Inflammatory Disease: Lower GI tract

Paul L. Crotty

Department of Pathology

Trinity Medical Student Lecture

October 2007

Outline of Lecture

Mechanism of diarrhoea

Chronic Inflammatory Bowel Disease

Crohn’s disease

Ulcerative colitis

Infective enterocolitis

Vascular disease

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: CIBD

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

important to first exclude infective and ischaemic colitis

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?

Important new information since 2001

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

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

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

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

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

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

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

Vascular disease of the intestines

SMA, IMA -> mesenteric arcadescollateral supplywatershed areas: splenic flexurevenous drainage

acute, subacute, chronic

Vascular disease of the intestines

arterial thrombosis atherosclerosis, dissection, hypercoagulation

arterial embolism atherosclerosis, arrhythmias, SBE

venous thrombosis hypercoagulation

generalised hypoperfusion hypotensive shock, CCF

Vascular disease of the intestinesTransmural infarction

acute occlusion (arterial or venous, thrombotic or embolic) -> acute abdomen

perforation/gangrene if untreatedMucosal/submucosal infarction

acute/subacute hypoperfusion can mimic acute colitis

Fibrosis and mucosal atrophy chronic, strictures: can mimic Crohn’s

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 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

Summary

Mechanism of diarrhoea

Chronic Inflammatory Bowel Disease

Crohn’s disease

Ulcerative colitis

Infective enterocolitis

Vascular disease