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Flashcards in lecture 15 Deck (29):
1

What are the infective causes of ulcer-inflammatory conditions of the intestines?

Viral
- rotavirus
- norovirus

Bacterial
- enteroinvasive E. coli, enteropathogenic E. coli, enterohemorrhagic E. coli, Shigella, Salmonella, Campylobacter, Yersinia enterocolitica, Clostridium difficile, Mycobacterium tuberculosis

Parasitic
- ameobic, Schistosomiasis, Giardia lamblia

2

What are non-infective causes of ulcero-inflammatory conditions of the intestines?

- inflammatory bowel disease (IBD)
-- ulcerative colitis
-- crohn's disease
- ischaemic enterocolitis
- radiation-induced enterocolitis
- drug, chemical, foodstuff related
- immune mediated, e.g. graft vs host disease

3

What is inflammatory bowel disease?

- chronic inflammatory and ulcerating disorders of the gastrointestinal tract due to dysregulated, over-exuberant response to intestinal flora, causing diarrhoea, abdominal pain and rectal bleeding and extraintestinal manifestations
- ulcerative colitis and crohn's disease are the two major forms

4

What is ulcerative colitis?

- a chronic inflammatory disease of the colon, a defining feature of which is involvement of the rectal mucosa and varying portions of the large intestine in continuity with the rectal disease
- usually occurs as a chronic disease with mild to severe exacerbations but occasionally occurs in an acute fulminating form

5

What are clinical features of U.C?

- diarrhoea, blood loss p.r., abdominal pain
- systemic signs such as fever, joint pains and inflammation of the eye

6

What is the gross anatomy of the colon?

- ascending colon
- transverse colon
- descending colon
- sigmoid colon leading to
- rectum

- 3 bands of longitudinal muscle which contract longitudinally, and circular muscle all the way around
- keep colon short to allow redundancy
- haustra = small pouches caused by sacculation as a result of 'purse string longitudinal muscles)

- rectum has smooth muscle right around for extra contraction

- hepatic and splenic flexure

7

What are the macroscopic changes to the colon in UC?

- mucosa - hyperaemic (lots of blood/heavily inflamed), granular or shallow ulceration with mucosal bridges which later re-epithelialise as healing occurs resembling polyps (pseudopolyps)
- colon shortened and without haustra
- wall of normal thickness
- serosa intact
- ileum spared

8

What are the microscopic changes in ulcerative colitis?

Salient features of active disease
1. distorted tubular architecture and irregular mucosal surface with luminal pus
2. goblet cell depletion and reactive hyperplasia of epithelium
3. focal polymorph infiltration of crypt epithelial lining and crypt abscesses
4. increased chronic inflammatory cell content of lamina propria and oedema
5. vascular congestion
6. loss of epithelium with ulceration

salient features of colitis in remission
1. loss of tubular parallelism with branching
2. short tubules, separated from one another and from the muscularis mucosae
3. thickening of the muscularis mucosae
4. Paneth cell metaplasia
5. epithelial dysplasia

9

What is the histology of normal colonic mucosa?

Evenly distributed parallel tubules occupying full depth of mucosa down to m.m.
Tubules replete with goblet cells and light infiltrate of chronic inflammatory cells in lamina propria

10

What is the histology of UC mucosa?

- marked inflammatory activity
- distorted tubular architecture
- loss of mucin from goblet cells
- crypt abscesses
- inflamed tubules eroded surface epithelium and dense inflammatory cell infiltrate in full thickness of lamina propria

11

What part of the colon does UC typically affect?

- characterised as a mucosal disease with marked distortion of tubular architecture, normal submucosa, normal muscle coat and inflamed pericolic fat

12

What is narrowing of the colon due to in UC?

- hypertrophy of muscularis mucosa

13

What is dysplasia in IBD?

- an unequivocal neoplastic transformation of the intestinal epithelium confined by the basement membrane that can be recognised by abnormal cellular and architectural alterations

14

What are the histological features of dysplasia?

- glands lined by cells showing loss of mucin, nuclear enlargement, nuclear pleomorphism, loss of polarity, pseudostratification and abnormal mitoses
- may see villous transformation or glands lying back-to-back
- classified as low or high grade dysplasia

15

What are the factors determining development of carcinoma in UC?

- disease of longer than 10 years duration
- onset of disease in childhood
- severe first attack and evidence of continuing activity
- extent of colitis (pan colitis)

16

When do we do cancer surveillance in UC?

- annual colonoscopy with biopsy after 7 years of disease (now every two or three years)
- colectomy if high grade dysplasia or carcinoma is identified

17

What are the complications if you have ulcerative colitis?

- bleeding
- cancer
- pseudopolyps
- perforation
- deep ulceration: goes into muscle coat where the nerves are, affecting peristalsis, colon dilates, can't force food forward
- leaking fluid, hard to control: can go into shock and die

systemic complications
- inflammation of the eye
- changes in the spinal column that occur in some, but not all, individuals: ankylosing spondylitis
- sclerosing cholangitis
- erythema nodosum
- arthritis
- pyoderma gangrenosum

18

What is crohn's disease?

- chronic inflammatory condition, potentially involving any part of the alimentary tract from mouth to anus; most commonly the distal small intestine and proximal colon, with the rectum frequently spared
- characterised by segmental areas of involvement, with normal intervening bowel and transmural extension of the disease process

19

What are clinical features of CD?

