Abstract The statements produced by the Consensus Conference on Diverticular Disease promoted by GRIMAD (Gruppo Italiano Malattia Diverticolare, Italian Group on Diverticular Diseases) are reported. Topics such as epidemiology, risk factors, diagnosis, medical and surgical treatment of diverticular disease (DD) in patients with uncomplicated and complicated DD were reviewed by a scientific board of experts who proposed 55 statements graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. Comparison and discussion of expert opinions, pertinent statements and replies to specific questions, were presented and approved based on a systematic literature search of the available evidence. Comments were added explaining the basis for grading the evidence, particularly for controversial areas. Introduction Colonic diverticulosis has been recognized as an increasingly common clinical condition in industrialised countries, the highest rates occurring in the United States and Europe. This condition nowadays ranks as fifth most important gastrointestinal disease in terms of direct and indirect costs. Diverticular disease (DD) is a term generally used to include diverticulosis and diverticulitis. 1, 2 While most people with colonic diverticulosis remain asymptomatic, about 20% experience abdominal symptoms and, eventually, complications, episodes of diverticulitis or bleeding. 3, 4 Symptoms of DD can be acute or chronic, ranging from gastrointestinal symptoms similar to those of irritable bowel syndrome (IBS) (e.g. abdominal pain and discomfort, bloating, constipation and diarrhoea) to acute symptoms resembling appendicitis (e.g. fever, acute abdominal pain and leucocytosis), chronic abdominal pain or recurrent severe attacks of abdominal pain, fever or acute abdomen. [5] [6] [7] Acute diverticulitis is characterised by inflammation, micro-perforation and abscess formation; about one third of affected patients may experience recurrent episodes. 8, 9 In patients with gastrointestinal symptoms without overt diverticulitis, low-grade inflammation, altered intestinal microbiota, visceral hypersensitivity and abnormal colonic motility have been identified as factors leading to symptom generation. 5, 10 Although the pathogenesis and management of diverticulosis and DD remain uncertain, new hypotheses and observations are changing the pharmacological and surgical management of DD. It is currently believed that medical therapy is generally required in symptomatic DD to treat infection, improve symptoms, and prevent recurrence of symptoms or development of complications. Recommendations for the diagnosis and treatment of DD have been issued by many medical societies in various countries. [11] [12] [13] Most available guidelines, however, are dated, and no international guidelines with grades of recommendations, based on level of evidence, are yet available. Introduction Despite the large epidemiological and economic burden of DD, there is surprisingly limited knowledge about this condition. This generates uncertainties in the clinician and dissatisfaction in patients. It has been proposed that DD should be viewed as a potentially chronic illness with implications on everyday outpatient practice, and that clinicians should be prepared to address its impact beyond acute diverticulitis. 14 We have summarised the current Italian perspective on DD in this consensus conference report, aiming to develop guidelines for the clinical, diagnostic and therapeutic management of DD. Methods The primary aim of this document was to provide clinical guidelines for appropriate definition, diagnosis and management of DD. The promoter of this initiative was the Italian Study Group of Diverticular Disease (Gruppo Italiano Malattia Diverticolare (GRIMAD)) -see Appendix 1. GRIMAD identified a scientific board of experts (BA, GB, RC, FP), who defined the methodology and targets, and acted as developers and reviewers. Methods The methodology to process the guidelines consisted of six steps: Methods 1. The scientific board selected four main areas of interest in DD: (a) definition and epidemiology, (b) pathophysiology, (c) diagnosis, and (d) medical and surgical therapy. 2. For each topic, a working party was created, which included a coordinator and at least two experts. The latter were chosen on the basis of their recognised scientific expertise in DD. Together with the scientific board, the working party selected a number of clinically relevant, clear, answerable questions, focusing on current practice and areas of controversy. The questions were circulated among the working parties to share relevance, improve clarity, and avoid duplication. A preliminary meeting of the working parties was held in Bologna (June 2011) to share methods, aims, timelines, and the entire guideline process. 3. The working parties independently carried out a systematic search for, and analysis of, the literature relevant to their topics during October 2012, using Medline/PubMed and the Cochrane Database. Each recommendation was graded according to the Oxford Centre for Evidence-Based Medicine, according to the level of evidence (EL) (Supplementary Material, Table 1S ). 4. By November 2012 the working parties issued initial statements and attributed them a grade (strength) of recommendation (RG), from AÀD, consistent with the level of evidence (Table 1) . Each coordinator drafted provisional statements that were circulated within his/her group. 5. Subsequently, each coordinator (BA, GB, RC, FP) evaluated the preliminary statements produced and the related grades of evidence. A redrafted document containing the statements was then prepared and submitted to all participants for an online session, for a first round of votes and comments, using a simplified scale (agreement/disagreement); the participants voted using a modified Delphi procedure until a minimum agreement level of at least 67% was achieved for each statement. Statements were then submitted to the scientific board, who wrote an advanced version, and fed back the new statements to the working parties. 