diverticular disease as a chronic illness: evolving epidemiologic and clinical insights

The American Journal of GASTROENTEROLOGY VOLUME 107 | OCTOBER 2012 www.amjgastro.com

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CLINICAL AND SYSTEMATIC REVIEWS

OVERVIEW Diverticular disease imposes a signifi cant burden on Western and

industrialized societies ( 1 – 3 ). Th e prevalence of diverticulosis

increases with age, aff ecting ~ 70 % of individuals aged 80 years

or older in the United States ( 2,4 ). Patients with diverticulosis

may experience a range of both acute and chronic complications

including abdominal pain, diverticulitis, peritonitis, obstruction,

fi stulization, or abscess formation ( 5,6 ). Th ese complications

account for over 300,000 hospital admissions, 1.5 million inpa-

tient care days, and 2.4 billion dollars in direct costs annually in

the United States ( 1,7,8 ). Th e incidence of diverticular complica-

tions appears to be increasing, and the number of patients aff ected

by diverticular disease will continue to rise as the population

ages and expands ( 9 ). Th ese epidemiologic trends are already

familiar to any endoscopist who performs colon cancer screening,

as diverticulosis is the most commonly reported lesion found on

routine colonoscopy ( Figure 1 ) ( 1 ).

Despite the large epidemiologic and economic burden of

diverticular disease, there is surprisingly little known about

this condition; providers still lack reliable answers to common

clinical questions. For example, consider how best to respond to

these patient inquiries:

“ My colonoscopy report says there is “ diverticulosis. ” Should I worry about this? What is the chance that I ’ ll develop a problem from having this inside my colon? ”

“ What can I do to prevent the diverticulosis from causing prob-lems? Will taking fi ber help? Are there medications I can take? ”

“ I have irritable bowel syndrome. I also have diverticulosis. Are those related to each other? Did one cause the other? ”

“ Did diverticulosis cause my Crohn ’ s disease? ”

“ I ’ ve felt depressed ever since I had a diverticulitis attack last year. Is this all in my head? Can diverticulitis aff ect my quality of life this long aft er the attack? ”

Th ese are common and legitimate questions; clinicians need

evidence to answer these questions accurately. Moreover, these

questions indicate that diverticular disease may have a chronic

component in some patients, that providers should be prepared to

address the illness as part of everyday outpatient practice, and that

Diverticular Disease as a Chronic Illness: Evolving Epidemiologic and Clinical Insights Lisa L. Strate , MD, MPH 1 , Rusha Modi , MD 2 , Erica Cohen , MD 3 and Brennan M.R. Spiegel , MD, MSHS 2 – 5

Diverticular disease imposes a signifi cant burden on Western and industrialized societies. The traditional pathogenesis model posits that low dietary fi ber predisposes to diverticulosis, and fecalith obstruction prompts acute diverticulitis that is managed with broad-spectrum antibiotics or surgery. However, a growing body of knowledge is shifting the paradigm of diverticular disease from an acute surgical illness to a chronic bowel disorder composed of recurrent abdominal symptoms and considerable psychosocial impact. New research implicates a role for low-grade infl ammation, sensory-motor nerve damage, and dysbiosis in a clinical picture that mimics irritable bowel syndrome (IBS) and even infl ammatory bowel disease (IBD). Far from being an isolated event, acute diverticulitis may be the catalyst for chronic symptoms including abdominal pain, cramping, bloating, diarrhea, constipation, and “ post-diverticulitis IBS. ” In addition, studies reveal lower health-related quality of life in patients with chronic diverticular disease vs. controls. Health-care providers should maintain a high index of suspicion for the multifaceted presentations of diverticular disease, and remain aware that it might contribute to long-term emotional distress beyond traditional diverticulitis attacks. These developments are prompting a shift in therapeutic approaches from widespread antimicrobials and supportive care to the use of probiotics, mesalamine, and gut-directed antibiotics. This review addresses the emerging literature regarding epidemiology, pathophysiology, and management of chronic, symptomatic diverticular disease, and provides current answers to common clinical questions. Am J Gastroenterol 2012; 107:1486–1493; doi: 10.1038/ajg.2012.194; published online 10 July 2012

1 Division of Gastroenterology, Department of Medicine, Harborview Medical Center, University of Washington Medical School , Seattle , Washington , USA ; 2 UCLA / VA Center for Outcomes Research and Education , Los Angeles , California , USA ; 3 Division of Gastroenterology, Department of Medicine, VA Greater Los Angeles Healthcare System , Los Angeles , California , USA ; 4 Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA , Los Angeles , California , USA ; 5 Department of Health Services, UCLA School of Public Health , Los Angeles , California , USA . Correspondence: Brennan M.R. Spiegel, MD, MSHS , 11301 Wilshire Blvd., Building 115, Room 215, Los Angeles , California 90073 , USA . E-mail: [email protected] Received 7 February 2012; accepted 23 May 2012

© 2012 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Chronic Diverticular Disease

patients may harbor long-term concerns about the diagnosis even

outside of symptomatic episodes.

