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ARTICLE IN PRESS+ModelGASTRO-884; No. of Pages 10Gastroenterol Hepatol. 2015;xxx(xx):xxx---xxx

www.elsevier.es/gastroenterologia

Gastroenterologa y Hepatologa

PROGRE

Colonic diverticular disease. Treatment and prevention

Carla J.

a Digestive b Aragon Hec Universityd CIBERehd,

Received 4

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PALABREnfermediverticuDiverticuTratamiePrevenciRifaximiMesalaziProbiotic

CorrespoE-mail ad

http://dx.d0210-5705/te this article in press as: Gargallo Puyuelo CJ, et al. Colonic diverticular disease. Treatment and prevention.terol Hepatol. 2015. http://dx.doi.org/10.1016/j.gastrohep.2015.03.010

Gargallo Puyueloa,b,, Federico Sopenaa,b,c,d, Angel Lanas Arbeloaa,b,c,d

Diseases Service, University Clinic Hospital Lozano Blesa, Zaragoza, Spainalth Research Institute (IIS Aragn), Zaragoza, Spain

of Zaragoza, Spain Zaragoza, Spain

February 2015; accepted 11 March 2015

RDSlar disease;litis;nt;on;n;ne;s

Abstract Diverticular disease represents the most common disease affecting the colon inthe Western world. Most cases remain asymptomatic, but some others will have symptomsor develop complications. The aims of treatment in symptomatic uncomplicated diverticulardisease are to prevent complications and reduce the frequency and intensity of symptoms.Fibre, probiotics, mesalazine, rifaximin and their combinations seem to be usually an effectivetherapy. In the uncomplicated diverticulitis, outpatient management is considered the optimalapproach in the majority of patients, and oral antibiotics remain the mainstay of treatment.Admission to hospital and intravenous antibiotic are recommended only when the patient isunable to intake food orally, affected by severe comorbidity or does not improve. However,inpatient management and intravenous antibiotics are necessary in complicated diverticulitis.The role of surgery is also changing. Most diverticulitis-associated abscesses can be treated withantibiotics and/or percutaneous drainage and emergency surgery is considered only in patientswith acute peritonitis. Finally, patient related factors, and not the number of recurrences, playthe most important role in selecting recipients of elective surgery to avoid recurrences. 2015 Elsevier Espaa, S.L.U. and AEEH y AEG. All rights reserved.

AS CLAVEdadlar;litis;nto;n;na;na;os

Enfermedad diverticular clica. Tratamiento y prevencin

Resumen La enfermedad diverticular es la enfermedad clica ms frecuente en el mundoOccidental. La mayora de los pacientes permanecern asintomticos a lo largo de su vida,pero un porcentaje no despreciable presentarn sntomas o desarrollarn complicaciones. Elobjetivo del tratamiento en la enfermedad diverticular no complicada sintomtica es prevenirlas complicaciones y reducir la frecuencia e intensidad de los sntomas. La bra, los probiticos,la mesalazina, la rifaximina y sus combinaciones parecen ser terapias ecaces. En la divertic-ulitis no complicada, el manejo extrahospitalario se considera actualmente el manejo ptimo,siendo los antibiticos administrados por va oral la piedra angular del tratamiento. El ingreso

nding author.dress: carlajerusalen@hotmail.com (C.J. Gargallo Puyuelo).

oi.org/10.1016/j.gastrohep.2015.03.010 2015 Elsevier Espaa, S.L.U. and AEEH y AEG. All rights reserved.SS IN ENDOSCOPY

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hospitalario solo ser necesario en pacientes con intolerancia oral, comorbilidad grave oausencia de mejora. Sin embargo, el manejo intrahospitalario es preciso en las diverticuli-tis complicadas. La mayora de los abscesos podrn ser tratados con antibiticos y/o drenajepercutneo, reservando la ciruga urgente para pacientes con peritonitis aguda. La indicacin deciruga electiva para prevencin de recurrencias debe ser indidualizada y no basarse nicamente

diver y AE

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r disease of the colon represents the most com-e affecting the large bowel in the Western world.ence of diverticular disease has increased overentury throughout the world, probably because

in lifestyle, such as smoking, overweight, andysical inactivity and low bre diet. The preva-ases with age, ranging from approximately 5% inger than 40 years of age to 50---70% among those

age or older; 80% of patients who present withis are 50 or older. Diverticula can present in num-litary to hundreds, they are typically 5---10 mm inut can exceed 2 cm in size. Diverticulosis occurs

