Presentation on theme: "New Approaches to Diverticulosis and Diverticulitis Management"— Presentation transcript:
1New Approaches to Diverticulosis and Diverticulitis Management Neil Stollman MD, FACGChairman, Department of MedicineAlta Bates Summit Medical CenterOakland, CAAssociate Clinical Professor of MedicineUniversity of California San FranciscoSan Francisco, CA
2Outline Epidemiology Anatomy / Etiology Fiber as risk factor for DD (Diverticular Disease)Fiber as treatment for DDOther risk factors: nuts/seeds?SUDD: a new paradigm of chronic DD?Diverticulitis: 5-ASA, antibiotics, probioticsSurgical timing change?Diverticular Bleeding
3Let’s Play: Separated at birth? Example: “Teenage Mutant Ninja tic?”
4EpidemiologyTrue incidence difficult to measure as most patients asymptomaticNo sex predilection generally“Disease of Western Civilization”Rare in rural Africa & Asia, common in US, Europe, AustraliaJapanese migrating to Hawaii have rate intermediate b/w native Japanese and mainland born, suggesting ‘westernization’ of colon.
5Prevalence increasing over time (worldwide) Jun S, Stollman N. Epidemiology of Diverticular Disease. Ballieres Clin Gastroenterol 2003
6Epidemiology: Increasing over time (US) Nationwide inpatient sample (NIS) data (HCUP)26% increase in admissions82% increase in ages 18-4429% increase in surgeries73% increase in ages 18-44M>F for patients <45 yearsF>M for patients >45 yearsLower rates in west, c/w rest of country (?diet, ?obesity)Etzioni DA et al. Ann Surg 2009;249:210-17Nguyen GC et al. World J Gastroenterol 2011;28:1600-5
7Pathologic Anatomy I Typically arise in 2 or 4 parallel rows: Along the mesenteric sides of the anti-mesenteric taenia and along both sides of the mesenteric taeniaCorresponds to sites of arterial penetration through smooth musclePseudo-diverticula in that mucosa and submucosa herniate through the muscle, but tic does not include all layers of wall.
8Diverticula form at sites of vascular penetration
9Pathologic Anatomy II Western individuals: Asian individuals: 90% left-sided 15% right-sidedAsian individuals:25% left-sided 75% right-sidedVary in number from solitary to hundredsTypically 5-10mm in diameter, although ‘giant’ diverticula described.
13Etiology / Pathogenesis I Colonic Wall Resistance No evidence that atherosclerosis or venous changes predispose>200% increase in elastin deposition, laid down in contracted form, Þ shortening of taenia and bunching of circular musclePrecocious diverticulosis occurs in patients with connective tissue disorders (Ehlers-Danlos, Marfan’s)
14Etiology / Pathogenesis II Disordered Motility Ý resting, post-prandial, & neostigmine-induced luminal pressures demonstrated in patients with tics vs. controls withoutSymptomatic pts have higher motility indices than asymptomatic patientsHigher right-sided pressures seen in Asian patients with right-sided diverticulaWynne-Jones: westernized urban lifestyle “impermissive of flatus” air retention increased intraluminal pressures & tic formation (Lancet 1975;2:211-12)
15Etiology / Pathogenesis III: Painter’s “Little Bladders” Theory: Simultaneous manometry & cineradiography.Contractions by haustra cause ‘segmentation’ in which colon is not continuous tube but series of discrete ‘little bladders’, which can attain ‘locally’ high pressures, favoring herniation.Might have physiologic role in delaying transit and augmenting water reabsorption.Western diet may enhance this occurrence.