Yet, diverticular disease is oft en conceived as abrupt, disruptive,

and acute diverticulitis attacks surrounded by periods of relative

clinical silence. Th is may not be true for everyone. As discussed

in this article, patients with diverticular disease not only experi-

ence lower health-related quality of life (HRQOL) than matched

controls ( 10,11 ), but their HRQOL decrement may occur well

beyond acute diverticulitis attacks; for some patients, true diver-

ticulitis may persist beyond the overt fl ares and evolve into a more

chronic illness. Other patients may suff er from depression or

anxiety related to chronic abdominal pain or related illness expe-

riences ( 12 ). Still others may develop irritable bowel syndrome

(IBS) symptoms in the setting of diverticular disease — an as-yet

unproven causal link, but a relationship with growing epidemio-

logic data, discussed below ( 12 – 15 ). And if diverticular disease

causes long-standing pain, discomfort, or IBS symptoms, then it

suggests the condition may become a chronic bowel disorder in

some patients — not merely an intermittent condition within the

purview of surgeons.

Current treatment practices in diverticular disease are

based largely on theories and studies dating to the mid-20th

century. However, recent work calls into question traditional

dogma, and reveals new insights into the epidemiology, patho-

physiology, and clinical course of this disease. Rather than fram-

ing diverticular disease as a relatively asymptomatic disorder

punctuated by acute, self-limited attacks of diverticulitis, this

article reframes the condition as a potentially chronic illness with

everyday outpatient practice implications, and emphasizes why

providers should be prepared to address its impact beyond acute

diverticulitis.

In the sections that follow, we summarize evolving data and

concepts regarding chronic diverticular disease. We discuss the

potential role infl ammation and gut microbiota may play in illness

expression, and summarize shift ing clinical paradigms for diag-

nosing and managing chronic diverticular disease. Th e article ends

with recommendations on how this information might impact the

practicing gastroenterologists, now and in the future.

SETTING DIVERTICULAR TERMINOLOGY STRAIGHT Th e diverticulosis literature is replete with terms of unclear sig-

nifi cance such as diverticular disease, symptomatic diverticulosis,

and symptomatic uncomplicated diverticular disease (SUDD).

We present the scheme in Figure 2 to help organize the diver-

ticular terminology. “ Diverticulosis ” is merely the presence of

colonic diverticula; these may, or may not, be symptomatic or

complicated. “ Diverticular disease ” is clinically signifi cant and

symptomatic diverticulosis; this may be from true diverticulitis

or from other less well-understood manifestations (e.g., visceral

hypersensitivity in the absence of verifi able infl ammation ( 16 )).

Th e overarching term “ diverticular disease ” implies that the path-

ologic lesion (diverticulosis) rises to the level of an illness. SUDD

is a subtype of diverticular disease in which there are persistent

abdominal symptoms attributed to diverticula in the absence of

macroscopically overt colitis or diverticulitis. In contrast, “ diver-

ticulitis ” is the macroscopic infl ammation of diverticula with

related acute or chronic complications. Diverticulitis can be

acute or chronic. In its chronic form, patients may have recur-

rent bouts of low-grade or overt diverticulitis. A small subset of

patients may develop segmental colitis associated with diverticu-

losis (SCAD) — a unique form of chronic diverticulitis that occurs

in areas marked by diverticulosis that may be a variant or fore-

runner of infl ammatory bowel disease (IBD), as discussed later in

this article ( 17,18 ). Our primary focus in this article is on chronic

forms of diverticular disease, including SUDD, recurrent chronic

diverticulitis, and SCAD.

EVOLVING PATHOPHYSIOLOGIC MECHANISMS OF DIVERTICULAR DISEASE Diverticula are thought to develop from age-related degenera-

tion of the mucosal wall and segmental increases in colon pres-

sure resulting in bulging at points of weakness, typically at the

insertion of the vasa recta. Diverticulitis, in turn, is tradition-

ally ascribed to fecaliths obstructing a diverticular sac, prompt-

ing barotrauma, mucosal abrasion, infl ammation, and bacterial

overgrowth. Alternatively, poorly digested food components, like

75

60

45

30

15

20–39

Normal exam/no findings Hemorrhoids Diverticulosis Polyp

Multiple polypsPolyp > 9 mm/suspect malignant tumor Mucosal abnormality-colitis

40–49 50–59

Age in years

Per

cent

age

(%)

60–69 70–79 80+0

Figure 1 . Major colonoscopic fi ndings in the US Population — data by age strata (adopted from Everhart et al. ( 1 )).


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without overt colitis. In another series of 930 patients undergo-

ing surgery for SUDD but not overt diverticulitis, Horgan et al.

