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DIVERTICULAR DISEASE AS A CHRONIC ILLNESS: EVOLVING EPIDEMIOLOGIC AND CLINICAL INSIGHTS* Brennan M. R. Spiegel, MD, MSHS, FACG Overview Diverticular disease imposes a significant burden on Western and industrialized societies.1-3 The prevalence of diverticulosis increases with age, affecting approximately 70% of individuals aged 80 years or older in the United States.2,4 Patients with diverticulosis may experience a range of both acute and chronic complications including abdominal pain, diverticulitis, peritonitis, obstruction, fistulization, or abscess formation.5,6 These complications account for over 300,000 hospital admissions, 1.5 million inpatient care days, and $2.4 billion in direct costs annually in the United States.1,7,8 The incidence of diverticular complications appears to be increasing, and the number of patients affected by diverticular disease will continue to rise as the population ages and expands.9 These epidemiologic trends are already familiar to any endoscopist who performs colon cancer screening, as diverticulosis is the most commonly reported lesion found on routine colonoscopy.1 Despite the large epidemiologic and economic burden of diverticular disease, there is surprisingly little known about this condition; providers still lack reliable answers to common clinical questions. Moreover, these questions indicate that diverticular disease may have a chronic component in some patients, that providers should be prepared to address the illness as part of everyday outpatient practice, and that patients may harbor long-term concerns about the diagnosis even outside of symptomatic episodes. Yet diverticular disease is often conceived as abrupt, disruptive, and acute diverticulitis attacks surrounded by periods of relative clinical silence. This may not be true for everyone. As discussed in this article, patients with diverticular disease not only experience lower health related quality of life (HRQOL) than matched controls,10,11 but their HRQOL decrement may occur well beyond acute diverticulitis attacks; for some patients, true diverticulitis may persist beyond the overt flares and evolve into a more chronic illness. Other patients may suffer from depression or anxiety related to chronic abdominal pain or related illness experiences.12 Still others may develop irritable bowel syndrome (IBS) symptoms in the setting of diverticular disease – an as yet unproven causal link, but a relationship with growing epidemiologic data, discussed below.12-15 And if diverticular disease causes * Based on Strate LL, Modi R, Cohen E, Spiegel BM. Diverticular disease as a chronic illness: Evolving epidemiologic and clinical insights Am J Gastroenterol 2012:107:1486-1493.

longstanding pain, discomfort, or IBS symptoms, then it suggests the condition may become a chronic bowel disorder in some patients – not merely an intermittent condition within the purview of surgeons.

Setting Diverticular Terminology Straight The diverticulosis literature is replete with terms of unclear significance such as diverticular disease, symptomatic diverticulosis, and symptomatic uncomplicated diverticular disease (SUDD). The scheme in Figure 1 helps to organize the diverticular terminology. “Diverticulosis” is merely the presence of colonic diverticula; these may, or may not, be symptomatic or complicated. “Diverticular disease” is clinically significant and symptomatic diverticulosis; this may be from true diverticulitis or from other less well understood manifestations (e.g., visceral hypersensitivity in the absence of verifiable inflammation16). The overarching term “diverticular disease” implies that the pathologic lesion (diverticulosis) rises to the level of an illness. SUDD is a sub-type of diverticular disease in which there are persistent abdominal symptoms attributed to diverticula in the absence of macroscopically overt colitis or diverticulitis. In contrast, “diverticulitis” is macroscopic inflammation of diverticula with related acute or chronic complications. Diverticulitis can be acute or chronic. In its chronic form, patients may have recurrent bouts of low-grade or overt diverticulitis. A small subset of patients may develop segmental colitis associated with diverticulosis (SCAD) – a unique form of chronic diverticulitis that occurs in areas marked by diverticulosis that may be a variant or forerunner of inflammatory bowel disease (IBD), as discussed later in this article.17,18 The primary focus in this article is on chronic forms of diverticular disease, including SUDD, recurrent chronic diverticulitis, and SCAD. Evolving Pathophysiologic Mechanisms of Diverticular Disease Diverticula are thought to develop from age-related degeneration of the mucosal wall and segmental increases in colon pressure resulting in bulging at points of weakness, typically at the insertion of the vasa recta. Diverticulitis, in turn, is traditionally ascribed to fecaliths obstructing a diverticular sac, prompting barotrauma, mucosal abrasion, inflammation, and bacterial overgrowth. Alternatively, poorly digested food components, like seeds or nut particles, are hypothesized to lodge within diverticula and result in localized trauma, tissue ischemia, focal necrosis and micro-perforation. These predominantly anatomical theories are outlined in previous review 1A: Luminal GI Conditions