16Etiology IV: Fiber as RISK FACTOR for DD Historically, felt to be ‘fiber deficiency’ diseaseWorldwide striking geographic correlation with low dietary fiber intake (eg Africans with high fiber diet less DD c/w British with lower fiber intake)Develops in the west after the introduction of millingHumans & domesticated animals on low-fiber diets are only species to develop diverticulaSuggest preventable and/or correctable by ↑ fiberProblems: assumes uniform diets within population, uncontrolled for other confounding factors such as lifespan
17Etiology: dietary fiber Stool weights & transit times (n=1200)UK patients: western low-fiber dietRural Ugandans: high fiber dietTransit time WeightUK 80 hours 110 gm/dUgandans hours 450 gm/dPainter NS, Burkitt DP. Br Med J 1971;2:450–54
18Etiology: dietary fiber Ý transit-times & ß stool volume may Ý intraluminal pressures and lead to diverticulaSupported by rats fed diets of varying fiber content over natural lifespan:Low-fiber diet: 45% developed diverticulaHigh-fiber diet: 9% developed diverticulaHistologically similar to human diverticula, but mainly right-sided
19Fiber as RISK FACTOR for developing DD Cross section study of >2000 screening colonoscopies, years old, captured dietary / lifestyle info42% overall had diverticulosis, increasing with ageFiber intake: highest quartile vs lowest:prevalence ratio for diverticulosis: 1.3 ( )BMs: >15/week vs <7/weekprevalence ratio for diverticulosis: 1.7 ( )Physical activity, fat or red meat intake: no association“Hypotheses regarding risk factors for asymptomatic diverticular disease should be reconsidered”Peery AF et al. Gastroenterology 2012;142:266-72
20Peery: Limitations Diet history taken after pts told they had DD Possible recall bias if aware of fiber/DD hypothesisDietary hx one year only, lifetime intake most relevant (is current diet reflective of lifelong habits?)Perhaps instructed to take fiber from prior dxPerhaps taking more fiber because having symptomsEven if accurate, data do not undermine possible benefit of fiber in Rx of symptomatic DD
21Fiber: risk for Sxs or complications? 2 large prospective cohort studies have shown inverse relationship b/w fiber intake and diverticular complicationsHPFU study, >43K men, US, , no prior colonic dzRR for symptomatic disease in highest vs lowest fiber groups = 0.63 ( ) (insoluble fiber, esp cellulose)EPIC Oxford Study, 47K M & F, UK, 12 year f/u812 cases (806 hospitalizations, 6 deaths)Adjusted Relative RiskHighest vs lowest fiber intake: ( )Vegetarians vs meat eaters: ( )Aldoori WH et al. J Nutr 1998;128:714-19Crowe FL et al. BMJ 2011;343:
22Does Evidence Support a Restriction on Nuts, Corn, and Popcorn? ACG Practice Guidelines 19991“Controlled studies that support this belief are lacking….no role for ‘elimination’ diet”Strate et al [US Health Professionals Study follow-up]47,000 men free of DD on entry, followed 18 years801 incident cases of diverticulitisHazard ratio for highest vs lowest consumptionNuts: (0.63 – 1.01), P = 0.04Popcorn: (0.56 – 0.92), P = 0.007Not only ‘no association’ but nuts and popcorn may actually have inverse / protective effectMODIFIED1. 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 Nov;94(11):2. Strate LL, Liu YL, Syngal S, Aldoori WH, Giovannucci, EL. Nut, corn and popcorn consumption and the incidence of diverticular disease. JAMA August 27; 300(8): 907–914.EDITED SOME ABOVE1. Stollman NH, Raskin JB. Am J Gastroenterol. 1999;94(11):3110.2. Strate LL et al. JAMA. 2008;300(8):907.
24Natural HistoryMajority of patients (+/-80%) will never have symptomatic diseaseSerial barium studies reveal that disorder is generally not progressive, ie. pattern develops early and remains fairly static.
