Presentation on theme: "New Approaches to Diverticulosis and Diverticulitis Management Neil Stollman MD, FACG Chairman, Department of Medicine Alta Bates Summit Medical Center."— Presentation transcript:
New Approaches to Diverticulosis and Diverticulitis Management Neil Stollman MD, FACG Chairman, Department of Medicine Alta Bates Summit Medical Center Oakland, CA Associate Clinical Professor of Medicine University of California San Francisco San Francisco, CA
Outline Epidemiology Anatomy / Etiology Fiber as risk factor for DD (Diverticular Disease) Fiber as treatment for DD Other risk factors: nuts/seeds? SUDD: a new paradigm of chronic DD? Diverticulitis: 5-ASA, antibiotics, probiotics Surgical timing change? Diverticular Bleeding
Epidemiology True incidence difficult to measure as most patients asymptomatic No sex predilection generally “Disease of Western Civilization” – Rare in rural Africa & Asia, common in US, Europe, Australia – Japanese migrating to Hawaii have rate intermediate b/w native Japanese and mainland born, suggesting ‘westernization’ of colon.
Prevalence increasing over time (worldwide) Jun S, Stollman N. Epidemiology of Diverticular Disease. Ballieres Clin Gastroenterol 2003
Epidemiology: Increasing over time (US) Nationwide inpatient sample (NIS) data (HCUP) 26% increase in admissions – 82% increase in ages % increase in surgeries – 73% increase in ages M>F for patients <45 years F>M for patients >45 years Lower rates in west, c/w rest of country (?diet, ?obesity) Etzioni DA et al. Ann Surg 2009;249: Nguyen GC et al. World J Gastroenterol 2011;28:1600-5
Pathologic 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 taenia – Corresponds to sites of arterial penetration through smooth muscle – Pseudo-diverticula in that mucosa and submucosa herniate through the muscle, but tic does not include all layers of wall.
Diverticula form at sites of vascular penetration
Pathologic Anatomy II Western individuals: – 90% left-sided15% right-sided Asian individuals: – 25% left-sided75% right-sided Vary in number from solitary to hundreds Typically 5-10mm in diameter, although ‘giant’ diverticula described.
Sigmoid Diverticula: BE
Pan-colonic diverticula: BE
Separated at birth?
Etiology / 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 muscle Precocious diverticulosis occurs in patients with connective tissue disorders (Ehlers-Danlos, Marfan’s)
Etiology / Pathogenesis II Disordered Motility resting, post-prandial, & neostigmine- induced luminal pressures demonstrated in patients with tics vs. controls without Symptomatic pts have higher motility indices than asymptomatic patients Higher right-sided pressures seen in Asian patients with right-sided diverticula Wynne-Jones: westernized urban lifestyle “impermissive of flatus” air retention increased intraluminal pressures & tic formation (Lancet 1975;2:211-12)
Etiology / 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.
Etiology IV: Fiber as RISK FACTOR for DD Historically, felt to be ‘fiber deficiency’ disease – Worldwide 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 milling – Humans & domesticated animals on low-fiber diets are only species to develop diverticula – Suggest preventable and/or correctable by ↑ fiber Problems: assumes uniform diets within population, uncontrolled for other confounding factors such as lifespan
Etiology: dietary fiber Stool weights & transit times (n=1200) – UK patients: western low-fiber diet – Rural Ugandans: high fiber diet Transit time Weight UK80 hours110 gm/d Ugandans 34 hours450 gm/d Painter NS, Burkitt DP. Br Med J 1971;2:450–54
Etiology: dietary fiber transit-times & stool volume may intraluminal pressures and lead to diverticula Supported by rats fed diets of varying fiber content over natural lifespan: – Low-fiber diet:45% developed diverticula – High-fiber diet:9% developed diverticula – Histologically similar to human diverticula, but mainly right-sided
Fiber as RISK FACTOR for developing DD Cross section study of >2000 screening colonoscopies, years old, captured dietary / lifestyle info 42% overall had diverticulosis, increasing with age Fiber intake: highest quartile vs lowest: – prevalence ratio for diverticulosis: 1.3 ( ) BMs: >15/week vs <7/week – prevalence 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
Peery: Limitations Diet history taken after pts told they had DD – Possible recall bias if aware of fiber/DD hypothesis – Dietary hx one year only, lifetime intake most relevant (is current diet reflective of lifelong habits?) – Perhaps instructed to take fiber from prior dx – Perhaps taking more fiber because having symptoms Even if accurate, data do not undermine possible benefit of fiber in Rx of symptomatic DD