( 25 ) documented chronic infl ammation in and around diverticula

in three-quarter of the resected specimens. However, the extent

of infl ammation did not correlate well with symptom intensity. In

addition, 5-ASA drugs traditionally used in IBD appear to reduce

diverticulitis recurrence and minimize symptoms following an

attack of acute diverticulitis (discussed below) ( 26 ). Together, this

evidence suggests that microscopic infl ammation occurs in the

setting of diverticulosis, and that its presence might contribute to

symptom development in some patients with diverticular disease.

Beyond microscopic infl ammation, macroscopic colitis has been

widely reported in association with diverticula. Th ese observations

led investigators to defi ne SCAD as a separate disorder ( 27,28 ).

SCAD is a form of chronic colitis limited to areas of the colon with

diverticula and sparing the rectum. Although now recognized as

a distinct clinico-pathological entity, the histological features of

SCAD bear close resemblance not only to idiopathic IBD, but also

to infectious and ischemic colitis ( 29 ). Cryptitis, crypt abscesses,

and even granulomas and chronic architectural distortion are

described in patients with SCAD ( 29 ). Case series reveal that in

a small subset of patients ( ~ 10 % ), SCAD evolves into frank IBD

( 17 ), suggesting that SCAD may be a forme fruste of IBD. SCAD is

perhaps the most powerful example that infl ammation and diver-

ticulosis can go hand-in-hand, and that traditional explanations

for diverticular disease involving local trauma and obstruction are

probably insuffi cient.

INTESTINAL MICROBIOTA Another putative mechanism of chronic diverticular disease

involves shift s in intestinal microbiota leading to chronic infl am-

mation, similarly to theoretical models for IBS ( 30 ). Fecal stasis

may lead to chronic dysbiosis, in turn promoting formation of

seeds or nut particles, are hypothesized to lodge within diverticula

and result in localized trauma, tissue ischemia, focal necrosis, and

micro-perforation. Th ese predominantly anatomical theories are

outlined in the previous review articles and guidelines ( 6,19 – 22 ).

In contrast, more recent theories de-emphasize these anatomic

mechanisms, and instead posit infl ammation, microbiome shift s,

visceral hypersensitivity, and abnormal motility as potential etio-

logic factors, especially for chronic diverticular disease ( Figure 3 ).

We briefl y explore each theory in the sections below.

INFLAMMATION Th e role of infl ammation in acute diverticulitis is well accepted.

However, a growing body of literature indicates that low-grade

infl ammation may also have a role in chronic diverticular disease.

Th e infl ammation may be microscopic, identifi ed only through

diverticular biopsies, or macroscopic, presenting in a manner

similar to IBD.

Case series demonstrate chronic infl ammation in biopsy speci-

mens taken from within and around diverticula of patients without

overt diverticulitis or colitis. As early as 1976, Kealy and colleagues

observed a higher density of lymph node aggregates in macro-

scopically disease-free portions of colonic mucosa in subjects with

vs. without diverticulosis ( 23 ). Floch ( 24 ) later found abnormal

pathology in random biopsies taken from 16 of 17 patients with

diverticulosis, with most demonstrating a lymphocytic infi ltrate

Diverticulosis

Chronicdiverticulitis

Chronic recurrentDiverticulitis

Acutediverticulitis

Diverticulitis SUDD

SCAD

Diverticulardisease

Asymptomaticdiverticulosis

Figure 2 . Proposed taxonomy of diverticular-related terms. Diverticulosis is the mere presence of diverticula in the colon — this may be symptomatic or asymptomatic. “ Diverticular disease ” implies symptoms; this may be from verifi able macroscopic diverticulitis — i.e., infl ammation of the diverticula — or in the absence of overt diverticulitis, called symptomatic uncomplicated diverticular disease (SUDD). Diverticulitis can be acute or chronic. Some patients with chronic diverticulitis have a unique form of the disease called segmental colitis associated with diverticula (SCAD), which is a distinct clinic-pathologic entity more like infl ammatory bowel disease than traditional diverticulitis. Others with chronic diverticulitis have recurrent episodes of traditional diverticulitis rather than SCAD. See text for details.

5-ASA drugs Rifaximin Probiotics Fiber

Alterations in gutmicrobiota

Low-gradeinflammation

Abnormal colonmotility

Diverticular disease

Visceralhypersensitivity

Figure 3 . Evolving pathophysiologic mechanisms for diverticular disease. Traditional theories of diverticular pathogenesis involve trauma to or obstruction of a diverticulum. Current theories suggest that chronic infl ammation, alterations in the commensal gut microbiota, visceral hypersensitivity, and abnormal colon motility have likely inter-related roles in the development of diverticular disease. In addition to fi ber, newer treatments including 5-ASA drugs, rifaximin, and probiotics are directed at these potential mechanisms.


