REVIEW URRENT C OPINION
Diverticular disease: evolving concepts in classification, presentation, and management Sasan Mosadeghi a, Taft Bhuket a, and Neil Stollman b
Purpose of review Diverticular disease is the most commonly reported finding at the time of colonoscopy and one of the most common gastrointestinal indications for hospitalization. Much of our previous understanding of diverticular disease has recently been challenged. Recent findings There is emerging evidence that the long-accepted hypothesis of diverticulosis as a consequence of fiber deficiency may be more complex than commonly thought, with recent evidence suggesting that high-fiber diet and frequent bowel movements are associated with a greater and not lower prevalence of diverticular disease. There is also emerging support for the concept of low-grade inflammation in symptomatic uncomplicated diverticular disease (SUDD), and the role of anti-inflammatory treatment with mesalamine is being actively investigated. Additionally, elective ‘prophylactic’ surgery after diverticulitis, previously considered after a second confirmed diverticulitis episode, is being increasingly deferred. Summary The pathogenesis of diverticular disease is likely multifactorial and complex. More studies are needed to evaluate the role of fiber in the pathogenesis and treatment of diverticular disease. The search for an effective medical therapy for SUDD and to prevent recurrent diverticulitis is being actively investigated. The efficacy of mesalamine does not appear to be strong data supported. Keywords diverticular disease, mesalamine, symptomatic uncomplicated diverticular disease
INTRODUCTION Diverticular disease is the sixth leading outpatient gastrointestinal diagnosis in the United States, accounting for about 2.6 million visits in 2009 [1], and is one of the most common reasons for hospitalization, with 313 000 first-listed and 815 000 alllisted diagnoses [2]. It is also the most commonly reported finding at colonoscopy, identified in over 40% of all exams and in more than 70% of patients older than 80 years [2]. Further, the incidence seems to be increasing in both Europe and the United States [3–6], and the rate of hospitalizations because of diverticular diseases rose greater than 15% between 1996 and 2004 [2], accounting for $2.6 billion per year in inpatient costs [1]. In this article, we will review the recently published literature concerning pathogenesis, risk factors, and treatments of diverticular disease.
PATHOGENESIS OF COLONIC DIVERTICULOSIS The pathogenesis of diverticulosis remains to be definitively elucidated and is likely multifactorial. www.co-gastroenterology.com
The role of a low-fiber diet, originally suggested over 40 years ago by Burkitt and Painter, has remained a widely accepted thesis [7], although more recent observations may be changing this paradigm.
Fiber A recent study challenging the ‘fiber deficiency’ theory was published by Peery et al. [8 ], who observed that a high-fiber diet was associated with greater, and not lower, prevalence of diverticulosis as might have been expected. The validity of this conclusion has been questioned because they evaluated only recent dietary history and included &&
a
Alameda Health System, Highland Hospital and bAlta Bates Summit Medical Center, Northern California Gastroenterology Consultants, Inc., Oakland, California, USA Correspondence to Neil Stollman, MD, FACP, FACG, AGAF, 300 Frank H Ogawa Plaza, Suite 450, Oakland, CA 94612, USA. Tel: +1 510 444 3297; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:50–55 DOI:10.1097/MOG.0000000000000145 Volume 31 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diverticular disease Mosadeghi et al.
Genetics
KEY POINTS The incidence of diverticular disease appears to be increasing. The role of dietary fiber in the pathogenesis of diverticular disease is complex and evolving. Evidence in support of the efficacy of mesalamine in treating SUDD has been conflicting and inconsistent. NSAIDS and aspirin are associated with increased risk of diverticular complications. Elective ‘prophylactic’ surgical resection for recurrent diverticulitis is being increasingly deferred.
patients with a known diverticular diagnosis, including both symptomatic and asymptomatic patients. This known diagnosis may have altered the patients’ recent fiber intake or reporting, altering the results [9,10]. Subsequently, a large prospective study of middle-aged women, excluding women who changed their diet after their diagnosis, reported a statistically significant reduced risk of diverticular disease associated with higher fiber intake, particularly cereal and fruit fiber [11]. Using data from The Million Women Study, the main outcome was first hospitalization or cause of death with a ‘mention’ of diverticular disease. As noted by the authors, the results may not accurately reflect a true relationship between fiber intake and diverticular disease as women with low-fiber diet are more likely to develop constipation, for example, and hospitalization for further investigation of the same could have skewed their results.