Fiber: risk for Sxs or complications? 2 large prospective cohort studies have shown inverse relationship b/w fiber intake and diverticular complications HPFU study, >43K men, US, , no prior colonic dz – RR 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/u – 812 cases (806 hospitalizations, 6 deaths) Adjusted Relative Risk – Highest vs lowest fiber intake: 0.59 ( ) – Vegetarians vs meat eaters: 0.69 ( ) Aldoori WH et al. J Nutr 1998;128: Crowe FL et al. BMJ 2011;343:
Does Evidence Support a Restriction on Nuts, Corn, and Popcorn? ACG Practice Guidelines – “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 years – 801 incident cases of diverticulitis – Hazard ratio for highest vs lowest consumption Nuts: 0.80 (0.63 – 1.01), P = 0.04 Popcorn: 0.72 (0.56 – 0.92), P = Not only ‘no association’ but nuts and popcorn may actually have inverse / protective effect 1. Stollman NH, Raskin JB. Am J Gastroenterol. 1999;94(11): Strate LL et al. JAMA. 2008;300(8):907.
Separated at birth?
Natural History Majority of patients (+/-80%) will never have symptomatic disease Serial barium studies reveal that disorder is generally not progressive, ie. pattern develops early and remains fairly static.
Rate 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 unknown Retrospective review LA-VAMC 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 patients Likely lower than we’ve thought Shahedi K et al. DDW 2012, Plenary Presentation, #847
SUDD: 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 patients Possible mechanisms: – Inflammatory damage to enteric nerves (and aberrant re- innervation leading to hypersensitivity, enhanced afferent response to stimuli) – Altered neuropeptides – Subacute obstruction secondary to fibrotic reaction – Muscle hypertrophy with increased intraluminal pressure
Predicting recurrent pain / SUDD Humes et al. British Journal of Surgery. 2008;95: patients with diverticulosis on barium enema 136 provided bowel / psych symptoms 170 eligible for follow up Excluded 91 Deceased 61 Declined FU 21 Misc 9 Recurrent pain 45 Asymptomatic 79 Pain Pain free
SUDD: Association between symptoms & postprandial contractions 30 healthy volunteers 115 patients with colonic diverticula – 30 asymptomatic (ADD) – 30 symptomatic uncomplicated (SUDD) – 55 symptomatic complicated (SCDD) Cortesini et al Dis Colon Rectum 1991;34(4):339-42
Increased expression of galanin & tachykinins in SUDD Prospective study Detailed bowel symptom questionnaire – 17 symptomatic – 15 asymptomatic DD pts Unprepared flexible sigmoidoscopy – Mucosal biopsy peridiverticular & rectal Normal appearance on routine histology No evidence of inflammation Simpson et al Neurogastroenterol Motil 2009;21:
Inflammation in DD Fecal 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 AD FC levels correlated with inflammatory infiltrate FC levels decreased with Rx in AD and SUDD Tursi A, et al. Int J Colorectal Dis 2009;24:49-55
Visceral hypersensitivity in SUDD Rectal barostat study in healthy volunteers (HV), asymptomatic DD (DDA) and symptomatic DD (DDS) Humes et al Neurogastroenterol Motil 2012;24:318-e163 P<0.002 DDS vs DDA
Post – 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 Sxs Cohen ER et al. DDW 2012, abstract 1363
Emerging 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
Meta-analysis: 4 PRCTs, 1660 patients Pooled Rate Difference (RD) Sx relief (1 year)29% (CI %) p<0.0001NNT=3 All Complications (1 year)2% (CI %) p=0.03NNT=59 Recurrent diverticulitis2% (CI %) p=0.0057NNT=50 Bianchi M et al. Aliment Pharmacol Ther 2011;33: Cyclic Rifaximin in SUDD (400mg BID, 7 days/month)
Mesalamine in DD At least 6 Italian studies have evaluated 5-ASA either after acute diverticulitis (3) or in SUDD (3) Generally favorable results – Daily superior to cyclic – But data very heterogeneous – Not double blinded, not placebo controlled – Subjective endpoints – Dose / regimen unclear
DIVA Trial 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 Dx Patients randomized to: – Standard care (abx, dietary advice as per local MD) – Standard care, plus mesalamine 2.4gm QD – Standard 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
Median Global Symptom Score All results NS vs placebo
Global Symptom Score Responders Responder = score of 0 or 1 for all symptoms # Significant difference vs. placebo # # #
Recurrent Diverticulitis (ITT) PLACEBO (n=41) 5-ASA (n=40) 5-ASA + Probiotic (n=36) Withdrew due to surgery 1 (2.4%)2 (5.0%)0 (0%) Recurrent Diverticulitis 8 (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
DIVA Conclusions Treatment with mesalamine after an attack of CT-confirmed acute diverticulitis led to: – Lower (but NS) GSS at all time points – Significant increase in responders (GSS=0 or 1) at some (but not all) time points – No effect on recurrence rates or surrogate markers Limitations: relatively underpowered, short treatment duration, GSS not validated previously, probiotic / mesalamine interaction?
