Abstract
Objective:
The size, number and distribution of diverticula vary greatly in patients with diverticulosis. We aimed to study the association between the morphology of diverticulosis assessed on colonoscopy and risk of diverticulitis.
Methods:
We performed a retrospective, case-control study of cases with a history of diverticulitis and controls with diverticulosis without diverticulitis matched on sex, age (within 5 years) and year of colonoscopy. Diverticulosis characteristics were obtained from endoscopy reports and were categorized according to severity, extent, number and size. We used conditional logistic regression on matched pairs to calculate the odds of diverticulitis among patients with diverticulosis according to differing morphologic characteristics.
Results:
We identified 85 cases with CT documented diverticulitis and 85 matched controls with diverticulosis without a diagnosis of diverticulitis. In cases, 60% had left-sided only diverticulosis, 2% had right-sided only, and 38% had both right and left-sided diverticulosis; whereas in controls, the distribution was 53%, 18%, and 29%, respectively. Cases were more likely to have large diverticula (OR 3.33; 95% CI, 1.30-8.56 for left colon only and 1.89, 95% CI, 0.78-4.57 for both right and left). Similarly, when severity of diverticulosis was compared between the groups, cases were more likely to have moderate or severe diverticulosis (OR 3.44; 95% CI, 1.51-7.84 for moderate and OR 8.87; 95% CI, 2.98-26.37 for severe).
Conclusions:
Diverticulitis cases were more likely to have large diverticula and severe diverticulosis when compared to controls suggesting that size and severity are novel risk factors for diverticulitis.
Keywords: Diverticulitis, diverticulosis, morphology, size, severity, extent, location
Introduction
Diverticulosis, or the presence of outpouchings in the colon wall, is the most common finding on screening colonoscopy.[1] The presence of diverticulosis increases with age; fewer than 20% of individuals younger than 40 years of age have diverticulosis compared to 60% of those older than 70 years [1–3]. Although usually asymptomatic, diverticula can be associated with a number of complications that place a significant burden on the health system most notably diverticulitis[4,5]. Approximately 4% of patients with diverticulosis experience diverticulitis[6]. Complications such as perforation and abscess develop in 15% of patients with acute diverticulitis, and 15-30% of patients will experience a recurrence[7].
The ability to predict the likelihood of progression from asymptomatic diverticulosis to diverticulitis is limited. Studies have identified a number of clinical and lifestyle risk factors for diverticulitis including obesity, physical inactivity, diet, and the use of certain medications[8–16]. Genetics also influence the tendency to develop diverticulosis and diverticulitis[17,18]. The size and distribution of diverticula in the colon varies greatly between individuals. However, it remains unclear how diverticular morphology contributes to the development of diverticulitis.
Elucidating the relationship between diverticular morphology and disease outcomes is important for predicting risk of diverticulitis as well as understanding its etiopathogenesis. Therefore, we sought to characterize and categorize the morphologic spectrum of diverticulosis diagnosed on colonoscopy with a focus on size and distribution and assess whether morphologic characteristics are associated with diverticulitis after matching for age and sex. We hypothesized that size and extent of diverticulosis in the absence of overt inflammation or colon narrowing would predict diverticulitis.
Methods
Study Design and Participants
This was an IRB- approved retrospective, case-control study of adult patients undergoing colonoscopy by the same endoscopist from 11/2014 – 8/2019 at an academic, safety-net hospital. We utilized an electronic endoscopy database to identify 85 individuals with diagnostic codes for diverticulosis and the electronic medical record to identify 85 individuals with diverticulitis using ICD codes (ICD9 562.11, 562.13, and ICD10 K57.20, K57.21, K57.32, K57.33, K57.40, K57.41, K57.52, K57.53, K57.80, K57.81, K57.92, K57.93). We narrowed the potential cases and controls to those who had undergone a colonoscopy by single provider (LLS) within the above time frame to minimize inconsistencies in reporting. We then matched cases with diverticulitis by sex assigned at birth, age within 5 years and colonoscopy date within one year to controls with diverticulosis without a diagnosis of diverticulitis. We reviewed the medical record of each patient to verify the presence or absence of diverticulosis (on colonoscopy) and diverticulitis (verified by CT scan). We recorded data on race and ethnicity, body mass index, nonsteroidal anti-inflammatory drugs (NSAIDs), opiates and/or laxatives, and the presence or absence of irritable bowel syndrome (IBS), diabetes, prediabetes and hypertension as potential predictors of diverticular morphology and /or diverticulitis[3,10,16,19]. In diverticulitis cases, we also recorded the location of diverticulitis and the presence of any complications (perforation, abscess, fistula).
