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Human Diseases > W6 26 gastointestinal tract pathology > Flashcards

W6 26 gastointestinal tract pathology Flashcards

1
Q

What is GORD?

A

Gastro-oesophageal reflux disease is leakage of the gastric contents into the distal oesophagus

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2
Q

What are the aetiological causes of GORD and what do they do?

A

Alcohol
Cigarettes
Obesity
Pregnancy
Hiatus hernia

These reduce the tone of the lower oesophageal sphincter causing reflux of gastric contents into the distal oesophagus.

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3
Q

What is the pathogenesis of GORD?

A
  1. Gastric acid in the distal oesophagus injures the lining squamous epithelium
  2. Damage associated molecular patterns (DAMPs) produced by the damaged epithelium stimulate an acute inflammatory response
  3. Squamous epithelium is infiltrated by eosinophils and neutrophils
  4. Epithelium’s undergoes basal zone hyperplasia
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4
Q

What are the consequences of GORD?

A

Oesophageal ulceration
Haematemesis and melena (from bleeding)
Oesophageal stricture - caused by excess healing and repair response leading to fibrosis leading to stricture
Barret oesophagus

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5
Q

What is Barret oesophagus?

A

Intestinal metaplasia within the squamous epithelium of the distal oesophagus.
Metaplastic response of the distal oesophagus to chronic irritation from refluxed acid.

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6
Q

Aetiology of Barret oesophagus

A

GORD

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7
Q

What is the pathogenesis of Barret oesophagus? (Pg289 img)

A

New columnar epithelium is generated from re-programmed stem cells, which may arise from:
1. Squamous epithelium (present in the base of normal oesophageal mucosa)
2. Submucosal oesophageal glands (normally present beneath squamous epithelium)
3. Stomach

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8
Q

Why is Barret oesophagus bad?

A

It is pre-malignant. Majority of oesophageal adenocarcinomas are associated with Barret oesophagus. Associated with accumulation of mutations (dysplasia).

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9
Q

What is gastritis?

A

Inflammation of the stomach

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10
Q

Why does gastritis occur (pathogenesis)?

A

Gastritis occurs due to a breakdown in the normal balance between the damaging (acid) and defensive forces acting in the gastric mucosa.

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11
Q

What are the damaging forces of the stomach?

A

Gastric acidity
Peptic enzymes

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12
Q

What are the defensive forces of the stomach?

A

Protective layer of mucus
Mucus has neutral pH due to secretion of bicarbonate
Rich blood supply in lamina propria washes away any acid - consequently damage to gastric epithelium bleeds a lot
Prostaglandins synthesis drives bicarbonate secretion and increases vascular perfusion

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13
Q

What is acute gastritis?

A

Infiltration of gastric mucosa by neutrophils (acute inflammation’

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14
Q

What is the aetiology for acute gastritis, factors causing direct damage to gastric epithelium?

A

NSAIDs - direct damage and reduces PG synthesis
Alcohol
Radiotherapy and chemotherapy
Splanchnic vasoconstriction during severe physiological stress leading to ischaemia
Gastric acid hypersecretion (from vagal nerve stimulation) - bile reflux

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15
Q

What factors cause impaired defence of the gastric epithelium in acute gastritis?

A

Reduced PG synthesis
Splanchnic vasoconstriction leading to increased pH of mucosa
Reduced mucin synthesis in the elderly

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16
Q

What is chronic gastritis?

A

Infiltration of the gastric mucosa by lymphocytes and plasma cells with or without neutrophils
Symptoms less severe but more persistent than acute gastritis

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17
Q

Aetiology of chronic gastritis

A

Helicobacter-associated gastritis
Autoimmune chronic gastrritis
Reactive gastritis - chronic bile reflux, NSAIDs

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18
Q

What are the virulence factors of Helicobacter pylori that allow it to survive in the hostile stomach?

A

Flagella - allowing motility in mucus
Urease - generating ammonia from urea, elevating local pH
Adhesins - allows bacteria to adhere to foveolar cells
Toxins - eg cytotoxic-associated gene A (CagA)

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19
Q

What is the pathogenesis of autoimmune gastritis?

A
  1. Immune-mediated damage to parietal cells in the gastric body (H+/K+ ATPase is the main autoantigen)
  2. Reduced gastric acid secretion (achlorhydria)
  3. Hypergastrinanemia and G-cell hyperplasia in antrum
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20
Q

How is autoimmune gastritis associated with pernicious anaemia?

