inflammatory disease: lower gi tract paul l. crotty department of pathology trinity medical student...
TRANSCRIPT
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Inflammatory Disease: Lower GI tract
Paul L. Crotty
Department of Pathology
Trinity Medical Student Lecture
October 2007
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Outline of Lecture
Mechanism of diarrhoea
Chronic Inflammatory Bowel Disease
Crohn’s disease
Ulcerative colitis
Infective enterocolitis
Vascular disease
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Fluid dynamics
Food intake: ~2 litres/d
Saliva: ~1 litre/d
Gastric secretions: ~2 litres/d
Bile: ~1 litre/d
Pancreas: ~2-3 litres/d
Small intestinal secretions: ~1 litre/d
Total 9-10 litres/d
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Fluid dynamics
Re-absorption:
Small intestine: ~6 litres/d
Large intestine: normally ~2-3 litres/d
but with capacity to increase up to ~6 litres/d
Average stool weight 200-250g/d
of which 65-85% is water
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Mechanisms of Diarrhoea
Secretory: increased secretions: persists after fasting. Examples: cholera, some viral infections
Osmotic: some solute present: osmotic retention of fluid in stool, resolves on fasting. Examples: disaccharidase deficiency; some viral infections
Exudative: pus present: ulceration in bowel. Examples: invasive bacterial infection: CIBD
Dysmotility-associated: Examples: Irritable bowel syndrome, hyperthyroidism
Malabsorption: Steatorrhoea
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Chronic Inflammatory Bowel Disease
Most (but not all) can be separated into 1 of 2 patterns: (1) Crohn’s disease(2) Ulcerative colitis
based on clinical, endoscopic and pathological features
important to first exclude infective and ischaemic colitis
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Features of both Crohn’s disease and ulcerative colitis
Idiopathic chronic inflammatory diseasesBoth have acute exacerbations and remissions
Typically onset 15-40 y: (small second peak ~ 65-70y)
- Active inflammation during acute exacerbation- Neutrophils in crypts (cryptitis, crypt abscesses)
- Over time: destruction of mucosal architecture
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Crohn’s disease
- Granulomatous inflammation- May involve any part of bowel- Typically small intestine and/or colon (one third each)- Discontinuous: ‘skip lesions’ typically with rectal sparing - Aphthous ulcers early: linear ulcers later- Transmural inflammation- Wall thickening/strictures with luminal narrowing- Deep fissures/fistulas- Extra-intestinal disease- Probable small increased risk of colorectal carcinoma
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Ulcerative colitis
- NOT granulomatous- Colon only involved (no small bowel involvement)- Extends variable distance in continuity from rectum- Rectum always involved- Has well-defined proximal limit- No skip lesions- Broad-based ulcers with pseudo-polyps- Mucosal-based inflammation: NOT transmural- No wall thickening, no strictures,- No fissures , no fistulas- Extra-intestinal disease: also P.S.C.- Significant risk of dysplasia and carcinoma
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Normal colonic mucosa
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Crypt abscesses
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Transmural inflammation, serosal granulomasCrohn’s colitis
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Granulomas in Crohn’s disease
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Fissure in Crohn’s disease
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Normal
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Crohn’s disease
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Crohn’s disease
Crohn: 1932 [Morgagni: 1761: “ileal passion”]initially termed terminal/regional ileitis
- later identified could also have colonic involvement- later still recognised colonic-only pattern of disease
“Idiopathic”: but what do we know about its causes?
Important new information since 2001
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Crohn’s disease
Genetic predisposition:Sibling risk: 15-40x risk of general populationMZ twin concordance: 40-50% DZ twin concordance: 3-7%
Linkage to loci on 16 (IBD1) also chromosome 3, 12
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Crohn’s disease
linkage to locus on chromosome 16: high LOD score ~ 5.8
2001: NOD2 (nucleotide-binding oligomerisation domain)- normal function as signalling protein in macrophages- activates NFkB in response to bacterial LPS
- 40% of Crohn’s disease patients: NOD2 polymorphism- but polymorphism also in ~15% of general population
- heterozygous 2-4x risk/ homozygous 40x risk
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Crohn’s disease
Smoking: 2-3X increased risk of Crohn’s diseasecounterbalanced by decrease in risk of ulcerative colitis
Urban > Rural“Good” hygiene > Poor
? Theory: Delayed exposure to antigens/bacteria
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Crohn’s disease
Is there an infectious agent?
Animal models do not develop disease if kept in a strict germ-free environment
Candidates??Atypical mycobacteria??Measles virus
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Crohn’s disease
Is there immune dys-regulation?
Is there a defect in the normal mechanisms of suppressionof the inflammatory response to normal gut flora?
