Diverticular disease: update on pathophysiology, classification and management

Abstract

Colonic diverticulosis is prevalent, affecting approximately 70% of the western population by 80 years of age. Incidence is rapidly increasing in younger age groups. Between 10% and 25% of those with diverticular disease (DD) will experience acute diverticulitis. A further 15% will develop complications including abscess, bleeding and perforation. Such complications are associated with significant morbidity and mortality and constitute a worldwide health burden. Furthermore, chronic symptoms associated with DD are difficult to manage and present a further significant healthcare burden. The pathophysiology of DD is complex due to multifactorial contributing factors. These include diet, colonic wall structure, intestinal motility and genetic predispositions. Thus, targeted preventative measures have proved difficult to establish. Recently, commonly held conceptions on DD have been challenged. This review explores the latest understanding on pathophysiology, risk factors, classification and treatment options.

Key points.

• Incidence of diverticular disease is rapidly increasing in younger age groups.

• Most complications related to diverticulitis occur during the primary episode.

• High fibre/vegetarian diet is recommended.

• Vigorous activity and healthy body mass index reduces diverticulitis risk.

• Antibiotics should be used selectively in uncomplicated diverticulitis.

• Mesalazine/rifaximin not indicated for diverticulitis recurrence. Possible benefit in symptomatic uncomplicated diverticular disease.

• Elective surgery should be decided on a case-by-case basis, not by number of episodes.

Introduction

Diverticular disease (DD) is highly prevalent in western countries with approximately 70% acquiring diverticulosis by 80 years old.¹ It is encountered less frequently in the developing world.² The risk of acquiring DD increases uniformly with age: approximately 40% of people over 60 years are affected in developed countries. Although most prevalent among the elderly, incidence in younger age groups is rapidly rising.³ Diverticular complications may be severe and include pain, inflammation, infection and bleeding. Although the majority are asymptomatic, between 10% and 25% will experience an episode of acute diverticulitis (the principal inflammatory complication of diverticulosis). A further 15% of those will experience complicated diverticulitis which may include serious complications such as abscess, fistula or perforation.⁴ Furthermore, up to 25% will experience chronic symptoms related to DD known as symptomatic uncomplicated diverticular disease (SUDD) in the literature. These symptoms are similar in nature to irritable bowel syndrome (IBS) and may occur with or without an episode of diverticulitis.⁵ The cost burden of DD is rising with a reported annual cost of US$5.5 billion in the USA in 2019.⁶

Pathophysiology

The pathophysiology of DD is complex and multifactorial (see figure 1). It involves the major aspects listed below; however, the precise pathophysiological mechanisms are not fully understood.

Figure 1.

Pathophysiology of diverticular disease (DD).⁶² BMI, body mass index; NSAIDs, non-steroidal anti inflammatory drugs.

Diet

In western societies, a lack of dietary fibre is proposed to be the major cause of diverticula formation. This may be due to transmission of contractile force to the colon wall rather than to lumen contents which leads to mucosal herniation.⁷ Studies to support this theory include Aldoori et al who in a prospective study of 47 888 men demonstrated an association between low fibre intake and symptomatic DD.⁸ Additionally, a UK study by Crowe et al following 47 033 people over 12 years found an association between low fibre intake and hospital admission and deaths related to DD. Vegetarianism conferred a 30% reduction in acquiring DD. The group with the highest fibre intake had a 41% risk reduction for DD compared with the group consuming the least fibre.⁹ There are, however, conflicting studies. A smaller study by Peery et al describe a link between reduced frequency of bowel motions and hard stools with a lower risk of DD. Furthermore, no correlation was seen between low fibre intake and DD.¹⁰ Links between chronic inflammation and dietary factors have been investigated in the literature. A prospective study published in 2020 followed 46 418 men between 40 and 75 years over a 28-year period. Ma et al demonstrated a link between proinflammatory dietary factors (including low fibre and high red meat intake) and an increased risk of diverticulitis.¹¹

Lifestyle risk factors

Several modifiable risk factors have been associated with diverticulitis. The major risk factors for hospitalisation include smoking, obesity, hyperlipidaemia, high red meat consumption and sedentary lifestyle.¹² A large US cohort study of 47 228 men demonstrated that a high fibre diet and vigorous exercise is protective against diverticulitis and diverticular bleeding.¹³ Regular non-steroidal anti-inflammatory drugs (NSAIDs) and (to a lesser extent) aspirin are associated with an increased risk of diverticulitis and diverticular bleeding. This is due in part to a reduction in prostaglandins and reduced platelet aggregation.¹⁴ Concurrent use of corticosteroids as well as opiate analgesia is associated with an increased rate of diverticular perforation.¹⁵