Constipation The role of constipation in the pathogenesis of diverticular disease was also challenged by Peery et al. [8 ], who observed that increased bowel frequency, rather than the expected decrease, was noted in patients with diverticulosis, although this finding is subject to the same critiques noted above. In a subsequent study by the same authors [12 ], they conducted a crosssectional study assessing patients with newly diagnosed diverticular disease. Consistent with the above, individuals with fewer bowel movements (7 per week). Individuals with ‘hard stool’ also had a reduced odds ratio. Unlike Peery’s prior study (above) challenging the fiber deficiency thesis, in this cohort no association was observed between dietary fiber intake and diverticulosis. &&
&&
Although the pathogenesis of diverticular disease has historically been felt to be largely environmental (mainly diet related), there are emerging data suggesting that genetic and heritable factors may contribute, and account for some of the phenotypic variation seen. A study from Denmark used the Danish National Registry and identified 10 420 index siblings from both inpatient and outpatient settings [13]. They observed a relative risk of 2.92 for diverticular disease in siblings compared to the general population. Monozygotic twins had a higher odds ratio of 14.5 compared with dizygotic twins of 5.5. They estimated that the heritable contribution to diverticular disease was 53%.
NSAIDs/ASPIRIN AND RISK FOR DIVERTICULAR COMPLICATIONS Diverticular bleeding is the most common cause of lower gastrointestinal bleeding [14] and reported risk factors include obesity, hypertension, anticoagulant use, diabetes mellitus, and ischemic heart disease [15–17]. An association between diverticular bleeding and use of NSAIDs and aspirin has been previously reported [18–21], and recent studies appear to confirm this observation, including a recent meta-analysis [15] which reported a relative risk of 2.48 (95% confidence interval 1.86–3.31). Another meta-analysis of 23 articles reviewed the interaction between diverticular perforation and bleeding with the use of various medications [22]. The odds of perforation and abscess formation increased with NSAIDs, steroids, and opioids at 2.49, 9.08, and 2.52, respectively. The odds of diverticular bleeding from NSAIDs, aspirin, and calcium-channel blockers were also increased at 2.69, 3.24, and 2.5, respectively. A prospective, single-center, cross-sectional study from Japan [23] investigated the association of NSAIDs, low-dose aspirin, and antiplatelet agents with diverticular bleeding. Alcohol consumption, smoking index, NSAIDs, low-dose aspirin, and nonaspirin antiplatelet drugs were all identified as independent risk factors. Also, dual therapy carried a higher risk than monotherapy.
SYMPTOMATIC UNCOMPLICATED DIVERTICULAR DISEASE Historically, diverticular disease has generally been conceptualized as either being asymptomatic or presenting as clinically overt acute diverticulitis. More recent evidence suggests the presence of low-grade chronic inflammation in patients with symptomatic disease, who do not manifest severe
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
51
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Large intestine
or acute symptoms, but rather low-level and indolent complaints, a condition that has been termed symptomatic uncomplicated diverticular disease (SUDD). The true prevalence of SUDD is unclear, likely because of the clinical similarities and perhaps similar pathophysiology between SUDD and irritable bowel syndrome (IBS). A recent retrospective study, for example, reported that in patients without prior diagnosed functional bowel disease, IBS was 4.7 times more likely to develop after an index episode of diverticulitis. Subsequent mood disorders were also 2.2 times more likely to develop, and the authors posit a ‘postdiverticular IBS’, akin to ‘postinfectious IBS’ [24 ]. In a direct comparison, however, fecal calprotectin was shown to be higher in patients with SUDD compared with normal controls and patients with IBS [25,26]. Also, severe and prolonged abdominal pain in patients with SUDD may differentiate them from patients with IBS [26,27]. &
