.2)
(4.7-20.3)
(1.5-9.5)
(4.3-11.9)
2.0
5.2
4.9
6.9**
0
2.5
(2.0-6.0)
(3.1-7.3)
(3.0-6.8)
(0.9-13.0)
2.0
2.9
2.9
2.8
3.1
3.0
(1.4-4.5)
(1.4-4.3)
(-0.1-6.7)
(0.1-6.2)
(0.6-5.4)
33.6
33.4
25 *
13.4
17.6
(29.1-38.0)
(29.2-37.6)
(14.8-35.2)
(7.4-19.4)
(12.322.9)
(-2.0-6.0) Abdominal pain/ discomfort
32.0
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(18.6-45.4)
High frequency defecation
Low frequency defecation Bloating
(0.3-4.2)
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34.0
33.8
33.8
37.5 ***
14.2
22.6
(20.4-47.6)
(29.4-38.2)
(29.6-38.0)
(26.0-49.0)
(8.0-20.3)
(16.828.5)
14.0
15.2
15.1
19.4***
3.9
9.5
(4.0-24.0)
(11.8-28.6)
(11.9-18.2)
(10.1-28.2)
(0.5-7.4)
(5.4-13.7)
30.0
25.9
26.3
26.4
22.0
23.6
(16.8-43.2)
(21.7-30.0)
(22.4-30.2)
(16.0-36.8)
(14.7-29.4)
(17.729.6)
6.0
10.2
9.8
9.7
5.5
7.0
(-0.8-12.8)
(7.4-13.0)
(7.1-12.4)
(2.7-16.7)
(1.5-9.5)
(3.4-10.2)
30.0
35.4
34.8
19.4
18.9
19.1
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Mushy stools
Lumpy stools
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IBS-Constipation
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IBS-Diarrhea
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Div +
(13.6-
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(30.6-39.1)
(10.1-28.8)
(12.0-25.8)
24.6)
26.0
28.3
28.1
33.3**
14.2
21.1
(13.4-38.6)
(24.1-32.6)
(24.1-32.1)
(22.2-44.5)
(8.0-20.3)
(15.426.8)
34.0
32.0
32.2
29.2
19.7
23.1
(20.4-47.6)
(27.6-36.3)
(28.0-36.3)
(18.4-39.9)
(12.7-26.7)
(17.229.0)
38.0
37.0
37.1
31.9*
18.9
23.6
(24.1-51.9)
(32.4-41.5)
(32.8-41.4)
(20.9-43.0)
(12.0-25.8)
(17.729.6)
14.0
9.3
9.8
8.3
3.9
5.5
(4.0-24.0)
(6.6-12.0)
(7.1-12.4)
(1.8-14.9)
(0.5-7.4)
(2.3-8.7)
8.0(0.2-15.8)
6.6(4.3-8.9)
6.7(4.5-8.9)
13.9(5.7-221)
13.9(7.4-19.4)
13.6(8.818.4)
Number (N)
50
465
HADS- A % (95%CI)
24.0(11.7-36.3)
HADS- D % (95%CI)
6.0(-0.8-12.8)
Self-rated health (N)
50
Excellent %
10.0
Very good %
36.0
Good %
40.0
Fair % Poor %
Feeling of incomplete bowel movement
Passing mucous
Fecal incontinence Anxiety, depression and self-rated health
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Defecation straining
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Urgency
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(16.8-43.2)
79
137
216
24.3(20.428.2)
24.3(20.228.0)
17.7(9.1-26.3)
16.8(10.523.1)
17.1(12.1 -22.2)
13.3(10.216.4)
12.6(9.7-15.5)
11.4(4.2-18.6)
9.5(4.5-14.5)
10.2(6.114.3)
443
493
72
127
199
11.5
11.3
16.7
14.2
15.1
38.6
38.3
40.3
31.5
34.7
33.2
33.9
26.4
38.6
34.2
14
14.9
14.8
16.7
14.2
15.1
0
1.8
1.6
2.8
0
1.0
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EP
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515
Div (+)= Diverticulosis, Div (-) =No diverticulosis, HADS –Hospital Anxiety (A) and Depression (D) Scale *p< .05 **p< .01 ***p< .001
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ACCEPTED MANUSCRIPT Table II. Differences in background variables and presence of gastrointestinal symptoms between participants with and without diverticulosis calculated with logistic regression analysis
95% CI
Age
1.10***1
1.08-1.13
Women
0.902
0.60-1.36
BMI
1.03
0.98-1.08
IBS
1.65
0.88-3.09
IBS-D
2.06
0.73-5.78
IBS-C
0.91
0.23-3.53
Abdominal pain/discomfort
1.59
Mushy stools
1.94**
High frequency defecation
2.14*
Lumpy stools
1.41
Low frequency defecation
1.00
0.47-2.16
Bloating
1.04
0.63-1.72
Urgency
1.67*
1.04-2.68
0.98-2.59
1.23-3.06
1.17-3.89
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0.86-2.30
1. 36
0.85-2.16
Feeling of incomplete bowel movement
1.50
0.96-2.37
Passing mucous
2.26*
1.08-4.73
Fecal incontinence
1.03
0.53-2.03
Anxiety
1.02
0.96-1.08
Depression
0.95
0.88-1.03
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Defecation straining
1
Gender adjusted
2
Age adjusted
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OR
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Background variables
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and presented as odds ratios (OR) and 95% confidence intervals (95%CI).