the sigmoid and descending colon in more thanents, but may be prevalent in varying degrees in

the colon.1

re several diverticular-related terms that will this review. The presence of diverticula in thee absence of overt inammation is called diver-r uncomplicated diverticular disease (UDD). Itmptomatic or asymptomatic. The term acuteerticulitis (ACD) is used to describe inamma-e diverticula, which may or may not progressations (complicated ACD). There is also chronicis, because of recurrent diverticulitis or becauseelopment of a segmental colitis associated withcula. Summarily, the clinical spectrum of diver-ase is wide.on the natural history of the disease point oute majority of patients with diverticula (aboutemain asymptomatic throughout their life. Of

who develop symptoms, approximately 1/4 willhave an episode of symptomatic painful divertic-e without inammation, and up to 10---25% willpisode of ACD. About 1---2% will require hospi-nd 0.5% surgery. Diverticula are responsible for

ty (24---42%) of episodes of lower gastrointestinal-4

relatebiota, result See Fifamouexcessinsufintralutrude in theovergrto pertried ting divof UDDBased to preand porecentintakeepidemesis suemergan incinactiv

Theease (evidenbe a cneuroma chroa sensopmenora cfor lowthe fachronisic primThese phy, ate this article in press as: Gargallo Puyuelo CJ, et al. Colonic dterol Hepatol. 2015. http://dx.doi.org/10.1016/j.gastrohep.201

thology and symptom development

iverticulum is a herniation of mucosa and submu-sponding to a weak point where the vasa rectithe tunica muscularis. The pathogenetic mech-diverticular disease are still poorly understood,

is generally recognized that these are probably

nally, to sAs we m

ticulosis recomplicatiwe focus ondepend on foration, tbodys abilticulitis.G. Todos los derechos reservados.

complex interactions among diet, colonic micro-tic factors, colonic motility and structure thateir formation of colonic diverticula over time.5

. In 1971, Painter and Burkitt published theirothesis that diverticular disease was caused by

ssure in the colon due to segmentation based on intake of dietary bre. In response to increasedl pressure, outpouchings may develop and pro-eas of potential weakness.6 Stasis or obstructionow necked diverticulum may lead to bacterial

and local tissue ischaemia ultimately leadingion.7 Since then, numerous observational studiesmonstrate the possible effect of bre on prevent-ular disease. Most of them concluded that the risk

inversely associated with dietary bre intake.8---10

ese evidences, a high bre diet is recommended diverticular disease in most current guidelinesn papers.11---15 However, this hypothesis has beenallenged since: (1) the inverse association of brediverticulosis has been questioned in some recentgical studies16,17 and (2) new pathogenic hypoth-s the neuropathic and myopathic hypothesis are8---22 Other factors that have been associated withed risk of diverticular disease include physicalconstipation, obesity, and smoking.23---27

ciation between uncomplicated diverticular dis-) and symptoms is uncertain. There is someo suggest that painful diverticular disease maytion related to inammation and its effects onular function in the colon.22---28 The presence oflow-grade intestinal inammation would inducemotor dysfunction, leading to symptom devel-d/or persistence. Changes in intestinal micro

be one of the putative mechanisms responsiblede inammation. Bacterial overgrowth aided bystasis inside the diverticula could contribute to-grade inammation that sensitizes both intrin-

efferent and extrinsic primary afferent neurons.rations could lead to smooth muscle hypertro-creased sensitivity to abdominal distension, andiverticular disease. Treatment and prevention.5.03.010

ymptom development.3,22 See Fig. 1.entioned above, most people with colonic diver-main asymptomatic, but eventually can developons as ACD or diverticula bleeding. In this article

ACD. The clinical manifestation of this event willa number of factors, including the size of the per-he level of extracolonic contamination, and theity to contain this contamination.29,30

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ARTICLE IN PRESS+ModelGASTRO-884; No. of Pages 10Colonic diverticular disease 3

Geneticpredisposition Colonic motility

sis

EnvironmentalinfluencesDiet, microbiota Natural degenerationAltered receptor

sensitivity

Figure 1 latedcolon struc matoSource: Ada

Managem

Managem(UDD)

In patientsbe recommt in preveis no evide

There isymptomainal pain, by defecatare nauseaof patientstherapeutiwill becomdevelop co

Five agFig. 2):