25Rate of progression to AD in incidentally found diverticulosis? Risk of AD widely quoted at 15-25% in reviews, texts and ACG guidelines. Based on older data when true denominator unknownRetrospective review LA-VAMC2127 pts with baseline diverticulosis (97% men)130 month follow up:Liberal criteria dx AD: 4.3%Strict criteria dx AD: 1.0% (CT or surgery confirmed)Risk highest in younger patientsLikely lower than we’ve thoughtShahedi K et al. DDW 2012, Plenary Presentation, #847
26SUDD: a new paradigm?We’ve historically thought of DD as all or none, (asymptomatic or complicated) but now conceptualizing a “middle ground” of SUDD (Symptomatic Uncomplicated Diverticular Disease), and evidence accumulating demonstrating subclinical inflammation in such patientsPossible mechanisms:Inflammatory damage to enteric nerves (and aberrant re-innervation leading to hypersensitivity, enhanced afferent response to stimuli)Altered neuropeptidesSubacute obstruction secondary to fibrotic reactionMuscle hypertrophy with increased intraluminal pressure
27Predicting recurrent pain / SUDD 261 patients with diverticulosis on barium enema136 provided bowel / psych symptoms170 eligible for follow upExcluded 91Deceased 61Declined FU 21Misc 9Recurrent pain 45Asymptomatic 79Pain 422715Pain free186419992006Those with recurrent pain more likely to have history of diverticulitis (prolonged pain / antibiotics) more likely to be anxious HAD > 7 and had a higher PHQ15 scoreHumes et al. British Journal of Surgery. 2008;95:
28SUDD: Association between symptoms & postprandial contractions 30 healthy volunteers115 patients with colonic diverticula30 asymptomatic (ADD)30 symptomatic uncomplicated (SUDD)55 symptomatic complicated (SCDD)Cortesini et al Dis Colon Rectum 1991;34(4):339-42
29Increased expression of galanin & tachykinins in SUDD Prospective studyDetailed bowel symptom questionnaire17 symptomatic15 asymptomatic DD ptsUnprepared flexible sigmoidoscopyMucosal biopsy peridiverticular & rectalNormal appearance on routine histologyNo evidence of inflammationSimpson et al Neurogastroenterol Motil 2009;21:
30Inflammation in DDFecal calprotectin (FC) levels in healthy controls, IBS pts, asymptomatic DD, SUDD, acute diverticulitis (AD)FC values normal in healthy controls, IBS & asymptomatic DD; higher in SUDD and ADFC levels correlated with inflammatory infiltrateFC levels decreased with Rx in AD and SUDDTursi A, et al. Int J Colorectal Dis 2009;24:49-55
31Visceral hypersensitivity in SUDD Rectal barostat study in healthy volunteers (HV), asymptomatic DD (DDA) and symptomatic DD (DDS)P<0.002DDS vs DDANo difference in compliance All groups showed increase in tone postprandially both is rectum and sigmoidColonoscopy study showed pain related to looping except in DDHumes et al Neurogastroenterol Motil 2012;24:318-e163
32Post – diverticulitis IBS? Retrospective review of 1102 pts LAVAMC with AD b/w 1996 and 2011, without prior Dx of IBS (96% men, mean 64 years)Hazard Ratio for subsequent Dx IBS or FBD =4.6 ( , P=0.005)Supports hypothesis that AD might trigger long-term IBS/functional GI SxsCohen ER et al. DDW 2012, abstract 1363
33Emerging Treatments for SUDD If there is indeed a symptomatic state of DD marked by low-grade inflammation, and/or visceral hypersensitivity and/or abnormal motor function, can we intervene in such patients?Historically, we’ve prescribed fiber or anti-spasmodics, although data in support is weak? Antibiotics, ? Anti-inflammatories, ? Probiotics
36Mesalamine in DDAt least 6 Italian studies have evaluated 5-ASA either after acute diverticulitis (3) or in SUDD (3)Generally favorable resultsDaily superior to cyclicBut data very heterogeneousNot double blinded, not placebo controlledSubjective endpointsDose / regimen unclear
37DIVA Trial 12 week Rx with 40 week additional f/u (52 week total) 52 week, randomized, multi-center, double-blind, double-dummy, placebo-controlled, proof-of-concept study (first in US)Required CT scan confirmed acute diverticulitis, excluded IBS DxPatients randomized to:Standard care (abx, dietary advice as per local MD)Standard care, plus mesalamine 2.4gm QDStandard care, plus mesalamine 2.4gm QD plus B. infantis QD (after Abx completed)12 week Rx with 40 week additional f/u (52 week total)Stollman N et al. American College of Gastroenterology 2010 Annual Scientific Meeting (ACG 2010). Abstract 49. Accepted Journal Clinical Gastroenterology, publication pending
38Median Global Symptom Score All results NS vs placebo
39Global Symptom Score Responders # Significant difference vs. placebo###Responder = score of 0 or 1 for all symptoms
40Recurrent Diverticulitis (ITT) PLACEBO(n=41)5-ASA(n=40)5-ASA + Probiotic (n=36)Withdrew due to surgery1 (2.4%)2 (5.0%)0 (0%)Recurrent Diverticulitis8 (20%)5 (12.5%)4 (11.8%)-Secondary Endpoints only, study not powered for this-Recurrent Diverticulitis diagnosed by patient and physician assessment, without CT scan documentation-No statistical significance for any comparisons
41DIVA ConclusionsTreatment with mesalamine after an attack of CT-confirmed acute diverticulitis led to:Lower (but NS) GSS at all time pointsSignificant increase in responders (GSS=0 or 1) at some (but not all) time pointsNo effect on recurrence rates or surrogate markersLimitations: relatively underpowered, short treatment duration, GSS not validated previously, probiotic / mesalamine interaction?