6. On 19 and 20 February 2013, a consensus meeting was held in Bologna. The consensus group included 33 participants, who were selected taking into account diverse expertise in various aspects of DD, and geographical distribution. The consensus group was led by a non-voting chairman (GG) and the non-voting members of the scientific board (BA, GB, RC, FP), and included experts of working parties and multi-disciplinary professionals/experts such as gastroenterologists, gastrointestinal (GI) endoscopists, pharmacologists, surgeons, radiologists, pathologists, and general practitioners. Overall, 76 statements were submitted to the global consensus group for an open discussion driven by the nonvoting chairman and the non-voting members of the scientific board. Following a plenary discussion held before voting, 21 statements were deleted, and 45 were partially rephrased. The final 55 statements Symptomatic uncomplicated diverticular disease (SUDD) is a syndrome characterized by recurrent abdominal symptoms (i.e. abdominal pain and bloating resembling or overlapping irritable bowel syndrome (IBS) symptoms) attributed to diverticula in the absence of macroscopically evident alterations other than the presence of diverticula. Methods 1c B 1.1.4 Acute diverticulitis is an acute episode of severe, prolonged, lower abdominal pain (usually on the left side), change in bowel movements, low-grade fever and leucocytosis. The clinical presentation has a broad spectrum ranging from mild self-limiting episodes to abscess, perforation and peritonitis. were then submitted to the global consensus group for anonymous keypad voting (Delphi process) without any explanation or justification. The Delphi process brought to a change of view from a position previously held, avoiding any uneasiness among participants or influence on individual votes. The agreement/disagreement level was scored on a six-point Likert scale as follows: Aþ: strongly agree; A: agree with minor reservations; AÀ: agree with major reservations; DÀ: disagree with major reservations; D: disagree with minor reservations; Dþ: strongly disagree. Level of agreement was expressed as percentage of each point of the scale. Immediate feedback was given to participants on a screen, who were prompted by the non-voting chairman and the non-voting members of the scientific board to discuss the statements, and suggest changes in case of controversy (<67% agreement). Consensus was defined a priori as agreement by at least 67% of respondents. The entire work and discussions were tape-recorded. 1.1.4 The format of the following recommendations comprises the question, the statement, its level of evidence and strength of recommendation, and the percentage agreement of the global consensus group on the final version. 1.1.4 In the present document the statements are accompanied by comments made by each working party and reviewed by the scientific board taking into account relevant observations and suggestions made during the plenary discussion. In some areas the Rifaximin plus fibre is more effective than fibre alone in preventing acute diverticulitis with a low therapeutic advantage. 1.1.4 2b B 4.2.5 There is no clear evidence that mesalazine alone is effective in reducing symptoms. 2b B 4.2.6 There is no clear evidence that mesalazine reduces acute episodes of diverticulitis. 4.2.6 There is insufficient evidence that probiotics are effective in reducing symptoms. Colonic diverticula are usually acquired and do not involve all the wall layers, but are rather herniations of the mucosa and submucosa; hence they would be more appropriately defined as pseudo-diverticula. Their number can vary from one to literally hundreds; they can occur anywhere in the colon, although they are mainly present in the left colon, at least in Western populations. [14] [15] [16] 1.1.2 Statement (EL 1c -RG B): Colonic diverticulosis is the finding of diverticula in patients without abdominal complaints who undergo evaluation for other indications (e.g. cancer screening). 4.2.6 Consensus levels of agreement: Aþ 69%; A1 6%; AÀ 3%; Dþ 12%. Statement (EL 1c -RG B): Symptomatic uncomplicated diverticular disease (SUDD) is a syndrome characterised by recurrent abdominal symptoms (i.e. abdominal pain and bloating resembling or overlapping IBS symptoms) attributed to diverticula in the absence of macroscopically evident alterations other than the presence of diverticula. Statement (EL 1c -RG B): Consensus levels of agreement: Aþ 71%; A 19%; AÀ 7%; DÀ 3%. Statement (EL 1c -RG B): A significant but not yet well defined proportion of DD patients complain of symptoms -mainly abdominal pain (broadly ranging from abdominal discomfort to more prolonged painful episodes), bloating, altered bowel habits. In addition, considering the high prevalence of both IBS (10-20%) and diverticulosis (up to 65% in the elderly), the two conditions may frequently coexist by chance. Both conditions presumably also share some underlying predisposing (i.e. mild inflammation) or pathophysiological factors (i.e. visceral sensitivity). The clear differentiation between the two conditions is challenging and should mainly be based on clinical history (i.e. duration of symptoms, age at symptoms onset, documented episode of acute diverticulitis). 7, [17] [18] [19] 1.1.4 Statement (EL 1c -RG B): Acute diverticulitis is an acute episode of severe, prolonged, lower abdominal pain (usually on the left side), change in bowel movements, low-grade fever and leukocytosis. The clinical presentation has a broad spectrum ranging from mild self-limiting episodes to abscess, perforation and peritonitis. Statement (EL 1c -RG B): Consensus levels of agreement: Aþ 78%; A 16%; AÀ 6%. Statement (EL 1c -RG B): As many as 10-25% of patients with known DD may suffer from diverticulitis. This event may represent the first manifestation of an otherwise previously unidentified colonic diverticulosis. The clinical presentation of acute diverticulitis varies according to the extent and severity of the disease process, which encompasses a broad spectrum of manifestations from mild self-limiting episodes to acute abdomen. In classic cases, patients report constipation and abdominal pain involving the left lower abdominal quadrant. Abdominal or perirectal fullness, or 'mass effect' may be present, and low-grade fever and leucocytosis are common. Alternative diagnoses for lower abdominal pain must be considered. The severity and progression of the disease is presumably associated with the depth of the perforation. A clear-cut diagnosis and evaluation of complications requires the use of imaging techniques (see further). In this context the Hinchey, Buckley, and Ambrosetti classifications further sub-classify acute diverticulitis on the basis of computerised tomography (CT) scan findings. [20] [21] [22] [23] [24] [25] 1.1.6 Statement (EL 4 -RG C): A small subset of patients with diverticulosis may develop segmental colitis associated with diverticulosis (SCAD). Statement (EL 1c -RG B): Consensus levels of agreement: Aþ 66%; A 25%; AÀ 9%. Statement (EL 1c -RG B): SCAD is a recently defined clinical entity with specific macroscopic and microscopic features (see further) characterised by chronic, sometimes relapsing, mucosal inflammation in an area with presence of diverticula -usually the sigmoid-descending colon, sparing the proximal and rectal colon. In a recent meta-review the prevalence of SCAD in patients with diverticulosis ranged from 0.3-1.3%, with a male prevalence and a mean age of 63.6 years (range . The most common presenting symptoms were rectal bleeding, diarrhoea and abdominal pain. Many of these patients showed a benign course even with spontaneous resolution, or responded to 5-aminosalicylates or steroids. 