A

Parietal cell loss also produces intrinsic factor which binds vitamin B
Parietal cell loss leads to vitamin B deficiency leading to megaloblastic anaemia

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21
Q

Describe the mechanisms behind the pathogenesis of autoimmune gastritis.

A
  • Driven by CD4+ T cells, driving an inflammatory response, (TH1 or TH17) response, releasing IFN-y
  • Auto reactive CD8 cells will damage parietal cells either by Fas/FasL interactions or perforin punching holes in membrane allowing granzyme enzymes to come in, causing apoptosis
  • Stimulates B cells to make antibodies, including those against intrinsic factor
  • The loss of acid production due to damage of parietal cells leads to hyperplasia of the gastrin producing cells (ECL), which could lead to tumour
  • Inflammation within the wall of the stomach can alter the healing and repair functions, MMOs degrading the ECM and mediating fibrosis development
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22
Q

What are the consequences of gastritis?

A

Acute peptic ulceration
Peptic ulcer disease
Intestinal metaplasia
Gastric cancer

23
Q

Where does acute peptic ulceration occur, and does it heal?

A

Can occur throughout stomach and duodenum
No fibrosis or scarring
Tends to heal within a few days if stimulus is removed

24
Q

Where does peptic ulcer disease occur and does it heal?

A

Tends to occur in proximal duodenum and gastric antrum
Associated with fibrosis and scarring
Tends to be chronic recurring lesions

25
Q

What are some causes of acute peptic ulceration?

A

NSAIDs
Sepsis/shock/trauma - reduced perfusion of blood vessels since defensive barrier compromised
Severe burns
Intracranial disease

26
Q

What are some causes of peptic ulcer disease?

A

H pylori infection
NSAIDs
Rarities like Zollinger-Ellison syndrome

27
Q

What is intestinal metaplasia?

A

Under conditions of chronic irritation, goblet epithelium can show intestinal metaplasia. Characterised by goblet cells within the gastric epithelium. Signifies increase risk of progression to cancer.

28
Q

What are most tumours in gastric cancer?

A

Most tumours are adenocarcinomas (gland-forming).
Often an ulcerated tumour.

29
Q

What is a major risk factor for gastric cancer?

A

Helicobacter-associated chronic gastritis is a major risk factor. Chronic gastritis/inflammation can lead to tumours.

30
Q

What is inflammatory bowel disease?

A

Chronic inflammation of the bowel resulting from inappropriate mucosal immune activation.

31
Q

Classifications of IBD

A

Ulcerative colitis
Crohns disease

32
Q

What is the pathogenesis of inflammatory bowel disease? (Pg295)

A
  1. Defects in the mucosal epithelial barrier of colonic epithelium (eg loss of tight junctions) allows influx of bacterial components (from gut lumen) to the lamina propria
  2. Inappropriately sustained mucosal T-cell response, including TH1, TH17, and possible TH2 subtypes
  3. Immune-mediated damage to the mucosa and (in somer cases) the deeper tissues
33
Q

What happens in health if bacteria get into the cells from the gut lumen?

A

Immune system should not mount a significant inflammatory response, as this is not helpful for the organism. Bacteria are helpful for gut function in the lumen but not in cells.

34
Q

What is the T-cell response that occurs in IBD (stage 2 of pathogenesis)?

A

Dendritic cells and APCs will process bacterial antigens, display them in MHC class II molecules, which will activate naive CD4+ T cells. TH cells have various subsets with different functions.
In IBD, multiple subsets are activated at the same time, having diverse functions on the bowel:
- formation of the TH1 cells in response to IL12, characterised by the production of IFN-y, activating macrophages, destroying bacteria and surrounding host tissues
- macrophages also produce acute inflammatory mediators eg TNF eliciting inflammation at the site and damage to surrounding tissues
- TH17 response characterised by IL17 and neutrophil recruitment. Neutrophils abundant in IBD.
- TH2 response will drive fibrosis for healing, by TGF-b

35
Q

What cells are abundant in IBD?

A

Neutrophils

36
Q

How is the morphology of the bowel different in IBD?

A

Normally crypts are long and thin, uniform and close together like test tubes.
In IBD, glands are convoluted, various shapes due to damage by inflammation and healing distortion.

37
Q

What parts of the bowel does UC affect? (IMG PG297)

A

Only the large bowel
In cross section it shows mucosal ulceration, with preserved islands of epithelium in between, forming pseudo-polyps.
Inflammation limited to the mucosa, not extending to the muscularis propria layer, so no thickening or fibrosis of the deep tissues of the bowel.