Treatment Although the pathophysiology of SUDD is incompletely understood, chronic low-grade inflammation may play a role. Recently, endoscopic examination after remission from acute uncomplicated diverticulitis revealed ongoing endoscopic and active histological inflammation in 27.67 and 36.6% of the patients, respectively [28], and was also a predictor for the recurrence of diverticulitis [28]. Consequently, inflammation has become a new potential therapeutic target, with increasing investigation of the use of mesalamine for symptomatic disease [29,30] and for preventing recurrence of diverticulitis [31]. A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial from Germany [29] evaluated the efficacy and safety of mesalamine versus placebo in patients with SUDD. They randomized a total of 117 patients and of those, 98 patients completed the study. The median change in the lower abdominal pain was not statistically different between the two groups. After a post hoc adjustment for confounding factors, there was still no statistical difference in the intention-totreat (ITT) group, although statistical significance was achieved in the per-protocol population. The authors acknowledged that this study was likely underpowered to detect a statistical difference between the two groups. They concluded that a daily dose of 3 g of mesalamine was well tolerated and may potentially achieve pain relief in patients with a painful flare of SUDD. A subsequent multicenter, randomized, doubleblind, placebo-controlled, pilot study was conducted to evaluate the role of mesalamine in 52
www.co-gastroenterology.com
preventing diverticulitis, as well as to assess the associated symptoms with diverticular disease [31]. This was a smaller study in which 96 patients with a recent episode of uncomplicated diverticulitis were randomized to receive mesalamine twice daily for 10 days every month versus a placebo. The patients were followed for 24 months. In an ITT analysis, the recurrence in the mesalamine group was 11 and 13% compared to the placebo group of 12 and 28% at 12 months and 24 months, respectively. Although the observed differences were not statistically significant, after evaluating the physical condition and quality of life using a Therapy Impact Questionnaire, the mesalamine-treated group had significantly improved scores at 24 months. Also, average additional drug consumption was significantly lower in the mesalamine group compared with placebo. The DIVA trial [32] evaluated the utility of a 12-week course of mesalamine 2.4 g/day with or without a probiotic (Bifidobacterium infantis) versus placebo in patients after a computed tomography (CT)-confirmed case of acute diverticulitis, who were followed for 1 year. Although a global symptom score of 10 gastrointestinal symptoms was consistently lower in the mesalamine group, the results were not statistically significant. This study too was likely underpowered. The addition of probiotic had no discernable effect. A large, multicenter, double-bind, placebocontrolled clinical trial was performed in Italy, assessing the effectiveness of mesalamine and probiotics in maintaining symptomatic remission in SUDD [33]. They had zero occurrences in the combination group versus 13.7% with mesalamine alone, 14.5% with Lactobacillus alone, and 46% in the placebo group. The results demonstrated that both cyclic mesalamine and Lactobacillus were statistically superior to placebo for maintaining remission of SUDD. Of note, this study had multiple exclusion criteria, which may limit the general applicability of the results. Another Italian study also assessed the effectiveness of two different mesalamine-based treatments in preventing the recurrence of uncomplicated diverticulitis and the occurrence of other complications during a long-term follow-up [34 ]. They retrospectively identified patients with a diagnosis of uncomplicated diverticulitis in four different centers in Italy and randomized them into two groups: mesalamine 1.6 g/day for 10 days per month versus mesalamine 1.6 g daily. The patients were followed for a mean of 3 years. Overall, complications were seen more frequently in the intermittent treatment group, attaining statistical significance. Daily mesalamine treatment was likely superior to intermittent &
Volume 31 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diverticular disease Mosadeghi et al.
