Disease of the small bowel Flashcards
1
Q
what is coeliac disease
A
- immunologically mediated disease in genetically susceptible individuals
- driven by gluten found in wheat, rye and barley
- results in chronic inflammation of the small bowel mucosa
2
Q
treatment for coeliac disease
A
gluten free diet
3
Q
prevalence of coeliac disease
A
1:100
4
Q
what is the genetic association with coeliac disease
A
HLA-DQ2 and HLA-DQ8
5
Q
at what age does coeliac disease manifest itself
A
can be any time in life from infancy to late adulthood
- two peaks though - infancy and 30-50
6
Q
where is most of the proliferation occurring of the cells in the mucosa
A
in the proliferative zone (above the stem cells)
7
Q
what do paneth cells secrete
A
defensin - important against infection - helps keep microbiota in control
8
Q
what is the normal ratio to IELs to enterocyte
A
1 per 5 enterocytes
9
Q
what type of T cell are IELs
A
CD8 (innate)
10
Q
where are IELs found
A
on the surface of the villi and some in the crupts
11
Q
where are CD4 cells found in the duodenum
A
in the lamina propria
12
Q
which parts of the small intestine does coeliac disease affect the most
A
the duodenum and the jejenum (only severe cases affect the ileum)
13
Q
features of stage/type 1 coeliac disease
A
increased ratio of IELs to enterocytes
14
Q
features of stage/type 2 coeliac disease
A
- crypts enlarge to keep up with the increased number of cells being lost (crypt hyperplasia)
- increased ratio of IELs to enterocytes
15
Q
features of stage/type 3 coeliac disease
A
- crypts are large (crypt hyperplasia) and surface is flat due to atrophy and apoptosis (villous atrophy)
- increased ratio of IELs to enterocytes
16
Q
which zone of the crypt enlarges during
- increased ratio of IELs to enterocytes
A
the proliferative zone
17
Q
what are some other causes of IELs, villous atrophy and crypt hyperplasia other than coeliac disease
A
- tropical sprue
- small bowel bacterial overgrowth (common in immune deficiencies)
- common variable ID
- autoimmune eteropathy
- drugs
18
Q
clinical presentation of coeliac disease
A
- GI upset: diarrhoea, bloating, abdominal cramps, flatulence
- anaemia
- vitamin deficiencies
- malabsorption of nutrients
- failure to thrive as an infant
- osteoporosis
- lethargy, migraines, infertility, mouth ulcers
- increased prevalence of autoimmune diseases
- can be completely ASYMPTOMATIC
19
Q
what is the “look” of the diarrhoea in a person with coeliac disease
A
greasy –> because they are not absorbing nutrients (especially fat)
20
Q
4 elements in the pathogenesis of coeliac disease
A
- genetics
- environment
- T cells
- gluten
21
Q
how does the environment contribute to coeliac disease
A
- breast feeding is protective
- timing/amount of gluten introduced to infant diet (too much gluten, too soon –> increases risk)
- infections such as gastroenteritis
22
Q
gluten peptide is rich is which amino acids
A
proline and glutamine
23
Q
what does having a high content of proline in a peptide confer to it
A
makes it hard to digest - some resistance to digestion by intestinal proteases –> certain peptides pass through the intestinal epithelium intact
24
Q
what happens to the peptides that pass through the epithelial wall intact
A
glutamine is deamidated to glutamate by tissue transglutaminase (tTG)
25
what is special about glutamate
it is highly negatively charged
26
what does glutamate do
binds to HLA-DQ2 in the 4,6 and 7 positions by its negative charges --> presented to CD4 T cells
27
what happens when glutamate is presented to CD4 T cells
activated:
- produce cytokines (IL-4, TNF-alpha and IFN-gamma) --> damages the enterocytes
- help plasma cells to produce anti-tTG
28
what is the significance of anti-tTG produced by plasma cells
it is a test for coeliac disease
| can be seen in the blood
29
what is the major cause of damage to enterocytes in CD?