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0.93
0.74-1.16
BMI- body mass index; IBS – irritable bowel syndrome; D- diarrhea; C- constipation; *p< .05 **p< .01
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***p< .001
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Figure legends:
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Figure 1: Prevalence of diverticulosis per age group presented as % and 95%CI.
Figure 2. Adjusted OR with 95% CI for each gastrointestinal symptom evaluating the interaction of antibiotics and diverticulosis in all four different groups. The reference group is ” No Antibiotics, No Diverticulosis ” with OR: 1.00. The other groups are ”Recent Antibiotics, Positive Diverticulosis”;
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“Recent Antibiotics, No Diverticulosis” and “No Antibiotics, Positive Diverticulosis”.
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ACCEPTED MANUSCRIPT References:
1 Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500-1511.
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2 Painter NS, Burkitt DP. Diverticular disease of the colon: a deficiency disease of western civilization. Br Med J 1971;2:450–454.
3 Hughes LE. Postmortem survey of diverticular disease of the colon. Gut 1960;10:336
population of Oxford area. Br Med J 1967;23;3(5568):762-763.
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4 Manuosos ON, Truelove SC, Lumsden K, et al. Prevalence of colonic diverticulosis in general
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5 Delveux M. Diverticular disease of the colon in Europe: epidemiology, impact on citizen health and prevention. Aliment Pharmacol Ther 2003;18:71-74.
6 Parks TG. Natural history of diverticular disease of the colon. Clin Gastroenterol 1975;4:53-69. 7 Jung HK, Choung RS, Locke III GR, et al. Diarrhea predominant irritable bowel syndrome is
661.
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associated with diverticular disease: a population based study. Am J Gastroenterol 2010;105(3):652-
8 Yamada E, Inamori M, Uchida E, et al. Association between the location of diverticular disease and
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the irritable bowel syndrome: a multicenter study in Japan. Am J Gastroenterol 2014;109:1900-1905.
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9 Elisei W, Tursi A. Recent advances in the treatment of colonic diverticular disease and prevention of acute diverticulitis. Ann of Gastroenterol 2016;29(1):24-32. 10 Kohler L, Sauerland S, Neugebauer E. Diagnosis and treatment of diverticular disease: results of a consensus development conference. The Scientific Committee of the European Association for Endoscopic Surgery. Surg Endosc 1999;13:430–436. 11 Annibale B, Lahner E, Maconi G. Clinical features of symptomatic uncomplicated diverticular disease: a multicenter Italian survey. Int J Colorectal Dis 2012:27:1151-1159.
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ACCEPTED MANUSCRIPT 12 Tursi A, Elisei W, Picchio M, et al. Moderate to severe and prolonged left lower abdominal pain is the best symptom characterizing symptomatic uncomplicated diverticular disease of the colon: a comparison with fecal calprotectin in clinical setting. J Clin Gastroenterol 2015;49:218-221.
clinical insights. Am J Gastroenterol 2012;107:1486-1493.
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13 Strate LL, Modi R, Cohen E. Diverticular disease as a chronic illness: evolving epidemiologic and
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14 Spiller RC. Is it diverticular disease or is it irritable bowel syndrome? Dig Dis 2012;30:64-69. 15 Cuomo R, Barbara G, Andreozzi P, et al. Symptom pattern can distinguish diverticular disease
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from irritable bowel syndrome. Eur J Clin Invest 2013; 43 (11): 1147-1155.
16 Cohen E, Fuller G, Bolus R, et al. Increased risk for irritable bowel syndrome after acute diverticulitis. Clin Gastroenterol Hepatol 2013;11:1614-1619.
17 Kjellström L, Molinder H, Agréus L, et al. A randomly selected population sample undergoing
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colonoscopy: prevalence of the irritable bowel syndrome and the impact of selection forces. Eur J Gastroenterolog and Hepatol 2014;26(3):268-275.