42PREVENT: MMX Mesalamine in Recurrent Diverticulitis (Shire, Lialda) Two identical Phase III RCTsPREVENT 1 and 2: both worldwideIntended 590 pts enrolled each, both completed enrollmentMesalamine 1.2, 2.4, 4.8 gm/day vs placebo, 2 year follow-upPress Release 3/30/12: “PREVENT 2 did not meet the primary endpoint in reducing the rate of recurrence of diverticulitis over a 2-year treatment period. In addition, mesalamine did not show a significant difference compared to placebo on the key secondary endpoint of the study…..Although the results of the second trial are pending, it is our current intention not to pursue a regulatory filing for this indication for MMX® mesalamine.”
43Other Mesalamine Trials Dr. Falk Pharma, Mesalazine, GermanyMesalazine Granules vs. Placebo for the Prevention of Recurrence of Diverticulitis“Terminated” according to clinicaltrials.govTwo Doses Mesalazine Granules Versus Placebo for the Prevention of Recurrence of Diverticulitis“currently recruiting”Conclusions still unclear as to role of 5-ASA in DD, but reasonable for challenging cases
44Probiotics for Diverticulitis ProtocolDD StageFollow up (N)OutcomeE. Coli Nissle plus antibiotic plus active charcoal1SUDD2.4 (15)Prolonged remission period, improved symptomsL. casei, 5-ASA, or both212 mos (90)Increased remission rateL. casei plus 5-ASA324 mos (75)VSL#3 plus balsalazide42 mos (30)Improved symptomsL. Acidophilus plus L. helviticus plus Bifidobacterium56 mos (45)Prevented recurrence, improved symptomsB. infantis6AD12 mos (40)No effect + 5-ASAOne study compared an antibiotic/active charcoal to an antibiotic/active charcoal/probiotic (E. coli, Nissle strain) regimen. The addition of the probiotic produced longer intervals of disease quiescence and a greater degree of symptom relief than the antibiotic/absorbent regimen alone [Fric 2003]. The second study investigated the efficacy of Lactobacillus casei DG in combination with mesalamine in patients with symptomatic uncomplicated diverticular disease that was in remission. [Tursi 2006] The third study evaluated a high-potency probiotic in combination with balsalazide. in patients with acute uncomplicated diverticulitis in remission, respectively. [Tursi 2007] In both studies, the probiotic/5‑ASA combination was associated with greater symptom improvement and fewer relapses compared to the 5-ASA regimen. [Tursi 2006]1. Fric P, Zavoral M. Eur J Gastroenterol Hepatol. 2003;15: ; 2. Tursi A et al. J Clin Gastroenterol. 2006;40: ;3. Tursi A et al. Hepatogastroenterology. 2008;55: ; 4. Tursi A et al. Int J Colorectal Dis. 2007;22:5. Lamiki P et al. J Gastrointestin Liver Dis. 2010;19: Stollman N et al. ACG 2010 Annual Scientific Meeting Abstract 49
45Can we prevent diverticular complications? Many studies have implicated ASA and NSAIDs but small and non-detailedFollow up of US Health Professionals study; >45K men, followed since 1986Relative Risk Diverticulitis Div Bleeding-ASA >2x/wk-NSAID >2x/wkStrate L et al. Gastroenterology 2011; 140: 1427.
47Complicated diverticulosis Diverticulitis Inflammation and/or infection associated w/ diverticulaAffects 15-20% of patients with diverticula450,000 US admissions / year2 million outpatient visits US / yearGenerally the result of perforation of a single diverticulum, probably due to obstruction by inspissated stool.Bacteria breach mucosa, extend process through wall, and cause (often limited) perforation.
