L16 Chronic infection and carcinogenesis

Question 1

What is peptic ulcer disease?

Answer 1

Break in the lining of stomach/small intestine

Question 2

What are the symptoms of peptic ulcer disease?

Answer 2

Upper abdominal pain, belching (gas/bloating), bomiting, weight loss, bleeding

Question 3

What is the history behind the disease being discovered?

Answer 3

Used to be related with stress, treated with antacid. Barry Marshall proved it was du to infection by drinking a culture, followed by antibiotics.

Question 4

What is the organism behind peptic ulcer disease?

Answer 4

Helicobacter pylori (H. Pylori)

Question 5

What is the H. Pylori disease spectrum? Time?

Answer 5

Wide range, asymptomatic to deadly
After infection, it can take decades to get serious forms of disease progression.
Superficial active gastritis -> days-weeks
chronic active gastritis -> months to years
antral gastritis/pangatritis/chronic active gastritis -> decades
dyodenal gastric metaplasia/atrophy intestinal metaplasia/chornic active gastritis -> decades

Finally leads to duodenal ulcers/gastric cancer/ulcer/MALT lymphoma

Question 6

How does H. pylori survive in stomach?

Answer 6

Uses urease to produce a ‘cloud’ of ammonia to neutralise the stomach acid

Question 7

What structure of H. pylori gives it its motility?

Answer 7

Flagellum to swim fast through mucus layer
Helical shape for screw like movement which allows it to penetrate the mucus

Question 8

How does H. Pylori enter cells?

Answer 8

It raises pH, causing the mucus to de-gel as it enters in a crok-screw motion

Question 9

How does H. Pylori attach to epithelial cells?

Answer 9

BabA adhesion molecule attaches to cell via Lewis b carbohydrate receptor.

Question 10

How does H. pylori evade the immune system?

Answer 10

It’s LPS is poorly recognised by TLR4, and therefore less cytokines are produced. Its flagellum subunits are also poorly recognised by TLR5.

Question 11

How does H. Pylori inhibit the immune system?

Answer 11

• Vacuolating toxin A (VacA) inhibits phagosomal maturation, T/B proliferation, and iNOS generation.
• Coating with plasminogen and cholesterol (to mask)

Question 12

What is an ulcer?

Answer 12

A lesion in the mucous membrane

Question 13

What is a peptic ulcer?

Answer 13

Ulcer lining the stomach or duodenum, where hydrochloric acid and pepsin are present

Question 14

Which cells are found in the fundus (top of the stomach)?

Answer 14

Mucus secreting cells, parietal, and ECL cells (from top to bottom)

Question 15

What cells are found in the antrum (bottom of the stomach)?

Answer 15

G cells, ECL cells, D cells (aka SST cell) - from top to bottom.

Question 16

Chronic infection and inflammation –> Loss of function of cells in the inflamed area –> causes peptic ulcer disease

Question 17

Describe the process by which acid is produced in the stomach, and how this process is stopped/controlled.

Answer 17

Thought of food causes G cells to produce gastrin. Gastrin acts on ECL and P cells. ECL cells produce histamine which acts on P cells. P cells produce acid. Build up of acid causes D cells to produce somatostatin, which acts on G cells to inhibit production of gastrin. Thus, stop acid production.

Question 18

What happens when there is an infection in the antum?

Answer 18

Inflammation of the epithelial cells in the fundus, loss of function of D cells which produce somatostatin. No inhibition to stop acid production. Results in increased gastrin and acid hypersection. This causes acid to leak out into the duodenum –> inflammation and then duodenal ulcer

Question 19

What happens when there is an infection in the body/corpus/fundus of the stomach?

Answer 19

Inflammation, causing loss of function of Parietal cells. Loss of acid production. Resulting in gastric ulcer and acid hyposecretion.

Question 20

H. Pylori exposure is…

Answer 20

carcinogenic (leads to cancer) - rare

Question 21

What is a cag pathogenicity island?

Answer 21

It’s a region of DNA (part of bacteria) involved in pathogenicity. 30kb of 28 genes which make up a type 4 secretion system (T4SS), secrete proteins into the cell, pili-like structure.

Question 22

What does cagA stimulate?

Answer 22

Phosphorylation cascades once inside the gastric cell

Question 23

What does cagA induce in the cell?

Answer 23

Apoptosis, morphological change, cytokine production, cell proliferation

Question 24

cagA promotes release of ___ from __

Answer 24

ROS from mitochondria

Question 25

CagA stimulates which cell death pathway?

Answer 25

Oncogenic pathway (tend to cause tumour)

Question 26

What determines whether H. pylori will infect the top or bottom of the stomach?

Answer 26

• Duodenal ulcers are more common in india than japan
• gastric cancers are more common in japan than india
• There is something inherently different about the strains of bacteria which allow them to infect either the top of the bottom of the stomach.

Question 27

What are the H. Pylori virulence factors?

Answer 27

• Flagella for motility through acid and mucous layers
• Produce urease to neutralise acid and can cause damage to gastric epithelial cells
• Have outer proteins that alow them to adhere to host cells
• Produce VacA exotoxin caysing gastric mucosal injury
• Produces secretory enzymes –> causing damage to epithelial cells
• 4 secretion system, pump effector proteins inside - cagA.

Question 28

What condition does H. Pylori lead to for most people?

Answer 28

Chronic gastritis

Question 29

What factors is it influenced by?

Answer 29

Environmental - smoking and drinking
Host factors - gene variance, immune response, etc.

Question 30

What are some treatments available for gastritis?

Answer 30

First-line therapy - one week “triple therapy” - proton pump inhibitor and antibiotics such as clarithromycin and amoxicillin.