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abnormal metabolites leading to long-standing infl ammation.

Several lines of indirect evidence support a potential association

between the intestinal microbiota and diverticular disease. Rifax-

imin, a non-systemic antibiotic, may reduce attacks of recurrent

diverticulitis and treat gastrointestinal (GI) symptoms in patients

with SUDD ( 31,32 ). Low dietary fi ber intake, a putative risk fac-

tor for chronic diverticular disease, is associated with alterations

in the gut microbial composition ( 33 ). Additionally, in a study of

90 patients with a history of acute diverticulitis, 60 % were noted

to have small bowel bacterial overgrowth using the lactulose

hydrogen breath test ( 34 ), although it should be noted that the

lactulose hydrogen breath test may be a better measure of intes-

tinal transit than true overgrowth ( 35 ). Further research using

quantitative molecular techniques will better elucidate the

potential role of commensal gut microfl ora in the pathogenesis of

diverticular disease.

VISCERAL HYPERSENSITIVITY Evolving data suggest a strong epidemiologic overlap between

chronic diverticular disease and IBS, as discussed later in this

article ( 13,14 ). Th is overlap suggests that both conditions may

also share underlying pathophysiology. Visceral hypersensitivity,

although usually described in the context of IBS ( 36 ), may pro-

vide this common mechanism. For example, Clemens et al. ( 16 )

compared colonic visceral pain perception in response to luminal

distention in patients with SUDD, asymptomatic diverticulosis,

and healthy controls. Patients with SUDD not only demonstrated

a heightened pain perception in the sigmoid colon with diver-

ticula, but also in the unaff ected rectum. Th is phenomenon was

not observed in either the control subjects or those with asymp-

tomatic diverticulosis. Th ese fi ndings suggest that an IBS-like

process of generalized hyperalgesia may occur in diverticular

disease. Recent data suggest that the mechanism of hypersensi-

tivity may relate to increased neuropeptides and alterations in

enteric innervation in patients with diverticular disease — a “ post-

infl ammatory ” consequence that persists aft er acute diverticulitis

has passed ( 37 ).

COLONIC MOTILITY It is well accepted that abnormal colonic motility has a role in

IBS symptom expression ( 38 ). Altered motility may also be asso-

ciated with chronic symptoms in diverticular disease. In a study

by Bassotti et al. ( 39 ), patients with SUDD displayed increased

duration of rhythmic, low frequency, contractile activity, particu-

larly in the segments bearing diverticula — a pattern the authors

described as “ spastic colon. ” Although the relationship between

dysmotility and symptoms was imperfect, the authors concluded

that patients with diverticular disease have abnormal motor and

propulsive activities in the colonic segments exhibiting diverticu-

losis. In a separate study, these same authors demonstrated that

patients with diverticulosis have a signifi cantly reduced density

of interstitial cells of Cajal — the so-called “ pacemaker cells ” of the

intestine — compared with normal controls ( 40 ). A reduction or

loss of interstitial cells of Cajal function may disturb or decrease

colonic electrical slow wave activity, presumably resulting in

abdominal complaints including pain and constipation. Shift s

in the concentrations of mucosal vasoactive intestinal peptide

and other chemical mediators may also have a role, as suggested

by Milner et al. ( 41 ).

EPIDEMIOLOGY AND NATURAL HISTORY OF DIVERTICULOSIS: DOGMA VS. DATA Th e natural history of diverticulosis is poorly understood. Of

patients who harbor colonic diverticulosis, it is traditionally

believed that 15 – 25 % will progress to develop diverticulitis in

their lifetime ( 5,6,19,20,22 ). However, this widely cited fi gure is

based on the data predating population-based screening colon-

oscopy. Th erefore, the true denominator of individuals harboring

diverticulosis was not accounted for in these calculations.

Current population-based data suggest that the true incidence

of diverticulitis is much lower than previously estimated. Th e

number of hospitalizations for diverticulitis per year in the United

States ( ~ 300,000) is lower than that would be expected based on

the number of Americans estimated to have diverticulosis (see

Figure 1 ) ( 1 ). Recent population-based cohort studies indi-

cate that the incidence of diverticulitis among adults is between

1 and 2 % ( 42,43 ). Assuming that ~ 50 % of these individuals have

diverticulosis, the incidence of diverticulitis in patients with

diverticulosis would be < 5 % .

To more accurately calculate the true incidence of acute diver-

ticulitis, we performed a survival analysis in a large cohort of

patients with diverticulosis incidentally discovered during colon-

oscopy ( 16 ). We followed 2,127 patients over a median of nearly

7 years and tracked incident diverticulitis attacks confi rmed

through chart review. Figure 4 shows survival curves by decade of

life. Th e cumulative diverticulitis probability was 4.3 % when using

a liberal defi nition not requiring CT scan confi rmation, and only

1 % when requiring CT scan or surgery to confi rm the diagnosis of

acute diverticulitis. For every additional decade of life, there was

a 24 % lower risk of diverticulitis (Hazard ratio = 0.66; P = 0.008).