PREVENT: MMX Mesalamine in Recurrent Diverticulitis (Shire, Lialda) Two identical Phase III RCTs – PREVENT 1 and 2: both worldwide – Intended 590 pts enrolled each, both completed enrollment – Mesalamine 1.2, 2.4, 4.8 gm/day vs placebo, 2 year follow-up Press 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.”
Other Mesalamine Trials Dr. Falk Pharma, Mesalazine, Germany – Mesalazine Granules vs. Placebo for the Prevention of Recurrence of Diverticulitis “Terminated” according to clinicaltrials.gov – Two 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
Probiotics for Diverticulitis ProtocolDD StageFollow up (N) Outcome E. Coli Nissle plus antibiotic plus active charcoal 1 SUDD2.4 (15)Prolonged remission period, improved symptoms L. casei, 5-ASA, or both 2 SUDD12 mos (90)Increased remission rate L. casei plus 5-ASA 3 SUDD24 mos (75)Increased remission rate VSL#3 plus balsalazide 4 SUDD2 mos (30)Improved symptoms L. Acidophilus plus L. helviticus plus Bifidobacterium 5 SUDD6 mos (45)Prevented recurrence, improved symptoms B. infantis 6 AD12 mos (40)No effect + 5-ASA 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: Lamiki P et al. J Gastrointestin Liver Dis. 2010;19: Stollman N et al. ACG 2010 Annual Scientific Meeting Abstract 49
Can we prevent diverticular complications? Many studies have implicated ASA and NSAIDs but small and non-detailed Follow up of US Health Professionals study; >45K men, followed since 1986 Relative Risk DiverticulitisDiv Bleeding -ASA >2x/wk NSAID >2x/wk Strate L et al. Gastroenterology 2011; 140: 1427.
Complicated diverticulosis Diverticulitis Inflammation and/or infection associated w/ diverticula Affects 15-20% of patients with diverticula 450,000 US admissions / year 2 million outpatient visits US / year Generally 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.
Impacted fecolith with inflammation
Complicated diverticulosis Diverticulitis – Clinical Features Clinical Features Pain and tenderness, usually LLQ, but in Asians or those with redundant sigmoids, can be RLQ or suprapubic. Altered bowel habits Anorexia, nausea, vomiting Hematochezia rare Dysuria: sympathetic cystitis Fever common; shock or hypotension unusual WBC common; no other labs routinely useful Differential Diagnosis Acute Appendicitis Crohn’s Disease Colonic carcinoma Pseudomembranous or ischemic colitis Ovarian cyst / abscess / torsion Ectopic pregnancy
Complicated diverticulosis Diverticulitis - Diagnostic Modalities CT scanning - most accurate – Abd & Pelvic scans; oral / rectal / IV contrast – Findings: pericolic infiltration of fatty tissues, wall thickening, abscess – Sensitivity and Specificity: 85-95% – Severe disease predicts complications and poor prognosis.
Complicated 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.
Complicated 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: Augmentin IV: aminoglycoside/aztreonam/3rd gen ceph plus metronidazole or clindamycin. Single agents: Unasyn, Timentin, Cefoxitin. Sxs should w/in 2-3 days, advance diet. Continue Rx for 7-10 days
Complicated diverticulosis Diverticulitis - Treatment III Inpatients: NPO, IVF, IV Abx Consider: 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.