Structural abnormalities and colonic motility

Diverticula form at the site of vasa recta which form natural weak points in the colon wall. Structural changes associated with DD include shortened teniae, thickened circular muscle and narrowed lumen. Hypothesised causes for these changes include abnormal elastin deposition, abnormalities in collagen crosslinking and an increased ratio of type III collagen.¹⁶ Additionally, high levels of tissue degrading metalloproteinases have been discovered in areas of DD.¹⁷ Abnormal motor activity could increase luminal pressure and predispose to mucosal herniation.¹⁸ Colonic manometry studies in patients with DD have demonstrated greater intraluminal pressure and higher amplitude contractions following meals.¹⁹ It remains to be proven, however, that these findings precede diverticula formation.

Genetics

In western populations, DD is characteristically located in the left colon. Right-sided DD is common in Asian populations and is considered distinct, related largely to genetic predispositions.⁴ Extensive DD is associated with a number of genetically acquired connective tissue disorders, including Marfan’s syndrome, Ehlers-Danlos syndrome and Williams-Beuren syndrome.²⁰ Furthermore, population-based studies on migration demonstrate that on adopting a western diet, DD remains predominantly a right-sided disease in Asian immigrants. Two well-designed Scandinavian familial aggregation studies demonstrated a greater risk of hospitalisation for diverticular complications in siblings of those affected with DD. The association is stronger still between monozygotic twins as compared with dizygotic twins.^{21 22} However, one Swedish study confirmed that while non-western immigrants initially conferred a reduced risk of hospitalisation for DD, on assimilation the risk became similar to the native population.²

Gut microbiome

In recent years, the gut microbiome in DD has been more closely evaluated. Diets rich in fibre are associated with greater microbial diversity.²⁰ There is some evidence to support a depletion in anti-inflammatory microbiota such as Clostridium spp, Fusobacterium and Lactobacillaceae in DD. Proinflammatory bacteria, such as Subdoligranulum spp and Marvinbryantia spp, have also been identified in small studies.²³ The available studies are heterogeneous with few subjects. The results may reflect an association rather than causation; therefore, their significance is uncertain.

Classification

Currently, there is no single universally accepted classification for DD. DD may be classified as asymptomatic diverticulosis, complicated DD or SUDD (see figure 2).

Figure 2.

Classification of diverticular disease (DD). ⁶³ IBS, irritable bowel syndrome.

Asymptomatic diverticulosis

Typically, an incidental finding noted on radiological or endoscopic investigation for IBS-like symptoms. Patients with incidental asymptomatic diverticulosis do not require routine treatment or follow-up.²⁴ They should be informed of the natural history of the condition.

Complicated DD

The most common complication of DD is acute diverticulitis, which is defined as DD with signs and symptoms of diverticular inflammation.²⁵ The presumed pathophysiology of diverticulitis is diverticulum obstruction with a faecolith. This leads to mucosal abrasion which triggers an inflammatory response, mucus secretion, bacterial overgrowth and microperforations with translocation of bacteria.²⁴ Complicated diverticulitis most frequently involves a pericolonic abscess (~70%), followed by colonic perforation with purulent or faecal peritonitis (~27%), followed by fistula (~14%). Stricture and bowel obstruction are uncommon.⁴

Diverticular haemorrhage is a frequent complication that occurs in 5%–15% of patients.²⁶ Usually bleeding is high volume, irregular and in the majority resolves spontaneously. Haemodynamically compromised patients as well as those with suspected active bleeding (ie, those with ongoing rectal bleeding or a shock index >1), should undergo immediate CT angiogram as per British Society of Gastroenterologyguidance.²⁷ CT angiogram provides the quickest way of identifying the bleeding source and informs treatment planning with either interventional radiology or endoscopy. Following a large bleed, stable patients (shock index <1) should be admitted for inpatient colonoscopy to identify and treat potential bleeding point(s). In minor bleeding cases (ie, where rectal bleeding has stopped and there has been no haemodynamic compromise) patients may be safely discharged with outpatient investigation.²⁷

Symptomatic uncomplicated diverticular disease

SUDD is characterised by non-specific episodes of lower abdominal pain, typically in the left iliac fossa without macroscopic evidence of inflammation. Bloating and change in bowel habit may also occur.²⁰ The pathogenesis of SUDD is likely to be related to factors including low-grade inflammation, changes in gut microbiota and the enteric nervous system.²⁸ Patients with SUDD have been found to experience a greater perception of distention in diverticular segments.²⁹ A small study identified nerve fibre overgrowth around diverticula in SUDD patients compared with asymptomatic patients.³⁰ The authors conclude that this may contribute to SUDD; however, nerve fibre sprouting has also been found in IBS patients. Many of the symptoms associated with SUDD are akin to those typical of IBS. Indeed, the overlap between diverticulosis and IBS has been recognised to some extent in the literature. A retrospective study of over 1000 patients with diverticulitis found the group were ×4.7 more likely to acquire a diagnosis of IBS compared with controls. This poses the possible diagnosis of ‘postdiverticulitis IBS’.⁵ Further work is needed in this area.