In short, contrary to dogma that 25 % with diverticulosis develop

diverticulitis, we found an overall incidence of < 5 % over 11 years

of follow-up. However, younger patients had a considerably higher

diverticulitis incidence per year of life vs. older patients. Th ese

data question traditional perception about the rate of progression

from incidental diverticulosis to acute diverticulitis, but also sug-

gest that younger patients may harbor more risk of developing

diverticulitis.

Traditionally, diet has been regarded as a major risk factor for

diverticulosis as well as the progression to diverticular complica-

tions. However, recent data dispute many long-standing dietary

theories including that low dietary fi ber is associated with the

development of diverticulosis ( 44 – 46 ). and that nuts, corn, and

seeds provoke diverticulitis ( 43 ). Nonetheless, evidence from large

prospective cohort studies suggests that dietary fi ber intake and a

vegetarian diet in general may reduce the risk of diverticular com-

plications ( 42,47 ). Of other dietary components, red meat and fat


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indicate that even patients with uncomplicated diverticulosis have

lower HRQOL compared with the general population; the eff ect

is most pronounced for the pain, vitality, and emotional HRQOL

domains ( 11 ). Other research fi nds a higher incidence of anxiety

and depression in diverticulitis patients vs. controls ( 12 ).

It remains unknown whether ongoing symptoms aft er a diver-

ticulitis attack result from recurrent low-grade diverticulitis vs.

underlying IBS or other functional GI disorders. It may even be

possible that acute diverticulitis might uncover or precipitate

IBS symptoms — a model similar to post-infectious IBS where an

abrupt illness triggers long-standing symptoms. We performed a

survival analysis to compare the incidence of post-diverticulitis

IBS in patients with acute diverticulitis vs. age and sex-matched

controls seeking care for other conditions. Aft er excluding patients

with baseline IBS, we found that diverticulitis cases were 4.6 times

more likely to receive an IBS diagnosis over a 9-year follow-up vs.

non-diverticulitis controls (Hazard ratio = 4.6; 95 % CI = 1.6 – 13.6;

P = 0.005) ( 14 ). Th ese data corroborate previous cross-sectional

data by both Jung et al. ( 13 ) and Simpson et al. ( 14 ), both of whom

found a strong overlap between diverticulosis and IBS. Taken

together, these studies support the hypothesis that diverticuli-

tis might trigger long-term GI symptoms that persist outside of

acute attacks.

Th ese studies indicate that diverticular disease may contribute

to long-term emotional distress beyond the diverticulitis event

itself, and that diverticular disease may become a chronic disorder

in some patients — not merely an acute illness. Awareness of this

potential risk is important as comorbid depression and HRQOL

defi cits may worsen outcomes and increase cost. Despite this fi nd-

ing, diverticulosis guidelines do not make recommendations about

HRQOL assessments in clinical care ( 6,19,22,56 ); it is possible that

providers do not routinely consider HRQOL when assessing diver-

ticular patients, and that ongoing symptoms and illness impact

might fl y under the clinical radar in some patients.

have shown a positive although generally weak relationship with

diverticular disease ( 47 ). Smoking appears to be a particularly strong

risk factor for perforated diverticulitis ( 48,49 ). Several medica-

tions are also associated with an increased risk of diverticulitis and

diverticular bleeding including non-steroidal anti-infl ammatory

drugs ( 50,51 ), steroids ( 49 ), and opiate analgesics ( 49 ), while cal-

cium channel blockers ( 52 ) and statins ( 49 ) may have a protective

eff ect. Finally, physical inactivity and obesity are associated with

an increased risk of diverticulitis and diverticular bleeding

( 53 – 55 ). Nonetheless, the identifi cation of these potential risk

factors has not led to clinically useful means of identifying indi-

viduals at risk of diverticular complications or chronic diverticular

disease. Consequently, it is diffi cult to predict the natural his-

tory of diverticular disease in individual patients, and to prevent

diverticular complications.

New insights about chronic symptoms and quality of life Although there are extensive data regarding the management

and outcomes of acute diverticulitis attacks, as summarized in

the previous guidelines and reviews ( 6,19,22,56 ), there is surpris-

ingly little research evaluating life aft er the storm has cleared; the

inter-critical period of diverticular disease remains largely unex-

plored. However, if diverticular disease is truly a chronic medical

illness, then we would expect patients to have a persistently worse

HRQOL even in the period aft er an attack.

