The Ilioanal Pouch Reservoir The Ilioanal Pouch Reservoir and and

PouchitisPouchitis

What is it?What is it?Why do some patients get it?Why do some patients get it?

Dr. Matt. JohnsonDr. Matt. Johnson

ProctocolectomyProctocolectomy

• UCUC– 10-20% all UC patients10-20% all UC patients– For medical refractory disease or For medical refractory disease or

dysplasiadysplasia

• FAPFAP– Mean age at diagnosis of cancer = 39yMean age at diagnosis of cancer = 39y

History of the IAPouchHistory of the IAPouch

• 1944 Proctocolectomy + Ileostomy 1944 Proctocolectomy + Ileostomy (Strauss + Strauss)(Strauss + Strauss)

• 1969 Intra-Abdominal Ileal Reservoir 1969 Intra-Abdominal Ileal Reservoir (Kock)(Kock)

• 1978 Restorative Proctocolectomy 1978 Restorative Proctocolectomy – (Parks + Nicholls)(Parks + Nicholls)

• 1987 J-Pouch Modification 1987 J-Pouch Modification – (Nicholls)(Nicholls)

• A Normal PouchA Normal Pouch

Pathological changes within a Pathological changes within a normal Healthy Pouchnormal Healthy Pouch

• 6/526/52– plasma cell infiltrationplasma cell infiltration– raised eosinophilsraised eosinophils– Later = lymphocyte infiltrationLater = lymphocyte infiltration

• 6/126/12– Villous atrophyVillous atrophy

• >6/12>6/12– ““Normal adaptation” with cell influx stabilizingNormal adaptation” with cell influx stabilizing– Tendency to colonic metaplasia “colonic type Tendency to colonic metaplasia “colonic type

mucosa”mucosa”

Pouchitis SymptomsPouchitis Symptoms

• A) Post Op Stool FrequencyA) Post Op Stool Frequency• B) Rectal BleedingB) Rectal Bleeding• C) Faecal Urgency* +/- CrampsC) Faecal Urgency* +/- Cramps• D) Fever (unusual)D) Fever (unusual)

• * usually due to inflammation at the distal/efferent * usually due to inflammation at the distal/efferent limb of the pouchlimb of the pouch

• There is often poor correlation between symptoms There is often poor correlation between symptoms and either the endoscopic or histology appearance and either the endoscopic or histology appearance

Endoscopic Findings in Endoscopic Findings in PouchitisPouchitis• OedemaOedema• GranularityGranularity• FriableFriable• Loss of vascularLoss of vascular• Mucosal exudatesMucosal exudates• UlcerationUlceration

• These changes can be patchyThese changes can be patchy• Inflammation is often worse in the Inflammation is often worse in the

posterior/dependent segment of the pouch)posterior/dependent segment of the pouch)

• PouchitisPouchitis

Histological ChangesHistological Changes

• 1986 Moskowitz Histopathological Scoring System1986 Moskowitz Histopathological Scoring System• > 4/12 = Pouchitis> 4/12 = Pouchitis

• AcuteAcute– Acute PMNC infiltration into the crypts and Acute PMNC infiltration into the crypts and

surface epithelium (3/3)surface epithelium (3/3)– Superficial ulceration (3/3)Superficial ulceration (3/3)

• ChronicChronic– Chronic (lymphocytic) infiltration (3/3)Chronic (lymphocytic) infiltration (3/3)– Degree of villous atrophy (3/3)Degree of villous atrophy (3/3)

Pouchitis Disease Activity Index,Pouchitis Disease Activity Index,Sandborn 1994 Sandborn 1994 >7 = Acute Pouchitis>7 = Acute Pouchitis

Who Gets It ?Who Gets It ?

UCUC

Clinical PatternClinical Pattern

• After 6/12 patients fall into 3 After 6/12 patients fall into 3 catagories;catagories;

• 1) No pouchitis (45%)1) No pouchitis (45%)

• 2) Relapsing + Remiting Pouchitis 2) Relapsing + Remiting Pouchitis (42%)(42%)

• 3) Chronic Pouchitis (13%)3) Chronic Pouchitis (13%)– > 4/52> 4/52– Recurrent courses of antibiotics neededRecurrent courses of antibiotics needed

Association with UCAssociation with UC

• Pouchitis occurs almost exclusively in UC patients Pouchitis occurs almost exclusively in UC patients • Pathologically similar to UCPathologically similar to UC• Backwash IleitisBackwash Ileitis

– Seen in 75% of pancolitis resection specimensSeen in 75% of pancolitis resection specimens– prevalence correlates closely with disease extentprevalence correlates closely with disease extent– It is a distinct entity from backwash ileitis It is a distinct entity from backwash ileitis

