Colonic Diverticula Are Not Associated With Mucosal Inflammation or Chronic Gastrointestinal Symptoms

Anne F. Peery; Temitope O. Keku; Cassandra Addamo; Amber N. McCoy; Christopher F. Martin; Joseph A. Galanko; Robert S. Sandler

Disclosures

Clin Gastroenterol Hepatol. 2018;16(6):884-891. 

In This Article

Discussion

In this large colonoscopy-based study of individuals without a history of diverticulitis or overt peridiverticular inflammation, we found that colonic diverticulosis was not associated with mucosal inflammation. We also found no association between colonic diverticulosis and chronic gastrointestinal symptoms. We explored whether markers of mucosal inflammation were increased among participants with chronic gastrointestinal symptoms and diverticulosis compared with those without diverticulosis. There was no evidence for mucosal inflammation in individuals with diverticulosis and chronic gastrointestinal symptoms, so-called SUDD.

The evidence that colonic diverticulosis without overt inflammation in an asymptomatic population without a history of diverticular disease is associated with low-grade mucosal inflammation is limited. A study from Italy assessed whether colonic mucosa from asymptomatic patients with diverticula was associated with markers of inflammation compared with those without diverticula.[4] Similar to our work, there was no difference in T-cell and mast cell counts between groups. Colonic macrophages were increased significantly in patients with colonic diverticula compared with those without diverticula. Notably, this was a pilot study of 30 participants and was limited to bivariate comparisons that did not control for confounding variables.

In Western countries, there is an increasing incidence of chronic inflammatory diseases of the gastrointestinal tract in the absence of overt infection.[15] To evaluate a potential role for the mucosal immune system in the etiology of diverticulosis, we assessed immune markers and cytokine levels, which have been implicated in inflammatory bowel disease and irritable bowel syndrome. The inflammatory response in Crohn's disease consists mainly of T cells and macrophages whereas the inflammation of ulcerative colitis is restricted to the mucosa with predominant infiltration by neutrophils.[15] There is some evidence for an imbalance of mucosal proinflammatory TNF-α and anti-inflammatory IL10 in irritable bowel syndrome, a condition previously considered a motility disorder.[16] Increased mucosal mast cell infiltration also has been reported in several studies of patients with irritable bowel syndrome.[17] Despite assessing an array of immune markers and cytokine levels, our work found no evidence that colonic diverticulosis is associated with mucosal inflammation, which suggests that chronic mucosal inflammation is not likely to be responsible for the development of diverticulosis.

SUDD has been defined as a subtype of diverticular disease in which there are persistent abdominal symptoms in the absence of macroscopically overt colitis or diverticulitis.[18,19] Once colonic diverticula form, there is the potential for numerous complications. The most common diverticular complication is acute diverticulitis. Beyond diverticulitis, there is growing evidence for a spectrum of chronic diverticular-related bowel disorders. Many of these disorders remain ill-defined, however, each likely has a separate pathophysiology. SUDD should not be confused with chronic or smoldering diverticulitis, segmental colitis associated with diverticular disease, or the chronic gastrointestinal symptoms experienced after an episode of diverticulitis.

Whether SUDD is a valid condition independent of irritable bowel syndrome is controversial. There are no consistent definitions of SUDD in the literature. Some investigators have defined SUDD as abdominal pain and changes in bowel habits attributed to diverticula in the absence of alternate etiologies.[5,20,21] Although other investigators have defined SUDD as abdominal pain in patients with diverticulosis in the absence of any complications (stenosis, abscess, and fistulas) and in which the presence of abdominal pain is noted in the left lower quadrant lasting for more than 24 hours.[18,22,23] Because of the possible overlap between IBS and SUDD, clinical criteria have been developed to differentiate the 2 entities.[22] Patients with SUDD are older than IBS patients, lack the female predominance of IBS, and have prolonged episodes of pain.[22] The pain is thought to arise from muscular contractions. Based on 24-hour manometry studies, patients with diverticulosis had a significant increase in regular patterns of phasic pressure activity compared with controls, and 30% reported cramping and lower abdominal pain during colonic contractions.[24] The study was based on small numbers (12 patients) and painful episodes and, although associated with contractions, lasted for 5 to 10 minutes.

