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

• • • • • • 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 10 3 cfu/g of dry weight stool – Ileum 10 5-8 – Caecum 10 11-12 The proportion of anaerobes increases distally – Ileostomy = Flora increase by *80 • – Caecum = 1000:1 – Ileal Pouch = 100:1 • Anaerobe : aerobe (remains the same) 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 • T9 (transferrin receptors) • CD25 CD+UC CD+UC CD only

Cytokine Immunity

• • Opsonisation > Phagocytosis > Presentation to CD4 cells Naïve T cells in the presence of; – IL 12 develop into Th1 cells – IL 4 develop into Th2 cells • • • • Th0 clones (secrete a mixture of Th1 + Th2)

Th1 Th2

(predominantly secrete IL2, IL12, TNFa and IFNg) - activates inflammatory and cytotoxic response - induces delayed type hypersensitivity (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 secreted by macrophages (increased in UC) – IL1 – IL6 – IL8 “ “ recruitment of neutrophils (in CD+ UC)

IBD Immune Balance APCs Ag CD4+ T-cells Th1 (pro-inflammatory) IL 1,2,6,12, TNFa + IFNg Th2 (anti-inflammatory) 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* lactobacilli – 3* bifidobacteria – 1* Strep Salivarius – 1* 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 – 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