38
Q

What parts of the bowel does Crohn’s disease affect? (IMG PG297)

A

Often has a patchy distribution that can go all the way from the rectum to the oesophagus.
In cross section it is associated with deep fissuring ulcers rather than shallow
Associated with transmural inflammation, where it extends through the entire thickness of the muscularis propria
Associated with fibrosis and thickening of the walls
Can get a fat wrap - cirrhosis fat wraps around outside of the bowel

39
Q

What is there the presence of in crohn’s but not UC which is important for distinction?

A

Microscopically, the presence of granulomas in Crohn’s disease but not UC. Part of the type IV hypersensitivity response.

40
Q

What is the pathogenesis of fibrosis in Crohn’s disease?

A

As a consequence of the bacteria proteins within the lamina propria, there is activation of pathways which stimulate fibrosis. Chiefly among these is TGF-b.
This stimulates production of collagen and scar tissue from activated myofibroblasts.
Under the influence of cytokines and growth factors, these produce ECM, and lays down the collagen that causes the fibrosis.

41
Q

Differences between Crohn’s and UC - table pg299

A

HAVE A READ OF THIS TABLE 299!

42
Q

What are the consequences of inflammatory bowel disease?

A

Diarrhoea, fever, abdominal pain
Toxic megacolon (UC)
Perforation, sometimes due to obstruction of a stricture
Haemorrhage
Strictures and fistulae (Crohn’s)
Cancer

43
Q

What is the aetiology for colorectal cancer?

A

Environmental (predominantly) and genetic causes
Dietary factors:
- low intake of fibre
- high intake of refined carbohydrates
- high intake of fat

44
Q

What is the pathogenesis of colorectal cancer?

A

Stepwise accumulation of genetic alterations

45
Q

How can some mechanisms by dietary factors cause oncogenic alteration predisposing to colorectal cancer?

A

Reduced stool bulk - increased duration of contact between stool and epithelium (more time for carcinogenic substances to be exposed to and cause damage to the DNA)
Altered intestinal microbiome - toxic products from bacterial metabolism
Increased cholesterol and bile production - formation of carcinogens by gut bacteria
Vitamin A, C and E deficiency - reduced free radical scavenger capacity

46
Q

What are the 2 different pathways for colorectal cancer?

A
  1. Adenoma carcinoma pathway
  2. Mismatch repair deficiency pathway
47
Q

What is the adenoma carcinoma pathway?

A

Accumulation of mutations gradually leading to the development of an adenoma and subsequent progression to carcinoma
APC mutated related to beta-catenin
Further mutations eg KRAS, p53

48
Q

What is the mismatch repair deficiency pathway?

A

Defects in mismatch repair proteins, which are important for correcting errors in DNA, where a nucleotide is mispaired (no mutations in genes). So leads to the defective repair of mutations.
Accumulation of further mutations can lead to formation of an adenoma. Mutations tend to accumulate in clusters, forming microsatellite repeats.
Further accumulation leading to carcinoma.

49
Q

What is the role of b-catenin in normal cells?

A

In normal cells, b-catenin would be bound to the cell-surface adhesion molecules (like E cadherin) or it can be bound to a destruction complex which includes the APC protein, which degrades b-catenin.
- When there is stimulation of the receptor pathway on the surface (WNT pathway), this leads to signals that detach APC and the destruction complex from b-catenin. Thus allows b-catenin to get into the nucleus and activation transcription factors which stimulate proliferation.
- This might be appropriate in response to injury of the epithelium for example

50
Q

What happens if there is a defect in the APC?

A

If there is a defect in the APC, we get constitutive long term activation of the b-catenin in the absence of any stimulating factor acting on the receptor. The consequence of this is uncontrolled cell proliferation.

51
Q

What are the consequences of colorectal cancer?

A

Bowel obstruction
Perforation
Rectal bleeding (left sides)
Iron deficiency anaemia (right sided)
Weight loss - through systemic affects of cancer, mediated by cytokines like TNF

52
Q

What is adenocarcinoma?

A

Gland forming (in microscopy)

53
Q

Difference in formation of well differentiated adenocarcinomas in comparison with poorly differentiated ones?

A

Well differentiated adenocarcinomas tend to form well-formed large glands, whereas ooorly differentiated ones tend to form solid islands and small gland structures within the stroma

Human Diseases (75 decks)

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