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DIVERTICULAR DISEASE NEW APROACH TO THERAPY

HINT OF HISTORY. Cruveilhier-1849- first described colonic involvement by diverticular disease.Term

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DIVERTICULAR DISEASE NEW APROACH TO THERAPY

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    1. DIVERTICULAR DISEASE NEW APROACH TO THERAPY ELISA TIOMNY M.D. G.I. DEPATMENT T-A MEDICAL CENTER

    2. HINT OF HISTORY Cruveilhier-1849- first described colonic involvement by diverticular disease. Term “ diverticulosis” – first used in 1914. Acute diverticulitis recognized at the turn of the 20th century (due to” excess of roughage”!). Burkitt &Painter-geografic distribution of the condition (Western vs.Third world)-due to industrialization of milling of FLOUR. Diverticulosis is a DEFICIENCY disease!!

    3. COLON DIVERTICULOSIS NEW ASPECTS OF AN OLD DISEASE Disease of age:30%<50y, 66%>85 y-on P.M.studies. m=f, at the beginning of 20th century m>f. Western countries~35%,left sided Eastern~4%,rt.sided. Unheard before1900- with introduction of milling of the flour which removes 2/3 of fiber content. In USA crude fiber intake felt by 30% from 1900?1975.

    4. NUMBERS AND PATHOPHYSYOLOGY Up to 5%, life long, will develop complications, if by symptoms-up to 25%. 2%, life long, will need hospitalisation-50% of those will require surgery. 30%-persistence of symptoms or recurrent diverticulitis in 5y after first attack.

    5. NUMBERS AND PATHOPHYSIOLOGY Colonic wall-Circular muscle & 3 bands of longitudinal tenia coli. “Pseudo diverticula”-weakest point at blood vessel entry on mesenteric site-herniation of mucosa+ submucosa through muscularis to serosa. Increased intraluminal pressure>120mm Hg: less fibers-less volume, more constipation -higher pressure by LaPlace law?outporcketing. Sigmoid has the smallest diameter-more diverticuli. Lack of physical activity in elderly-independent factor for DD. Elastin deposition in DD in tenia is 200% more than in normals. Low fecal bile acid output –in DD. In DD-symptomatic uncomplicated- 24 h colon motility studies show increased duration of regular phasic patern -30%vs 6% in normal. Low fiber diet results in micro-ecology changes -anaerobic /aerobics bacteria, change in immune response, low grade inflammation, relative ischemia of diverticular segment.

    6. Diverticulitis development

    7. STAGING OF DIVERTICULOSIS

    8. CLINICAL PRESENTATION 1 Asymptomatic diverticulosis. Acute diverticulitis: complicated uncomplicaded Chronic recurrent diverticulitis. Symptomatic uncomplicated disease (diverticular colitis).

    10. CLINICAL PRESENTATION 1 Asymptomatic diverticulosis. Acute diverticulitis: complicated uncomplicaded Chronic recurrent diverticulitis. Symptomatic uncomplicated disease (diverticular colitis).

    11. ACUTE DIVERTICULITIS WITH OBSTRUCTION

    12. CLINICAL PRESENTATION 1 Asymptomatic diverticulosis. Acute diverticulitis: complicated uncomplicaded. Chronic recurrent diverticulitis. Symptomatic uncomplicated disease (diverticular colitis-up to 2 %).

    15. CLINICAL PRESENTATION 2 Special groups *IBD & DD -concomittent/develops *IBS & DD concomittent / develops? *Adolescent & young adults< 40y *Elderly population> 65 y

    18. CLINICAL PRESENTATION 2 Special groups *IBS & DD concomittent / develops? *DD & IBD-concomittent/develops? *Adolescent & young adults< 40y *Elderly population> 65 y

    22. THERAPY

    23. CONSERVATIVE THERAPY 1 Fibers. Antibiotics Mesalazine. Probiotics. Miscellaneous: Ca-channel blockers, Glucagone, Antimuscarinic, antispasmotics.

    24. CLINICAL PRESENTATION 1 Asymptomatic diverticulosis. Acute diverticulitis :complicated uncomplicaded Chronic recurrent diverticulitis. Symptomatic uncomplicated disease (diverticular colitis).