Complicated 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?
When to consider surgery? Prior guidelines, including ASCRS and ACG recommended ‘considering’ prophylactic surgical resection after 2 nd attack Most recent ASCRS recommendations 1 – “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 approach Markov Model (WA State database) 2 – Colectomy after fourth (rather than 2 nd ) 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 analysis 1. Rafferty J et al. Dis Colon Rectum. 2006;49: Salem L et al. J Am Coll Surg 2004;199:904-12
Recurrence is infrequent and not more complicated Broderick-Villa G et al. Arch Surg. 2005;140: % (n=2551) No surgery 7% (n=178) had elective colectomy, typically young or had abscess 13% (n=314) Recurrence <2% per year Younger age had slightly higher risk 1 st recurrence predicted re- recurrence All re- recurrences treated non- operatively 13% (n=314) Recurrence <2% per year Younger age had slightly higher risk 1 st recurrence predicted re- recurrence All re- recurrences treated non- operatively 3.9% (n=92) 2 or more recurrences 9.4% (n=222) single recurrence 3165 patients hospitalized with acute diverticulitis (Kaiser NorCal) 19% (n=601) Required surgery during index admission 2366 followed 9 years (mean)
Are Antibiotics Obligate? First RCT: 623 Swedish patients CT-confirmed acute diverticulitis without complications No antibiotics vs antibiotics at MD’s discretion for >7 days Chabok A et al. British Journal of Surgery. 2012;99:532. Abscess, perforation (P = 0.3) Recurrent diverticulitis (P = 0.88) No antibiotics6 (1.9%)47 (16.2%) Antibiotics3 (1.0%)46 (15.8%)
Complicated 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 risk of recurrences & complications. This, plus low operative risk in younger patients, suggests considering elective resection earlier after well-documented diverticulitis in younger patients.
Complicated diverticulosis Abscess Suggested by persistent fever or WBC CT scan: diagnose & follow course Stage I (small pericolic abscesses): 70-80% success with medical tx alone Stage II (distant abscesses): – CT-guided percutaneous drainage – Allows 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.
Complicated diverticulosis Abscess II CT-guided percutaneous drainage – Assuming primary management role – Allows 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.
Complicated diverticulosis Hemorrhage I Most common cause of LGIB (30-50%) 5-10% of patients with diverticula bleed While 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.
Complicated 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 defecate – Never consider tics as cause of Heme+ stool – 75-80% stop bleeding spontaneously. – 25-35% recurrent bleeds; consider surgery after recurrent episodes.
Complicated diverticulosis Hemorrhage III Diagnosis / Management – Fluid & blood product resuscitation – Exclude UGIB with NGT or EGD – Urgent Flex Sig, if negative for source: Tagged RBC Nuclear Scan angiography OR “Rapid Purge” and colonoscopy; although endoscopic Rx much less effective than in UGIB – Surgery if endoscopy or angiography fails- segmental vs. subtotal colectomy.
Complicated diverticulosis Hemorrhage IV 121 pts w/ severe hematochezia & diverticulosis Rapid oral purge with PEG solution Colonoscopy 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 stigmata Jensen DM et al. NEJM 2000; 342: 78-82
Complicated diverticulosis Hemorrhage V Surgical (’86-’92) Colonoscopic (’94-’98) DEFINITE Div Hemorrhage 17 (23%)10 (21%) ENDOSCOPIC FINDINGS Active bleeding 6 (35%)5 (50%) Non-bleeding VV 4 (24%)2 (20%) Adherent Clot 7 (41%)3 (30%) Additional bleeding9 (53%)0 (0%) Emergency colectomy 6 (35%)0 (0%) Median time to discharge 5 days2 days Complications 2 (12%)0 (0%) Late re-bleeding 0 (0%)0 (0%) Issues: historical cohort only, small number of patients (n=10)
Endoscopic 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
Endoscopic control of bleeding: Endoclips Patient with LGIB, ‘visible vessel’ within diverticulum, tx’d with endoclip Courtesy of T Hargrave MD
Summary / Key points Increasing problem Fiber: unsettled as to cause / etiology but likely DOES help diminish complications, and seeds/nuts need not be forbidden Is 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