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Brennan M. R. Spiegel, MD, MSHS, FACG Figure 1: Diverticulitis Incidence in Subjects with Baseline Asymptomatic Diverticulosis Found on Screening Colonoscopy Stratified by Decade of Life. The cumulative diverticulitis probability over 130 months was 4.3%. For every additional decade of life, there was a 24% lower risk of diverticulitis. Diverticulitis progression peaked at 11% for 40-year-old patients.

articles and guidelines.6,19-22 In contrast, more recent theories de-emphasize these anatomic mechanisms, and instead posit inflammation, microbiome shifts, visceral hypersensitivity, and abnormal motility as potential etiologic factors, especially for chronic diverticular disease.

Inflammation The role of inflammation in acute diverticulitis is well accepted. However, a growing body of literature indicates that low-grade inflammation may also play a role in chronic diverticular disease. The inflammation may be microscopic, identified only through diverticular biopsies, or macroscopic, presenting in a manner similar to IBD. Case series demonstrate chronic inflammation in biopsy specimens taken from within and around diverticula of patients without overt diverticulitis or colitis. As early as 1976, Kealy and colleagues observed a higher density of lymph node aggregates in macroscopically disease-free portions of colonic mucosa in subjects with versus without diverticulosis.23 Floch and colleagues later found abnormal pathology in random biopsies taken from 16 of 17 patients with diverticulosis, with most demonstrating a lymphocytic infiltrate without overt colitis.24 In another series of 930 patients undergoing surgery for SUDD but not overt diverticulitis, Horgan and colleagues documented chronic inflammation in and around diverticula in three-quarters of the resected specimens.25 However, the extent of inflammation did not correlate well with symptom intensity. In addition, 5-ASA drugs traditionally used in IBD appear to reduce diverticulitis recurrence and minimize symptoms following an attack of acute diverticulitis (discussed 20

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below).26 Together this evidence suggests that microscopic inflammation occurs in the setting of diverticulosis, and that its presence might contribute to symptom development in some patients with diverticular disease. Beyond microscopic inflammation, macroscopic colitis has been widely reported in association with diverticula. These observations led investigators to define SCAD as a separate disorder.27,28 SCAD is a form of chronic colitis limited to areas of the colon with diverticula and sparing the rectum. Although now recognized as a distinct clinico-pathological entity, the histological features of SCAD bear close resemblance not only to idiopathic IBD, but also to infectious and ischemic colitis.29 Cryptitis, crypt abscesses, and even granulomas and chronic architectural distortion are described in patients with SCAD.29 Case series reveal that in a small subset of patients (approximately 10%), SCAD evolves into frank IBD,17 suggesting that SCAD may be a forme fruste of IBD. SCAD is perhaps the most powerful example that inflammation and diverticulosis can go hand-in-hand, and that traditional explanations for diverticular disease involving local trauma and obstruction are probably insufficient.

Intestinal Microbiota Another putative mechanism of chronic diverticular disease involves shifts in intestinal microbiota leading to chronic inflammation, similar to theoretical models for IBS.30 Fecal stasis may lead to chronic dysbiosis, in turn promoting formation of abnormal metabolites leading to long-standing inflammation. Several lines of indirect evidence support a potential association between the intestinal microbiota and diverticular disease.

Brennan M. R. Spiegel, MD, MSHS, FACG Figure 2: Proposed Taxonomy of Diverticular-Related Terms. Diverticulosis is the mere presence of diverticula in the colon – this may be symptomatic or asymptomatic. “Diverticular disease” implies symptoms; this may be from verifiable macroscopic diverticulitis – i.e., inflammation of the diverticula – or in the absence of overt diverticulitis, called symptomatic uncomplicated diverticular disease (SUDD). Diverticulitis can be acute or chronic. Some patients with chronic diverticulitis have a unique form of the disease called segmental colitis associated with diverticula, or SCAD, which is a distinct clinico-pathologic entity more like inflammatory bowel disease than traditional diverticulitis. Others with chronic diverticulitis have recurrent episodes of traditional diverticulitis rather than SCAD. See text for details.