• Similar responses to smoking Similar responses to smoking – 25% non-smokers, 33% ex-smokers, 6% smokers25% non-smokers, 33% ex-smokers, 6% smokers

• Extra GI Manifestations of IBD Extra GI Manifestations of IBD – especially PSC, though no obvious association with especially PSC, though no obvious association with

ArthropathyArthropathy

• Treatment response similar with 5ASAs and SteroidsTreatment response similar with 5ASAs and Steroids

Aetiology of PouchitisAetiology of Pouchitis

• Flora (10x as much bacteria as cells in the body)Flora (10x as much bacteria as cells in the body)– Prox jejunum 10Prox jejunum 103 3 cfu/g of dry weight stoolcfu/g of dry weight stool– Ileum 10Ileum 105-85-8

– Caecum 10Caecum 1011-12 11-12

• The proportion of anaerobes increases distally The proportion of anaerobes increases distally – Ileostomy = Flora increase by *80 Ileostomy = Flora increase by *80

• Anaerobe : aerobe (remains the same)Anaerobe : aerobe (remains the same)– Caecum = 1000:1 Caecum = 1000:1 – Ileal Pouch = 100:1Ileal Pouch = 100:1

• Colonic type flora (bacterioides, bifidobacteria)Colonic type flora (bacterioides, bifidobacteria)

• Bacterial profiles are genetically determined and remain stable lifelongBacterial profiles are genetically determined and remain stable lifelong• Pouchitis = no diff in bacterial qualitative + quantitative stool studiesPouchitis = no diff in bacterial qualitative + quantitative stool studies• Response to Abs suggests a pathogenic role for bacteriaResponse to Abs suggests a pathogenic role for bacteria• Diverting ileostomy is therapeutic in CD (recurs 6/12 post re-anastamosis)Diverting ileostomy is therapeutic in CD (recurs 6/12 post re-anastamosis)

Aetiology of PouchitisAetiology of Pouchitis

• StasisStasis– Does affect flora but no obvious relationship foundDoes affect flora but no obvious relationship found

• Intra luminal Intra luminal – Bile Acids = No obvious relationshipBile Acids = No obvious relationship– Short Chain Fatty Acids (SCFAs) Short Chain Fatty Acids (SCFAs)

• produced by anaerobes fermenting endogenous produced by anaerobes fermenting endogenous mucus and undigested CHO in the large bowelmucus and undigested CHO in the large bowel

• Important in colonic epithelial metabolism, healing Important in colonic epithelial metabolism, healing and proliferation (?protective)and proliferation (?protective)

• The quantity in pouch faeces is inversely proportional The quantity in pouch faeces is inversely proportional to the degree of villous atrophy to the degree of villous atrophy

• Depleted levels seen in active UCDepleted levels seen in active UC

Immunology of IBDImmunology of IBD

•1) Humoral1) Humoral•2) Cell Mediated2) Cell Mediated•3) Cytokines3) Cytokines•4) Flora Tolerance4) Flora Tolerance•5) Innate Immunity5) Innate Immunity

Humoral ImmunityHumoral Immunity

• Normal patients have IgA plasma cells provide Normal patients have IgA plasma cells provide immunity by immune exclusionimmunity by immune exclusion

• IBD the increased number of plasma cells IBD the increased number of plasma cells secreting all classes of Ig (IgG*30, low IGA)secreting all classes of Ig (IgG*30, low IGA)– IgG1 (UC>CD) = increases the activation of the IgG1 (UC>CD) = increases the activation of the

complement cascade in response to soluble complement cascade in response to soluble protein Agprotein Ag

– IgG2 (CD>UC) = increases in response to CHO IgG2 (CD>UC) = increases in response to CHO + bacterial Ags+ bacterial Ags

•CD = ASCA, anti-Saccharomyces cerevisiaeCD = ASCA, anti-Saccharomyces cerevisiae•UC = pANCA, perinuc antineut cytoplasmicUC = pANCA, perinuc antineut cytoplasmic

Cell Mediated ImmunityCell Mediated Immunity

• Plasma cells are clearly increased + activated Plasma cells are clearly increased + activated in IBD in IBD

• The relative contributions of B cells and the T The relative contributions of B cells and the T cell subtypes remain unclear in IBDcell subtypes remain unclear in IBD

• T cells play a more important role in CD (esp T cells play a more important role in CD (esp CD4cell)CD4cell)

• Markers of T cell activity includeMarkers of T cell activity include•4F24F2 CD+UCCD+UC•T9 (transferrin receptors)T9 (transferrin receptors) CD+UCCD+UC•CD25CD25 CD onlyCD only

