Left-sided colonic diverticular disease is a common

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1 ORIGINAL CONTRIBUTION Diverticular Disease Associated with Inflammatory Bowel Disease-Like Colitis: A Systematic Review Aaron M. Mulhall, B.A. 1 & Suhal S. Mahid, M.D., Ph.D. 1 & Robert E. Petras, M.D. 2 Susan Galandiuk, M.D. 1 1 Price Institute of Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 2 Ameripath Institute of Gastrointestinal Pathology and Digestive Disease, Oakwood Village, Ohio PURPOSE: Diverticular-associated colitis significantly overlaps clinically with primary inflammatory bowel disease. However, the clinical and the pathologic features of diverticular-associated colitis suggest that it is a distinct clinical entity. METHODS: We performed a systematic review by use of multiple health care databases and gray literature, following predefined inclusion and exclusion criteria to determine the clinical, endoscopic, and pathologic features of diverticular-associated colitis, and recurrence rates following medical and surgical treatment. RESULTS: Two hundred twenty-seven participants were selected from 18 eligible studies, including our own patients (n = 13). The average age of disease onset was 64 years. The typical symptoms included tenesmus, hematochezia, and diarrhea. One hundred sixty-three of the 227 patients in these studies were classified as having diverticular-associated colitis, of which 142 were managed medically. Twenty-eight patients eventually required an operation. One-quarter (37 of 163) of the patients had recurrence of symptoms with an average follow-up time of three years. CONCLUSIONS: Diverticular-associated colitis is a distinct entity that presents with segmental colitis and a variety of clinical, endoscopic, and pathologic features. Diverticular-associated colitis should be considered in the presence of recurrent symptoms after resection for diverticulitis. Supported in part by the John and Caroline Price Trust. Address of correspondence: Susan Galandiuk, M.D., Department of Surgery, University of Louisville, Louisville, Kentucky s0gala01@louisville.edu Dis Colon Rectum 2009; 52: 1072Y1079 DOI: /DCR.0b013e31819ef79a BThe ASCRS 2009 KEY WORDS: Diverticular colitis; Inflammatory bowel disease; Crohn s disease; Ulcerative colitis; Segmental colitis; Crescenteric colitis. Left-sided colonic diverticular disease is a common condition of Western populations and affects as many as 30 to 50 percent of individuals over the age of 60. 1,2 Diverticular disease can be characterized by the pathologic triad of a thickened muscularis propria of the sigmoid colon, penetration of the diverticulum, including the mucosa and muscularis mucosa, through the muscle, and the redundancy of surface mucosal folds. Recent studies have emphasized coexisting luminal inflammatory changes in a subset of patients with diverticular disease, citing clinical and pathologic overlaps with primary inflammatory bowel disease (IBD). This overlapping can cause problems with differential diagnosis and subsequent patient management. 3Y7 Segmental colitis in an area of coexisting diverticula is referred to as diverticular diseaseassociated colitis (DAC). Prior reports indicate that this is a heterogeneous condition, with some patients having a benign course, whereas others progress on to developing overt IBD. Luminal inflammation in patients with diverticular disease can be encountered in three main variants or clinical scenarios. Encountered in the first scenario are patients with clinical diverticulitis requiring resection. In some circumstances, there may be coexisting Crohn s disease (CD). In a second scenario patients with symptoms secondary to mucosal inflammation in addition to the presence of diverticular disease are encountered. The etiologic options in this case are mucosal trauma and/ or prolapse, comorbid infection, or nonsteroidal antiinflammatory drug-related lesions. Another possible etiology for this scenario is primary IBD-like inflammation limited to areas involved with diverticula. This has been referred to by a number of terms such as DAC, segmental colitis associated with diverticula, crescenteric mucosal fold disease, etc. 6,8Y16 The third scenario involves patients with known IBD who also have diverticular disease in 1072 DISEASES OF THE COLON & RECTUM VOLUME 52: 6 (2009)

