Pathogenesis of Diseases of the Large

Intestine

Dr Paul L. Crotty

Department of Pathology

AMNCH, Tallaght

October 2008

Large intestine: by aetiology• 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 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

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 granulomasCrohn’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 populationMZ 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 diseasecounterbalanced 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 suppressionof the inflammatory response to normal gut flora?

New NOD2 data supportive of this theory

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

Ulcerative colitis

Pseudopolyps in ulcerative colitis

Mucosal-based inflammation and ulcerationUlcerative 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 concordanceHLA association

? Infection ? Allergy ? Immune dys-regulation

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

Ulcerative colitis

Complications:

Fulminant colitis: Toxic megacolon

Extra-intestinal manifestationsIncluding primary sclerosing cholangitis

Significant risk of dysplasia and malignancyespecially with pan-colitis, long duration

Large intestine: by aetiology• 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 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

Viral enterocolitis

Rotavirusinfects enterocytes lining villi in small intestinenear-normal/minimal shortening of villimain effect is absence of lactase => osmotic diarrhoea

Norwalk virusAdenovirusAstrovirus

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

Shigella

=> stimulates its own endocytosis

=> proliferates within cell

=> rapid cell death, lysis

=> infects adjacent cells

Large intestine: by aetiology• 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• 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

• 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• 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

• 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

• Complications

• Inflammation

• Abscess formation

• Perforation

• Bleeding