Evolving data suggest that the epidemiologic and economic bur-

den of diverticular disease is amplifi ed by its impact on HRQOL

resulting from physical, psychological, and social stressors engen-

dered by the disease and its treatment. For example, data from the

United Kingdom indicate that patients with diverticular disease

have a lower HRQOL than controls ( 10 ). Bolster and Papagrigori-

adis ( 10 ) found that diverticular disease is not only associated with

higher GI symptom severity, but also tracks with higher emotional

distress and impaired social functioning. Similarly, Italian data

Cumulative hazards0.12

Cum

ulat

ive

haza

rd

Months from diverticulosis

0.10

0.08

0.06

0.04

0.02

0.00

0 25 50 75 100 125

40Age 50 60 70

Figure 4 . Diverticulitis incidence in subjects with baseline asymptomatic diverticulosis found on screening colonoscopy stratifi ed by decade of life. The cumulative diverticulitis probability over 130 months was 4.3 % . For every additional decade of life, there was a 24 % lower risk of diverticulitis. Diverticulitis progression peaked at 11 % for 40-year-old patients.


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Treatment approaches for chronic symptoms and disease prophylaxis Because diverticular disease has generally been regarded as an

acute or episodic disorder, little is known about how best to man-

age its chronic manifestations. With an appreciation for the pos-

sible role of infl ammation and the intestinal microbiota, recent

studies have focused on the use of 5-ASA agents (mesalamine),

antibiotics, and probiotics in managing and preventing chronic

diverticular disease. Th ese newer treatments may extend our ther-

apeutic options beyond the traditional use of fi ber supplementa-

tion. Th e sections below review data for old and new treatments

for managing long-term symptoms and disease prophylaxis.

Fiber supplementation Despite the long-standing belief that fi ber is benefi cial in diverticu-

lar disease, the evidence is inconclusive. Recent studies call into

question low dietary fi ber as a primary risk factor for the develop-

ment of diverticulosis ( 44,57 ). It also remains unclear whether die-

tary interventions can modify the risk of subsequent complications

and symptoms ( 57 ). Early work in diverticular disease focused on

fi ber as a means to modulate colon motility and pressures and

thereby symptoms. Th ere are several, small, randomized controlled

trials that examined the use of fi ber in SUDD with mixed results

( 58 – 61 ). Th e largest trial followed 58 patients for 4 months and

found that fi ber improved constipation, but not other GI symp-

toms ( 58 ). More recently, investigators posited that in addition to

its potential eff ects on colon motility and pressure, fi ber may alter

the intestinal microbiota and infl ammation cascade, and therefore

be of benefi t in diverticular disease ( 62 ). Indeed, the strongest evi-

dence regarding fi ber comes from two large prospective trials that

found an inverse association between dietary fi ber and diverticuli-

tis or diverticular disease (relative risk of 0.6 for the highest intake

of fi ber compared with the lowest in both studies) ( 42,47 ). Addi-

tional work is needed to determine if fi ber is an eff ective therapy

for managing chronic diverticular disease, and to better evaluate

the role of fi ber in the development of diverticulosis.

Mesalamine (5-ASA) 5-ASA derivatives are primarily used as a fi rst-line therapy for

patients with IBD. Given their anti-infl ammatory properties,

these agents may be eff ective in managing the symptoms and

complications of chronic diverticular disease.

Th ere are many studies of varying quality that evaluate the effi -

cacy of mesalamine in the management of SUDD and recurrent

diverticulitis. Trepsi et al. ( 23 ) conducted an open-label rand-

omized trial of 166 patients with acute diverticulitis. Following the

initial treatment with antibiotic therapy, patients were randomized

to mesalamine 400 mg twice daily or placebo for 8 weeks and fol-

lowed for 4 years. Fift een percent in the mesalamine group had

symptomatic relapse vs. 46 % in the placebo group ( P = 0.0005). Th e

duration of abdominal pain was shorter in the mesalamine group

( P = 0.0002). Tursi et al. ( 63 ) randomized 40 patients with SUDD to

receive continuous (daily) vs. cyclic (10 days / month) mesalamine at

a dose of 1.6 g / day. Seventy-eight percent remained symptom free

on continuous therapy at 24 months vs. 56 % on cyclic treatment

( P < 0.005). Di Mario et al. ( 64 ) studied 170 patients with SUDD

randomized to variable doses of rifaximin or mesalamine taken

for 10 days / month. Each group demonstrated clinical improve-

ment except for those patients on low dose rifaxmin ( P < 0.0001).

Mesalamine 800 mg twice daily yielded the most signifi cant clinical

improvement at 3 months. A systematic review of 6 randomized

controlled trials and 818 patients with either uncomplicated acute

diverticulitis or SUDD found that mesalamine was signifi cantly

better in relieving symptoms and preventing recurrent diverticu-

litis than placebo, and that daily dosing was superior to cyclical

dosing ( 26 ). However, existing studies are heterogeneous and in

general of suboptimal quality.