Diverticulosis Characteristics
We reviewed electronically available endoscopy reports to assess the location, size, and severity of diverticula. An electronic data collection tool was utilized to systematically document diverticulosis characteristics. The endoscopy reporting software included pre-specified drop-down menus for diverticular location by segment (cecum, ascending, transverse, descending, and sigmoid), number (few, scattered, many, multiple), size (small, medium, large and small and large) and severity per segment (mild, moderate and severe). Diverticula were considered small if the estimated diameter was < 3mm; medium if the diameter was ≥ 3 and < 7mm; and large ≥ 7mm. Diverticula with small, slit-like openings were also classified as small. We defined severe diverticulosis as many/multiple densely spaced diverticula of any size in any segment. Moderate diverticulosis was categorized as scattered diverticula throughout the colon, or moderately dense diverticula limited to one segment. Mild diverticulosis was defined as single, few, or scattered diverticula limited to one part of the colon. In reports missing language regarding severity (2%), we reviewed endoscopy report photos to determine the severity.
Statistical analysis
We used McNemar Chi-Square analysis to compare baseline characteristics including race, use of medications, and presence of IBS, diabetes and hypertension between cases and controls.
Conditional logistic regression was used on matched pairs to calculate the odds of diverticulitis among patients with diverticulosis according to differing morphologic characteristics of diverticulosis. To reduce model parameters and simplify interpretation, we categorized location of diverticulosis into left only (sigmoid and descending) and any right (either both left and right or right-sided only). We also collapsed size into only small diverticula and large size (including any medium and/or large size or mixed sizing). Severity was assessed separately from morphology, as severity was a composite of the other morphological components. P-values of < 0.05 were used to determine statistical significance.
Results
Patient Characteristics
We identified 85 cases with CT documented diverticulitis and 85 matched controls with diverticulosis without a diagnosis of diverticulitis. Baseline characteristics for cases and controls are summarized in Table 1. The only statistically significant difference between groups was a higher prevalence of IBS documented in cases with diverticulitis (13% vs 4%, p=0.043).
Table 1.
Demographic characteristics of individuals with and without diverticulitis
| Characteristic | Case n=85 |
Control n=85 |
P Value |
|---|---|---|---|
| Age: mean(range)* | 53.8 (57) | 53.9 (56) | 0.98 |
| Male | 52 (61%) | 52 (61%) | |
| Female | 33 (39%) | 33 (39%) | |
| White | 64 (75%) | 58 (68%) | 0.40 |
| Black | 8 (9%) | 13 (15%) | 0.36 |
| Asian | 3 (4%) | 8 (9%) | 0.23 |
| Other | 10 (12%) | 6 (7%) | 0.18 |
| Hispanic Ethnicity | 15 (18%) | 8 (9%) | 0.45 |
| Body Mass Index: mean (range) | 30 (35) | 30 (55) | 0.98 |
| NSAIDs | 33 (39%) | 35 (41%) | 0.86 |
| Opiates | 21 (25%) | 14 (16%) | 0.28 |
| Laxatives | 20 (24%) | 22 (25%) | 0.84 |
| Diabetes | 8 (9%) | 16 (19%) | 0.15 |
| Irritable Bowel Syndrome | 11 (13%) | 3 (4%) | 0.043 |
| Hypertension | 31 (36%) | 34 (41%) | 0.69 |
age at colonoscopy
Diverticulitis Characteristics
When looking at the prevalence of diverticulitis and diverticular complications, most of the disease was found in the left colon (84%), and specifically in the sigmoid colon in 69% (Table 2). There was a low prevalence of diverticulitis in the right colon in this population (4%).
Table 2.
Diverticulitis characteristics
| Characteristic | % |
|---|---|
| Complication | 23 (27%) |
| Microperforation | 4 (5%) |
| Perforation | 9 (11%) |
| Abscess | 8 (9%) |
| Obstruction | 0 (0%) |
| Fistula | 2 (2%) |
| Location | |
| Sigmoid | 58 (69%) |
| Descending | 7 (8%) |
| Transverse | 0 (0%) |
| Ascending | 1 (1%) |
| Cecum | 2 (2%) |
| Left (not otherwise specified) | 6 (7%) |
| Right (not otherwise specified) | 1 (1%) |
| Unknown | 10 (12%) |
Diverticulosis Characteristics
The morphologic characteristics of diverticulosis are shown in Table 3. In general, there was fairly even distribution across the size and severity categories with a predominance of left-sided diverticulosis (90%) and only small-sized diverticula (56%), which is concurrent with present literature[1,20].
Table 3.