treatment in preventing the occurrence of diverticular disease complications after an attack of acute diverticulitis. A study comprised of two identical but separate large phase III studies investigated the efficacy and safety of multimatrix mesalamine in the prevention of recurrent diverticulitis [35 ]. This was a multicenter, randomized, doubled-blind, placebocontrolled study. Together, both studies included a total of 1182 patients (590 in PREVENT1 and 592 in PREVENT2). Mesalamine (1.2, 2.4, or 4.8 g) or placebo was given once daily. After 104 weeks, mesalamine did not reduce the rate or the time to diverticulitis recurrence compared with placebo. This negative study is likely the best designed and largest report to date, and casts a pessimistic light on the potential of mesalamine in treating diverticular disease. Changes in the intestinal microflora may also contribute to the pathogenesis of SUDD by causing chronic inflammation [36]. There is also evidence implying the presence of microscopic and subclinical infection in such patients [25,29,37]. Given that premise, the use of rifaximin has been evaluated in SUDD with some promising initial reports [38,39]. Recently, the efficacy of intermittent rifaximin to prevent the recurrence of diverticulitis revealed inconclusive results [40,41]. &&
ANTIBIOTICS IN ACUTE DIVERTICULITIS Antibiotics are a standard treatment for acute diverticulitis despite a paucity of data supporting their use [42 ], a strategy that has been recently questioned [43,44]. Chabok et al. [42 ] conducted a multicenter, randomized trial of patients with acute uncomplicated diverticulitis in Sweden. They recruited 623 patients who were randomized to treatment with or without antibiotics. There was no difference observed in the length of hospital stay or recurrence of diverticulitis requiring hospitalization at 1-year follow-up. Although numerically fewer complications such as perforation or abscess formation were found in the antibiotic arm of the study, the results were not statistically significant. This study has not been replicated in the USA but questions the obligate use of broad-spectrum antibiotics in all cases of acute diverticulitis. &
&
SURGICAL TREATMENT Historically, surgical evaluation for possible prophylactic resection has been advocated after a second attack of confirmed diverticulitis [45], a position echoed in the earlier guidelines from the American
Society for Colon and Rectal Surgery (ASCRS) [46]. The most recent ASCRS guidelines, however, were updated to recommend that elective sigmoid colectomy after recovery from acute diverticulitis should be made instead on a ‘case-by-case’ basis [47]. A recent retrospective study from the Netherlands evaluated 105 patients who underwent elective resection for recurring or persisting complaints after an episode of diverticulitis [48]. The elective procedure appeared to improve the general quality of life and reduced the discomfort caused by abdominal pain. However, many patients did continue to have symptoms despite the improvement. Given the retrospective nature of the study, it may have been susceptible to recall bias. Another study, from Italy [49], evaluated patients who underwent treatment for diverticular disease and divided their population into three groups: medical treatment, elective surgery, and emergency surgery. The total qualityof-life scores were found to be similar in the three groups, and no long-term advantages for colonic resection were found. However, Regenbogen et al. [50 ] conducted a systemic review of the recent primary reports on the decision-making, technical aspects, and outcomes of surgery for acute, recurrent, and chronic sigmoid diverticulitis. They found that complicated recurrence after recovery from an uncomplicated episode of diverticulitis was rare (
Diverticular disease: evolving concepts in classification, presentation, and management Sasan Mosadeghi a, Taft Bhuket a, and Neil Stollman b
Purpose of review Diverticular disease is the most commonly reported finding at the time of colonoscopy and one of the most common gastrointestinal indications for hospitalization. Much of our previous understanding of diverticular disease has recently been challenged. Recent findings There is emerging evidence that the long-accepted hypothesis of diverticulosis as a consequence of fiber deficiency may be more complex than commonly thought, with recent evidence suggesting that high-fiber diet and frequent bowel movements are associated with a greater and not lower prevalence of diverticular disease. There is also emerging support for the concept of low-grade inflammation in symptomatic uncomplicated diverticular disease (SUDD), and the role of anti-inflammatory treatment with mesalamine is being actively investigated. Additionally, elective ‘prophylactic’ surgery after diverticulitis, previously considered after a second confirmed diverticulitis episode, is being increasingly deferred. Summary The pathogenesis of diverticular disease is likely multifactorial and complex. More studies are needed to evaluate the role of fiber in the pathogenesis and treatment of diverticular disease. The search for an effective medical therapy for SUDD and to prevent recurrent diverticulitis is being actively investigated. The efficacy of mesalamine does not appear to be strong data supported. Keywords diverticular disease, mesalamine, symptomatic uncomplicated diverticular disease
INTRODUCTION Diverticular disease is the sixth leading outpatient gastrointestinal diagnosis in the United States, accounting for about 2.6 million visits in 2009 [1], and is one of the most common reasons for hospitalization, with 313 000 first-listed and 815 000 alllisted diagnoses [2]. It is also the most commonly reported finding at colonoscopy, identified in over 40% of all exams and in more than 70% of patients older than 80 years [2]. Further, the incidence seems to be increasing in both Europe and the United States [3–6], and the rate of hospitalizations because of diverticular diseases rose greater than 15% between 1996 and 2004 [2], accounting for $2.6 billion per year in inpatient costs [1]. In this article, we will review the recently published literature concerning pathogenesis, risk factors, and treatments of diverticular disease.
