Transcript Investigations of the Bacterial Pathogenesis of the

The Management of
Pouchitis and Cuffitis
Dr. Matt. Johnson
Prof R.J.Nicholls
Dr. A.Forbes
Prof P.Ciclitira
Proctocolectomy
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UC
10-20% all UC patients
 For medical refractory disease or dysplasia
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FAP
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Mean age at diagnosis of cancer = 39y
A Pouch
Pathological changes within a
normal Healthy Pouch
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6/52
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6/12
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plasma cell infiltration
raised eosinophils
Later = lymphocyte infiltration
Villous atrophy
>6/12
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“Normal adaptation” with cell influx stabilizing
Tendency to colonic metaplasia “colonic type mucosa”
Pouch Flora
 Prox
jejunum
 Ileum
 Pouch
 Caecum
103 (cfu/g of dry stool)
105-8
107-10
1011-12
{Nicholls RJ, 1981}{Tabaquhali S, 1970}
Pouch Flora
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The proportion of anaerobes increases distally
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Ileum =
1:1
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Caecum =
1000:1
(Anaerobe : aerobe)
{Philipsin, 1975}
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Ileal Pouch =
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100:1
Colonic type flora (bacterioides, bifidobacteria)
{Shepherd NA, 1989}
Bowel Flora
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10x as many bacteria as cells in the body
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1kg of our weight
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55% of stool
“the neglected organ”
{Bocci V,1992}
Bacterial profiles are genetically determined and
remain stable lifelong
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{Farrell RJ,2002}
{van de Merwe JP, 1988}
Pouchitis
Endoscopic Findings in Pouchitis
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Oedema
Granularity
Friable
Loss of vascular
Mucosal exudates
Ulceration
These changes can be patchy
Inflammation is often worse in the posterior/dependent
segment of the pouch)
Histological Pouchitis Definitions
1986 Moskowitz Histopathological Scoring System
> 4 = Pouchitis
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Acute
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Acute PMNC infiltration into the crypts and surface epithelium (3/3)
1. Mild
2. Moderate + Crypt Abscesses
3. Severe + Crypt Abscesses
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Superficial ulceration (3/3)
1. <25% of field
2. 25-50%
3. >50%
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Chronic
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Chronic (lymphocytic) infiltration (3/3)
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Degree of villous atrophy (3/3)
Pouchitis Symptoms
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A) Post Op Stool Frequency
B) Rectal Bleeding
C) Faecal Urgency* +/- Cramps
D) Fever (unusual)
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* usually due to inflammation at the distal/efferent limb of the
pouch
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There is often poor correlation between symptoms and either
the endoscopic or histology appearance
Pouchitis Disease Activity Index,
Sandborn 1994
>7 = Acute Pouchitis
Clinical Pattern
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After 6/12 patients fall into 3 catagories;
1.
No pouchitis (45%)
Episodic Pouchitis (42%)
Chronic Pouchitis (13%)
2.
3.
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= > 4/52
Relapsing / Remitting (>3-4 a year)
Antibiotic Dependent
Persistent / Refractory Pouchitis
Causes of Pouchitis
Known Causes of Pouch Inflammation
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Crohn’s
Ischaemia
Radiation
Specific pathogenic infections (CDT, CMV)
Localised infection (pelivic abscess)
?Reaction to secondary bile acids
?Stasis (no association found)
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Dysbiosis (alteration in the balance of the normal bowel flora)
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Bacterial Aetiology for IBD - UC
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In 1989 a case report with active refractory UC
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Rx= Antibiotics and an enema of “normal” faecal bacteria
Benefits were maintained for 6 months
{Bennet JD, 1989}
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Antibiotics
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Reduce severity and duration of UC
{Dickinson RJ, 1985}{Mantzaris GJ, 1994}{Turunen UM, 1998}{Present DH, 1998}{Cummings JH, 2001}
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Improve Pouchitis - endoscopy and histology
{Madden MV, 1994}{Kmiot WA, 1993}{Hurst RD, 1996/8}{Shen B, 2001}{Scott AD, 1989}{Gionchetti P,
1999}{Mimura T, 2002}
Treatment of Acute Pouchitis
1.
