Unit 9: Major Peptic Ulcer

Question 1

What is a peptic ulcer?

Answer 1

A discontinuation in the mucosa of the digestive tract, typically found in the stomach (gastic ulcer) or as a duodenal ulcer

Question 2

Describe how NSAIDs can be damaging to the gastric mucosa?

Answer 2

NSAIDs - inhibit cox-1 and cox-2 enzymes, this inhibits the conversion of arachidonic acid into prostanoids.
In particular prostaglandin E2 is reduced.
Prostaglandin E2 binds to EP2/3R on ECL cells to reduce the production of histamine.
Therefore, in the absence of PGE2 histamine release is unihbited, leading to more gastric acid secretion via histamine action on parietal cells.
PGE2 also acts on mucus neck cells and surface lining cells to secrete bicarbonate ions and mucus - these protective substances are lost with NSAID use.
Prostaglandins also maintain mucosal blood flow, helping to supply bicarbonate ions and remove H+.
COX-2 selective NSAIDs - lower risk as less effect of PGE2

Question 3

What does H.pylori look like on a gram stain?

Answer 3

Gram negative spiral shaped bacterium

Question 4

What are the typicall symptoms of an acute H.pylori infection?

Answer 4

Majority of individuals are asymptomatic

Question 5

How is H.pylori normally transmitted?

Answer 5

Gastro-oral
Fecal-oral route

Question 6

With reference to h.pylori virulence factors describe how h.pylori is able to colonise the stomach?

Answer 6

1.Is trasmitted by the fecal oral route to enter the stomach.
2. Urease on the surface of h.pylori breaks urea down to ammonia, ammonia reacts with HCL in a neutralisation reaction increasing the pH
3. This allows h.pylori to migrate through the stomach acid layer to the mucus layer.
4. H.pylori secretes mucinases and proteases to degrade the mucus layer
5. Oligosaccharides aid adhesion to the epithelial layer
5. Virulence factors VacA, HP-NAP and CagA are released infliciting damage and triggering inflammation.

Question 7

Describe the role of CagA in causing damage from H.pylori infection?

Answer 7

Injected into host epithelial cells
Results in IL-8 secretion which acttracts neutrophils and monocytes, which are activated by HP-NAP.
Activated secrete reactive oxygen species damaging epithelial cell membrane, causing apoptosis of cells.
Also indirect damage from inflammation.

Question 8

Describe how CagA from h.pylori infection leads to cancer?

Answer 8

CagA gene injection into host cell, interfere with host cell DNA, resulting in turning on of oncogenes (EGFR)and loss of function in tumour suppressor genes (e-cadherin).
Results in loss of cell integrity and structure

Question 9

Describe the damage that VacA from h.pylori infection causes?

Answer 9

Is a pore-forming toxin, produces vacuoles in the cell membrane of epithelial cells in the stomach.
Results in apoptosis of the epithelial cells.

Question 10

Describe how h.pylori can lead to ulcer formation?

Answer 10

1. Expose epithelium to gastric acid
2. Increase gastric acid secretion
3. Direct damage of epithelial cells contributes to erosion of the epithelial layer

Question 11

What are the two mechanism by which h.pylori can increase stomach acid secretion?

Answer 11

1. Inflammatory mediators and damage to D cells inhibit somatostatin production, leads to disinhibited gastrin release from G cells stimulating acid secretion
2. Ammonium hydroxide (high pH) produced by the action of h.pylori induced urease, stimulates pariteal cells to secrete gastric acid.

Question 12

Explain why PPI must be taken for longer than antibiotics in successful treatment of h.pylori infection?

Answer 12

Antibiotics kill bacteria faster
During infection, increased number of parietal cell, PPIs must be taken until the number of parietal cells decreases to ensure limited acid secretion to prevent a repeat of the ulcer
This process takes longer.

Question 13

What is the reaction carried out by h.pylori urease?

Answer 13

Converts urea and water to
ammonia and carbon dioxide

Question 14

What are the non-invasive methods of testing for h.pylori infection?