Classification systems

The most commonly used classification system to describe complicated diverticulitis is the Hinchey and more recently the modified Hinchey classification (table 1). The Hinchey classification originally described complicated diverticulitis based on intraoperative findings. The modified classification grades patients I–IV based on CT findings. The score at index presentation directly correlates with risk of recurrence and complications.³¹ Clinically, the score guides management with Hinchey I treated conservatively, Hinchey II considered for interventional radiology and Hinchey III and IV requiring surgery.²⁰

Table 1.

Hinchey and modified Hinchey classifications

Hinchey classification	Modified Hinchey classification
I Pericolic abscess/phelegmon	I Pericolic abscess
II Pelvic/intra-abdominal/retroperitoneal abscess	IIa Distant abscess amenable to percutaneous drainage IIb Complex abscess with fistula
III Generalised purulent peritonitis	III Generalised purulent peritonitis
IV Faecal peritonitis	IV Faecal peritonitis

Diverticular inflammation and complication assessment classification

The diverticular inflammation and complication assessment (DICA) classification developed by Tursi et al is the first endoscopic classification for DD.³² Patients are grouped into DICA 1, 2 or 3 with 3 being the most severe (table 2). DICA scores were found to correlate with CRP and median pain scores. It is proposed that clinically the scores may represent: DICA 1: simple diverticulosis, DICA 2: severe diverticulosis to mild diverticulitis and DICA 3: complications related to diverticulitis.³²

Table 2.

DICA classification

Diverticula location
Left colon	2
Right colon	1
No of diverticula (in each area)
Up to 15: grade I	0
>15: grade II	1
Presence of inflammatory signs
Oedema/hyperaemia	1
Erosions	2
SCAD	3
Presence of complications
Rigidity of the colon	4
Stenosis	4
Pus	4
Bleeding	4
DICA 1	1–3
DICA 2	4–7
DICA 3	>7

DICA, diverticular inflammation and complication assessment; SCAD, segmetal colitis associated with diverticulosis.

A retrospective validation of 1651 patients demonstrated the predictive value of DICA score for disease recurrence and probability of surgery. Interestingly, use of mesalazine as a preventative treatment did not reduce recurrence in DICA 1 or 3 groups. However, DICA 2 patients were less likely to have recurrence or require surgery following mesalazine treatment. The authors speculate that DICA 2 patients are more likely to have inflammation confined to the mucosa where mesalazine is effective.³³

Treatment

Treatment is largely targeted at complications related to DD rather than prevention (see figure 3). Surgical treatment of complicated diverticulitis is well established.³⁴ Conversely, prophylactic treatment options that reduce the risk of complications are not well defined.³⁵ Furthermore, much of the morbidity associated with uncomplicated DD are chronic IBS-like symptoms that have limited effective treatment options.²³

Figure 3.

Treatment of diverticular disease. ⁶⁴ BMI, body mass index. CRP, C-reactive protein. CTA, computed tomography angiography, IP, inpatient; IR, interventional radiology.

Lifestyle and dietary modifications

As discussed, a vegetarian diet and high fibre consumption is associated with a reduced risk of diverticulitis. A balanced diet with fibre-rich foods such as vegetables, fruits and whole grains is advised. Avoiding red meat, processed foods, high fat dairy and refined sugar is likely to reduce the risk of complicated DD.³⁶ Contrary to previous beliefs, consumption of popcorn, nuts, corn and seeds is not associated with an increased risk of diverticulitis. A prospective cohort study of 47 228 men disproves this and in fact demonstrated a protective potential of nuts and corn.³⁷ Smoking cessation, regular vigorous exercise and a body mass index between 18.5 and 24.9 kg/m² are also protective.¹² Avoidance of regular NSAIDs and aspirin (other than therapeutic) is recommended.³⁶