The evidence for colonic diverticulosis and associated gastrointestinal symptoms is limited. A population-based, colonoscopy-based study from Sweden found that participants with diverticulosis were more likely to report loose stools (OR, 1.88; 95% CI, 1.20–2.96) and high stool frequency (OR, 2.02; 95% CI, 1.11–3.65). There was no significant association with abdominal pain, irritable bowel syndrome, or irritable bowel syndrome subtypes. In analyses limited to individuals older than age 60, participants with diverticulosis had an increased risk of abdominal pain (OR, 2.10; 95% CI, 1.01–4.37) and diarrhea-predominant irritable bowel syndrome (OR, 9.55; 95% CI, 1.08–84.1) compared with participants without diverticulosis.[5] In this study, colonic diverticula were not assessed in a standard manner and the gastroenterologist who performed the colonoscopy many times also performed the preprocedure medical examination.[25] If the gastroenterologist believed that a patient's gastrointestinal symptoms were associated with colonic diverticulosis, they may have been biased to overdetect and over-report colonic diverticula in patients with symptoms. The prevalence of colonic diverticulosis was substantially lower in this Swedish study (10%–25% of participants aged 50–59 years) compared with the prevalence of diverticulosis in US populations (33%–40% of adults aged 50–59 years).[1,2] This may reflect a difference in the prevalence of diverticulosis in these 2 countries or under-reporting in the Swedish study.

Diverticulosis also was associated with irritable bowel syndrome in a study that used a survey and chart review.[6] Again, colonic diverticulosis was not assessed in a standard manner and there was the same potential for bias as in the Swedish study. In a study design similar to our own, distal diverticulosis was associated with irritable bowel syndrome in a study from Japan.[26] In contrast with prior work, we found no association between colonic diverticulosis and chronic abdominal pain or irritable bowel syndrome.

The evidence that low-grade diverticular inflammation is associated with chronic gastrointestinal symptoms is of very low quality. The most commonly cited evidence is a case series of 17 patients with diverticulosis and gastrointestinal symptoms, 94% had histopathology findings of chronic nonspecific inflammation.[7] This case series was published in abstract form only, did not include controls, and included patients with a spectrum of gastrointestinal symptoms (diarrhea, constipation, rectal bleeding, weight loss, and bloating). A small Italian study found no evidence for mucosal inflammation when comparing patients with SUDD and asymptomatic controls.[8] A pilot study found that patients with SUDD compared with asymptomatic controls without diverticula had higher levels of mucosal mast cells and macrophage counts.[4] Notably, the controls in both studies did not have colonic diverticula. Because there is evidence for mucosal inflammation in irritable bowel syndrome, these were not appropriate controls.[16]

We explored whether markers of mucosal inflammation were increased among participants with chronic gastrointestinal symptoms who had diverticulosis compared with participants with symptoms who did not have diverticulosis. Because there is evidence that irritable bowel syndrome is associated with mucosal inflammation, we did not compare patients with and without irritable bowel syndrome. Instead, we were interested in whether there might be a subtype of individuals with irritable bowel syndrome (or chronic abdominal pain) with low-grade inflammation secondary to colonic diverticula. We found no evidence for mucosal inflammation in individuals with diverticulosis and the symptoms of irritable bowel syndrome or chronic abdominal pain. This finding has clinical implications. Based on the theory that SUDD is the result of chronic peridiverticular mucosal inflammation, some investigators recommend treatment with mesalamine.[9] Our findings strongly question the rationale for treating SUDD with mesalamine.

Our work had notable strengths. This was a prospective study designed to study factors associated with colonic diverticula. Every participant had a complete colonoscopy and assessment for diverticula. Colon biopsy specimens were obtained in a uniform manner. Gastrointestinal symptoms were assessed using Rome criteria. Confounding variables were measured and accounted for in our analyses. The panel of inflammatory markers allowed us to assess both local inflammation and immune activation in the colonic mucosa. Our work also had limitations. Because we included only patients presenting for a screening colonoscopy, we had a small number of participants with IBS in our sample. Moreover, we did not have a measure of IBS severity or IBS subtypes. Although we studied several immune markers and cytokines, there are other potential markers that may be associated with chronic inflammation. Multi-analyte profiling could be used to assess an array of cytokines, and markers for macrophages (CD68), global T cells (CD3), and B cells (CD19). Whether there is utility in further studies given our negative results is debatable.

In summary, we found no evidence that colonic diverticula are associated with mucosal inflammation or chronic gastrointestinal symptoms. Our data challenge the concept that colonic diverticulosis is a state of chronic inflammation and suggest that chronic mucosal inflammation is not likely to be responsible for the development of diverticulosis. Our work also raises questions about whether symptomatic uncomplicated diverticular disease is a legitimate condition. We found no evidence of inflammation, suggesting that there is no basis for treatment with anti-inflammatory agents such as mesalamine in these patients.

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