2 Diseases of the Colon & Rectum Volume 52: 6 (2009) 1073 which the IBD predisposes to inflammation within the diverticula or who have symptoms as the result of diverticular disease requiring resection. The prevalence of DAC is often unclear because of the difficulty in clinically identifying the overlap of diverticular disease and IBD. It has been reported to occur infrequently 17 (prevalence, 1.3 to 3.8 percent), with the mean age of onset between 60 and 70 years coinciding with the second peak of onset in IBD. 14,18,19 With use of a strict definition of DAC, we report a systematic review of the literature and include a cohort of 13 patients from a single institution over a 14-year period to further clarify the nature and clinical significance of these luminal inflammatory changes. We describe the clinical, endoscopic, and histologic features of DAC and the recurrence rates following medical and surgical treatment. We hypothesize that DAC is a distinct clinical entity. PATIENTS AND METHODS Study Selection A search was conducted by use of Medline (January 1966 to August 2008), EMBASE, and Cochrane databases. We used PubMed, Ovid, and Google Scholar as our search engines. The following medical subject heading (MeSH) terms were used with no language restriction: inflammatory bowel disease, colitis, ulcerative colitis, Crohn s disease, diverticulitis, diverticular associated colitis, segmental colitis, and segmental colitis associated with diverticular disease. Additional studies cited within the literature were also searched. Boolean operators ( not, and, or ) were used to narrow and widen our search. The number of hits was increased when we used the Ovid search engine_s explode and related article functions. Based on the title and abstract of the publication, we either downloaded or requested full articles through our library. To locate unpublished material and avoid systematic (i.e., publication) bias, 20Y22 we manually searched the references of original/review articles and evaluated gray literature 23 (symposia proceedings, poster presentations, abstracts) from major gastrointestinal and surgical meetings, including the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), the British Society of Gastroenterology (BSG), and the Society for Surgery of the Alimentary Tract (SSAT) over a 11-year period (1998 to 2008). An investigative team developed the inclusion and exclusion criteria. Inclusion Criteria Abstracts, full articles, and gray literature that met the primary screening procedure were retrieved and then analyzed for the presence of the following: Case-control studies, prospective and retrospective cohorts, and case reports. Patients with a diagnosis of DAC based on accepted clinical, endoscopic, or histologic findings. The clinical symptoms of tenesmus, hematochezia, diarrhea, bloody diarrhea, abdominal pain, and nausea. Endoscopic findings including focal erythema, submucosal ecchymosis, erosions, and ulcers. Histologic criteria of luminal inflammation in biopsy or resection specimens. A specialist gastrointestinal pathologist reviewed the histologic criteria of articles chosen for inclusion to ensure that they provided adequate histology data. Reports containing clinical data such as age of onset, treatment, recurrence of symptoms, and follow-up time. Exclusion Criteria Based on our primary screening procedure criteria, we excluded letters, comments, and reviews with insufficient details. Family/genetic studies were also excluded. Data Extraction Data were abstracted by two independent reviewers (AMM, SSM). Each article was comprehensively reviewed to determine whether it met the inclusion and exclusion criteria. Each investigator used a standardized data collection form to reduce reporting bias. A consensus decision was made in the cases of a discrepancy. Each investigator abstracted the following data from each report: first author, year of publication, journal, the number of cases, and population demographics. Data are presented as mean T standard deviation of the mean (SD) unless otherwise indicated. We also included in this systematic review data on 13 patients admitted to our University Section of Colon and RectalSurgery(Louisville,KY)overa14-yearperiodwho met the study inclusion criteria (Galandiuk et al., unpublished data). Patient data were retrieved following Institutional Review Board approval according to the University of Louisville Institutional Review Board guidelines. Clinical data included age, gender, symptoms, endoscopy results, and histology suggestive of concurrent diverticular disease and IBD, treatment (medical and surgical), interval between treatment and last examination, and recurrence of symptoms. Symptoms of DAC included abdominal pain (primarily left lower quadrant), rectal bleeding, and diarrhea. The clinical diagnosis of DAC was made based on the results of endoscopic, radiologic, and pathologic studies, and clinical diverticulitis in patients with IBD. Diagnostic criteria included endoscopic findings of inflamed friable, edematous mucosa, predominantly in an area of colon affected with diverticula. After initial diagnosis, a gastrointestinal pathologist with a special interest in IBD reviewed endoscopic biopsies or surgical specimens in all 13 patients. Histologic alterations included mucosal inflammation, distorted crypt architecture, crypt abscesses, granulomas, and crypt plasmacytosis.