Antibiotics

Antibiotic therapy has been the primary treatment for diverticulitis in recent decades. Use of antibiotics, however, has been questioned in recent years. An inflammatory rather than infectious process is hypothesised in a subgroup of patients. Several randomised trials have demonstrated that antibiotic therapy is not beneficial in uncomplicated diverticulitis.³⁸ A 2012 multicentre randomised controlled trial (RCT) by Chabok et al randomised 623 patients to either antibiotic treatment or no antibiotic treatment. They reported that antibiotics did not accelerate recovery time, therefore, should be reserved for complicated cases.³⁹ A 2016 multicentre RCT by Daniels et al randomised 528 patients to either antibiotic therapy or no antibiotics. There was no significant difference in recovery time, readmission rate, recurrence or surgical intervention. In fact, hospital stay was significantly shorter in the no antibiotics group.⁴⁰ A 2018 systematic review (SR) and meta-analysis of antibiotic treatment versus observation in uncomplicated diverticulitis analysed 9 studies combining 2565 patients. The SR by Emile et al reported no significant difference in treatment failure, length of stay, recurrence rate, surgical intervention, readmissions or mortality. Patient comorbidities were the only factor associated with treatment failure. This review suggests that treatment without antibiotics is safe and feasible.⁴¹ The described studies support the latest guidelines from the European Society of Coloproctology as well as the American Gastroenterological Association (AGA). The guidelines advocate avoiding antibiotic treatment in immuno-competent patients with uncomplicated diverticulitis. It is, however, recommended that all immunocompromised patients and patients with complicated disease are treated with antibiotics.^{36 42}

Rifaximin

Rifaximin is a poorly absorbed antibiotic, which targets the gastrointestinal tract. Cyclical use of rifaximin has been proposed for SUDD.²⁰ Meta-analyses evaluating rifaximin^{43 44} review a number of RCTs including a double-blind placebo-controlled trial.⁴⁵ The studies conclude that rifaximin combined with a high fibre diet significantly improved symptoms at 1-year follow-up compared with high fibre in isolation. There is insufficient evidence, however, to support the use of rifaximin in diverticulitis prevention. The limitations within the current evidence mean that rifaximin is not recommended for SUDD. Indeed, the latest AGA guidance advises against use of rifaximin as a preventative treatment.³⁶

Aminosalicylates

Mesalazine, mesalamine or 5-aminosalicylic acid (5-ASA) is an anti-inflammatory drug used principally in the management of inflammatory bowel disease. More recently, the efficacy of mesalazine in the treatment of DD, particularly SUDD has been described. Two recent SRs report on the use of mesalazine for DD.^{46 47} The SR by Picchio et al analyses seven studies including six RCTs. Notably, a four-armed placebo-controlled study⁴⁸ which followed up 210 patients over 1 year. Patients were randomised to intermittently receive either 1.6 g mesalazine or a probiotic containing Lactobacillus or mesalazine plus probiotic or placebo. A 93% symptom resolution was seen in the mesalazine group vs 54% in the placebo group. Diverticulitis was noted in seven patients, six of whom were in the placebo group. Episodes of symptomatic DD were noted in 14.5% in the mesalazine group vs 46% in the placebo group. No SUDD recurrence was seen in the mesalazine plus probiotic group. The authors conclude that mesalazine is more effective than rifaximin, high fibre diet or placebo in controlling symptomatic DD. There are, however, data limitations, notably the inclusion criteria. The 2018 SR by Iannoe et al ⁴⁶ analysed 13 RCTs (3028 patients) and drew similar conclusions. They concluded that mesalazine may reduce SUDD; however, it is not preventative for diverticulitis. This is supported by a Cochrane review of 7 studies (1805 patients) which determines that there is no conclusive evidence supporting the use of 5-ASA in preventing recurrent diverticulitis.⁴⁹

Probiotics

Probiotics may lead to an increase in anti-inflammatory microbiota and inhibit colonic bacterial overgrowth.⁵⁰ A small number of studies have proposed the use of probiotics as a treatment for DD.⁵¹ A 2016 SR evaluating 11 studies (764 patients) on the use of probiotics in DD did not demonstrate enough high-quality evidence to draw a significant conclusion.⁵² The probiotics used were heterogeneous. The most used bacteria were strains of Lactobacilli with Bifidobacteria used less frequently. Eight studies used single strains and three used multiple strains. The studies are heterogeneous in bacterium strains, methodology and outcome measures to the extent that no meaningful conclusions could be drawn. Based on the current evidence, there are insufficient data available to confidently recommend probiotics for DD. Questions remain as to how best define and target microbiota specific to DD in order to establish effective therapy.