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18 Agréus L. The abdominal symptom study.An epidemiological survey of gastrointestinal and other abdominal symptoms in the adult population of Östhammar, Sweden. Thesis. Uppsala University,
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Uppsala, Sweden 1993.
19 Agréus L, Svärdsudd K, Nyrén O, et al. Reproducibility and validity of a postal questionnaire. The abdominal symptom study. Scand J Prim Health Care 1993;11:252-262. 20 Agréus L, Svärdsudd K, Nyrén O, et al. Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time. Gastroenterology 1995;109:671-680. 21 Drossman DA. Rome II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus, 2nd edition. McLean, VA: Degnon Associates, 2000.
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ACCEPTED MANUSCRIPT 22 Bjelland I, Dahl A, Tangen HT, et al. The validity of the hospital anxiety and depression scale- an updated literature review. J of Psychosom Res 2002;52:69–77. 23 DeSalvo KB, Bloser N, et al. Mortality prediction with a single general self-rated health question.
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A meta-analysis. J Gen Intern Med 2006;21(3):267-275. 24 Stollman NH, Raskin JB. Ad hoc practice parameters committee of the American College of
Gastroenterology. Diagnosis and management of diverticular disease of the colon in adults. Am J
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Gastroenterol 1999;94:3110-3121.
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25 Zollinger RW. The prognosis in diverticulitis of the colon. Arch Surg 1968;97:418-422. 26 Simpson J, Neal R, Scholefield JH, et al. Patterns of pain in diverticular disease. Eur J Gastroenterol Hepatol 2003;15:1005-1010.
27 Kay L. Prevalence, incidence and prognosis of gastrointestinal symptoms in a random sample of
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an elderly population. Age Ageing 1994;23:146–149.
28 Österberg E, Blomquist L, Krakau I, et al. A population study on irritable bowel syndrome and
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mental health. Scand J Gastroent 2000; 264- 267.
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29 Szurswewski JH, Holt PR, Schuster M, et al. Proceedings of a workshop entitled neuromuscular function and dysfunction of the gastrointestinal tract in aging. Dig Dis Sci 1989;34:1135-1146. 30 Smiths GJ, Lefebvre RA. Influence of age on cholinergic and inhibitory nonadrenergic noncholinergic responses in the rat ileum. Eur J Pharmacol 1996;303:79-86. 31 Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 1996;111:1683-1699. 32 Böttner M, Wedel T. Abnormalities of neuromuscular anatomy in diverticular disease. Dig Dis 2012; 30:19–23.
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ACCEPTED MANUSCRIPT 33 Högenauer C, Hammer HF, Krejs GJ, et al. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis 1998;27(4):702-710. 34 Drossman DA. The functional gastrointestinal disorders and the Rome III process.
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Gastroenterology 2006;130:1377-1390.
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SUPPORTING TABLES
1.10***1 1.102 1.03 1.55 1.85 1.22 1.69
1.07-1.13 0.71 -1.71 0.97-1.09 0.77-3.12 0.53-5.78 0.30-4.92 1.00-2.87
1.67* 1.5
1.01-2.76 0.76-3.09
1.36 1.09
0.80-2.32 0.49-2.44
1.21 1.33 1. 38 1.56
0.70-2.07 0.78-2.26 0.83-2.28 0.95-2.54
2.39* 0.89 1.00 0.93 0.89
1.08-5.26 0.41-1.91 0.94-1.07 0.85-1.01 0.70-1.13
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1 2
Gender adjusted Age adjusted
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95% CI
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Background variables Age Women BMI IBS IBS-D IBS-C Abdominal pain or discomfort Mushy stools High frequency defecation Lumpy stools Low frequency defecation Bloating Urgency Defecation straining Feeling of incomplete bowel movement Passing mucous Fecal incontinence Anxiety Depression Self-rated health
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OR
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Table III. Differences in age, gender and prevalence of symptom reports between participants with and without diverticulosis excluding all with colitis and antibiotic exposure. Age and gender adjusted logistic analysis.
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BMI- body mass index; IBS – irritable bowel syndrome; Ddiarrhea; C- constipation; *p<.05 **p<.01 ***p<.001
Table IV. Recent antibiotic exposure by diverticulosis status and age groups excluding participants with IBD and microscopic colitis.
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DIV (-) Age group Age group >60 <60 77 464 14(18.2) 52(11.2) 63(81.8) 412(88.8)
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N (%) Antibiotics No Antibiotics
DIV (+) Age group <60 49 7 (14.3) 42(85.7)
Age group >60 136 16 (11.8) 120 (88.2)
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