26 1.2 Is the prevalence of DD increasing in Western countries? Statement (EL 2c -RG B): The prevalence of diverticulosis and DD is increasing in Western countries in parallel with increased life-expectancy. Statement (EL 2c -RG B): Consensus levels of agreement: Aþ 72%; A 19%; AÀ 9%. Statement (EL 2c -RG B): DD is one of the most frequently reported findings diagnosed during colonoscopy, particularly in elderly patients. 27 Two studies carried out in Oxford on asymptomatic volunteers reported an increasing prevalence of diverticulosis with age, with a prevalence of 34.9% in those over 60 years of age. 28, 29 A study conducted in Edinburgh estimated that the incidence of DD in patients referred for barium enema was 1.55 per 1000 population. There was a female predominance and increased occurrence with age, with an incidence rate of 5.74 per 1000 population in those over 75 years. 30 From these studies is possible to conclude that the prevalence of DD is increasing in the Western world largely because the population is getting older. Consensus levels of agreement: Aþ 56%; A 28%; AÀ 13%; DÀ 3%. Statement (EL 2c -RG B): There are no studies reporting on mortality for diverticulosis. Mortality associated with DD, acute diverticulitis and complicated DD has been reported in case series, national audits and population-based data. 31 The age-standardised mortality rates associated with a death certificate diagnosis of DD using the International Classification of Diseases, Ninth Revision (ICD-9), codes for England failed to show any consistent change in rates from 1979-1999. 32 The rates were consistently higher among females than males. Data from the United States National Inpatient Sample (NIS) database reported that hospital mortality related to acute diverticulitis decreased from 1.6% to 1.0% from 1998 to 2005, 33 and surgical mortality decreased from 5.7% to 4.3% during the same time period. 30 Mortality associated with DD was substantially higher among females than males. Statement (EL 2c -RG B): There is still little information in the scientific literature on the economic impact of DD. A retrospective study performed in a large UK department, aimed at reviewing costs for inpatient and outpatient investigations, treatment and hospitalisation of all patients treated for DD during one financial year in a district hospital. 34 A total of 148 patients were treated; 83 of them were admitted for more than one day, 55 of whom were emergency admissions. The study shows that DD poses a major clinical problem (for instance, inpatient mortality rate was 6%, and peri-operative mortality 26.3%) for a surgical department, showing considerable financial implications, with an impact on the global budget as high as 5.3% of the annual resources for general surgery. Statement (EL 2c -RG B): An almost identical study has been conducted more recently in Italy, 35 taking into consideration the clinical workload and the financial impact of DD in a large university hospital over a seven-year period. A total of 738 patients were treated and 840 hospital discharge records were reviewed. As many as 193 surgical operations were performed, with a total cost of this activity equal to 0.2% of the total hospital budget. Statement (EL 2c -RG B): 1.4 What are the time trends of hospital admission and surgery rates for DD? Statement (EL 2c -RG B): During the last 10-20 years there has been an increasing rate of hospital admission for diverticulitis. Statement (EL 2c -RG B): Consensus levels of agreement: Aþ 42%; A 32%; AÀ 10%, À 3%, D 3%; Dþ 10%. Statement (EL 2c -RG B): The occurrence of acute diverticulitis has been reported in three studies using data from the United States NIS database and a study from the UK. Statement (EL 2c -RG B): The first of these studies reported a 26% increase in admissions coded as acute diverticulitis from 1998-2005 (120,500 to 151,000 admissions). 33 The greatest increase in admissions was in the age ranges of 15-44 and 45-64 years. A further study of NIS data from 1998-2005 reported an overall age-adjusted increase in hospital admissions from 61.8 per 100,000 to 75.5 per 100,000 hospitalisations, with equal gender and age distribution. 36 A further study of USA NIS data from 2002-2007 reported a 9.5% increase in emergency admissions over this time period but a smaller increase involving younger age groups. 37 Finally, in a study from the UK 38 relying on a database from 1996-2006, the primary outcomes examined were 30-day overall and one-year mortality, 28-day readmission rates and extended length of stay beyond the 75th percentile (median inpatient stay six days). In the time period considered, 560,281 admissions with a primary diagnosis of DD were recorded in England. The national admission rate increased from 0.56 to 1.20 per 1000 population/year. As many as 232,047 (41.4%) were inpatient admissions, of which 55,519 (23.9%) were elective and 176,528 (76.1%) were emergency. Surgery was undertaken in 37,767 (16.3%). Thirty-day mortality was 5.1% (n ¼ 6735) and oneyear mortality was 14.5% (n ¼ 11,567). Increasing age, comorbidity and emergency admission were independent predictors of all primary outcomes. There are few population-based data focusing on individual complications. A study from Northern Finland reported an increase in the prevalence of perforated diverticular disease from 2.4 per 100,000 in 1986 to 3.8 per 100,000 in 2000. 39 A further study, using UK primary care data to identify cases of perforated diverticular disease, reported a two-fold increase (incidence risk ratio (RR) 2.18, 95% confidence interval (CI) 1.79-2.95) in incidence rates from 1990-2005. 40 1.5 What is the time trend for mortality in severe/ complicated DD? Statement (EL 2c -RG B): Mortality in perforated disease remains elevated, due to the high rate of relevant comorbidity. Statement (EL 2c -RG B): Consensus levels of agreement: Aþ 48%; A 32%; AÀ 10%; Dþ 10%. Statement (EL 2c -RG B): The excess mortality associated with perforated DD compared to the general population was reported in a study from the General Practice Research Database. This study reported a six-fold increase in the mortality (hazard ratio (HR) 5.63, 95% CI 4.68-6.77) of patients diagnosed with perforated diverticular disease in the first year of follow-up. The greatest absolute risk was in those with the highest comorbidity. 