49Complicated diverticulosis Diverticulitis – Clinical Features Pain and tenderness, usually LLQ, but in Asians or those with redundant sigmoids, can be RLQ or suprapubic.Altered bowel habitsAnorexia, nausea, vomitingHematochezia rareDysuria: sympathetic cystitisFever common; shock or hypotension unusualÝ WBC common; no other labs routinely usefulDifferential DiagnosisAcute AppendicitisCrohn’s DiseaseColonic carcinomaPseudomembranous or ischemic colitisOvarian cyst / abscess / torsionEctopic pregnancy
50Complicated diverticulosis Diverticulitis - Diagnostic Modalities CT scanning - most accurateAbd & Pelvic scans; oral / rectal / IV contrastFindings: pericolic infiltration of fatty tissues, wall thickening, abscessSensitivity and Specificity: 85-95%Severe disease predicts complications and poor prognosis.
52Complicated diverticulosis Diverticulitis - Treatment I Determine need for hospitalization:Mild sxs, no peritoneal signs, tolerating POs, & supportive home networks may be candidates for outpatient Rx.Elderly, immunosuppressed, comorbid illness, or evidence of severe disease (high WBC or fevers): inpatient Rx.
53Complicated diverticulosis Diverticulitis - Treatment II Antibiotics: cover gut organisms (eg GNRs & anaerobes, esp E. coli and bacteroides)Little data to guide choice.Oral: consider T/S or cipro plus flagyl, Single agent: AugmentinIV: aminoglycoside/aztreonam/3rd gen ceph plus metronidazole or clindamycin. Single agents: Unasyn, Timentin, Cefoxitin.Sxs should ß w/in 2-3 days, advance diet.Continue Rx for 7-10 days
54Complicated diverticulosis Diverticulitis - Treatment III Inpatients: NPO, IVF, IV AbxConsider: Gram(-) coverage with aminoglycoside/aztreonam/3rd gen ceph plus metronidazole or clindamycin. Reasonable single agents: Unasyn, Timentin, Cefoxitin.Expect improvement in in 2-4 days, then advance diet; outpatient Abx X7-10 days.
55Complicated diverticulosis Diverticulitis - Treatment Outcome I Majority will respond to medical Rx; up to 25% will require surgery during admission.For those who respond, a complete colonic evaluation is required after resolution of clinically diagnosed case, to exclude other diagnoses, such as CA.Surgery to prevent recurrence?
56When to consider surgery? Prior guidelines, including ASCRS and ACG recommended ‘considering’ prophylactic surgical resection after 2nd attackMost recent ASCRS recommendations1“The number of attacks of uncomplicated diverticulitis is not necessarily an overriding factor in defining the appropriateness of surgery.”Advocate a case-by-case individualized approachMarkov Model (WA State database)2Colectomy after fourth (rather than 2nd) episode → 0.5% fewer deaths and saved $1,035/patient.Expectant management through 3 recurrent episodes with colectomy after the 4th was the dominant strategy across the variables tested in the sensitivity analysis1. Rafferty J et al. Dis Colon Rectum. 2006;49: Salem L et al. J Am Coll Surg 2004;199:904-12
57Recurrence is infrequent and not more complicated No surgery7% (n=178) had elective colectomy, typically young or had abscess13% (n=314)Recurrence<2% per yearYounger age had slightly higher risk1st recurrence predicted re-recurrenceAll re- recurrences treated non-operatively3.9% (n=92) or more recurrences9.4% (n=222) single recurrence3165 patients hospitalizedwith acute diverticulitis(Kaiser NorCal)19% (n=601)Required surgery during index admission2366 followed 9 years (mean)Rafferty J, Shellito P, Hyman NH, Buie WD, et al. Practice parameters for sigmoid diverticulitis. Dis Colon Rectum. 2006; 49: 939–944. Available atBroderick-Villa G et al. Arch Surg. 2005;140:576.
59Are Antibiotics Obligate? First RCT: 623 Swedish patientsCT-confirmed acute diverticulitis without complicationsNo antibiotics vs antibiotics at MD’s discretion for >7 daysAbscess, perforation (P = 0.3)Recurrent diverticulitis (P = 0.88)No antibiotics6 (1.9%)47 (16.2%)Antibiotics3 (1.0%)46 (15.8%)Chabok A et al. British Journal of Surgery. 2012;99:532.