Answer 14

Serological test (on bloods) - to detect IgG antibodies
13C-Urea breath test
Stool antigen test - immunoassay such as indirect ELISA against

Question 15

What are the invasive tests to identify a h.pylori infection?

Answer 15

Endoscopy to get a biopsy sample
Biopsy urease test - place in medium of urea and monitor for pH change
Histology - giemsa stain
Culture -

Question 16

What conditions must be followed for a 13-C urea breath test? Why?

Answer 16

No antibiotics for 4 weeks before
No antacids immediately before
No PPIs/H2 receptor antagonists for 2 weeks before

Ensure high acid content in the stomach, ensure no reduction in some population of H.pylori (later reproliferate) - leads to optimal urease expression so less likley to have a false negative result.

Question 17

What is the process involved in a C-13 Urea breath test?

Answer 17

1. Breath into tube to collect sample of CO2
2. Take 200ml drink of citric acid, take a 50mL drink containing a solution of C-13 Urea
3. Wait 30 minutes
4. Breath into tube to collect breath sample
5. Test for level of raised labelled carbon by isotope mass spectrometer.

Question 18

If PPI were unable to be administered, what alternative medication, with reference to their mechanism of action, could be prescribed?

Answer 18

H2 receptor antagonist - block action of histamine on parietal cells
Antacids - to neutralise the stomach acid.
Proglumide - competitive antagonist as CCK2R on parietal cells
Misoprostol - analogue of PGE2 agonist of EP2/3R on ECL cells to inhibit histamine production, increase bicarbonate and mucus secretion.
Atropine - competitive antagonist at M3 receptors.

Question 19

Draw a diagram to show the normal physiological process of acid secretion

Answer 19

Question 20

What is the mechanism of action of magnesium trisilicate in treatment of peptic ulcers?

Answer 20

Is an antacid
Reacts slowly with HCl to produce MgCl2 and silica acid H4Si3O8.
Silica acid then degrades to form metasilic acid H2SiO3 and silicon dioxide SiO2.
This picture can absorb pepsin and protect the ulcer from acid and peptic attack.
This provides longer term temporary relief (as does not alter the process of acid secretion)
Firms protective precipitate layer on stomach lining

Dose: 10-20ml for an adult, 3 times a day between meals and again before bed.
Can cause diahorrea.

Question 21

What is the mechanism of Aluminium Hydroxide in a peptic ulcer case?

Answer 21

Acts as an antacid to neutralise HCl producing aluminium chloride salts,
to prevent further acidic damage/erosion of the ulcer
Reacts further with phosphate ions in the GI tract to produce insoluble aluminium phosphate (AlPO4) which coats the stomach to provide immediate relief.
This is immediate relief.

Question 22

What anatomical regions of the stomach are parietal cells normally found?

Answer 22

Fundus and the cardia

Question 23

What is the mechanism of action of PPIs?

Answer 23

It adminstered orally, is basic and is a pro-drug.
Absorbed into bloodstream
Unionised so able to easily cross cell membranes, as a base is attracted to the acidic environment surrounding the parietal cell canaliculi
In this area the PPI is protonated, changes from a sulfoxide to a sulfenic acid, this form is not able to easily cross cell membranes
Leads to an accumulation of drug between the canaliculi of the parietal cell
Forms a disulfide bond with a cysteine residue in the proton pump H+K+ ATPase - this covalent bond is irreversible
This creates an inactive enzyme complex, unable to secrete H+ into the lumen of the stomach
Stomach H+ conc decreases and pH increases.

Question 24

What is the difference between esomeprazole and omeprazole?
Why does this make a difference to the medication you choose to prescribe?

Answer 24

Esomeprazole - s enantiomer only
Omeprazole - racemate

R and S enantiomers are metabolised in the liver differently, S enantiomers have a higher oral bioavailability and a more predictable effect so are considered the better enantiomer to prescribe.

Question 25

What is the mechanism of bismuth in the treatment of H.pylori?