Endoscopic techniques

Current endoscopic techniques applied to DD have been found to be safe and well tolerated by patients.⁵³ Colonoscopy is a well-established tool in the diagnosis of DD as well as offering a potential prognostic benefit.³³ The use of endoscopic clips in DD has been widely described, mainly to tackle diverticular bleeding.⁵¹ A feasibility study carried out at a tertiary referral centre evaluated the effectiveness of elective endoscopic clipping of diverticula in patients with a history of significant diverticular bleeding.⁵⁴ All visible diverticula were closed using endoclips. A diverticula closure rate of 87.2% (129/148) was demonstrated at follow-up colonoscopy. In this group, there were no postprocedural complications or further bleeding reported up to follow-up colonoscopy.⁵⁴ Notably, incidental complete resolution of chronic left-sided abdominal pain was noted in one subject. This study established the possibility to obtain restoration of normal colonic mucosa over colonic diverticula. Following this study, a randomised placebo-controlled trial ‘Prophylactic Endoscopic Clipping of Diverticula’ is currently underway to evaluate the effect of endoscopic clipping on symptoms related to DD and whether lasting closure of diverticula can be achieved (NCT03935100).

Surgical management

The surgical management of complicated diverticulitis has changed in recent years moving towards more conservative approaches. Accurate diagnosis using the modified Hinchey classification is a major component in directing management. Those with uncomplicated diverticulitis (Hinchy 0) who are clinically stable are increasingly being safely managed as outpatients.⁵⁵ Currently, radiologically guided percutaneous abscess drainage is favoured over surgery for Hinchy IIa/IIb. Patients classified as Hinchey III and IV, that is, those with generalised or faeculant peritonitis, as well as patients not responding to medical treatment require urgent surgical intervention.⁵⁶ Traditionally, the favoured approach for emergency surgery has been the Hartmann procedure (HP): a sigmoid colectomy with end colostomy formation. This procedure, however, is associated with major morbidity and a mortality rate between 2.6% and 7.3%. Additionally, elective major surgery is required to restore bowel continuity which is associated with further significant morbidity. Indeed, overall stoma closure rate is low.⁵⁷ Recently, a sigmoid colectomy and primary anastomosis with or without a diverting loop ileostomy has been proposed with a potential reduction in mortality compared with HP.⁵⁸ Typically, HP is recommended for Hinchey IV and clinically unstable patients, where primary anastomosis may be considered for Hinchey III cases (see figure 3).⁵⁹

Laparoscopic peritoneal lavage has previously been proposed as a bridging procedure for elective surgery in Hinchey III diverticulitis. Current guidelines, however, advise against this approach as the associated morbidity and mortality is higher compared with primary resection.⁶⁰

Elective surgery

Surgical resection is usually needed for complications including fistula or chronic obstruction secondary to diverticular stricture. Complicated diverticulitis most often occurs during the primary presentation (other than fistulating disease). The risk of complications decreases with further episodes.³⁶ There is an overall 20% risk of recurrence with 8% experiencing a further attack within the first year. Rate of recurrence increases following additional episodes: 18% at 1 year following a second episode and 40% at 3 years after a third episode.⁴ It is important to note that elective surgery does not eliminate diverticulitis recurrence. Furthermore, associated gastrointestinal symptoms including abdominal pain persist in up to 25% of patients following surgery.⁶¹ Therefore, national guidelines advise against elective resection based on the number of episodes and recommend a decision on a case-by-case basis, considering patient wishes, impact on quality of life and comorbidities (see box 1).³⁶

Box 1.

• Elective surgery should be decided on a case-by-case basis, not by number of episodes.

• Primary anastomosis±ileostomy may be considered for Hinchey III.

• LPL is not recommended in the surgical management of diverticulitis.

• Most complications related to diverticulitis occur during the primary episode.

Conclusion

DD is prevalent with complex pathophysiological mechanisms. Targeted preventative measures have, therefore, been difficult to establish. Recently, commonly held conceptions on DD have been challenged. Importantly, antibiotic therapy for uncomplicated diverticulitis should be used selectively. Similarly, elective surgery should not be routinely offered based on the number of episodes of diverticulitis. Instead, on a case-by-case basis, ensuring patients are fully informed of associated risks. Chronic symptoms associated with DD including SUDD and the reported ‘IBS-like’ symptoms are difficult to manage and present a significant healthcare burden. While rifaximin and mesalazine have shown some promise in symptom management there is no conclusive evidence for their use in secondary prevention. Further studies in this area, including prophylactic endoscopic clipping are eagerly awaited. Presently, patients should be encouraged to take a healthy lifestyle including a balanced, fibre rich diet.

Ethics statements

Patient consent for publication

Not applicable.