the activation of CD8 cells!! (CD4 activated damage is minor compared to this)
30
what is the role of the innate immunity for coeliac disease
gliadin causes the enterocytes to:
- start expressing atypical binding molecules (MIC-A and MIC-B)
- secrete IL-5 --> makes CD8 cells express NKG2D receptor --> binds to the MIC ligands on enterocytes --> secretes IFN-gamma and activates APOPTOSIS
31
what is the receptor on the CD8 cells called that binds to MIC A and MIC B
NKG2D
32
What are the atypical binding proteins expressed by enterocytes when exposed to gliadin
MIC A and MIC B
33
how does coeliac disease give you a higher chance of getting cancer
the CD8 cells, when they are activated indirectly through gliadin, become autoreactive, and proliferate at a higher level (can become malignant) --> cancer (T cell malignancy)
34
2 mechanisms that cause coeliac disease
activation of CD8 cells --> apoptosis
| activation of CD4 cells --> apoptosis
35
how do you diagnose coeliac disease
- serological testing (tTG, deamidated gliadin peptide)
- HLA-DQ haplotyping
- small bowel biopsy (best!)
36
long term risks of untreated coeliac disease
- osteoporosis (due to lack of absorption of vitamin D - fat soluble vitamin)
- autoimmune disease
- increased risk of cancer (small bowel lymphoma, small bowel adenocarcinoma, oesophageal cancer)
37
macroscopic look of chronic gastroenteristis
- no rugae in the bastric body of the stomach
- little haemorrhages on the surface
- antrum is normal
38
what protects the stomach epithelium from HCl
mucus cells produce:
- mucus
- bicarbonate --> into the mucus which neutralizes the HCl
- surface of mucus has phospholipid bilayer (repels water)
Right next to the epithelial layer the pH is neutral - keeping cells alive
39
what is intrinsic factor important for?
the absorption of B12
40
what endrocrine cells are located in the antrum of the stomach
G cells and D cells
41
what stimulates the secretion of somatostatin?
gastrin
42
what does somatostatin do?
- inhibits gastrin secretion by G cells
- inhibits HCl secretion by parietal cells
- inhibits histamine secretion by ECL cells
43
Where is gastrin produced and what does gastrin do?
made by G cells and activates parietal cells to produce HCL
44
what three factors do parietal cells need to produce HCl
Histamine (from ECL cells)
ACh (from enteric neurons)
Gastrin (from G cells)
45
what things can break down the mucus layer on the epithelial cells of the stomach
- bacteria
- NSAIDs
- bile (refluxed)
- alcohol
46
what happens if HCl is able to get through to the epithelial cells of the stomach (mucus has been degraded)
HCl goes into the lamina propria --> activates mast cells to produce histamine --> inflammation (oedema and inflammatory infiltrate)
47
normal role of prostaglandins and the mucus barrier of the stomach
- inhibit acid secretion
- stimulate HCO3 and mucus secretion
- increase mucosal blood flow
48
most common causes of acute gastritis
- chemical injury (alcohol or drugs - NSAIDS, aspirin, iron tablets and other drugs)
- stress
- shock
- burns
- head injury
- septicaemia
- staph food poisoning
49
what is acute gastritis due to
- breakdown of the gastric barrier directly or
| - microcirculatory changes accompanying shock or sepsis (reduced in blood flow --> ischaemia)
50
what is the inflammatory response in acute gastritis
inflammatory mediators result in vasodilatation, oedema, haemorrhage and erosions --> acute haemorrhagic or erosive gastritis
(oedema first --> then if continues --> erosion)
51
how long does acute gastritis last for
24-48 hours
52
histology of chronic gastritis
- large accumulation of lymphocytes, plasma cells and eosinophils
- cells atrophy
53
difference between an ulcer, an acute erosion and chronic erosion
ulcer - defect above the muscularis mucosae
acute erosion - defect down into the muscularis mucoase
chronic erosion - defect penetrates through the submucosa and into the serosal layer --> base becomes fibrosed
54
what are Curling ulcers
ulcers in the proximal duodenum associated with severe burns/trauma
55
what are Cushing ulcers
gastric and duodenal ulcers in persons with intracranial injury
56
what are NSAID-induced ulcers due to
inhibition of cyclooxygenase and prostaglandin synthesis which normally promotes bicarbonate secretion, mucin synthesis, vascular perfusion and inhibition of HCl secretion
57
3 main causes of chronic gastritis
ABC!