A) High bSeveral ranventional sUDD, but is recommtomatic UDthe curren

B) AntibiotThe rationUDD is notchanges in

ontrtionn ordcrobal ris

mos

in. withecreaFecal impactionmicroperforation

Postinflammatoryhypersensitivity

Chronic symptomsPain, diarrhea, constipation

Development of diverticulo

Diverticulitis

Symptoms development in diverticular disease is probably reture, intestinal motility low grade inammation and postinampted from Humes and Spiller.3

ent of diverticular disease

ent of uncomplicated diverticular disease

with asymptomatic UDD,2 a high bre diet mayended because of its possible prophylactic bene-nting symptomatic UDD and complications. Therence that other drugs are useful in these patients.

could cproduction. Iantimiminimbe theposed.Rifaximlogue may dte this article in press as: Gargallo Puyuelo CJ, et al. Colonic dterol Hepatol. 2015. http://dx.doi.org/10.1016/j.gastrohep.201

s more evidence on the benet of treatment intic UDD. The most frequent symptom is abdom-which may be exacerbated by eating and easedion or the passage of atus. Other symptoms, diarrhoea, constipation and bloating. Over 61%

with symptomatic UDD who are not taking anyc measure to prevent recurrence of symptomse symptomatic within 1 year, and about 4% willmplications.31

ents have been proposed for treatment (see

er diet or bulking agentsdomized controlled trials (RCT) and other inter-tudies evaluate the effect of bre in symptomaticwith inconsistent results.32---37 In any rate, breended in the prevention and treatment of symp-D, as well as in the prevention of ACD by most oft guidelines and position papers.11---15

ic therapyale for the use of antibiotics in symptomatic

clearly established. Recent studies suggest that gut microbiota (intestinal bacterial overgrowth)

faecal masThis antibprole.33,38

non-entericand the ristwo doubleof cyclic asymptoms and two meconcluded ing symptoof patientscompared The numbeplacebo to Summary, tbination of1 week eve

C) ProbiotiProbiotics asal gut odisease duCircular/longitudinalmuscle thickening

to complex interactions among genetic features,ry hypersensitivity.

ibute to symptoms development due to excessive of bowel gas through carbohydrate fermenta-er to avoid systematic effects, poorly absorbedials that act against enteric pathogens but havek of systematic toxicity or side effects seem tot appropriate antibiotics. Rifaximin has been pro-

Rifaximin is a non-systematic rifamycin ana- a broad spectrum of activity in vitro. Rifaximinse metabolic activity of bowel ora, increasingiverticular disease. Treatment and prevention.5.03.010

s, and may also eradicate bacterial overgrowth.iotic has a high safety and high tolerabilityPlasma level of rifaximin is minimum, therefore

pathogens are not exposed to selective pressurek of bacterial resistance is low.39 Three open and

blind RCTs40---44 have examined the effectivenessdministration of rifaximin and bre in reducingcompared with bre alone. A systematic reviewta-analysis have analysed these trials.44---46 Theythat combined treatment is effective in obtain-m relief at 1 year in patients with UDD. 35%

treated with bre alone were asymptomaticwith 64% in groups of combined treatment.r needed to treat was three for rifaximin vs.relieve symptom and nine to avoid complications.he best results have been obtained using a com-

soluble bre, such as glucomannan, and rifaximinry month.

csre live microorganisms that can restore commen-ra that may have been altered in diverticulare to stasis and reduced colonic transit time.47

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High fiber diet Lower the intraluminal pressure Prevent formation of additional diverticula

fr

Decrease metabolic activity of instinalbacterial flora

Mechanisms of action

r dis

Unfortunatuse in symand unconimproveme

Probioti5-aminosalducted thror combinappeared tUDD but thRCT publisboth cyclicparticularlfor maintasummary, tnot allow d

D) 5-ASA: MesalazineIn 2010, Greview thadiverticulabe effectieveryday mto preventnecessary placebo-coeffective iUDD.56 Alsa benet fon prevent

intaitic L

ichopermUncomplicateddiverticular

disease

Rifaximin

Probiotic

Mesalazine Mechanisms of action

Mechanisms of action

Mechanisms of action

Figure 2 Treatment of uncomplicated diverticula

ely, there are few data available about itsptomatic UDD and most of studies are smalltrolled. The majority of them show symptomsnt.48---50

cs have also studied in combination withicylate (5-ASA). Tursi and colleagues have con-

in maprobio

E) AntThe hite this article in press as: Gargallo Puyuelo CJ, et al. Colonic dterol Hepatol. 2015. http://dx.doi.org/10.1016/j.gastrohep.201

ee RCTs comparing 5-ASA alone, probiotic aloneation therapy.51---53 Both 5-ASA and probioticso be effective for the prevention of symptomaticeir combination was better. A recent double-bindhed by this same scientic group concluded that

mesalazine and Lactobacillus casei subsp DG,y in combination, seem to be better than placeboining remission of symptomatic UDD.54 But, inhe poor study designs and small size of them doenitive conclusions.