Answer 25

Is taken as bismuth subsalicylate - relativly insoluble so acts directly in the stomach. Reacts in stomach to form bismuth compounds:
Offers three mechanism of benefits:
1. antimicrobial action against H.pylori - inhibit protein, cell wall and ATP synthesis, inhibit virulence factors such as urease and protease
2. Induction of mucosal protective factors such as bicarbonate and PGE2, inhibits pepsin (bismuth subgallate)
3. Formation of protective coating - glycoprotein-bismuth complex

Can be taken over the counter

Question 26

When might bismuth treatment be offered to a patient with a H.pylori infection?

Answer 26

Concerns that patient is allergic to clarithromycin
Concern that H.pylori is resistant to clarithromycin

Question 27

What is the first line of treatment and the guidance for this by NICE for a patient with a H.pylori positive peptic ulcer?

Answer 27

PPI
Amoxicillin
Clarithromycin or metronidazole - choose the cost-effective treatment, and consider previous exposure to antibiotics.
To be given twice daily for seven days

Question 28

What is the second option of treatment for patients with a H.pylori peptic ulcer infection from NICE?

Answer 28

PPI
Clarithromycin
Metronidazole
To be given to those who are allergic to penicillin, Give for 7 days twice daily

Question 29

What is the third option of treament for a patient with a H.pylori peptic ulcer from NICE?

Answer 29

To be given if patient is allergic to penicillin and had a previous exposure to clarithromycin
PPI
Bismuth
Metronidazole
Tetracycline

Question 30

What is the mechanism of action of metronidazole?

Answer 30

Antimicrobial for anaerobic bacteria and parasites
The nitro group is reduced by the ferrodoxin or falvodoxin enzyme only found in target organism
This creates free nitrile radicals that are able to bind to and oxide DNA and electron transport proteins in the mitochondria.
This damages DNA, prevents DNA replication and ATP production and has cidal acitivity

Question 31

What is the mechanism of action of clarithromycin?

Answer 31

Is a macrolide
Binds to the 23sRNA of the 50s subunit of the ribosome, prevents the translocation of aminoacyl tRNA,hence protein production is inhibited, this is baceteriostatic activity (may be cidal depending on conditions).

Question 32

What is the mechanism of action of amoxicillin?

Answer 32

Is a beta lactam antibiotic
Contains a beta lactam ring that mimics D-ala-D-ala, binds to transpeptidase enzyme ( a penicillin binding protein) and inhibits the cross linking of proteoglycan.
This decreases cell wall integrity, bacteria dies due to osmotic lysis.

Question 33

What is the mechanism of action of tetracyclin?

Answer 33

Is a broad spectrum polyketide antibiotic
Diffuses through the bacterial membrane
Binds reversibly to the 30s subunit of the bacterial ribosome, inhibits the binding of aminoacyl tRNA to ribosome acceptor site
This inhibits translation hence no protein production
May also have some effect on 50s and cell membrane integrity.

Question 34

What are the side effects of antacids?

Answer 34

Diahorrea/constipation
Flatulence/wind
Stomach cramps
Feeling sick or vomitting

Question 35

What are the side effects of esomeprazole?

Answer 35

All PPIs: abdominal pain, constipation, diahorrea
Esomeprazole: aggression, agitation and bronchospasm

Question 36

What are the side effects of amoxicillin?

Answer 36

Nausea and diahorrea
Less common and concerning: skin rash (indicate an allergic reaction), pale poo and dark urine (indicate liver problems) and yellowing of eyes.

Question 37

What are the side effects of metronidazole?

Answer 37

Common: Nausea, vomitting, diahorrea, metallic taste in mouth
Less common: blood conditions such as bleeding gums, tiredness and mouth ulcer, liver problems yellowing eyes

Question 38

What are the side effects of tetracyclin?

Answer 38

Nausea, vomiting, diahorrea, black and hairy tongue, sore throat, dizziness, headache or rectal discomfort.

Question 39

What is the standard triple therapy to H.pylori treatment?

Answer 39

Clarithromycin
PPI
Amoxicillin or metronidazole

Question 40

What are the barriers to successful treatment of H.pylori?

Answer 40

Increasing resistance to antibiotics used - rapid mutation rate in bacteria and exchange of genes between populations and species
Poor patient compliance - not finishing the course of antibiotics
Ineffective eradication of H.pylori - antibiotic course too short or incorrect combination
Problems with drug availability and cost

Question 41

What are some new alternative treatments for H.pylori induced peptic ulcers?