40 A subsequent study detailing the excess mortality following a diagnosis of stricture or fistula demonstrated that patients with diverticular stricture had a 2.4-fold higher mortality rate compared to the general population and this was limited to the first year after diagnosis. In comparison, those with a fistula had a 2.6fold higher mortality, with a 41% increase in mortality in subsequent years. 41 The authors stated that a possible reason for this could be the excess comorbidity and the increased age of patients with diverticular fistulae. As recalled above, mortality associated with DD is substantial, although it appears to be decreased for acute diverticulitis (at least in the USA); conversely, patients with perforated DD have a significant oneyear mortality along with a substantial excess mortality compared to the general population. Statement (EL 2c -RG B): 1.6 Are there any relevant lifestyle risk factors for symptoms development? Statement (EL 4 -RG C): The analysis of the literature does not provide sufficient evidence to establish a clear-cut link between the absence of physical activity, and lower fibre, nut, corn, and popcorn consumption, or smoking with increased risk of DD. Increased body mass index (BMI) is a consistent risk factor for complicated DD. Statement (EL 4 -RG C): Consensus levels of agreement: Aþ 58%; A 16%; AÀ 23%; Dþ 3%. Statement (EL 4 -RG C): Lifestyle factors, along with aging, are considered to be major risk factors for the development of diverticulosis and its complications, diverticulitis and diverticular bleeding. Approximately 40% of the adult population in Western countries is estimated to have diverticulosis, and diverticulitis and diverticular bleeding are among the most common gastrointestinal indications for hospital and medical visits. 27 The following lifestyle factors have been evaluated for their risk on symptoms development: physical activity, diet (including fibre content and nut, corn and popcorn consumption), smoking habit and obesity. Strate et al. 42 studied physical activity and DD during an 18-year follow-up. Men in the highest quintile of vigorous physical activity had a 25% risk reduction of diverticulitis, and a 46% risk reduction of diverticular bleeding when compared to men who exercised the least. As to diet and risk of hospitalisation for DD in the European Prospective Investigation into Cancer and Nutrition (EPIC) Oxford study, a cohort of 47,033 healthy individuals were followed-up for five years. High fibre intake (25.5 g/day in women and 26.1 g/day in men) was associated with a relative risk of 0.58 (95% CI 0.46-0.73) when compared to those with the lowest fibre intake (<14 g/day). 43 In a retrospective study, 56 patients admitted with SUDD were later questioned regarding their fibre intake. Those with a high fibre intake (>25 g/day) were significantly less likely to have had symptoms (19% vs 44%) or diverticular complications (6.5% vs 32%). 44 In a study of 47,000 men followed for 18 years as part of the Health Professionals Follow-up Study, 45 consumption of nuts, corn or popcorn did not increase the risk of diverticulitis or diverticular bleeding. In fact, men who consumed nuts or popcorn at least twice weekly were at a lower risk of diverticulitis than those who consumed these foods less than once a month (RR 0.80; 95% CI 0.63-1.01; p for trend < 0.04 for nuts and 0.73; 95% CI, 0.56-0.92; p for trend < 0.007 for popcorn). In 36,000 women enrolled from 1997-2008 in the Swedish mammography cohort, past and current smokers had a 24% increased risk of hospitalisation for DD when compared to non-smokers, and no significant dose response was found. 46 In a male Swedish cohort of 7500 men followed for up to 28 years, current smokers had a RR 1.89 (95% CI 1.15-3.10) for perforated disease compared to non-smokers. 47 In the EPIC-Oxford cohort, individuals who smoked >15 cigarettes a day had a relative risk of 1.34 and those who smoked >15 cigarettes a day a relative risk of 1.86 of hospitalisation for DD compared to non-smokers. 43 Rosemar et al. 47 followed a cohort of 7500 men in Sweden for 28 years: men with a BMI > 30 had a four-fold increased risk of diverticulitis compared to men with a BMI of 20-22.5. Statement (EL 4 -RG C): Strate et al. 48 followed 47,000 men for 18 years: men with a BMI > 30 had 78% higher risk of diverticulitis and a threefold increased risk of diverticular bleeding compared to men with a BMI < 21. 1.7 What is the long term outcome of DD? Statement (EL 4 -RG D): In general, DD has a favourable long-term outcome with a very low incidence of complications. Symptomatic disease, acute diverticulitis and complicated DD represent distinct clinical entities among groups. Statement (EL 4 -RG D): Consensus levels of agreement: Aþ 42%; A 42%; AÀ 16%. Statement (EL 4 -RG D): The natural history of DD is largely unknown. Most studies are retrospective, and treatment recommendations are not based on recent literature. There is only one prospective, long-term study assessing the development of complications in patients with symptomatic diverticular disease. 18 A total of 163 patients were followed up for an average of five years. After the initial diagnosis, two patients (1.7%) presented with an episode of diverticulitis, which was treated conservatively. Only one patient (0.8%) required surgery for chronic symptoms; 97% had mild or no symptoms after a median follow-up of 66 months. The study showed that SUDD presents with a long-term benign course, and a very low incidence of subsequent complications. Statement (EL 4 -RG D): 1.8 Does DD predispose to colon cancer? Statement (EL 4 -RG C): DD does not increase the risk of colon cancer. Consensus levels of agreement: Aþ 89%; A 7%; AÀ 4%. Statement (EL 4 -RG C): DD does not increase the risk of colon cancer. It has been hypothesised that patients with DDespecially elderly patients -have an increased risk of colon cancer. Clear-cut evidence of this association is limited by the high prevalence of the two conditions, as the association may be just determined by a high chance of having both diseases. Data from a retrospective Swedish study 49 showed an association between diverticulosis and the risk of colon cancer with a 1.8 relative risk, 95% CI 1.1-2.7, for both genders and in all age groups. This risk was also present two or more years after the first hospital discharge, in relation to diverticulosis. Analysing the data by anatomical region, this risk seemingly existed only for the left colon. A subsequent retrospective study conducted on 288 patients treated for diverticulitis, with a mean follow-up of 12 years, showed a low prevalence of both colorectal cancer and colonic adenomas compared to expected lifetime risk. 50 Finally, a recent case-control study 51 performed in Sweden, which comprised 41,037 patients with colon cancer diagnosed between 1992-2006, reached the conclusion that the increased risk of colon cancer previously reported was most likely due to confounders related to indication and/or surveillance bias. Consensus level of agreement: Aþ 38%; A 22%; AÀ 28%; DÀ 6%; Dþ 6%. Pathophysiology of diverticular disease Lifestyle factors are considered key elements for the development of diverticulosis and its complications. Painter and Burkitt in 1971 reported for the first time that a low-fibre diet played a major role in the pathogenesis of diverticulosis. 