Download Investigations of the Bacterial Pathogenesis of the

The Ilioanal Pouch Reservoir
and
Pouchitis
What is it?
Why do some patients get it?
Dr. Matt. Johnson
Proctocolectomy
• UC
– 10-20% all UC patients
– For medical refractory disease or dysplasia
• FAP
– Mean age at diagnosis of cancer = 39y
History of the IAPouch
• 1944 Proctocolectomy + Ileostomy
(Strauss + Strauss)
• 1969 Intra-Abdominal Ileal Reservoir
(Kock)
• 1978 Restorative Proctocolectomy
– (Parks + Nicholls)
• 1987 J-Pouch Modification
– (Nicholls)
• A Normal Pouch
Pathological changes within a
normal Healthy Pouch
• 6/52
– plasma cell infiltration
– raised eosinophils
– Later = lymphocyte infiltration
• 6/12
– Villous atrophy
• >6/12
– “Normal adaptation” with cell influx stabilizing
– Tendency to colonic metaplasia “colonic type mucosa”
Pouchitis Symptoms
•
•
•
•
A) Post Op Stool Frequency
B) Rectal Bleeding
C) Faecal Urgency* +/- Cramps
D) Fever (unusual)
• * usually due to inflammation at the distal/efferent limb
of the pouch
• There is often poor correlation between symptoms and
either the endoscopic or histology appearance
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)
• Pouchitis
Histological Changes
• 1986 Moskowitz Histopathological Scoring System
• > 4/12 = Pouchitis
• Acute
– Acute PMNC infiltration into the crypts and surface
epithelium (3/3)
– Superficial ulceration (3/3)
• Chronic
– Chronic (lymphocytic) infiltration (3/3)
– Degree of villous atrophy (3/3)
Pouchitis Disease Activity Index,
Sandborn 1994
>7 = Acute Pouchitis
Who Gets It ?
UC
Clinical Pattern
• After 6/12 patients fall into 3 catagories;
• 1) No pouchitis (45%)
• 2) Relapsing + Remiting Pouchitis (42%)
• 3) Chronic Pouchitis (13%)
– > 4/52
– Recurrent courses of antibiotics needed
Association with UC
• Pouchitis occurs almost exclusively in UC patients
• Pathologically similar to UC
• Backwash Ileitis
– Seen in 75% of pancolitis resection specimens
– prevalence correlates closely with disease extent
– It is a distinct entity from backwash ileitis
• Similar responses to smoking
– 25% non-smokers, 33% ex-smokers, 6% smokers
• Extra GI Manifestations of IBD
– especially PSC, though no obvious association with Arthropathy
• Treatment response similar with 5ASAs and Steroids
Aetiology of Pouchitis
• Flora (10x as much bacteria as cells in the body)
– Prox jejunum 103 cfu/g of dry weight stool
– Ileum 105-8
– Caecum 1011-12
• The proportion of anaerobes increases distally
– Ileostomy = Flora increase by *80
• Anaerobe : aerobe (remains the same)
– Caecum = 1000:1
– Ileal Pouch = 100:1
• Colonic type flora (bacterioides, bifidobacteria)
•
•
•
•
Bacterial profiles are genetically determined and remain stable lifelong
Pouchitis = no diff in bacterial qualitative + quantitative stool studies
Response to Abs suggests a pathogenic role for bacteria
Diverting ileostomy is therapeutic in CD (recurs 6/12 post re-anastamosis)
Aetiology of Pouchitis
• Stasis
– Does affect flora but no obvious relationship found
• Intra luminal
– Bile Acids = No obvious relationship
– Short Chain Fatty Acids (SCFAs)
• produced by anaerobes fermenting endogenous mucus and
undigested CHO in the large bowel
• Important in colonic epithelial metabolism, healing and
proliferation (?protective)
• The quantity in pouch faeces is inversely proportional to the
degree of villous atrophy
• Depleted levels seen in active UC
Immunology of IBD
• 1) Humoral
• 2) Cell Mediated
• 3) Cytokines
• 4) Flora Tolerance
• 5) Innate Immunity
Humoral Immunity
• Normal patients have IgA plasma cells provide
•
immunity by immune exclusion
IBD the increased number of plasma cells
secreting all classes of Ig (IgG*30, low IGA)
– IgG1 (UC>CD) = increases the activation of
the complement cascade in response to
soluble protein Ag
– IgG2 (CD>UC) = increases in response to
CHO + bacterial Ags
• CD = ASCA, anti-Saccharomyces cerevisiae
• UC = pANCA, perinuc antineut cytoplasmic
Cell Mediated Immunity
• Plasma cells are clearly increased + activated in
•
•
•
IBD
The relative contributions of B cells and the T
cell subtypes remain unclear in IBD
T cells play a more important role in CD (esp
CD4cell)
Markers of T cell activity include
• 4F2
CD+UC
• T9 (transferrin receptors)
CD+UC
• CD25
CD only
Cytokine Immunity
• Opsonisation > Phagocytosis > Presentation to CD4 cells
• Naïve T cells in the presence of;
– IL 12
– IL 4
develop into Th1 cells
develop into Th2 cells
• Th0 clones (secrete a mixture of Th1 + Th2)
• Th1
(predominantly secrete IL2, IL12, TNFa and IFNg)
- activates inflammatory and cytotoxic
response
- induces delayed type hypersensitivity
• Th2
(IL 4, 5, 9, 10, 13)
- decreased in active disease
- activates Ab production
• Tr1 (regulatory)
(IL10, IFNg)
- gene deletions of IL10 +IL2 lead to IBD
Immunology of IBD
• Pro-Inflammatory Cytokines
– TNFa
UC)
– IL1
– IL6
– IL8
secreted by macrophages (increased in
“
“
recruitment of neutrophils (in CD+ UC)
IBD Immune Balance
APCs
Ag
CD4+ T-cells
Th1 (pro-inflammatory)
Th2 (anti-inflammatory)
IL 1,2,6,12, TNFa + IFNg
IL 4,5,6,9,10,13 + TGFb
TR1
regulatory
Immune Tolerance
• The host immune system is able to distinguish
•
•
•
between normal and pathogenic organisms
Tr1 cells are likely to play a critical role in
maintaining immunosuppressive constraints on
the highly antigenic bowel environment
Tolerance towards normal flora is broken in
active IBD (Duchmann 1995)
Normal bacteria flora is required to generate
inflammation (IL10 –ive mice = Madsen 1999)
Innate Immunity
• Phylogenetically older than the specific active
•
Tcell response
Uses receptors on APC (antigen presenting cells)
• PRR = Pattern recognition receptors
• TLR = Toll-like receptors
– Leading to release of pro-inflammatory CKs
(IL1, IL6, TNFa)
– This acute phase response is independent of a
specific Tcell response
Therapy for Pouchitis
• There appears to be a bacterial precipitant
• These bacteria appear to be Metronidazole sensitive G- anaerobes
• Antibiotics (Metronidazole or Ciprofloxacin)
• Probiotics VSL 3 / 4 (Gionchetti 1994)
–
–
–
–
4*
3*
1*
1*
lactobacilli
bifidobacteria
Strep Salivarius
S. thermaphiles
• Remission can be maintained in 92.5% at 9/12 Vs 0% in the
placebo group
Therapeutic Mechanisms
• Antibacterials
• Probiotics probably work by altering the hosts
immune response at the GI mucosal surface
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–
–
–
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
– Produce SCFAs and vitamins