Basic characteristics of diverticulosis in cases vs controls
| Cases | Controls | |
|---|---|---|
| Overall Severity | ||
| Mild | 20 (24%) | 50 (59%) |
| Moderate | 35 (41%) | 25 (29%) |
| Severe | 30 (35%) | 10 (12%) |
| Overall location | ||
| Both right and left | 32 (38%) | 25 (29%) |
| Right only | 2 (2%) | 15 (18%) |
| Left only | 51 (60%) | 45 (53%) |
| Size | ||
| Only small | 39 (46%) | 57 (67%) |
| Any Small | 58 (68%) | 73 (86%) |
| Only large | 11 (13%) | 2 (2%) |
| Any Large | 28 (33%) | 18 (21%) |
| Small and Large | 19 (22%) | 16 (19%) |
In general, we found that patients with large diverticula and left-sided only diverticula were at higher odds of diverticulitis (Table 4). In the analyses of patients with left-sided only diverticula, those with large diverticula had an odds ratio of 3.33 (OR 3.33; 95% CI, 1.30-8.56) when compared to those with only small diverticula. Similarly, patients with large diverticula and any right diverticula were at higher odds of diverticulitis compared to those with only small diverticula and any right diverticula (OR 3.8, 95% CI, 1.19-12.2). The odds of diverticulitis was particularly high in patients with large diverticula in the left colon only compared to those with small diverticula and any right diverticula (OR 6.72, 95% CI, 1.98-22.83).
Table 4.
Pairwise comparisons* of size and location of diverticulosis and odds of diverticulitis
| Only Small, Left (36 cases, 28 controls) |
Medium/Large, Left (23 cases, 9 controls) |
Only Small, Both** (12 cases, 23 controls) |
Medium/Large, Both (22 cases, 17 controls) |
|
|---|---|---|---|---|
| Only Small, Left | NA | 3.33 (1.30, 8.56)# p=0.012 | 0.5 (0.19, 1.32) p=0.161 | 1.89 (0.78, 4.57) p=0.159 |
| Medium/Large, Left | 0.3 (0.12, 0.77) p=0.012 | NA | 0.15 (0.04, 0.51) p=0.002 | 0.57 (0.2, 1.58) p=0.278 |
| Only Small, Both | 2.02 (0.76, 5.37) p=0.161 | 6.72 (1.98, 22.83) p=0.002 | NA | 3.8 (1.19, 12.2) p=0.025 |
| Medium/Large, Both | 0.53 (0.22, 1.28) p=0.159 | 1.77 (0.63, 4.94) p=0.278 | 0.26 (0.08, 0.84) p=0.025 | NA |
Column vs Row
Both=left and right;
OR (95%CI) and P-values
The severity of diverticulosis was also positively associated with risk of diverticulitis. Compared to patients with mild diverticulosis, those with moderate (OR 3.44, 95%CI, 1.51-7.84) and severe diverticulosis (OR 8.87, 95% CI, 2.98-26.37) were at increased odds of diverticulitis (Table 5).
Table 5.
Severity of diverticulosis and odds* of diverticulitis
| Mild (20 cases, 50 controls) |
Moderate (35 cases, 25 controls) |
Severe (30 cases, 20 controls) |
|
|---|---|---|---|
| Mild | NA | 3.44 (1.51, 7.84) p=0.00** | 8.87 (2.98, 26.37) p=<0.001 |
| Moderate | 0.29 (0.13, 0.66) p=0.003 | NA | 2.58 (0.90, 7.37) p=0.077 |
| Severe | 0.11 (0.04, 0.34) p=<0.001 | 0.39 (0.14, 1.11) p=0.077 | NA |
Column vs Row comparisons
OR (95% CI) and P-values
Discussion
Diverticulitis is a common disorder that places a large burden on healthcare and patients and is increasing in prevalence. The relationship between the size, location and severity of diverticulosis and the risk of diverticulitis remains uncertain. In this matched case-control study, we found that large size, left-sided only location, and globally severe diverticulosis were associated with increased odds of diverticulitis.
Only a few studies have examined the relationship between diverticulosis characteristics and diverticulitis. In a retrospective, single-center cohort study, severe diverticulosis based on size and number of diverticula as well as colon fold hypertrophy and tortuosity was associated with a 12% risk of surgery for diverticular disease on follow up, and patients with signs of acute diverticulitis at the time of colonoscopy had a 33% risk of surgery[21]. In a series of studies, the DICA classification (Diverticular Inflammation and Complication Assessment) was developed to classify findings on endoscopy including diverticular extent, number, and the presence of inflammation and complications. This score correlated with inflammatory markers (C-reactive protein) and abdominal pain scores[22], and was subsequently validated in a multicenter, prospective cohort study. In the latter study, the risk of diverticulitis over 3 years of follow up increased with increasing DICA score (DICA 1, 3%; DICA 2, 12%; and DICA 3, 22%)[23].