52 Accordingly, it was observed that DD was common in Western societies where fibre intake is low, but was rare in geographical areas where fibre intake is high (i.e. in Africa and Asia). Also, it was noted that DD developed with the adoption of a Western lifestyle. 29 The low-fibre hypothesis is further supported by case-control studies in vegetarians. Accordingly, diverticulosis was less prevalent in 56 vegetarians, compared to 264 non-vegetarian controls, who on average consumed less fibre (21.4 g/day vs 41.5 g/day; p < 0.001). 29 In addition, in a large prospective cohort of 47,033 subjects in England, vegetarians were 31% less likely to be hospitalised for DD compared with meat eaters. 43 Despite this evidence, the low-fibre hypothesis has been challenged. 1 In non-vegetarian subjects, fibre intake was not different between those with diverticulosis and those without (21.8 vs 22.1 g/day, respectively). 29 In addition, in a recent cross-sectional study, Song et al. found no association between fibre intake and diverticulosis. 53 However, the most surprising outcome has been reported in another recent study by Peery et al. who assessed the prevalence and risk factors of diverticulosis in 2104 subjects undergoing colonoscopy. Data analysis showed that a high fibre intake was positively associated with the presence of diverticulosis (prevalence ratio ¼ 1.30; 95% CI, 1.13 -1.50). 54 Although these studies seem to disprove the original fibre hypothesis, they should be taken with caution. For instance, the study by Song et al. 53 was performed in Korea. Most colonic diverticula in Asian subjects are right-sided and the pathogenesis of these forms is likely different from the left-sided diverticulosis described in Western populations. In addition, the cross-sectional design of the study by Peery et al. 54 who carried out a short term investigation of dietary habits before colonoscopy, failed to identify clear-cut pathogenetic elements. Pathophysiology of diverticular disease Incontrovertible evidence in favour of a high fibre diet in the treatment of diverticular disease is still lacking, although guidelines and position papers 12, 13, 55 recommend a high-fibre intake for the prevention of diverticulosis and diverticulitis, and in the treatment of symptomatic DD. Consensus levels of agreement: Aþ 45%; A 24%; AÀ 21%; D 7%; Dþ 3%. Pathophysiology of diverticular disease Increased resting and stimulated (meal, anti-cholinesterase agents) colonic intraluminal pressures and abnormal segmental and propagated motor activity have been detected in patients with diverticular disease, and are thought to contribute to the development of diverticula. [56] [57] [58] Indeed, intraluminal pressure is low in the right colon, and other factors, including a genetic component and structural wall alterations may be more strongly involved in the pathogenesis of diverticulosis in Asian populations. 59 The mechanisms underlying motor dysfunction in patients with diverticulosis remain poorly investigated. Neurotransmitter abnormalities in colonic specimens obtained from surgical resections have been described in patients with DD. [60] [61] [62] Bassotti et al. 63 found a marked decrease in the number of interstitial cells of Cajal and glial cells in full thickness colonic specimens of 39 patients with diverticulosis compared to control colonic specimens. These changes occurred in the absence of significant quantitative abnormalities in the neurons of the submucous or myentric plexuses. More recently, an altered pattern of factors involved in colonic smooth muscle contractility has been reported in patients with DD. 64 Taken together, these findings support a role for colonic neuromuscular dysfunction in the pathogenesis of left-sided diverticulosis and suggest the involvement of neuroanatomical changes at the neuromuscular gut wall level. 65 2.3 Do changes in the connective tissue of the colonic wall play a role in the pathogenesis of diverticulosis? Consensus levels of agreement: Aþ 47%; A 22%; AÀ 13%; DÀ 6%; D 6%; Dþ 6%. Pathophysiology of diverticular disease The concept that colonic wall abnormalities lead to increased rigidity and reduced resistance of the colon with subsequent diverticula formation has been introduced a long time ago. 66 The involvement of connective tissue is supported by indirect evidence from earlier literature showing a high prevalence of diverticulosis in the Ehlers-Danlos 67 and Marfan syndromes. 68 In diverticulosis, attention has been directed to two major extracellular matrix components, elastin and collagen. Elastin is increased only in the longitudinal muscle layer, with subsequent thickening of the colonic wall. 69 Collagen fibrils are smaller and more densely packed and show higher cross-linking, leading to increased rigidity of the wall. 70, 71 It has been hypothesised that the progressive elastosis of the taenie is at least partly attributable to the increased amino acid proline largely found in Western diets and used as additive by food industries. 69 2.4 Do changes in colonic motility and sensitivity play a role in the development of abdominal pain in SUDD? Statement (EL 4 -RG C): Changes in colonic motility and sensitivity play a potential role in the development of abdominal pain in SUDD. Statement (EL 4 -RG C): Consensus levels of agreement: Aþ 53%; A 17%; AÀ 13%; DÀ 3%; D 7%; Dþ 7%. Statement (EL 4 -RG C): Although colonic diverticulosis has been defined as a painless change due to aging, 72 up to 20% of subjects with diverticula experience abdominal pain. 73 As diverticulosis and IBS are both highly incident conditions, patients with symptomatic DD could well be patients with IBS in whom diverticulosis overlaps. Nonetheless, there are some clinical-epidemiological features that may help distinguish those with 'true' IBS from those with diverticula associated with 'IBSlike' symptoms. First, IBS incidence peaks in the second and third decades of life and declines thereafter, whereas diverticulosis increases with age, particularly after 60 years of age. 74 As a consequence, the overlapping conditions are predominantly present in middle-aged or older patients. Second, IBS is more frequent in females while diverticulosis affects equally males and females. 