- diarrhoea, abdominal pain and fever
- extraintestinal manifestations may be present
- complications include fistula formation and strictures (fibrous, tight, permanent)

20

What is the anatomic distribution of Crohn's disease?

- small bowel alone 33%
- ileocolic 45%
- colon alone 20%

21

What are the macroscopic features of CD?

- aphthoid ulcers (shallow ulcers that don't heal)
- long or short strictured segments with thickened indurated wall, inflammation of serosa, fibrinous and fibrous adhesions, extension of mesenteric fat around the intestine ('fat wrapping), with normal intervening areas - segmental lesions are called 'skip lesions'
- 'cobble-stone' appearance of mucosa due to oedema and cleft-like ulcers (fissures)
- fissures may extend through the entire wall and into an adjacent loop of bowel, bladder or skin (fistula formation)
- draining lymph nodes are enlarged.

22

What are the microscopic features of CD?

- transmural (full thickness of bowel wall) inflammation with lymphoid aggregates
- oedema with dilation of lymphatics
- granulomas with epitheloid histiocytes and multinucleated giant cells seen in 75% of cases in the bowel wall, and in draining lymph nodes in 25% of cases
- mucosa in affected areas may show pyloric gland metaplasia

23

What are the macroscopic differences between ulcerative colitis and crohn's disease?

UC vs Crohn's
-disease in continuity vs discontinuous 'skip lesions
- ileum spared vs ileum involved in 30%
- granular and ulcerated mucosa vs discretely ulcerated mucosa, cobblestone appearance
- no fissuring vs fissuring
- normal serosa vs serositis common
- no fat wrapping vs fat wrapping prominent
- thin wall vs thick oedematous wall
- muscular shortening of colon, muscularis mucosae hypertrophied vs shortening due to fibrosis
- fibrous strictures rare vs fibrous strictures common
- no spontaneous fistulae vs fistulae in 10%
- pseudopolyposis common vs inflammatory polyposis less common
- anal lesions in less than 25% vs anal lesions in 75%
- malignant change (adenocarcinoma) - 30x greater than general population vs malignant change (adenocarcinoma, lymphoma) - 6x greater than general population
- local complications – dilation (toxic megacolon), perforation, haemorrhage vs local complications – fistulae, strictures, blind loops
- systemic complications - joints, eyes, skin, liver (same)

24

What are the microscopic differences between UC and CD?

UC vs CD
- mucosal disease vs transmural inflammation
- little oedema vs lymphoedema marked
- width of submucosa normal or reduced vs width of submucosa normal or increased by lympoedema and chronic inflammation
- focal lymphoid hyperplasia restricted to mucosa and superficial submucosa vs transmural nodular lymphoid infiltrates
- crapt abscesses very common vs crypt abscesses fewer in number
- marked depletion of goblet cells in active phase vs slight decrease in goblet cells
- paneth cell metaplasia common vs rare
- pyloric metaplasia rare vs common
- no granulomas vs granulomas in 75%
- no fissures vs fissuring ulcers in 25%
- epithelial dysplasia in non-inflamed mucosa vs dysplasia not a feature
- anal lesions - non specific inflammation only vs granulomas present

25

What's the pathogenesis of IBD?

- genetic susceptibility
- luminal antigens
- environmental triggers

26

How does genetic susceptibility predispose to IBD?

Seen through concordance in twins:
- monozygotic: CD = 44-50%, UC = 5 - 14%
- dizygotic: CD = 8%, UC = 0%

- familial occurrence
- clinical pattern of Crohn's disease in families
- polygenic susceptibility
- genome wide search: chromosomes 12>12, 6, 5
- NOD 2 mutations on chromosomes 16 and cytokine cluster region of chromosome 5 in Crohn's disease
- genotype - phenotype correlations

27

What are the environmental risk factors for IBD?

- smoking (inhibits UC, makes CD worse)
- appendectomy (decreases UC, no impact on CD)
- high sanitation level in childhood (0 vs ^^)
- high intake refined carbs (0 vs ^)
- perinatal infections (? vs ^)
- breast feeding (v? vs ?)
- oral contraceptives (^? vs ?)

28

What are the pathways of T-lymphocyte activation?

- when APCs secrete IL-12 you get TH0 --> TH1
- TH1 secrete IFN-gamma, IL-2, TNF: this is cell-mediated granulomas and plays a role in crohn's disease and coeliac disease
- when APCs an excess of IL-4 you get TH2
- TH2 secrete IL-4, IL-5, IL-10: this is hypersensitivity, and plays a role in food allergy, helminth infection and probably UC
- if APCs secrete IL-10 you get TH3/Treg1
- these secrete TGF-beta and IL-10 which induce tolerance --> this is the normal response

29

What is the role of mutant NOD2 in the pathogenesis of Crohn's disease?

- cannot block toll-like receptor 2 (TLR2)
- peptidoglycans on normal bacteria (microflora) of our gut stimulate TLR2
- normally a product of these peptidoglycans stimulate another pathway involving NOD2 that stop TLR2 from mounting an immune response
- however when mutant it is unable to do this so we develop inflammation in response to gut microflora