Metronidazole 1-2g PO for 7/7{MaddenMV,1994}
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55% SEs = N+V, abdo discomfort,headache, skin rash,
metallic taste, disulfiram like reaction with Xol, peripheral
neuropathy
3.
Metronidazole suppositories (40-160mg/d) {Isaacs 1997}
Ciprofloxacin 500mg bd PO 7/7 {Shen 2001}
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7/7 course < 14/7 course < combination
2.
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Cipro + Metro {Mimura T, 2002}
Cipro + Rifampicin {Gionchetti P, 1999}
Prophylactic doses (increased resistance)
Other Treatments to Consider
1.
2.
3.
Pentasa 2g bd PO {Tytgat GN,1988}{Shepherd NA, 1989}
Budesonide 9mg PO {Shepherd NA, 1989}
Budesonide suppositories {Boschi, 1992}
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4.
5.
6.
60% relapse
Azathioprine {MacMillan 1999}
Bismuth Subsalicylate {Tremaine 1998}
Glutamine / Butyrate (SCFA) enemas/suppos
{de Silva HJ, 1989}
7.
Allopurinol 300mg bd PO {Levin KE, 1992}
Probiotic Therapy for Pouchitis
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VSL 3 (Gionchetti 1994)
 4x lactobacilli
 3x bifidobacteria
 1x Strep Salivarius
 1x S. thermaphiles
 Remission can be maintained in 92.5% at 9/12 Vs
0% in the placebo group
Probiotic Trials in Acute Pouchitis
High dose of probiotics is effective in the treatment of mild pouchitis. A pilot study.
Amanidini C, Gionchetti P et al. Digestive and Liver Disease 2002; 34 (Suppl. 1):A96
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Abstract
Positive results
NB = Not written up into a paper ?why
Probiotic Trials in Chronic Pouchitis
Oral bacteriotherapy as maintainance therapy in patients wih chronic pouchitis: a double blind placebo
controlled trial. Giochetti P, et al. Gastroenterology 2000; 119:305-309
40 Patients
Placebo
6g VSL 3
n = 20
n = 20
n = 20
Relapse
n=0
Remission
after 9/12
n=3
n = 17
Trials of Probiotics as Prophylaxis
Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo controlled trial.
Giochetti P, et al. Gastroenterology 2000; 124: 1202-1209
40 Patients
Placebo
6g VSL 3
n = 20
n = 20
n=8
Pouchitis
40%
n=2
10%
n = 12
Remission
n = 18
60%
after 12/12
90%
Probiotics as od Maintainance
Once daily high high dose probiotic therapy maintaining remission in recurrent/refractory pouchitis.
Mimura T, et al. GUT 2004; 124: 108-114
36 Patients
Placebo
6g VSL 3
n = 16
n = 20
n = 15
Pouchitis
93%
n = 2, +1
15%
n=1
Remission
n = 17
7%
after 12/12
85%
Probiotic Therapeutic Mechanisms
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Increasing the acidity (increases SCFAs)
Altering the hosts immune response at the GI mucosa
Produce antibiotic like substances (bacteriocins)
Increased IgA + IL 10 (anti-inflammatory)
Decreases IFNg and TNFa (pro-inflammatory)
Induces T cell shift towards Th2 (anti-inflammatory)
May competitively inhibit adherence of potentially pathogenic
bacteria
Increase intestinal mucus production
Produce SCFAs and vitamins
What’s on Offer
Name
Strain
Implant
Uses
Saccaromyces
boulardii
Yes
Diarrhoea
Prevention + Rx
Actimel
L.casei strain DN114001
Yes
Stoneyfield
Yogurt
L.reiteri
Yes
Arla
L.acidophilus NCFB
1748
Yes
L.rhamnosus VTT
E-97800
Yes
PrimaLiv
L.rhamnosus 271
Yes
Yakult
L.casei strain
Shirota
Yes
Culturelle
L.casei GG
Yes
CDT
Pro Viva
L.plantarum 299v
Yes
IBS
Diarrhoea Rx
VSL#3 Trial in Chronic Pouchitis
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Recently managed to acquire funding for 10 local
patients to receive 1 year of VSL#3
May be able to import for GPs who are prepared to pay
The group will be closely monitored to assess
Cost / Benefit ratio
Primary Culture Assays and PDAI before and 3/12
Assess long term outcome