17 Third, differently from IBS, pain is more often localised in the lower left quadrant, and patients suffer more frequently from long-lasting (>24 h) pain, sometimes for weeks, with longer periods of symptomatic quiescence. 6, 73 Fourth, only 15% of patients with DD fulfil the Rome I criteria for IBS. 73 This is mainly due to the fact that, differently from IBS, abdominal pain caused by DD is less frequently relieved by the passage of air or stool. 73 Although IBS and symptomatic DD could be different disorders, they share some of the mechanisms believed to be important for symptom generation. These include abnormal motor function and reduced threshold for perception of visceral sensitivity (referred to as visceral hypersensitivity). Patients with SUDD displayed increased duration of rhythmic, low-frequency, contractile activity, particularly in the segments bearing diverticula. 58 Colonic visceral pain perception in response to luminal distension was evaluated in patients with SUDD or asymptomatic diverticulosis, compared to healthy controls. 75 Only SUDD patients displayed an increased pain perception not only in the sigmoid colon with diverticula, but also in the unaffected rectum. 75 Consensus levels of agreement: Aþ 29%; A 13%; AÀ 26%; DÀ 10%; D 6%; Dþ 16%. Statement (EL 4 -RG C): Although dysbiosis and low-grade immune activation are known to play a role in the pathophysiology and development of pain in patients with IBS, 76,77 a similar paradigm for symptomatic DD has yet to be demonstrated; there is nevertheless recent evidence that these patients present increased colonic mast cells in all the layers of the colonic wall, which may contribute to pain development (78) . Colonic diverticula are pouches of the colonic wall, which may predispose to faecal entrapment and faecolith formation. The putative involvement of intestinal microbiota and low-grade inflammation in symptomatic DD is based on the hypothesis that trauma caused by faecoliths on the thin diverticular wall leads to epithelial breakdown and bacterial translocation which may eventually lead to diverticulitis. In this context, pain is an alarm response to the activity of immune cell reaction to the bacterial translocation evoked by a number of different mediators, which are released by inflammatory cells acting on sensory receptors located on sensory fibres conveying information to the brain. Examination of mucosal biopsies from symptomatic DD showed low-grade inflammation (i.e. lymphocytes and neutrophils) despite a normal mucosa, apart from diverticula, at colonoscopy. 79, 80 Post-inflammatory gut dysfunction following acute infectious gastroenteritis (postinfectious IBS) or in patients during periods of remission of ulcerative colitis is a well characterised phenomenon. 81 Similarly to these conditions, a recent study showed that patients with diverticulitis were 4.6 times more likely to develop IBS-like symptoms over the observation period compared to matched controls. 82 Diagnosis of DD 3.1 Is diverticular disease normally associated with histological changes in the mucosa surrounding diverticula? Statement (EL 1b -RG A): The vast majority of patients with DD have no evidence of histological changes in the mucosa surrounding diverticula (excluding diverticular lesions and their complications). Statement (EL 1b -RG A): Consensus levels of agreement: Aþ 88%; A 6%; AÀ 6%. Statement (EL 1b -RG A): The histopathological diagnosis of lesions associated with DD is a difficult field, due to the presence of alterations still needing a precise definition. While on surgical specimens the diagnosis (and also the differentiation from Crohn's disease or ulcerative colitis) is relatively simple, there are still numerous controversies on diagnostic and classification criteria to be used on biopsy material. 83, 84 3.2 Is SCAD a defined pathological entity? Statement (EL 1b -RG B) : SCAD is a defined pathological entity characterised by a chronic inflammatory response involving the inter-diverticular mucosa of a colonic segment involved. The rectum and the right colon are spared from inflammation. Hence, SCAD can be considered a separate pathological entity. Statement (EL 1b -RG B) Consensus levels of agreement: Aþ 75%; A 13%; AÀ 6%; DÀ 3%; Dþ 3%. Statement (EL 1b -RG B) Based on this definition it is also possible to suggest a correct terminology. Different synonyms are used in the literature to refer to this disease, such as segmental colitis, sigmoid colitis, crescentic colitis, diverticulosisassociated colitis, diverticular disease-associated segmental colitis, focal active colitis. However, none of these definitions clearly identifies this condition nor is any one definition accepted worldwide. DD associated with SCAD is a condition of chronic colitis localised in the colonic segment presenting diverticula. SCAD involves the interdiverticular mucosa. 83-85 Statement (EL 1b -RG B): The spectrum of histological lesions associated with SCAD is variable. It includes mild non-specific inflammation and inflammatory bowel disease (IBD)-like changes, making differential diagnosis difficult. Statement (EL 1b -RG B): Consensus levels of agreement: Aþ 88%; A 8%; AÀ 3%. Statement (EL 2a -RG B): Limitation of mucosal lesion to the diverticular segment is the most important diagnostic criterion for SCAD (rectal sparing). Rectal and descending colon biopsies are required to distinguish SCAD from IBD. Statement (EL 2a -RG B): Consensus levels of agreement: Aþ 91%; A 6%; AÀ 3%. Statement (EL 2a -RG B): A correct approach to biopsies in terms of sampling and number of specimens taken is of paramount importance. As a first step, it is important to take biopsies (minimum four samples) on the borders of the diverticula and in the apparently normal adjacent mucosa as well as biopsies in both the colon proximal to the diverticular area and the rectum. The second step is the evaluation of different morphological aspects, among which the most important is the differential diagnosis with IBD; two elements are fundamental for the diagnosis: (a) crypt architecture, because the internationally accepted guidelines stress crypt architectural distortion as one of the most