3 1074 MULHALL ET AL: DIVERTICULAR DISEASE ASSOCIATED COLITIS RESULTS A total of 478 studies were retrieved and 452 articles were excluded after reviewing the abstract and full-text reports because they were either irrelevant to IBD and diverticular disease (n = 420) or lacked clinical data (n = 32). The remaining 26 studies were screened further and 9 articles were excluded because, of these 9 articles, 6 were review articles, 2 were editorials, and 1 was a letter to the editor, leaving 17 studies. Eighteen studies including our own patient data met our predefined inclusion criteria (Fig. 1). 4,5,13Y16,18,19,23Y31 We selected 227 participants based on these criteria. Study Characteristics Of the 18 studies, 7, including our data, were reported from medical/surgical centers in the United States, 5,13,19,23,28,29 8fromEurope, 4,14,19,24Y26,27,30 2fromCanada, 16,31 and 1 from Australia (Table 1). 18 These studies were conducted over a 35-year period, ranging from 1974 to Most studies were retrospective (61 percent), and 33 percent were case reports. There was one prospective cohort study. The number of participants per report ranged from 1 to 34. Sixty-one percent of patients were male. Only three studies reported having more affected females than males, including our patient data. 4,18 The average age of disease onset was 63.7 T 5.2 years. In our 13 patients, 69 percent were women and the mean age of disease onset was 61 T 14 years. In our patients, there was no association between DAC and history of smoking, family history of colorectal cancer, or IBD. All of our patients had tenesmus (100 percent), and the majority had hematochezia (77 percent), or other symptoms including diarrhea (38 percent), constipation (38 percent), and nausea (31 percent). The description of DAC varied greatly among studies. Four studies described patients who had an inflammatory FIGURE 1. Flow chart of study inclusion and exclusion criteria.

4 Diseases of the Colon & Rectum Volume 52: 6 (2009) 1075 TABLE 1. Studies meeting inclusion criteria for systematic review Reference Study design n DAC cases (n) Age of onset (years) Gender (n male) Treatment (n) Recurrence of symptoms in DAC cases (n) Follow-up time (years) Bates and Kaminsky CR Surg a 0 1 Sladen and Filipe CR Med / 1 Surg b McCue et al RC Surg b Gore et al RC Med / 2 Surg b 0 NS Peppercorn RC Med 3 4 Hart et al RC Med Y7.75 c Van Rosendaal and CR Surg b 0 1 Andersen Burroughs et al RC Surg b Gledhill and Dixon RC Surg a,b Makapugay and Dean PC Med / 5 Surg b Y8 c Pereira CR Surg b Goldstein et al RC T Surg b 2 6 Evans et al CR Med / 2 Surg b Jani et al CR Med / 1 Surg b Koutroubakis et al RC Med / 4 Surg b Imperiali et al RC Med / 2 Surg b 7 7 Unpublished data RC T Med / 7 Surg a,b T 2 (Galandiuk et al. 2007) Freeman RC Med / 4 Surg b Totals (n, %) Y d (72%) 63.7 T 5.2 e 138 (61%) 50% Med, 28% Surg, 12% Med and Surg 37 (23%) 3.2 T 2.2 e DAC = diverticular disease-associated IBD-like colitis; RC = retrospective cohort; CR = case report; PC = prospective cohort; Med = medical; Surg = surgical; NS = not specified. a Total colectomy. b Segmental colectomy. c Mean not reported. d Not reported. e Values reported as mean T standard deviation. manifestation of diverticular disease that resembled CD, including pathologic findings such as transmural inflammation, creeping fat, granulomas, lymphoid aggregates, and vasculitis. 4,23,27,28 A number of studies reported a diverse range of histologic findings including an area of diverticular disease resembling ulcerative colitis (UC), CD, focal active colitis, and acute nonspecific colitis. 13,14,19,23,25 Six studies described their entire patient population as having DAC. 5,15,16,18,28,31 Evans et al. 16 reported four cases of DAC, with biopsies in two patients resembling UC, and CD in two others. In this present systematic review, three-quarters of patients from eligible studies (163 of 227) were classified as having DAC, whereas, of the remaining one-quarter (64 of 227), 21 patients had CD overlapping with diverticular disease with inflammatory changes in the proximal colon, 35 patients had focal active colitis in an area of diverticulosis, 4 had mucosal trauma/prolapse, 2 had UC coexisting with diverticular disease, 1 had ischemic colitis and diverticulosis, and 1 patient had diverticulitis alone. Five patients in our unpublished cohort of 13 patients who were initially classified as DAC were later found to have IBD coexisting with diverticular disease and inflammatory architectural changes in the proximal colon. Review of histology results by a specialist pathologist showed that three patients (23 percent) had DAC, three patients (23 percent) had focal active colitis in an area of diverticula, one (8 percent) had diverticulitis, and one (8 percent) had histologic findings characteristic of mucosal trauma/prolapse in an area affected by diverticula. Characteristic endoscopic findings in our patients included the presence of diverticula and mucosal inflammatory changes including proctosigmoiditis (31 percent), ulcers (23 percent), and band-like colitis in an area of the colon affected with diverticula (23 percent). More than half of the patients selected in this systematic review were managed medically (142 of 227). Twenty-eight patients eventually required surgical intervention (25 patients, segmental colectomy; 3 patients, total colectomy). One-quarter (37 of 163) of the patients with DAC had a recurrence of symptoms after treatment, mainly hematochezia and diarrhea. Of these, 19 recurrences were treated medically, whereas 12 received both medical and surgical treatment, and 6 developed recurrent symptoms after surgery. Seven studies reported only surgically treated patients and histologic data on resection specimens. 