mesalazine has anti-inammatory and antioxidant effects.atta et al.,55 published a Cochrane systematict evaluated the role of 5-ASA in patients withr disease. Authors concluded that 5-ASA mayve in the treatment of this disease and thatesalazine was better than cyclic administration

relapse. High quality well-designed RCTs areto conrm their observations. In fact, the rstntrolled double-blind trial found mesalazinen obtaining pain relief in patients with acuteo, there are two interesting RCTs that showedor mesalazine compared with rifaximin in termsing symptomatic recurrence and similar success

antispasmomight imprtion. But, t

F) Avoid NSeveral corisk factor ration anddevelop sy(RR: 1.5, Ccated divercompared tthis increaimpaired btranslocati

G) Levels oIt seems twith geogrMaguire et ies that shUV light extus) are aMore high recommenInhibition factors of inflammatory cascade andee redicalsAntioxidant effect

Decrease hydrogen and methane production Increase fecal mass Erradication of bacterial overgrowht

Competitive metabolic interations with pro-inflammatory organism Inhibiton of adherence and traslocaton ofpathogens Block activation of pro-inflammatorymolecules Inmunomodulation (innate and adaptative) Metabolic changes

ease. Mechanisms of action.

ning long-term remission compared with theactobacillus casei.53,57

linergic/antiespasmodic agentsotility of the colon in diverticulosis suggests thaniverticular disease. Treatment and prevention.5.03.010

dic agents such as dicyclomine and hyoscyamineove symptoms by decreasing muscular contrac-here are no RCTs that conrm this benet.

SAIDs treatmentntrolled studies have shown that NSAIDs are afor the development of symptoms, ACD, perfo-

bleeding.7,58---60 NSAID users have more risk tomptomatic diverticular diseases than non-usersI 95%: 1.1---2.1).58 And in patients with compli-ticular diseases there was a larger use of NSAIDso controls without disease. It was postulated thatsed risk was due to mucosal damage resulting inarrier function of the colonic mucosa allowingon of bacteria, which provoke inammation.

f vitamin Dhat the incidence of ACD has been associatedaphic and seasonal variation. Because of that,al. conducted two interesting observational stud-owed that lower levels of vitamin D and lowposure (UV exposure determines vitamin D sta-ssociated with signicantly higher risk of ACD.quality studies are necessary before making adation.61,62

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Acute colonic diverticulitis (ACD)

cm) : ivB plus

ey Ib

ute c

Treatmen

Although mtomatic, itdevelop annosis is notare indicatwithout sigin lower lC reactivediagnosis.6

tional strafollowed bis inconclutive approa50%. In 197which was ACD; stagecolic inamthe primaror retroperinammatistage IV, fa

TreatmentThe majorconservativOutpatientthe healthria for inp(include poral uids,severe combe sufcieinuencedusually rec

One of of uncompA recent

o msupprecoore,le. Pgns aemd retics

cepe, gn ofresced,

othantanou, client.tic

foodprovUcomplicated (ACD)

Inmunocompromised patient? Signs of generalized infection? Affected general condition? Severe comorbidity? Advanced age?

Small abcesses (50 mg/l, may be sufcient for the4,65 If imaging is indicated, probably, a condi-tegy with ultrasound as rst line technique andy computerized tomography (CT), if ultrasoundsive or doubtful, may represent the most effec-ch. The number of CT exams may be reduced by8, Hinchey et al. proposed a classication of ACD,modied later.66,67 It distinguishes ve stages of

0, clinically mild diverticulitis, stage I (a: peri-mation and b: abcess

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considered standard therapy for these patients. The choiceof operation is inuenced by patient conditions, operativendings and the surgeons experience. In critically illpatients with haemodynamic instability, Hartmanns proce-dure is recommended. However, in haemodynamically stablepatients, pcal diversio