Rifaximin, a non-systemic antibiotic, may reduce attacks of recurrent diverticulitis and treat gastrointestinal symptoms in patients with SUDD.31,32 Low dietary fiber intake, a putative risk factor for chronic diverticular disease, is associated with alterations in the gut microbial composition.33 Additionally, in a study of 90 patients with a history of acute diverticulitis, 60% were noted to have small bowel bacterial overgrowth using the lactulose hydrogen breath test (LHBT),34 although it should be noted that the LHBT may be a better measure of intestinal transit than true overgrowth.35 Further research using quantitative molecular techniques will better elucidate the potential role of commensal gut microflora in the pathogenesis of diverticular disease.

Visceral Hypersensitivity Evolving data suggest a strong epidemiologic overlap between chronic diverticular disease and IBS, as discussed later in this article.13,14 This overlap suggests that both conditions may also share underlying pathophysiology. Visceral hypersensitivity, although usually described in the context of IBS,36 may provide this common mechanism. For example, Clemens and colleagues compared colonic visceral pain perception in response to luminal distention in patients with SUDD, asymptomatic diverticulosis, and healthy controls.16 Patients with SUDD not only demonstrated a heightened pain perception in the sigmoid colon with diverticula, but also in the unaffected rectum. This phenomenon was not observed in either the control subjects or those with asymptomatic diverticulosis. These findings suggest that an IBS-like process of generalized hyperalgesia may occur in diverticular disease. Recent data suggest the mechanism of hypersensitivity may relate to increased neuropeptides and alterations in enteric innervation in patients with diverticular disease – a “post-inflammatory” consequence that persists after acute diverticulitis has passed.37 Colonic Motility It is well accepted that abnormal colonic motility plays a role in IBS symptom expression.38 Altered motility may also be

Diverticulosis Diverticular Disease

Diverticulitis

Acute Diverticulitis

Asymptomatic Diverticulosis

SUDD

Chronic Diverticulitis

Chronic recurrent Diverticulitis

SCAD

associated with chronic symptoms in diverticular disease. In a study by Bassotti and colleagues, patients with SUDD displayed increased duration of rhythmic, low frequency, contractile activity, particularly in the segments bearing diverticula – a pattern the authors described as “spastic colon.”39 Although the relationship between dysmotility and symptoms was imperfect, the authors concluded that patients with diverticular disease have abnormal motor and propulsive activities in the colonic segments exhibiting diverticulosis. In a separate study, these same authors demonstrated that patients with diverticulosis have a significantly reduced density of interstitial cells of Cajal (ICC) – the so called “pacemaker cells” of the intestine – compared to normal controls.40 A reduction or loss of ICC function may disturb or decrease colonic electrical slow wave activity, presumably resulting in abdominal complaints including pain and constipation. Shifts in the concentrations of mucosal vasoactive intestinal peptide and other chemical mediators may also play a role, as suggested by Milner and colleagues.41

Epidemiology and Natural History of Diverticulosis: Dogma vs. Data The natural history of diverticulosis is poorly understood. Of patients who harbor colonic diverticulosis, it is traditionally believed that 15-25% will progress to develop diverticulitis in their lifetime.5,6,19,20,22 However, this widely-cited figure is based on data predating population-based screening colonoscopy. Therefore, the true denominator of individuals harboring diverticulosis was not accounted for in these calculations. Current population based data suggest that the true incidence of diverticulitis is much lower than previously estimated. The 1A: Luminal GI Conditions

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Brennan M. R. Spiegel, MD, MSHS, FACG

number of hospitalizations for diverticulitis per year in the United States (approximately 800,000) is lower than would be expected based on the number of Americans estimated to have diverticulosis (see Figure 2).1 Recent populationbased cohort studies indicate that the incidence of diverticulitis among adults is between 1 and 2%.42,43 Assuming that approximately 50% of these individuals have diverticulosis, the incidence of diverticulitis in patients with diverticulosis would be less than 5%. To more accurately calculate the true incidence of acute diverticulitis, we performed a survival analysis in a large cohort of patients with diverticulosis incidentally discovered during colonoscopy.16 We followed 2,127 patients over a median of nearly 7 years and tracked incident diverticulitis attacks confirmed through chart review. The cumulative diverticulitis probability was 4.3% when using a liberal definition not requiring CT scan confirmation, and only 1% when requiring CT scan or surgery to confirm the diagnosis of acute diverticulitis. For every additional decade of life, there was a 24% lower risk of diverticulitis (HR=0.66; p=0.008). In short, contrary to dogma that 25% with diverticulosis develop diverticulitis, we found an overall incidence of