4,15,24,26Y29 Six studies, including our data, reported progression from DAC to overt IBD after medical and/or surgical therapy. 4,14,18,28,29 The mean length of follow-up in reported studies was 3.2 T 2.2 years (range, 1 month to 7 years). All of the 13 patients in our unpublished data were initially treated medically, with 7 patients ultimately

5 1076 MULHALL ET AL: DIVERTICULAR DISEASE ASSOCIATED COLITIS requiring surgery (Table 2). Four patients underwent segmental colectomy, two for perforated diverticulitis, one for a sigmoid stricture, and one for what had subsequently been diagnosed as IBD refractory to maximal medical therapy. The medical treatment for IBD in three other patients failed and required total proctocolectomy. Of the six patients requiring only medical therapy, three have developed recurrent symptoms including pericolic abscess, proctitis, and recurrent diverticulitis. Three patients who underwent surgical intervention have had recurrences. Two developed proctitis, and one developed an anal CD stricture. Another patient eventually required a total colectomy and later developed peristomal pyoderma gangrenosum. DISCUSSION DAC refers to mucosal inflammation, resembling IBD, in a segment of colon affected with diverticular disease and relative sparing of the rectum and proximal colon. 6,7,14,18 DAC is underrecognized and underdiagnosed as a distinct clinical entity. Prior clinical reports are not clear, in terms of disease definition or clinical course, with respect to recurrence after medical or surgical treatment. We therefore conducted a systematic review of the literature seeking to better define the clinical and demographic characteristics of this disorder and more accurately describe its clinical course. Early reports of DAC demonstrate difficulty in determining the histologic differences between IBD and diverticulitis. 32 It is also difficult to distinguish DAC from other forms of segmental colitis, including CD, UC, ischemic colitis, and infectious colitis. The overlap of IBD and diverticular disease can be difficult to distinguish both clinically and histologically, from DAC. Clinical manifestations of diverticular disease, such as hematochezia, urgency, and tenesmus, are similar to that seen with IBD. 18 Insights from our review of DAC may shed light on the pathogenesis of IBD. Included in these are various components, such as a genetically susceptible host, dysbiosis, and an abnormal immune response. 12,13,33,34 The diverticulum predisposes to dysbiosis caused by stasis, which in turn triggers the immune response in the susceptible host. There may also be a mass effect caused by subserosal peridiverticulitis and suppuration. 13,14,35Y37 Host genetics may determine whether the inflammation will remain localized, become UC-like, or CD-like with stricturing. The histologic features of affected sigmoid biopsies are not pathognomonic and can be associated with UC, CD, mucosal trauma/prolapse, or diverticulitis. 8,12,14,17,18 A clinical scenario can occur when patients have what appears to be IBD in the presence of diverticula, because diverticulitis shares many of the same histologic features as IBD, especially CD. 7 Some studies have attributed this overlap to the coincidental coexistence of IBD and diverticulosis. 38,39 Others have suggested that the inflammation from diverticulitis has endoscopic and histologic features that mimic IBD, such as inflammation, ranging from modest inflammatory changes with vascular ectasia, through classical mucosal prolapse changes, to florid active chronic inflammation, closely resembling chronic IBD. 4,6,8,10,12Y14,18,23,25,26 Patients with DAC may also have associated extraintestinal manifestations (arthritis, ankylosing spondylitis, pyoderma gangrenosum, and erythema nodosum) that can further confuse this disease with IBD, and lead to subsequent mismanagement. 40 A few cases described in the literature hypothesize that DAC may also progress to classical UC with a mean progression time of 18 months. 