PATHOGENESIS OF COLONIC DIVERTICULOSIS The pathogenesis of diverticulosis remains to be definitively elucidated and is likely multifactorial. www.co-gastroenterology.com
The role of a low-fiber diet, originally suggested over 40 years ago by Burkitt and Painter, has remained a widely accepted thesis [7], although more recent observations may be changing this paradigm.
Fiber A recent study challenging the ‘fiber deficiency’ theory was published by Peery et al. [8 ], who observed that a high-fiber diet was associated with greater, and not lower, prevalence of diverticulosis as might have been expected. The validity of this conclusion has been questioned because they evaluated only recent dietary history and included &&
a
Alameda Health System, Highland Hospital and bAlta Bates Summit Medical Center, Northern California Gastroenterology Consultants, Inc., Oakland, California, USA Correspondence to Neil Stollman, MD, FACP, FACG, AGAF, 300 Frank H Ogawa Plaza, Suite 450, Oakland, CA 94612, USA. Tel: +1 510 444 3297; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:50–55 DOI:10.1097/MOG.0000000000000145 Volume 31 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diverticular disease Mosadeghi et al.
Genetics
KEY POINTS The incidence of diverticular disease appears to be increasing. The role of dietary fiber in the pathogenesis of diverticular disease is complex and evolving. Evidence in support of the efficacy of mesalamine in treating SUDD has been conflicting and inconsistent. NSAIDS and aspirin are associated with increased risk of diverticular complications. Elective ‘prophylactic’ surgical resection for recurrent diverticulitis is being increasingly deferred.
patients with a known diverticular diagnosis, including both symptomatic and asymptomatic patients. This known diagnosis may have altered the patients’ recent fiber intake or reporting, altering the results [9,10]. Subsequently, a large prospective study of middle-aged women, excluding women who changed their diet after their diagnosis, reported a statistically significant reduced risk of diverticular disease associated with higher fiber intake, particularly cereal and fruit fiber [11]. Using data from The Million Women Study, the main outcome was first hospitalization or cause of death with a ‘mention’ of diverticular disease. As noted by the authors, the results may not accurately reflect a true relationship between fiber intake and diverticular disease as women with low-fiber diet are more likely to develop constipation, for example, and hospitalization for further investigation of the same could have skewed their results.
Constipation The role of constipation in the pathogenesis of diverticular disease was also challenged by Peery et al. [8 ], who observed that increased bowel frequency, rather than the expected decrease, was noted in patients with diverticulosis, although this finding is subject to the same critiques noted above. In a subsequent study by the same authors [12 ], they conducted a crosssectional study assessing patients with newly diagnosed diverticular disease. Consistent with the above, individuals with fewer bowel movements (7 per week). Individuals with ‘hard stool’ also had a reduced odds ratio. Unlike Peery’s prior study (above) challenging the fiber deficiency thesis, in this cohort no association was observed between dietary fiber intake and diverticulosis. &&
&&
Although the pathogenesis of diverticular disease has historically been felt to be largely environmental (mainly diet related), there are emerging data suggesting that genetic and heritable factors may contribute, and account for some of the phenotypic variation seen. A study from Denmark used the Danish National Registry and identified 10 420 index siblings from both inpatient and outpatient settings [13]. They observed a relative risk of 2.92 for diverticular disease in siblings compared to the general population. Monozygotic twins had a higher odds ratio of 14.5 compared with dizygotic twins of 5.5. They estimated that the heritable contribution to diverticular disease was 53%.
NSAIDs/ASPIRIN AND RISK FOR DIVERTICULAR COMPLICATIONS Diverticular bleeding is the most common cause of lower gastrointestinal bleeding [14] and reported risk factors include obesity, hypertension, anticoagulant use, diabetes mellitus, and ischemic heart disease [15–17]. An association between diverticular bleeding and use of NSAIDs and aspirin has been previously reported [18–21], and recent studies appear to confirm this observation, including a recent meta-analysis [15] which reported a relative risk of 2.48 (95% confidence interval 1.86–3.31). Another meta-analysis of 23 articles reviewed the interaction between diverticular perforation and bleeding with the use of various medications [22]. The odds of perforation and abscess formation increased with NSAIDs, steroids, and opioids at 2.49, 9.08, and 2.52, respectively. The odds of diverticular bleeding from NSAIDs, aspirin, and calcium-channel blockers were also increased at 2.69, 3.24, and 2.5, respectively. A prospective, single-center, cross-sectional study from Japan [23] investigated the association of NSAIDs, low-dose aspirin, and antiplatelet agents with diverticular bleeding. Alcohol consumption, smoking index, NSAIDs, low-dose aspirin, and nonaspirin antiplatelet drugs were all identified as independent risk factors. Also, dual therapy carried a higher risk than monotherapy.