important features in the differential diagnosis between IBD and non-IBD colitis. However, crypt distortion can be observed also in the context of diverticular disease where it may be associated with cystic dilatation of the crypts; (b) lamina propria cellularity: this morphological change is extremely variable, from a substantially nonspecific inflammation composed of plasma cells, lymphocytes, rare eosinophils, to an active inflammation with crypt aggression and complete crypt abscesses. On the basis of the above morphological changes it is possible to consider two different categories. The first category comprises the majority of cases in which the discovery of diverticula represents an incidental finding, in the absence of specific symptoms; in such cases the fundamental element -provided that a correct biopsy sampling is made -is the presence of cystically dilated crypts with mild inflammatory infiltrate in the lamina propria and no cryptitis. Another important feature is the absence of basal plasmocytosis, a critical finding in the differential diagnosis with IBD. The second category includes, as a rule, symptomatic cases in which the histological lesions may resemble or even be indistinguishable from those of ulcerative colitis. For these cases, the correct sampling is the main tool for the differential diagnosis (i.e. rectal sparing). Statement (EL 2a -RG B): Another challenging point is represented by the differential diagnosis with Crohn's disease. A Crohn-like reaction may be a localised reaction to diverticulitis alone. Pathologists should be cautious before making a diagnosis of sigmoid colonic Crohn's disease in the context of diverticulosis. Caution is required before making the diagnosis of coexistent conditions, in the absence of collateral evidence to support a diagnosis of Crohn's disease. [85] [86] [87] [88] [89] 3.4 Is a standardised classification of colonoscopic findings useful in DD? Statement (EL 5 -RG D): In the attempt to standardise colonoscopy findings, the following parameters may be considered: a. extent: the extent of diverticular disease (limited to or prevalent in the sigmoid colon or extended to the proximal colon) b. grading of wall rigidity: a three-grade scale for the evaluation of wall rigidity (absent, present, inability to pass strictures of the colonic segment bearing diverticula) c. mucosal abnormalities: presence/absence of mucosal abnormalities. Statement (EL 5 -RG D): Consensus levels of agreement: Aþ 33%; A 13%; AÀ 30%; DÀ 7%; Dþ 17%. Statement (EL 5 -RG D): In clinical practice the endoscopic findings related to DD are not standardised nor is specific literature available to this regard. Is colonoscopy necessary in acute lower GI bleeding of suspected diverticular origin? Statement (EL 2a -RG B): A prompt colonoscopy (i.e. within 12-24 h) is mandatory for diagnosis and to direct therapy. Massive bleeding should be managed with selective angiography. Statement (EL 2a -RG B): Consensus levels of agreement: Aþ 25%; A 44%; AÀ 28%; DÀ 3% Statement (EL 2a -RG B): Patients with severe lower gastrointestinal bleeding (LGIB) should undergo clinical evaluation and stabilisation as done with upper-GI bleeding. Colonoscopy is useful in the diagnosis and treatment of diverticular bleeding. Colonoscopy is recommended in the early evaluation of LGIB. The procedure should be performed after preparation of the colon by using polyethylene glycol-based solutions. Statement (EL 2a -RG B): Colonic preparation facilitates endoscopic visualisation, improves diagnostic yield, and may improve the safety of the procedure by decreasing the risk of perforation. The diagnostic yield of a colonoscopy ranges from 48-90%. The timing of colonoscopy after initial presentation varies among studies and ranges from 12-48 h. Early colonoscopy has been associated with shorter hospital stay. Several endoscopic treatment modalities can be used to achieve haemostasis when a source of LGIB is identified at the time of colonoscopy. In a large prospective study of urgent colonoscopies for diverticular haemorrhage, treatment of bleeding and non-bleeding visible vessels and adherent clots achieved haemostasis without recurrences. Endoscopic metallic-clip placement also serves as an alternative treatment for diverticular haemorrhage. Angiographic or surgical therapy may be necessary in cases of massive bleeding from a diverticulum not amenable to endoscopic treatment. [90] [91] [92] [93] [94] [95] 3.6 Can abdominal ultrasonography (US) be performed as first line imaging when suspecting acute diverticulitis (AD) and abdominal septic complications? Statement (EL 1b -RG A) : US can be used as a sensitive and specific diagnostic technique to detect acute diverticulitis and its septic abdominal complications, provided that the procedure is carried out by an expert investigator. Statement (EL 1b -RG A) Consensus levels of agreement: Aþ 9%; A 41%; AÀ 22%; DÀ 9%; D 6%; Dþ 13% US can identify the five layers that make up the intestine, assess bowel wall thickening, and its relationship with mesenteric fat, vessels and other adjacent organs. Moreover perintestinal fluid and collections or abscesses can be also visualised. Statement (EL 1b -RG A) Although US is able to identify colonic diverticula 96, 97 it cannot be considered the first line technique in diagnosing or ruling out diverticulosis because of the lack of appropriate studies on its performance. 98 AD can be detected by ultrasound 97,99-103 and so can its complications (i.e. abscesses and fistulae), 98, 99 provided that the procedure is carried out by an expert investigator. Statement (EL 1b -RG A) Although a systematic review 102 showed that US provides the best evidence for the diagnosis of diverticulitis, recent evidence from a multicentre Dutch study (Optima Study) 104 comparing US and CT scan accuracy of unselected patients, referred for acute abdominal pain to the emergency department, shows that CT is more sensitive than US (81% vs 61%) in detecting AD. Thus a conditional strategy with US as first-line method immediately followed by CT, whenever inconclusive or doubtful, seems to represent probably the most effective approach. 