    25. HINCHEY CLASSIFICATION for perforated divertuculitis

    26. CONSERVATIVE THERAPY 2 Acute attack: No change in the policy: I.V. fluids ,NPO,IV antibiotic combination for aerobic & anaerobic flora, no difference between the type of antibiot. Duration- from 3-7 days ,than gradually restore PO intake & therapy. Low mortality -0-5 %, high recurrence 7-42%.yearly risk of recurrence 3 %. CHANGE: Increasing use of a new unabsorbable antibiotic – Rifaximin in combination with Mesalazine.

    27. CONSERVATIVE OUTPATIENT MANAGEMENT OF ACUTE DIVERTICULITIS 3 Mizuki 2005,open,70pat,48 y(1997-2002). Mild to moderate acute DD :clinical signs + lab + US –Gr.1a-c. Gr c- peridiverticular abscess<2 cm.Gr 2- >2 cm with perforation 10days protocol: 3 days-1500ml sports drink+ free water+ oral cephalosporin.-on 4th day-clear liquid +on 7th day liquid diet. Clinical + lab FU every 3 days. US on 4thd. 61pat-rt.sided DD. 68pat completed ,follow up 31 mo: 24%-recurrence, majority in the same location, majority repeated the protocol. Cost-343 $ vs 2018 $ -conventional . US is not good for obese patients and in excess of gas . Rt. Sided diverticulosis has a benign course-relevance to our population??

    28. CONSERVATIVE THERAPY Fibers. Antibiotics Mesalazine. Probiotics. Miscellaneous: Ca-channel blockers, Glucagone, Antimuscarinic, antispasmotics.

    29. FIBERS 1-pathophysiology Increase colonic Transit Time. Decrease intraluminal pressure. Improve Bacterial homeostasis. Increase production of Butiric acid.

    30. FIBERS 2 Whole gut transit is twice slower in West than in Africans (fibers?). Transit time in IBS and Diverticulosis is faster than in normal (so uncoordinated colonic activity is the problem and not the transit). Maternal diet- animal model (rat)- has significant influence on offspring- depends on fiber rich or deficient diet before conception. Age dependence- declining strength of the collagen due to increase of cross-linking of collagen produced in elderly and fiber deficient patients.

    31. FIBERS 3 Fiber rich diet does NOT reverse diverticulosis. First RCT in 1976 by Brodribb & Humphrey-on 18 pats-significant symptomatic relief on fibers vs. normal diet. Gear-1979-Vegetarians, asymptomatic : use 42g/d(V)-vs.21g/d(N) : 2%m+0%f (V) vs.31%m+ 21%f(N)-develops diverticulosis. Hyland & Taylor-1980-100pts-6Y-after complicated dis.-91%remained symptom free on H.F. diet. Omstein1981-76 pts -4 mo.-bran7g/d vs.ispaghula 9g/d vs.placebo -lower abdominal symptom score,straining,soften the stool ,increase stool weight and frequency. Leahy-1985: 72 pats-retrospective-fewer complications & need for surgery. Aldoory-1998 -43881 pts-Type of fiber plays a role too: insoluble fibers mainly cellulose are the best in prevention of diverticular development!

    32. FIBERS 4 CONCLUSION Despite controversial data, fiber supplementation is recommended!

    33. CONSERVATIVE THERAPY Fibers. Antibiotics Mesalazine. Probiotics. Miscellaneous: Ca-channel blockers, glucagone, antimuscarinic, antispasmotics.

    34. RIFAXIMIN-New Kid On the Block1 Semi synthetic rifamycin deriv.-inhibits bacter. RNA synthesis.-gram +,less for gram ­,less for bacteroids, unabsorbed. Trials Papi -1992 open,multicenter-217pts -symptomatic uncomplicated DD:rif.800mg/d vs. rif+ glucomannan 2 gr/d-7d /mo.for 12 mo:58% symp. free on combined therapy vs.24%.+symptom score reduction: 64% vs. 48%. No side effects .DD complications-0,9%vs2,7%.

    35. RIFAXIMIN-New Kid On the Block2 Latella-2003, open: 968pts-symptomatic DD-glucomannan 4gr/d+rif.800mg vs.fiber only for 7d/mo. For 12 mo:56,5%- combination group vs.29%-symptom free.No side effects. DD complications- 1,3% vs 3,2%. Papi-1995,randomised-168 pt.s-symptomatic uncomplicated DD:2gr fiber+ 800mg rif.vs fiber + placebo for7d/mo for 12 mo.:69% in combination vs.40%-were asymptomatic. No side effects . No difference in DD complication rate. CONCLUSION Intermittent long term therapy with Rifaximin provides 30% benefit over fibers alone. QUESTION Does it really prevent recurrence and complications on the long run? (Baseline risk of complication in DD is 5 %/y).