If successful we will assess the effects of terminating
after 3-6/12
Where’s the Future Heading
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Pre-biotics
 “Non-Digestible Food (NDF) ingredients that beneficially
effect he host by selectively stimulating the growth and/or
activity of one or a limited number of bacteria in the colon,
that can improve host health” 1 {Gibson G. 1995}
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Such CHO – soluble fibre
 A) Encourages growth of beneficial (saccharolytic) bacteria
 B) Attract harmful (proteolytic) bacteria away from mucosa
(gut wall) by saturating the adhesin-CHO binding sites
Prebiotics Side Effects
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Flatulence + Bloating
Rx = Gradually increase fibre with time
Gradual increase in Bifidobacterium
 Decrease freely available NDF
 Decreases gas formed by other bacteria
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Prebiotics and the Pouch
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Inulin 24g a day for 21/7 (crossover trial)1
 Decreased inflammation in 19/19
pouches
1.
Welters C. et al. Effect of dietary inulin supplementation on
inflammation of pouch mucosa in patients with ileal pouch
anal anastamosis. Diseases of the colon and rectum 45: 621627
Natural Prebiotics
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Nutraceuticals = “functional foods”
Inulin / Fructo-oligosaccharides / Lactulose
Transgalacto-oilgosaccharides
Chicory (boiled root = 90% inulin)
Jerusalem artichoke
Onion
Leek
Garlic
Asparagus
Banana
(cereals eg. Oatmeal)
Proportion of pouch patients with nutritional deficiencies
70
60
50
40
Number
of patients
Normal
Deficient
30
20
33%
10
26%
15%
8%
14%
0
Hb
Iron
Folate
B12
Vit D
Conclusion
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Pouch histology can help guide the medical
management
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Acute pouch inflammation associated with
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Chronic pouch inflammation associated with
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Anaemia
Iron deficiency
Folate, Vitamin D and B12 deficiencies
Benefits of correcting deficiencies
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Prevent potential long term complications
Anecdotal considerable improvement in the QOL
FAP Pouches
Healthy
Inflamed
Chart 1
Percentage of FAP Pouches with Histological Evidence of
Significant Acute, and Mixed Inflammatory Changes
35
55 of 190 had evidence of
endoscopic inflammation
30
25
20
15
10
5
0
Acute
Chronic
Mixed
Histological Inflammation
Chart 2
Percentage of FAP Pouch Patients with PDAI Scores
Diagnostic of Active Pouchitis
Of those 55, 14% had a
PDAI of >7 suggestive of
active pouchitis
50
%
40
30
20
10
0
Histology Endoscopy Clinical
PDAI
PDAI Score and its Individual Components
This gave an overall
prevalence of pouchitis in
FAP pouches as 4%
Cuffitis
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Almost exclusive to those with a stapled
anastamosis
There is a 60% risk of leaving residual rectal
mucosa behind when stapling a pouch with a
1-2cm anal transition zone
Even after mucosectomy there is a 20% of
residual islands of rectal mucosa left on the
rectal cuff
Cuffitis Symptoms
1.
2.
3.
4.
Urgency
Diarrhoea (Frequency)
Burning Pain (pre/post-defecation)
Tenesmus
Treatment of Cuffitis
Is similar to the treatment of proctitis
1.
2.
3.
Mesalazine suppositories / enemas
Predsol suppositories / enemas
? Lignocaine gel
Consider
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Metronidazole suppositories
Pre – Pouch Ileitis
1.
2.
3.
Pentasa granules / PO
Azathioprine
Other Immuno-modulators