New NOD2 data supportive of this theory
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Crohn’s disease
Present with pain, variable diarrhoea, feverDiagnosis: Clinical, endoscopy, mucosal biopsies, barium
Complications:Strictures: obstructionFissures: abscessesFistulas: bladder, vagina, skin, entero-entericPeri-anal diseaseMalabsorption (terminal ileal disease, blind loops)Slight increased risk of cancer
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Ulcerative colitis
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Pseudopolyps in ulcerative colitis
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Mucosal-based inflammation and ulcerationUlcerative colitis
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Dysplasia in ulcerative colitis
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Ulcerative colitis
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Ulcerative colitis
Wilks: 1859 claim on first distinction from dysentery
1888: RSM in London debate on aetiology of the disease? Diet ? Infection ? Psychosocial
Genetic: MZ concordanceHLA association
? Infection ? Allergy ? Immune dys-regulation
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Ulcerative colitis
Mucosal inflammation leading to ulcerationChronicity leads to mucosal destruction, regeneration
40% rectum/ recto-sigmoid only40% extends from rectum to point x20% pan-colonic
Presents with diarrhoea, pain, weight lossDiagnosis: Clinical, endoscopy, biopsy
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Ulcerative colitis
Complications:
Fulminant colitis: Toxic megacolon
Extra-intestinal manifestationsIncluding primary sclerosing cholangitis
Significant risk of dysplasia and malignancyespecially with pan-colitis, long duration
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Infective organisms causing diarrhoeaWorld-wide: mortality 5 million /year, most children
Mechanisms by which infectious agents cause diarrhoea:(1) Pre-formed toxin in food
no live organisms ingested e.g. C botulinum, some S. aureus
(2) Live organisms: Non-invasive:
(a) organisms colonise gut and produces toxine.g. V. cholerae, C. difficile, some E. coli
(b) organisms bind to brush border e.g. Cryptosporidium
Invasive:(a) mucosal e.g. Shigella, most Salmonella, some E. coli
(b) deeper layers e.g. S. typhi, Yersinia
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Viral enterocolitis
Rotavirusinfects enterocytes lining villi in small intestinenear-normal/minimal shortening of villimain effect is absence of lactase => osmotic diarrhoea
Norwalk virusAdenovirusAstrovirus
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Winter vomiting bug
SRSVs (small round structured viruses)Non-cultivatable gastro-enteritis virusesrelated to Norwalk virus
1968: Norwalk, Ohionausea, vomiting, diarrhoea x 24hvolunteers: stool filtrates‘Norwalk agent’ <36nm, ether-resistant, heat stable
1972: 27nm virus on EM: specific antibody present
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Winter vomiting bug
ssRNA: classified as calicivirus (HuCV)first member of calicivirus group was Norwalk virus
Error-prone replication: 1 mutation per replication
Consensus PCR identifies >90% of strains (in UK)Different epidemics are slightly different in sequence
Infects enterocytes (short incubation)In animal models: causes enterocyte apoptosis
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NLVs
Genogroup I Norwalk virus (Hu/NLV/NV/8fIIa/1968/US) NV Southampton virus (Hu/NLV/SV/1991/UK) SV Desert Shield virus (Hu/NLV/DSV395/1990/SR) DSV Cruise ship virus (Hu/NLV/184-01388/1990/US) CSV
Genogroup II Snow Mountain agent (Hu/NLV/SMA/1976/US) SMA Hawaii virus (Hu/NLV/HV/1971/US) HV Mexico virus (Hu/NLV/MX/1989/MX) TV Toronto virus (Hu/NLV/TV/TV24/1991/CN) TV Lordsdale virus (Hu/NLV/LV/1993/UK) LV Grimsby virus (Hu/NLV/GRV/1995/UK) LV Gwynedd virus (Hu/NLV/GV/1993/UK) GV White River virus (Hu/NLV/WRV/290-12275/ 1994/US) WRV
SLVs Sapporo virus (Hu/SLV/Sa/1982/JA) Sa Manchester virus (Hu/SLV/Man/1993/UK) Sa Parkville virus (Hu/SLV/Park/1994/US) PV London virus (Hu/SLV/Lond/29845/1992/UK) LoV
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Vibrio cholerae
Toxin productionincludes binding units, catalytic unit
=> binds to glycolipid on surface of enterocyte=> catalytic unit taken up into enterocyte
=> activated intracellularly=> stimulates G-protein=> increases intracellular cAMP=> actively stimulates secretion of Na, Cl, water
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Shigella
=> stimulates its own endocytosis
=> proliferates within cell
=> rapid cell death, lysis
=> infects adjacent cells
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Pseudo-membranous colitis
Broad spectrum antibiotic
=> normal gut flora includes Clostridium difficile=> other bacteria eradicated by antibiotics=> Clostridium difficile proliferates=> selection of toxin producing forms
enterotoxin (A) and cytotoxin (B)=> disrupt cytoskeleton,toxin A also pro-inflammatory
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Vascular disease of the intestines
SMA, IMA -> mesenteric arcadescollateral supplywatershed areas: splenic flexurevenous drainage
acute, subacute, chronic
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Vascular disease of the intestines
arterial thrombosis atherosclerosis, dissection, hypercoagulation
arterial embolism atherosclerosis, arrhythmias, SBE
venous thrombosis hypercoagulation
generalised hypoperfusion hypotensive shock, CCF
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Vascular disease of the intestines
Transmural infarction acute occlusion (arterial or venous,
thrombotic or embolic) -> acute abdomen perforation/gangrene if untreated
Mucosal/submucosal infarction acute/subacute hypoperfusion can mimic acute colitis
Fibrosis and mucosal atrophy chronic, strictures: can mimic Crohn’s
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Crohn’s disease
- Granulomatous inflammation- May involve any part of bowel- Typically small intestine and/or colon (one third each)- Discontinuous: ‘skip lesions’ typically with rectal sparing - Aphthous ulcers early: linear ulcers later- Transmural inflammation- Wall thickening/strictures with luminal narrowing- Deep fissures/fistulas- Extra-intestinal disease- Probable small increased risk of colorectal carcinoma
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Ulcerative colitis
- Not granulomatous- Colon only involved (no small bowel except backwash)- Extends variable distance in continuity from rectum- Rectum always involved- Has well-defined proximal limit- No skip lesions- Broad-based ulcers with pseudo-polyps- Mucosal-based inflammation: not transmural- No wall thickening, no strictures,- No fissures , no fistulas- Extra-intestinal disease: also P.S.C.- Significant risk of dysplasia and carcinoma
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Summary
Mechanism of diarrhoea
Chronic Inflammatory Bowel Disease
Crohn’s disease
Ulcerative colitis
Infective enterocolitis
Vascular disease