In response to these limitations, there are a number of ongo-

ing multicenter double-blind placebo-controlled trials that may

help further clarify the confl icting evidence on the role of mesala-

mine in diverticular disease. For example, Kruis ( 65 ) is studying

the eff ect of mesalamine granules 3 g daily vs. placebo on recur-

rence of diverticulitis, GI symptoms, and quality of life in patients

with a prior episode of diverticulitis. Both Kamm and colleagues

( 66 ) and Raskin and colleagues ( 67 ) are examining variable-

dosage multimatrix mesalamine tablets on recurrence of diverticu-

litis and patient outcomes vs. placebo. Recently released prelimi-

nary data from Raskin and colleagues (PREVENT 2 trial) revealed

that the study did not meet its primary end point in reducing the

rate of diverticulitis recurrence over a 2-year period ( 68 ). How-

ever, the study focused on diverticulitis attacks rather than IBS-like

symptoms — it remains unknown whether the therapy may have

impacted chronic symptoms. We eagerly await the results of other

ongoing randomized trials.

Rifaximin Rifaximin, a poorly absorbed broad-spectrum antibiotic, holds

promise as a means to control symptoms and prevent recur-

rence in chronic diverticular disease perhaps through altering

gut microbiota. However, similarly to mesalamine, trials to date

have used an open-label design and oft en compared multiple

agents without a placebo arm; the true benefi ts of rifaximin in this

setting remain unclear.

Tursi et al. ( 31 ) enrolled 218 patients with recurrent diverticulitis

to receive rifaximin 400 mg b.i.d. for 7 days and then 7 days / month

with or without concomitant mesalamine (800 mg b.i.d.). At 1 year

follow-up, the combination treatment was superior to rifaximin

monotherapy in managing symptoms (86 % vs. 49 % , P < 0.0005),

normalizing bowel habits (79 % vs. 60 % , P < 0.0001), and preventing

recurrence (3 % vs. 18 % , P < 0.01). In a meta-analysis of four rand-

omized controlled trials, Bianchi et al. ( 69 ) calculated a number

needed to treat of 3 for rifaximin vs. placebo to achieve symptom

relief, and a number needed to treat of 59 to avoid a diverticular com-

plication. Additional studies evaluating mesalamine alone vs. com-

bination therapy with rifaximin are needed to further evaluate the

therapeutic role of these approaches in chronic diverticular disease.

Probiotics Probiotics, formulated from gut microorganisms, are used in

several GI disorders to modulate gut bacterial communities


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Strate et al.

Potential competing interests: Brennan Spiegel has served as an

advisor for Prometheus and Ironwood Pharmaceuticals, and has

received research support from Amgen, Ironwood Pharmaceuticals,

and Shire Pharmaceuticals. Lisa Strate has served as an advisor for

Shire Pharmaceuticals.

REFERENCES 1 . Everhart JE , Ruhl CE . Burden of digestive diseases in the United States part

II: lower gastrointestinal diseases . Gastroenterology 2009 ; 136 : 741 – 54 . 2 . Shaheen NJ , Hansen RA , Morgan DR et al. Th e burden of gastrointestinal

and liver diseases, 2006 . Am J Gastroenterol 2006 ; 101 : 2128 – 38 . 3 . Delvaux M . Diverticular disease of the colon in Europe: epidemiology,

impact on citizen health and prevention . Aliment Pharmacol Th er 2003 ; 18 (Suppl 3) : 71 – 4 .

4 . Everhart JE , Ruhl CE . Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas . Gastroenterology 2009 ; 136 : 1134 – 44 .

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6 . Stollman NH , Raskin JB . Diagnosis and management of diverticular disease of the colon in adults. Ad Hoc Practice Parameters Committee of the American College of Gastroenterology . Am J Gastroenterol 1999 ; 94 : 3110 – 21 .

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9 . Schmulson M , Chang L , Naliboff B et al. Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients . Am J Gastroenterol 2000 ; 95 : 152 – 6 .

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11 . Comparato G , Fanigliulo L , Aragona G et al. Quality of life in uncompli-cated symptomatic diverticular disease: is it another good reason for treatment? Dig Dis 2007 ; 25 : 252 – 9 .

12 . Humes DJ , Simpson J , Neal KR et al. Psychological and colonic factors in painful diverticulosis . Br J Surg 2008 ; 95 : 195 – 8 .

13 . Jung HK , Choung RS , Locke GR III et al. Diarrhea-predominant irritable bowel syndrome is associated with diverticular disease: a population-based study . Am J Gastroenterol 2010 ; 105 : 652 – 61 .

14 . Simpson J , Scholefi eld JH , Spiller RC . Origin of symptoms in diverticular disease . Br J Surg 2003 ; 90 : 899 – 908 .

15 . Cohen E , Fuller G , Bolus R et al. Evidence for Post-Diverticulitis Irritable Bowel Syndrome (PDV-IBS): longitudinal analysis reveals higher incidence of IBS in DV cases vs. controls. Digestive Disease Week, San Diego, California, 2012 .