    36. CONSERVATIVE THERAPY Fibers. Antibiotics Mesalazine. Probiotics. Miscellaneous: Ca-channel blockers, Glucagone, Antimuscarinic, antispasmotics.

    37. MESALAZINE OLD DRUG IN A NEW PLAY1 Di Mario, 2005, random. multicenter: 170pts (67y mean age): R1-rif. 400mg/d ; R2-rif. 800mg/d; M1-mes. 800mg/d; M2 mes.1600mg/d-for 10 d/mo. For 3 months. (symptom score of 11). In all groups but R1-3/11 symptoms improved. M2 – had the best results in symptom score reduction.

    38. MESAALZINE OLD DRUG IN A NEW PLAY 2 Tursi,2002,218pts (65y) GrA-rif.800mg/d+ mes.2,4 gr/d 7 days, follow-800 mg+1600mg for 7d/mo .Gr B -rif. 800mg/d 7 days follow 800mg/7d/mo for 12 mo. Significant symptom improvement in Gr A vs. Gr B. Acute DD recurrence-3 vs 13 pat (p<0.005).

    39. MESALAZINE OLD DRUG IN A NEW PLAY 3 Brandimarte 2004,open,90pts,67y with acute symptomatic uncomplicated DD, outpatients. rif.800mg+ mes.2,4 mg-for 10 days follow by mis.1,6 g/d for 8 weeks-total symptom score decreased from 1439-to 44 (p<0.001). 2 %-recurrent diverticulitis on misalazine alone phase. Side effects-4,4%-diarrhea on mesalzine+ 2% pruritus + epigastric pain.

    40. MESAALZINE OLD DRUG IN A NEW PLAY 4 Conclusion Mesalazine- based therapy is more effective than rifaximin based therapy in treating symptomatic DD + prevention of exacerbation.

    41. CONSERVATIVE THERAPY Fibers. Antibiotics Mesalazine. Probiotics. Miscellaneous: Ca-channel blockers, Glucagone, Antimuscarinic, antispasmotics.

    42. PROBIOTICS Fric 2003 first published trial, open:15 mildly symptomatic uncomplicaed DD outpatients,75y: 1 w antibiotics+2tab of E.Coli Nissle for 5w average ,FU for 8-40 mo. Previous 2 attacks with standard Rx –remission lasted 2,4 mo. After probiotics-14,1 mo (p<0.001). Symptom score:1,84?0,21(p<0,001). No controls , not randomized.

    43. CALCIUM CHANNEL BLOCKERS Morris 2003 - CCB vs Antimuscarinics in protection against perforated DD. Retrospect. Hospital charges for 5 y –serves 750000 popul. (NORFOLK,UK.). Oral intake of CCB and antimuscarinic immediately before the perforation. 120 pts+ 240 X2 matched controls (cataracts and BBC). Protective effect of CCB and not antimiscarinic:OR: 0,4

    44. LONG-TERM OUTCOME OF CONSERVATIVE THERAPY FOR DIVERTICULITIS Mueller, Munich, 2004,prospective ,252 pts, 7+13y FU. Conservatively treated during 1985-1991,64y-interwed in 1996+2002. 1FU-85 died-1from DD.53%asymptomatic+ 47% symptomatic10 % readmission+ 8 % surgery. 2FU-only 55% could be reached(45%lost for FU), 37%-recurrent symptoms.20%readmission,14%-surgery. conclusions High recurrence rate-34%,low mortality-0,8%,surgery-10% should be left for relief of symptoms rather than prevent death from complications.

    45. POSSIBLE FUTURE TRENDS IN THERAPY *Probiotics with or without Mesalazine –for mild to moderate uncomplicated attack. *New antibiotic-Rifaximin plus Mesalazine for acute uncomplicated attack. *Surgery for complications. *For chronic prevention (painful diverticulosis without inflammation)-fiber+/-5ASA?other? @@@@@@@ *WE ARE WITNESS TO AN ACTIVE EVOLUTION OF COMPLETELY NEW THERAPY IN DD. @@@@@@@ * MORE PROMISSING APROACHES STILL TO COME!!

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