3.7 Which imaging test should be considered as the best method for colonic examination when the clinical question is to confirm or rule out DD? Statement (EL 3b -RG C): Colonoscopy and CT colonography (CTC) must be considered the first-line test to diagnose or rule out colonic diverticula. The choice for CTC or colonoscopy depends on the patient's age, risk factors, clinical status and preference. Statement (EL 3b -RG C): Consensus levels of agreement: Aþ 35%; A 23%; AÀ 26%; DÀ 3%; D 13%. Statement (EL 3a -RG B): Diagnostic accuracy of double contrast barium enema (DCBE) for DD is similar to that of CTC. Use of DCBE should be considered only if CTC is unavailable. Consensus levels of agreement: Aþ 41%; A 22%; AÀ 34%; Dþ 3% Statement (EL 3a -RG B): Diagnostic accuracy of double contrast barium enema (DCBE) for DD is similar to that of CTC. Use of DCBE should be considered only if CTC is unavailable. A correct diagnosis of DD is challenging for clinicians. Patients' symptoms and laboratory findings are unspecific and overlap with other gastroenterological conditions (e.g. IBS) and, in young women (<40 years), also with gynaecological disorders. 11 Thus, imaging tests, and particularly CTC and/ or colonoscopy represent the best diagnostic methods. The choice of the first-line imaging examination depends mostly on the patient's age, risk factors, clinical status and preference, but also on imaging availability and local expertise. 105 In elderly individuals, especially if frail and with potential contraindication to colonoscopy and sedation (e.g. patients with concurrent severe chronic cardiopulmonary disease, in anticoagulant therapy, etc.), a less invasive approach using CTC might be preferred. On the other hand, in younger patients where symptoms might be related also to colonic inflammatory changes, colonoscopy should be the first-choice test. Statement (EL 3a -RG B): Diagnostic accuracy of double contrast barium enema (DCBE) for DD is similar to that of CTC. Use of DCBE should be considered only if CTC is unavailable. DCBE can effectively diagnose diverticulosis, 106,107 similarly to CTC, 108 the latter being preferred because of higher patient compliance, 109 shorter examination time, fewer complications, 110 and lower radiation exposure. 111 It is noteworthy that a 3-5 mSv exposure, which is still considered a quality standard in CTC, 112 will soon become obsolete with the advent of new technologies (i.e. first-and second-generation iterative algorithms). Iterative algorithms will reduce overall exposure to less than 1 mSv. 113, 114 Sub-mSv exposure should be compared with DCBE, which usually delivers a rough average of 7-9 mSv. 111 CTC also reveals therapeutically significant extra-colonic findings 'so that it is beginning to seem rather irresponsible to continue to offer routine DCBE examinations'. 115 The only true limitation of CTC is still the limited access in small centres and peripheral hospitals. This is the reason why today DCBE is still considered applicable, but only when CTC is unavailable. Statement (EL 3a -RG B): Diagnostic accuracy of double contrast barium enema (DCBE) for DD is similar to that of CTC. Use of DCBE should be considered only if CTC is unavailable. US does not play a major role in the first diagnostics approach, since it has many limitations in detecting (and conversely, in excluding) colonic diverticula, not only in the right colon (as expected), but also in the sigmoid colon, particularly when the lumen is filled with stools. 103 Magnetic resonance colonography (MRC) is an exciting potential alternative, particularly interesting because of the lack of ionising radiations. 116 Preliminary results, based on a limited number of studies, are promising. 117 However, MRC needs further technical refinements, since the examination is much longer than CTC, and MRC is more prone to motion artefacts, which is relevant in elderly patients. Thus, at present, MRC cannot be considered readily feasible for widespread use within the radiological community. 3.8 Which imaging test should be considered as the best method for colonic examination in case of patients presenting with acute abdominal symptoms and clinical suspicion of diverticulitis? Statement (EL 1b -RG A): Contrast-enhanced computerised tomography (CE-CT) should be considered as the first-line colonic examination since it offers a more comprehensive evaluation of uncomplicated and complicated forms; CE-CT can also be used to guide therapeutic interventions. Statement (EL 1b -RG A): Consensus levels of agreement: Aþ 58%; A 23%; AÀ 13%; DÀ 3%; D 3%. Statement (EL 4 -RG C): The use of DBCE using water-soluble iodinated contrast agent should be strongly discouraged because of its poor diagnostic performance. Statement (EL 4 -RG C): Consensus levels of agreement: Aþ 69%; A 13%; AÀ 9%; DÀ 3%; D 3%; Dþ 3%. Statement (EL 4 -RG D): The use of MRC in diagnosing diverticulitis is not sustained by robust data. Feasibility seems to be limited by the difficult access to MR scanners in emergency departments. Statement (EL 4 -RG D): Consensus levels of agreement: Aþ 67%; A 15%; AÀ 9%; DÀ 3%; D 3%; Dþ 3%. Statement (EL 4 -RG D): In case of a patient presenting in an acute setting, with clinical signs and symptoms highly suspicious for an acute inflammatory process (fever, leucocytosis), CE-CT should be considered as the first-line colonic examination. 23, [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] CE-CT examination, obtained with multi-detector technology, 120 offers a more comprehensive evaluation of uncomplicated and complicated forms, particularly in case of perforations with free peritoneal air. 121 The severity of diverticulitis on CT scan is also statistically predictive of the risk of medical treatment failure during the acute phase and of the chances of bad secondary outcome after a successful medical treatment of the first episode. 122 Additional benefits of CT imaging include guiding therapeutic interventions, and providing an alternative diagnosis in patients without diverticulitis. 123, 124 US has a similarly high (around 90%) diagnostic accuracy, but only in SUDD. 23, 118 A conditional strategy where CT scan follows a preliminary negative or inconclusive US might be advantageous, because the number of CT exams can be reduced by about 50%. 125, 126 The role of MRC in diagnosing acute diverticulitis is questionable since no robust data have been published in the literature. 127, 128 Practical feasibility seems also to be limited by the difficult access to MR scanners in emergency departments. Medical and surgical treatment of diverticular disease 4.1 What are the measures and treatments to prevent the progression of diverticulosis to DD? Statement (EL 2b -RG B): There is no rationale for drug treatment of asymptomatic diverticulosis, but there are limited indications to suggest an increase in dietary fibre. Consensus levels of agreement: Aþ 55%; A 36%; AÀ 9%. Statement (EL 2c -RG B): There is a
{'paper_id': '24141627', 'title': 'Italian consensus conference for colonic diverticulosis and diverticular disease', 's2_url': 'https://api.semanticscholar.org/CorpusID:24141627', 'source': 'S2ORC'}