- autoimmune
- bacterial - H. pylori
- chemical
58
what is autoimmune gastritis
- immune mediated destruction of acid secreting tubules followed by atrophy (total loss of parietal cells)
- consequent achlorhydria (no acid production) and loss of intrinsic factor
- leads to pernicious anaemia (B12 deficiency)
59
where is autoimmune gastritis seen
in the gastric corpus mucosa (antrum spared)
60
what is a rare consequence of autoimmune gastritis
loss of acid and parietal cells --> hypergastrinaemia --> linear and nodular ECL hyperplasia --> carcinoidosis
61
what causes autoimmune gastritis
circulating autoantibodies to parietal cell membrane and intrinsic factor and gastrin receptor
62
why does pernicious anaemia occur with autoimmune gastritis
intrinisc factor antibody secreted into the gastric lumen --> can complex with vitamin B12 --> prevents its absoprtion via receptors in the terminal ileum
63
how does autoimmune gastritis lead to hypergastrinaemia
D cells are not stimulated to make simvostatin (required for inhibition of G cells)
64
what causes the proliferation of ECL cells in autoimmune gastritis
hypergastrinaemia --> ECL proliferation
65
what causes chemical gastritis
- reflux of bile and alkaline duodenal juice due to altered antro-duodenal motility or gastro-jejunostomy
- long term use of NSAIDs
66
what happens in chemical gastritis
direct mucosal injury --> disruption of the mucus layer and gastric barrier --> epithelial dequamation with compensatory foveolar hyperplasia with elongation and tortuosity of gastric pits, vasodilatation and oedema and fibromuscular hyperplasia of the LP and only mild inflammatory cell infiltration --> erosions/ulceration
67
How does H. pylori survive in the GI system
it colonises the area under the mucus barrier (neutral pH)
- motility by flagella
- can live in very low oxygen tensions
- adhesins that make it stick to the epithelium and not be washed away
- urease - breaks down urea into ammonia --> can neutralise HCl
68
what does H pylori acute gastritis cause
neutrophilic gastritis --> infiltration with chronic inflammatory cells
69
what is the sequence from chronic gastritis to cancer
normal mucosa --> chronic gastritis --> atrophic gastritis --> intermediate metaplasia --> dysplasia --> adenocarcinoma
70
two major patterns of H. pylori gastritis
- antrum predominant
| - pan gastritis
71
gastric and duodenal pathology of antrum predominant H. pylori gastritis
```
gastric:
- chronic inflammation
- polymorphs
duodenal:
- gastric metaplasia
- active chronic inflammation
```
72
what happens to the acid output in antrum-predominant H. pylori gastritis
increased
73
gastric and duodenal pathology of pan-gastritis - H. pylori gastritis
```
gastric:
- chronic inflammation
- polymorphs
- atrophy
- intestinal metaplasia
duodenal = normal
```
74
acid output in pangastritis - H. pylori gastritis
reduced
75
which gastritis can lead to B cell lymphoma
H. pylori pan gastritis
76
What are some diseases associated with H. pylori infection
- peptic ulcer disease
- gastric adenocarcinoma
- gastric B-cell lymphoma of MALT
- iron deficiency anaemia
- atrophic gastritis
77
is H. pylori the more common cause of duodenal ulcer or gastric ulcer
duodenal ulcer
78
ratio of the prevalence between duodenal and antrum peptic ulcer disease
D:A = 4:1
79
4 histological layers of chronic peptic ulcer floor
- exudate of fibrin, neutrophils and necrotic debris
- narrow zone of fibrinoid necrosis
- zone of cellular granulation tissue
- zone of fibrosis including endarteritis and hypertrophied nerves
80
complications of peptic ulcer disease
- perforation
- haemorrhage
- penetration into adjacent organ
- stenosis
81
how does stenosis occur from peptic ulcer disease
due to cicatrisation or contraction of fibrous scar --> pyloric canal stenosis