Cytokine ImmunityCytokine Immunity

• Opsonisation > Phagocytosis > Presentation to CD4 cellsOpsonisation > Phagocytosis > Presentation to CD4 cells• Naïve T cells in the presence of;Naïve T cells in the presence of;

– IL 12 IL 12 develop into Th1 cellsdevelop into Th1 cells– IL 4 IL 4 develop into Th2 cellsdevelop into Th2 cells

• Th0Th0 clones clones (secrete a mixture of Th1 + Th2)(secrete a mixture of Th1 + Th2)• Th1Th1 (predominantly secrete IL2, IL12, TNFa and (predominantly secrete IL2, IL12, TNFa and IFNgIFNg))

- activates inflammatory and cytotoxic - activates inflammatory and cytotoxic responseresponse

- induces delayed type hypersensitivity- induces delayed type hypersensitivity• Th2Th2 ((IL 4IL 4, 5, 9, 10, 13), 5, 9, 10, 13)

- decreased in active disease- decreased in active disease - activates Ab production- activates Ab production

• Tr1Tr1 (regulatory) (regulatory) (IL10, IFNg)(IL10, IFNg) - gene deletions of IL10 +IL2 lead to IBD- gene deletions of IL10 +IL2 lead to IBD

Immunology of IBDImmunology of IBD

•Pro-Inflammatory CytokinesPro-Inflammatory Cytokines

– TNFaTNFasecreted by macrophages (increased in secreted by macrophages (increased in UC)UC)

– IL1IL1 ““– IL6IL6 ““– IL8IL8 recruitment of neutrophils (in CD+ UC)recruitment of neutrophils (in CD+ UC)

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

IBD Immune Balance

Immune ToleranceImmune Tolerance

• The host immune system is able to distinguish The host immune system is able to distinguish between normal and pathogenic organismsbetween normal and pathogenic organisms

• Tr1 cells are likely to play a critical role in Tr1 cells are likely to play a critical role in maintaining immunosuppressive constraints on maintaining immunosuppressive constraints on the highly antigenic bowel environment the highly antigenic bowel environment

• Tolerance towards normal flora is broken in Tolerance towards normal flora is broken in active IBD (Duchmann 1995)active IBD (Duchmann 1995)

• Normal bacteria flora is required to generate Normal bacteria flora is required to generate inflammation (IL10 –ive mice = Madsen 1999) inflammation (IL10 –ive mice = Madsen 1999)

Innate ImmunityInnate Immunity

• Phylogenetically older than the specific active Phylogenetically older than the specific active Tcell response Tcell response

• Uses receptors on APC (antigen presenting Uses receptors on APC (antigen presenting cells)cells)

• PRR = Pattern recognition receptorsPRR = Pattern recognition receptors

• TLR = Toll-like receptorsTLR = Toll-like receptors

– Leading to release of pro-inflammatory CKs Leading to release of pro-inflammatory CKs (IL1, IL6, TNFa) (IL1, IL6, TNFa)

– This acute phase response is independent This acute phase response is independent of a specific Tcell responseof a specific Tcell response

Therapy for PouchitisTherapy for Pouchitis

• There appears to be a bacterial precipitantThere appears to be a bacterial precipitant• These bacteria appear to be Metronidazole sensitive G- These bacteria appear to be Metronidazole sensitive G-

anaerobes anaerobes

• Antibiotics (Metronidazole or Ciprofloxacin)Antibiotics (Metronidazole or Ciprofloxacin)

• Probiotics VSL 3 / 4 (Gionchetti 1994)Probiotics VSL 3 / 4 (Gionchetti 1994)– 4* lactobacilli4* lactobacilli– 3* bifidobacteria3* bifidobacteria– 1* Strep Salivarius1* Strep Salivarius– 1* S. thermaphiles1* S. thermaphiles

• Remission can be maintained in 92.5% at 9/12 Vs 0% in Remission can be maintained in 92.5% at 9/12 Vs 0% in the placebo groupthe placebo group

Therapeutic MechanismsTherapeutic Mechanisms

• AntibacterialsAntibacterials

• Probiotics probably work by altering the hosts Probiotics probably work by altering the hosts immune response at the GI mucosal surfaceimmune response at the GI mucosal surface– Increased IgA + IL 10 (anti-inflammatory)Increased IgA + IL 10 (anti-inflammatory)– Decreases IFNg and TNFa (pro-inflammatory)Decreases IFNg and TNFa (pro-inflammatory)– Induces T cell shift towards Th2 (anti-inflammatory)Induces T cell shift towards Th2 (anti-inflammatory)– May competitively inhibit adherence of potentially May competitively inhibit adherence of potentially

pathogenic bacteriapathogenic bacteria– Produce SCFAs and vitamins Produce SCFAs and vitamins