Transcript Pathogenesis of Disease of the Large Intestine

Pathogenesis of Diseases of
the Large Intestine
Dr Paul L. Crotty
Department of Pathology
AMNCH, Tallaght
October 2008
Large intestine: by aetiology
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Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease
Acquired
Infection: Infective enterocolitis (viral, bacterial, protozoal)
Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse
Chemical/Toxic: NSAIDs
Circulatory disturbances: Ischaemic bowel disease
Immunological disturbance:
Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis
Idiopathic:: Crohn’s disease, ulcerative colitis
Psychosomatic: :
Pre-neoplastic/ Neoplastic:
– Adenoma -> adenocarcinoma
– CIBD -> dysplasia -> adenocarcinoma
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
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
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: idiopathic chronic inflammatory
bowel disease
Dysmotility-associated: Examples: Irritable bowel
syndrome, hyperthyroidism
Malabsorption: Steatorrhoea
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
Features of both Crohn’s disease and ulcerative colitis
Idiopathic chronic inflammatory diseases
Both 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
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
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
Normal colonic mucosa
Crypt abscesses
Transmural inflammation, serosal granulomas
Crohn’s colitis
Granulomas in Crohn’s disease
Fissure in Crohn’s disease
Normal
Crohn’s disease
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?
Crohn’s disease
Genetic predisposition:
Sibling risk: 15-40x risk of general population
MZ twin concordance: 40-50%
DZ twin concordance: 3-7%
Linkage to loci on 16 (IBD1) also chromosome 3, 12
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
Crohn’s disease
Smoking: 2-3X increased risk of Crohn’s disease
counterbalanced by decrease in risk of ulcerative colitis
Urban > Rural
“Good” hygiene > Poor
? Theory: Delayed exposure to antigens/bacteria
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
Crohn’s disease
Is there immune dys-regulation?
Is there a defect in the normal mechanisms of suppression
of the inflammatory response to normal gut flora?
New NOD2 data supportive of this theory
Crohn’s disease
Present with pain, variable diarrhoea, fever
Diagnosis: Clinical, endoscopy, mucosal biopsies, barium
Complications:
Strictures: obstruction
Fissures: abscesses
Fistulas: bladder, vagina, skin, entero-enteric
Peri-anal disease
Malabsorption (terminal ileal disease, blind loops)
Slight increased risk of cancer
Ulcerative colitis
Pseudopolyps in ulcerative colitis
Mucosal-based inflammation and ulceration
Ulcerative colitis
Dysplasia in ulcerative colitis
Ulcerative colitis
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 concordance
HLA association
? Infection ? Allergy ? Immune dys-regulation
Ulcerative colitis
Mucosal inflammation leading to ulceration
Chronicity leads to mucosal destruction, regeneration
40% rectum/ recto-sigmoid only
40% extends from rectum to point x
20% pan-colonic
Presents with diarrhoea, pain, weight loss
Diagnosis: Clinical, endoscopy, biopsy
Ulcerative colitis
Complications:
Fulminant colitis: Toxic megacolon
Extra-intestinal manifestations
Including primary sclerosing cholangitis
Significant risk of dysplasia and malignancy
especially with pan-colitis, long duration
Large intestine: by aetiology
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Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease
Acquired
Infection: Infective enterocolitis (viral, bacterial, protozoal)
Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse
Chemical/Toxic: NSAIDs
Circulatory disturbances: Ischaemic bowel disease
Immunological disturbance:
Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis
Idiopathic:: Crohn’s disease, ulcerative colitis
Psychosomatic: :
Pre-neoplastic/ Neoplastic:
– Adenoma -> adenocarcinoma
– CIBD -> dysplasia -> adenocarcinoma
Infective organisms causing diarrhoea
World-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 toxin
e.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
Viral enterocolitis
Rotavirus
infects enterocytes lining villi in small intestine
near-normal/minimal shortening of villi
main effect is absence of lactase
=> osmotic diarrhoea
Norwalk virus
Adenovirus
Astrovirus
Vibrio cholerae
Toxin production
includes 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
Shigella
=> stimulates its own endocytosis
=> proliferates within cell
=> rapid cell death, lysis
=> infects adjacent cells
Large intestine: by aetiology
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Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease
Acquired
Infection: Infective enterocolitis (viral, bacterial, protozoal)
Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse
Chemical/Toxic: NSAIDs
Circulatory disturbances: Ischaemic bowel disease
Immunological disturbance:
Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis
Idiopathic:: Crohn’s disease, ulcerative colitis
Psychosomatic: :
Pre-neoplastic/ Neoplastic:
– Adenoma -> adenocarcinoma
– CIBD -> dysplasia -> adenocarcinoma
Antibiotic-associated
(pseudomembranous) colitis
• Clostridium difficile in normal flora
• When other bacteria eradicated by
antibiotics, C. difficile proliferates
• Selection of toxin-producing forms
• Enterotoxin (A) and cytotoxin (B)
• Disrupt cytoskeleton, inflammation
• Cell death, confluent ulceration
Antibiotic-associated
(pseudomembranous) colitis
Large intestine: by aetiology
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Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease
Acquired
Infection: Infective enterocolitis (viral, bacterial, protozoal)
Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse
Chemical/Toxic: NSAIDs
Circulatory disturbances: Ischaemic bowel disease
Immunological disturbance:
Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis
Idiopathic:: Crohn’s disease, ulcerative colitis
Psychosomatic: :
Pre-neoplastic/ Neoplastic:
– Adenoma -> adenocarcinoma
– CIBD -> dysplasia -> adenocarcinoma
Ischaemic bowel disease
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SMA, IMA -> mesenteric arcades
collateral supply
watershed areas: splenic flexure
venous drainage
• acute, subacute, chronic
Ischaemic bowel disease
• Arterial thrombosis
– atherosclerosis, dissection, hypercoagulation
• Arterial embolism
– atherosclerosis, arrhythmias, SBE
• Venous thrombosis
– hypercoagulation
• Generalised hypoperfusion
– hypotensive shock, CCF
Ischaemic bowel disease
• 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
Large intestine: by aetiology
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Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease
Acquired
Infection: Infective enterocolitis (viral, bacterial, protozoal)
Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse
Chemical/Toxic: NSAIDs
Circulatory disturbances: Ischaemic bowel disease
Immunological disturbance:
Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis
Idiopathic:: Crohn’s disease, ulcerative colitis
Psychosomatic: :
Pre-neoplastic/ Neoplastic:
– Adenoma -> adenocarcinoma
– CIBD -> dysplasia -> adenocarcinoma
Diverticular disease
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Diverticulum: blind pouch off GI tract
Incidence: 40-50% in >60 years in West
Diet low in fibre -> decreased stool volume
Chronic increased intraluminal preseeure
Acquired ‘blow-out’ diverticuli
– at points of focal weakness in wall of colon
where vessels cross muscle layer
Diverticular disease
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Complications
Inflammation
Abscess formation
Perforation
Bleeding