SYMPTOMATIC UNCOMPLICATED DIVERTICULAR DISEASE Historically, diverticular disease has generally been conceptualized as either being asymptomatic or presenting as clinically overt acute diverticulitis. More recent evidence suggests the presence of low-grade chronic inflammation in patients with symptomatic disease, who do not manifest severe
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
51
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Large intestine
or acute symptoms, but rather low-level and indolent complaints, a condition that has been termed symptomatic uncomplicated diverticular disease (SUDD). The true prevalence of SUDD is unclear, likely because of the clinical similarities and perhaps similar pathophysiology between SUDD and irritable bowel syndrome (IBS). A recent retrospective study, for example, reported that in patients without prior diagnosed functional bowel disease, IBS was 4.7 times more likely to develop after an index episode of diverticulitis. Subsequent mood disorders were also 2.2 times more likely to develop, and the authors posit a ‘postdiverticular IBS’, akin to ‘postinfectious IBS’ [24 ]. In a direct comparison, however, fecal calprotectin was shown to be higher in patients with SUDD compared with normal controls and patients with IBS [25,26]. Also, severe and prolonged abdominal pain in patients with SUDD may differentiate them from patients with IBS [26,27]. &
Treatment Although the pathophysiology of SUDD is incompletely understood, chronic low-grade inflammation may play a role. Recently, endoscopic examination after remission from acute uncomplicated diverticulitis revealed ongoing endoscopic and active histological inflammation in 27.67 and 36.6% of the patients, respectively [28], and was also a predictor for the recurrence of diverticulitis [28]. Consequently, inflammation has become a new potential therapeutic target, with increasing investigation of the use of mesalamine for symptomatic disease [29,30] and for preventing recurrence of diverticulitis [31]. A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial from Germany [29] evaluated the efficacy and safety of mesalamine versus placebo in patients with SUDD. They randomized a total of 117 patients and of those, 98 patients completed the study. The median change in the lower abdominal pain was not statistically different between the two groups. After a post hoc adjustment for confounding factors, there was still no statistical difference in the intention-totreat (ITT) group, although statistical significance was achieved in the per-protocol population. The authors acknowledged that this study was likely underpowered to detect a statistical difference between the two groups. They concluded that a daily dose of 3 g of mesalamine was well tolerated and may potentially achieve pain relief in patients with a painful flare of SUDD. A subsequent multicenter, randomized, doubleblind, placebo-controlled, pilot study was conducted to evaluate the role of mesalamine in 52
www.co-gastroenterology.com
preventing diverticulitis, as well as to assess the associated symptoms with diverticular disease [31]. This was a smaller study in which 96 patients with a recent episode of uncomplicated diverticulitis were randomized to receive mesalamine twice daily for 10 days every month versus a placebo. The patients were followed for 24 months. In an ITT analysis, the recurrence in the mesalamine group was 11 and 13% compared to the placebo group of 12 and 28% at 12 months and 24 months, respectively. Although the observed differences were not statistically significant, after evaluating the physical condition and quality of life using a Therapy Impact Questionnaire, the mesalamine-treated group had significantly improved scores at 24 months. Also, average additional drug consumption was significantly lower in the mesalamine group compared with placebo. The DIVA trial [32] evaluated the utility of a 12-week course of mesalamine 2.4 g/day with or without a probiotic (Bifidobacterium infantis) versus placebo in patients after a computed tomography (CT)-confirmed case of acute diverticulitis, who were followed for 1 year. Although a global symptom score of 10 gastrointestinal symptoms was consistently lower in the mesalamine group, the results were not statistically significant. This study too was likely underpowered. The addition of probiotic had no discernable effect. A large, multicenter, double-bind, placebocontrolled clinical trial was performed in Italy, assessing the effectiveness of mesalamine and probiotics in maintaining symptomatic remission in SUDD [33]. They had zero occurrences in the combination group versus 13.7% with mesalamine alone, 14.5% with Lactobacillus alone, and 46% in the placebo group. The results demonstrated that both cyclic mesalamine and Lactobacillus were statistically superior to placebo for maintaining remission of SUDD. Of note, this study had multiple exclusion criteria, which may limit the general applicability of the results. Another Italian study also assessed the effectiveness of two different mesalamine-based treatments in preventing the recurrence of uncomplicated diverticulitis and the occurrence of other complications during a long-term follow-up [34 ]. They retrospectively identified patients with a diagnosis of uncomplicated diverticulitis in four different centers in Italy and randomized them into two groups: mesalamine 1.6 g/day for 10 days per month versus mesalamine 1.6 g daily. The patients were followed for a mean of 3 years. Overall, complications were seen more frequently in the intermittent treatment group, attaining statistical significance. Daily mesalamine treatment was likely superior to intermittent &
Volume 31 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diverticular disease Mosadeghi et al.