Traditioendoscopy tal cancer.opinions. Rreview75---80

rather low.tive stratepatients wcious CT recommen

Managem

PreventionAfter one eACD, and aanother attreatment new episodA) High bhigh bre drences. Buhas had inatic reviewthat investACD.26,81 Scally avoiddiverticulutive study ACD. Thereshould be cessation opreventionB) Antibiotthat assessrence of ACa pathophyineffectivebe that a cyrial populapopulationimin. Howecyclic rifaxods of rem10.4% of paalone. Mora higher risBut, furtherecommensupport theC) Probiotirole of procari et al.of Lactoba

post diverticulitis colon stenosis. 88% of patients remainedasymptomatic for a period of 12 months.87 This observa-tional study was the rst that suggested a possible roleof probiotics in this setting. A more recent study evalu-ated combined treatment; balsalazide and VSL#3 (an eight

s pro com

3% ontics ut wSA.

ed thnfor

salaz et aal pNT2)cebotreatral d ontienor toery.

nded of cby rsed ant t risms.ent enigpse erm ( 0.05).52 In summary,seem to be effective in preventing recurrence ofell designed studies are lacking.

Several double-blind and open RCTs havee role of mesalazine in preventing recurrence oftunately most of them have not found a benetine over placebo in preventing recurrence.88---90

l. have recently published two interesting andhase 3 double-blind, placebo RCTs (PREVENT1 and

that also show that mesalazine is not superior in preventing recurrent ACD.91 Also the com-ment, 5-ASA plus rifaximin, has been evaluatedstudies. Trivedi and Das reviewed data from vee open-labelled study, collectively involving overts, and concluded that combination seems to be

rifaximin alone for preventing recurrent ACD.92

Until a few years ago elective surgery was rec- after two attacks of uncomplicated ACD or oneomplicated ACD to reduce morbidity and mor-ecurrence. But elective surgery also carries anrisk of morbi-mortality.93 Because of that, it isto weigh morbidity and mortality due to surgeryk of complicated recurrences and severity of

data show that natural history of ACD is muchn that thought in the past.73,94 The long term riskis more lower than previously believed, and therisks of subsequent emergency surgery (3---7%),) and stoma formation (0---4%) are also quite low.ence of multiple episodes did not increase the riskmplications. In 2009, Pittet et al.95 showed thats with rst ACD were urgent operated compared

in relapsing cases, and that the 30-day mortal- episode was also higher compared to recurrent

vs. 0%). As a matter of fact, the majority ofesenting with complicated ACD lack a history of.96 It is also proposed that recurrent ACD may pro-t perforation, possibly due to adhesion formationinammation.95 Therefore, a policy of electiveer ACD does not decrease the likelihood of fur-y (up to 3%) and does not fully protect against. On the other hand, improved diagnostics andmodalities have reduced the morbi-mortality ofd ACD. Because of these new data, The AmericanColon and Rectum Surgeons in their most recentecommend that elective sigmoid resection afterom ACD should be made on a case-by-case basis14

er that the number of previous episodes is not aator for the selection of candidates to electiveysicians should consider the medical condition

the patient, the frequency and severity of thend the presence of persistent symptoms after thede.14

y difcult to anticipate which cases of ACD will graded severity of rst episode of ACD seems to

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be a predictor of an adverse natural history. Left side ACD,>5 cm of colon involved and a retroperitoneal abscess werepredictors of recurrence and must be taken into account.97

There is no consensus regarding whether young age (

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ieJ.

36. Pain19

37. Plea

38. Scot20

39. PiRiw

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41. PaoncoSt

42. PatrA Ph

43. LaMca20

44. Droin20

45. Lacoto

46. BietmPh

47. Nam20

48. Frinco

49. Anofsytic20

50. Laetla

51. Tuansioco

52. TBainpl20iverticular disease. Treatment and prevention.5.03.010

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Colonic diverticular disease. Treatment and preventionIntroductionPhysiopathology and symptom developmentManagement of diverticular diseaseManagement of uncomplicated diverticular disease (UDD)A) High fiber diet or bulking agentsB) Antibiotic therapyRifaximin

C) ProbioticsD) 5-ASA: mesalazineE) Anticholinergic/antiespasmodic agentsF) Avoid NSAIDs treatmentG) Levels of vitamin D

Treatment of acute colonic diverticulitis (ACD)Treatment of uncomplicated ACD (Hinchey stage 0 or Ia)Treatment of complicated ACD (Hinchey stage Ib to IV)ACD Hinchey Ib or II: abcessACD Hinchey III or IV: purulent or faecal peritonitis

Management following an episode of ACDPrevention of recurrent ACDA) High fiber dietB) AntibioticsC) ProbioticsD) 5-ASAE) Surgery

Treatment of sequelaeA) FistulaB) Obstruction

Management of segmental colitis associated with diverticulosis

ConclusionsAuthors contributionsConflict of interestReferences