60Complicated diverticulosis Diverticulitis - The Young Patient Historically, 2-4% of episodes occur in pts <40 y/o (but might be increasing)M>F and worse outcome, with 30-80% requiring urgent surgery during initial attack, and Ý risk of recurrences & complications.This, plus low operative risk in younger patients, suggests considering elective resection earlier after well-documented diverticulitis in younger patients.
61Complicated diverticulosis Abscess Suggested by persistent fever or WBCCT scan: diagnose & follow courseStage I (small pericolic abscesses): 70-80% success with medical tx aloneStage II (distant abscesses):CT-guided percutaneous drainageAllows for rapid control of sepsis without operative risk, allows for temporary drainage and single-stage procedure in 3-4 weeks.15-25% may still require primary surgical therapy if multiloculated or inaccessible.
62Complicated diverticulosis Abscess II CT-guided percutaneous drainageAssuming primary management roleAllows for rapid control of sepsis without risk of anesthesia, allowing for temporary drainage and a subsequent single-stage procedure in 3-4 weeks in 75-85% of cases.15-25% may still require primary surgical therapy if multiloculated or inaccessible.
67Complicated diverticulosis Hemorrhage I Most common cause of LGIB (30-50%)5-10% of patients with diverticula bleedWhile most tics in left colon, bleeding may occur more often from right colonic tics.Arterial bleed from vasa recta coursing over dome of tic.Increased risk with NSAID use.
69Complicated diverticulosis Hemorrhage II Clinical Features:Rarely occurs with diverticulitis.Abrupt, painless onset of maroon / red blood or clots; melena uncommon.Mild lower abd cramps / urge to defecateNever consider tics as cause of Heme+ stool75-80% stop bleeding spontaneously.25-35% recurrent bleeds; consider surgery after recurrent episodes.
70Complicated diverticulosis Hemorrhage III Diagnosis / ManagementFluid & blood product resuscitationExclude UGIB with NGT or EGDUrgent Flex Sig, if negative for source:Tagged RBC Nuclear Scan Þ angiography OR“Rapid Purge” and colonoscopy; although endoscopic Rx much less effective than in UGIBSurgery if endoscopy or angiography fails- segmental vs. subtotal colectomy.
71Complicated diverticulosis Hemorrhage IV 121 pts w/ severe hematochezia & diverticulosisRapid oral purge with PEG solutionColonoscopy within 6-12 hours: 73 patients treated medically and surgically, if recurrent or severe bleeding: 48 patients treated medically and with colonoscopic therapy for select stigmataJensen DM et al. NEJM 2000; 342: 78-82
72Complicated diverticulosis Hemorrhage V Surgical (’86-’92) Colonoscopic (’94-’98)DEFINITE Div Hemorrhage 17 (23%) 10 (21%)ENDOSCOPIC FINDINGSActive bleeding 6 (35%) 5 (50%)Non-bleeding VV 4 (24%) 2 (20%)Adherent Clot 7 (41%) 3 (30%)Additional bleeding 9 (53%) 0 (0%)Emergency colectomy 6 (35%) 0 (0%)Median time to discharge 5 days 2 daysComplications 2 (12%) 0 (0%)Late re-bleeding 0 (0%) 0 (0%)Issues: historical cohort only, small number of patients (n=10)
73Endoscopic control of bleeding: Epinephrine injection Patient with LGIB, ‘visible vessel’ in diverticulum, oozing with Epi injection but ultimately, cessation of bleeding. Courtesy of F Ramirez MD
74Endoscopic control of bleeding: Endoclips Patient with LGIB, ‘visible vessel’ within diverticulum, tx’d with endoclip Courtesy of T Hargrave MD
76Summary / Key points Increasing problem Fiber: unsettled as to cause / etiology but likely DOES help diminish complications, and seeds/nuts need not be forbiddenIs SUDD a real entity marked by subclinical inflammation and/or visceral hypersensitivity?If so, can we treat it with probiotics, 5-ASA and/or Abx?Will this simply improve symptoms or actually lower recurrent diverticulitis or complication rates?Surgery: increasingly less aggressive approach