14,18,25,28 Most of the reported cases of DAC progressing to UC occur in patients who have already undergone segmental resection for DAC. 14,18,28 This can be difficult to predict because patients with DAC progressing to UC had rectal sparing both endoscopically and histologically. It is speculated by Ludeman et al. 6 that there is a possible pathogenetic relationship between DAC and UC, and that several factors including fecal stasis, changes in bacterial flora, and mucolysis are involved in the pathogenesis of UC. A study by Shepard 12 speculated that DAC could be an atypical manifestation of UC. This is a possible etiology because of the blind pouch effect in which UC patients can have segmental diseases in blind-ended areas of the large intestine (i.e., the appendix and cecum). Support of this hypothesis also comes from the development of pouchitis after surgical management of UC, but not for familial polyposis. 12,18,35 There is a lack of uniformity regarding the precise diagnostic criteria for DAC. In addition, three studies use the same criteria to establish a diagnosis of DAC, including IBD-like inflammation in an area of diverticula with sparing of the remaining colon. 8,13,30 Other studies describe more of a coexistence of colitis and diverticular disease. 4,10,18,25 DAC may respond well to medical therapy utilized for IBD, 15,24,26 and treatment of segmental colitis with 5-aminosalicylic acid medication is largely successful. When surgery is required, postoperative recurrences have been reported to be relatively infrequent, with follow-up times ranging from 1 to 7 years. 4,5,15,24,26,27 However, in our own patient series, three of the seven patients requiring surgery developed recurrent symptoms within a 2.5-year to 6-year follow-up. Patients with classical mucosal trauma/prolapse changes mimicking IBD should be treated with fiber products and antispasmodics. Patients with unsuspected primary IBD who undergo resection should be placed on some type of maintenance medical therapy to reduce the risk of symptom recurrence. In this latter group of patients, one-quarter eventually demonstrate symptoms

6 Diseases of the Colon & Rectum Volume 52: 6 (2009) 1077 TABLE 2. Patient demographics of Louisville retrospective cohort Patient Age of onset (years) Gender Pathology Clinical presentation Endoscopy Specimen Histology Treatment Treatment outcome Follow-up time (years) 1 26 Male T, N Diverticulitis Biopsy Nonspecific inflammation Med Recurrent diverticulitis Female T, B, D, C, N Erythema, edema, sigmoid Biopsy FAC Med Pericolonic abscess, T, B 2 diverticula 3 55 Male T, D Band-like colitis in sigmoid Biopsy FAC Med Asymptomatic 1 colon, diverticula 4 57 Female T, B, C Band-like colitis, diverticula, Biopsy Nonspecific inflammation Med Asymptomatic 6 mucosal prolapse 5 62 Male T, B, D Sigmoid colitis with rectal Biopsy IBD-like inflammation Med Proctitis, T, B, D 3 sparing, diverticula 6 64 Female T Sigmoid colitis with rectal Resection IBD-like inflammation Med / Surg a Asymptomatic 2 sparing, diverticula 7 65 Female T, B Edema, erythema, diverticula Biopsy / resection Granulomas, Med / Surg b Asymptomatic 4.5 IBD-like inflammation Med Asymptomatic Female T, B, C, N Edema, erythema and sigmoid diverticula 9 66 Male T, B, D Erythema, edema, sigmoid diverticula Female T, B Erythema, edema, sigmoid diverticula Female T, B, N Erythema, edema, sigmoid diverticula Female T, B, D, C Erythema, edema, sigmoid stricture, diverticula Female T, B, C Sigmoid colitis with rectal sparing, diverticula Biopsy Granulomas, IBD-like inflammation Resection Ulceration, granulomas, IBD-like inflammation Med / Surg b Asymptomatic 2 Biopsy / resection FAC Med / Surg a Asymptomatic 2 Resection Crypt abscesses, IBD-like inflammation Biopsy / resection Ulceration, IBD-like inflammation Biopsy / resection Crypt abscesses, IBD-like inflammation Total (%) 61 T 14 c 69% female Y d Y d Y d Y d 54% Med and Surg, 46% Med Med / Surg b Proctitis, anal CD stricture Med / Surg b Proctitis, T, B, D 6 Med / Surg a Pyoderma gangrenosum Y d 3.5 T 2 c IBD = inflammatory bowel disease; CD = Crohn s disease; FAC = focal active colitis; Med = medical; Surg = surgical; T = tenesmus; B = rectal bleeding; D = diarrhea; C = constipation; N = nausea; SD = standard deviation. a Total colectomy. b Segmental colectomy. c Data reported as mean T standard deviation. d Not reported.

7 1078 MULHALL ET AL: DIVERTICULAR DISEASE ASSOCIATED COLITIS compatible with CD (skip lesions, anal canal stricture, etc.). Approximately 10 percent will have symptoms similar to UC, whereas the remainder will have localized sigmoid inflammation that can be controlled medically. In this systematic review using predefined inclusion and exclusion criteria we selected 163 study participants that met our definition of DAC. DAC is a distinct clinical entity characterized by the concurrent presence of endoluminal inflammation, often with IBD-like histology and diverticular disease. The clinical and pathologic overlap of DAC with IBD makes the differential diagnosis critical because misdiagnosing the patient_s disease can lead to medical mismanagement. A diagnosis of IBD, especially CD, may be present or may subsequently develop in some patients who are treated as having conventional diverticular disease. We propose that these patients may indeed have DAC. 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