16 . Clemens CH , Samsom M , Roelofs J et al. Colorectal visceral perception in diverticular disease . Gut 2004 ; 53 : 717 – 22 .

17 . Mulhall AM , Mahid SS , Petras RE et al. Diverticular disease associated with infl ammatory bowel disease-like colitis: a systematic review . Dis Colon Rectum 2009 ; 52 : 1072 – 9 .

18 . Peppercorn MA . Th e overlap of infl ammatory bowel disease and diverti-cular disease . J Clin Gastroenterol 2004 ; 38 : S8 – 10 .

19 . Wong WD , Wexner SD , Lowry A et al. Practice parameters for the treat-ment of sigmoid diverticulitis — supporting documentation. Th e Standards Task Force. Th e American Society of Colon and Rectal Surgeons . Dis Colon Rectum 2000 ; 43 : 290 – 7 .

20 . Surgical treatment of diverticulitis. Patient Care Committee of the Society for Surgery of the Alimentary Tract (SSAT) . J Gastrointest Surg 1999 ; 3 : 212 – 3 .

21 . Stollman NH , Raskin JB . Diverticular disease of the colon . J Clin Gastro-enterol 1999 ; 29 : 241 – 52 .

22 . Kohler L , Sauerland S , Neugebauer E . Diagnosis and treatment of diverti-cular disease: results of a consensus development conference. Th e Scientifi c Committee of the European Association for Endoscopic Surgery . Surg Endosc 1999 ; 13 : 430 – 6 .

23 . Trepsi E , Colla C , Panizza P et al. Th erapeutic and prophylactic role of mesalazine (5-ASA) in symptomatic diverticular disease of the large intestine. 4 year follow-up results . Minerva Gastroenterol Dietol 1999 ; 45 : 245 – 52 .

through production of antimicrobials, competitive interaction

with pro-infl ammatory organisms, and inhibition of pathogen

translocation. Th e role of a number of diff erent probiotics agents

in preventing recurrence of SUDD has been investigated in small

studies. Lamiki et al. ( 70 ) reported an open-label study of a mix-

ture containing Lactobacillus acidophilus and Bifi dobacterium spp.

in 46 patients with SUDD. During a 6-month follow-up, 70 % were

rendered symptom free; 77 % described the treatment as “ eff ective ”

or “ very eff ective. ” Serial stool studies and PCR revealed coloniza-

tion of the probiotics in 70 % of patients during the study.

In theory, the combination of probiotics with mesalamine would

simultaneously target infl ammation while seeking to correct dysbio-

sis. Tursi et al. ( 63 ) evaluated remission following diverticulitis attacks

in 30 patients treated with balsalazine plus VSL #3, a proprietary

mixture of probiotics, vs. VSL #3 alone. Th e authors found no statis-

tical diff erence in remission rates between groups over a 12-month

period, although symptom scores for constipation, pain, and bloating

were signifi cantly lower in the combination group ( P < 0.05).

Implications for current practice A growing body of knowledge is shift ing the paradigm of diver-

ticular disease from an acute surgical illness to a chronic bowel

disorder composed of recurrent abdominal symptoms and psy-

chosocial impact. Although there are standardized guidelines for

the management of acute diverticulitis, less is known about how

best to manage chronic bowel symptoms related to diverticular

disease. Current treatment is aimed at symptom relief. Greater

understanding of infl ammatory pathways and gut microbiota has

expanded therapy to include the use of probiotics, mesalamine,

and gut-directed antibiotics, although more research is neces-

sary to validate the safety, eff ectiveness, and cost-eff ectiveness of

these evolving interventions. Physicians should maintain a high

index of suspicion for the multifaceted presentations of divertic-

ular disease, and remain aware that it might contribute to long-

term emotional distress beyond traditional diverticulitis attacks.

Diverticular disease may become a chronic disorder in some

patients and is associated with psychosocial distress. Th e evolv-

ing research improves our understanding of how diverticular

disease impacts patients ’ long-standing HRQOL outside of acute

diverticulitis attacks, and may ultimately providers select manage-

ment approaches better tailored to each patient ’ s symptom profi le

and HRQOL decrement — the subject of future research as our

understanding of diverticular disease as a chronic medical illness

continues to evolve.

ACKNOWLEDGMENTS Th e opinions and assertions contained herein are the sole views of

the authors and are not to be construed as offi cial or as refl ecting

the views of the Department of Veteran Aff airs.

CONFLICT OF INTEREST Guarantor of the article: Brennan M.R. Spiegel, MD, MSHS.

Specifi c author contributions: Each author contributes to the

writing and editing of the manuscript.

Financial support: None.


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diverticular disease as a chronic illness: evolving epidemiologic and clinical insights

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