Our study builds on these findings in several important ways. First, we focused on size, number, and location of diverticulosis as we hypothesized that these specific characteristics might contribute to the etiopathogenesis of diverticular inflammation. Prior studies used a combination of findings on endoscopy to classify the severity of diverticulosis so that it was not possible to assess the contribution of individual features. In addition, although all existing efforts to categorize diverticular morphology rely to some extent on subjective assessment, features such as the difficulty of colonoscopy, colon tortuosity and colon fold thickness are particularly difficult to assess and quantify. Second, prior studies included findings of overt inflammation or ongoing diverticulitis in the prediction of subsequent diverticulitis. Since past diverticulitis is strongly associated with the risk of subsequent diverticulitis, it is not surprising that current inflammation predicts future diverticulitis and need for surgery. Third, we statistically tested the relationship between diverticulosis characteristics and diverticulitis. Prior studies assigned points to specific findings a priori. For example, left colon location was assigned more points than right based on the prevalence in the population (not the risk of subsequent diverticulitis) and severity of complications (rigidity, segmental colitis) was arbitrarily graded [22]. Our findings suggest that diverticular morphology, in the absence of overt inflammation or stricture, is associated with risk of diverticulitis.
The biological mechanisms underlying the development of diverticulitis are not known. Theories supported by data linking plasma inflammatory markers and an inflammatory diet posit that diverticulitis develops in the setting of chronic inflammation. Dietary, lifestyle and other risk factors may act through changes in the gut microbiome to incite an inflammatory cascade and mucosal inflammation[20,24]. Other theories hypothesize that, similar to appendicitis, retained fecal matter in diverticula can cause inflammation, possibly by translocating pathogens or causing trauma[25]. In either of these situations, the size, location and severity of diverticulosis may contribute to the pathogenesis of diverticulitis. The size and location of diverticula may contribute to retention of fecal matter (fecaliths) and local bacterial stasis resulting in inflammation. The composition of the gut microbiome changes over the course of the intestinal tract including from the right to left colon[26] and could contribute to differences in diverticulitis risk based on location of diverticula. In general, left-sided diverticulitis is much more common than right in Western populations[27] at least in part because diverticulosis is more common in the left colon[1]. In addition, intracolonic pressure is higher in the left colon and elevated pressure may contribute to micro and macroperforation which are hallmarks of diverticulitis[28].
When looking at demographic factors and potential confounding variables, we found that the prevalence of IBS was significantly higher in patients with diverticulitis compared to controls. This finding is in line with the existing literature that indicates that patients with diverticulitis are 5 times more likely to develop IBS and 2.5 times more likely to develop functional bowel disease compared to controls without diverticulitis[29].
Our study has several strengths. First, we included cases and controls who had colonoscopies performed by a single physician to mitigate issues relating to the subjectivity of reporting the size, severity and distribution of diverticulosis despite the use of predetermined categories in the endoscopy reporting software. In addition, we compared cases and controls according to a number of important potential confounders of the relationship between diverticulosis and diverticulitis and matched on two of the most important – age and sex. Our analytic approach took into consideration the complicated combination of size and location of diverticulosis in addition to a global, but more subjective, measure of severity.
Several limitations must also be considered. Ideally, the size, number and location of diverticula would be assessed prospectively. However, even in this situation, assessment is difficult as diverticula are seen differentially on scope insertion and withdrawal. As noted above, we attempted to reduce inconsistency and reporting bias by including endoscopies performed by a single endoscopist. In addition, the aims of this study were developed after the endoscopies were performed. Therefore, knowledge of a history of diverticulitis was unlikely to have influenced the way diverticulosis morphology was reported. CT reports and images were not available for a few patients and therefore the location of diverticulitis was unknown. The size of our study was modest, and the confidence intervals were relatively wide for some of the analyses. Notably, the sparsity of prior data correlating diverticular morphology to risk of diverticulitis, made it difficult to perform meaningful sample size calculations.
In conclusion, this study found that the odds of diverticulitis are highest in patients with large diverticula isolated to the left colon and those with severe diverticulosis based on size, extent and/or number. These findings may help to identify patients at risk of diverticulitis based on findings at endoscopy, and support the use of endoscopic classification systems such as the validated DICA classification[23] when diverticula are detected. Future studies are needed to develop a more sophisticated understanding of how diverticular morphology relates to risk of diverticulitis.
Acknowledgements:
We thank Wynn Burke for his assistance in identifying study participants.
Conflicts of Interest and Source of Funding:
All authors have no conflicts of interest to disclose. This study was funded in part by a grant from the National Institutes of Health (R01DK101495). The funding source played no role in the design, analysis or reporting of our findings.
Abbreviations:
- IBS
Irritable Bowel Syndrome
- DICA
Diverticular Inflammation and Complication Assessment
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