treatment in preventing the occurrence of diverticular disease complications after an attack of acute diverticulitis. A study comprised of two identical but separate large phase III studies investigated the efficacy and safety of multimatrix mesalamine in the prevention of recurrent diverticulitis [35 ]. This was a multicenter, randomized, doubled-blind, placebocontrolled study. Together, both studies included a total of 1182 patients (590 in PREVENT1 and 592 in PREVENT2). Mesalamine (1.2, 2.4, or 4.8 g) or placebo was given once daily. After 104 weeks, mesalamine did not reduce the rate or the time to diverticulitis recurrence compared with placebo. This negative study is likely the best designed and largest report to date, and casts a pessimistic light on the potential of mesalamine in treating diverticular disease. Changes in the intestinal microflora may also contribute to the pathogenesis of SUDD by causing chronic inflammation [36]. There is also evidence implying the presence of microscopic and subclinical infection in such patients [25,29,37]. Given that premise, the use of rifaximin has been evaluated in SUDD with some promising initial reports [38,39]. Recently, the efficacy of intermittent rifaximin to prevent the recurrence of diverticulitis revealed inconclusive results [40,41]. &&
ANTIBIOTICS IN ACUTE DIVERTICULITIS Antibiotics are a standard treatment for acute diverticulitis despite a paucity of data supporting their use [42 ], a strategy that has been recently questioned [43,44]. Chabok et al. [42 ] conducted a multicenter, randomized trial of patients with acute uncomplicated diverticulitis in Sweden. They recruited 623 patients who were randomized to treatment with or without antibiotics. There was no difference observed in the length of hospital stay or recurrence of diverticulitis requiring hospitalization at 1-year follow-up. Although numerically fewer complications such as perforation or abscess formation were found in the antibiotic arm of the study, the results were not statistically significant. This study has not been replicated in the USA but questions the obligate use of broad-spectrum antibiotics in all cases of acute diverticulitis. &
&
SURGICAL TREATMENT Historically, surgical evaluation for possible prophylactic resection has been advocated after a second attack of confirmed diverticulitis [45], a position echoed in the earlier guidelines from the American
Society for Colon and Rectal Surgery (ASCRS) [46]. The most recent ASCRS guidelines, however, were updated to recommend that elective sigmoid colectomy after recovery from acute diverticulitis should be made instead on a ‘case-by-case’ basis [47]. A recent retrospective study from the Netherlands evaluated 105 patients who underwent elective resection for recurring or persisting complaints after an episode of diverticulitis [48]. The elective procedure appeared to improve the general quality of life and reduced the discomfort caused by abdominal pain. However, many patients did continue to have symptoms despite the improvement. Given the retrospective nature of the study, it may have been susceptible to recall bias. Another study, from Italy [49], evaluated patients who underwent treatment for diverticular disease and divided their population into three groups: medical treatment, elective surgery, and emergency surgery. The total qualityof-life scores were found to be similar in the three groups, and no long-term advantages for colonic resection were found. However, Regenbogen et al. [50 ] conducted a systemic review of the recent primary reports on the decision-making, technical aspects, and outcomes of surgery for acute, recurrent, and chronic sigmoid diverticulitis. They found that complicated recurrence after recovery from an uncomplicated episode of diverticulitis was rare (