Answer 41

Developing new drug targets to overcome antibiotic resistance
Developing bacteriophages
Probiotics - yoghurts or supplements
Requires suspecitibility based therapy - requires colonising infection to test before adminstering.

Question 42

What antibiotics has H.pylori started to show resistance against and by what method?

Answer 42

Macrolides, riframycins, tetracyclin and beta lactams - mutation of target
Nitroimidazole, nitrofurans - mutatino of bacterial nitroreductases
Levofloxacin - mutation of gyraA

Question 43

What virulence factors are associated with h.pylori virulence effects?

Answer 43

VacA
CagA

Question 44

How does VacA from h.pylori lead to cancer?

Answer 44

Activates oncogenes such as RGFR and MET

Question 45

How does CagA from h.pylori lead to cancer?

Answer 45

Triggers inflammation - leading to oncogene activation, abberant hypermethylation turning of TSG, production of ROS?RNS leading to DNA breakage.
Also recruiters - tumour associated macrophages to the area to promote cancer
Causes miRNA alterations.

Question 46

Describe the process by which a peptic ulcer forms.

Answer 46

1. H pylori colonises the stomach
2. Mucinases and proteases dissolve the mucin layer of the stomach exposing the vulnerable epithelial cells to stomach acid and digestive enzymes (peptin)
3. Urease - increased pH. H.pylori induced damage to D cells - leads to increased H+ secretion from parietal cells - increases quantity and decreasing pH of stomach acid
4. PAMPs from H.pylori and CagA influcne trigger inflammation of the area causing indirect damage to epithelial cells
5. THe vulnerable epithelial cells are eroded by gastric acid and enzymes, necrotic epithelial cells are shredded leading to ulceration in the mucosa layer
6. Acute ulceration typically leads to erosion of the mucosa layer only
7. Chronic ulercation typically extends down to the muscularis mucosa layer and development of fibrous tissue at the bottom of the ulcer.

Question 47

What are the three main complications of a peptic ulcer?

Answer 47

Haemorrhage - erosion of a blood vessel naturally present or capillary from granulation tissue found at base during healing process
Penetration - Erosion through the stomach wall allows content to escape into the peritoneum, can lead to sepsis.
Gastric outlet obstruction - malfunction of repair process, edema or fibrous scar tissue blocks the passage or narrows the pylorus.

Question 48

A patient presents with pain in the epigastric region what organs should be considered?

Answer 48

Stomach
Liver
Duodenum
Pancreas

Question 49

What blood vessels is most commonly eroded causing hemorrhage in a proximal duodenal ulcer?

Answer 49

Gastroduodenal (branch of common hepatic)

Question 50

What are the common symptoms of peptic ulcers?

Answer 50

Nausea - block passage of food through the digestive tract, increase intrabdominal pressure
Belching or bloating
Burning pain in the abdomen - activation of submucosal plexus, ENS
Heartburn - acid reflux into oesophagus
Loss of appetite - psychological pain associated with eating
Upper abdominal tenderness on examination

Question 51

What symptoms of a peptic ulcer can indicate more serious complications?

Answer 51

Dark/bloody stools - (hemorrhage into GIT)
Unexplained weight loss - perforation or cancer
Vomitting or vomiting blood - obstruction or hemorrhage
Persistent abdominal pain

Question 52

Describe how pain related to meal times can differentiate between a gastric and a duodenal ulcer?

Answer 52

Duodenal - pain relief during eating, worsens 2-3 hours after = immediate during meal, pyloric sphincter closes to allow chyme time to digest in the stomach - reduces passage of stomach acid into duodenal, after meal sphincter opens as peristalsis in the distal stomach means pressure in the pylorus is greater than in the antrum so sphincter opens - causing acid leakage and pain

Gastric - pain during meal, protein stimulates acid secretion, expose lumen of stomach to more acid.

Question 53

Explain why night pain is common in peptic ulcers?

Answer 53

When stomach is full acid preferentially acts on chyme
When empty stomach lining is vulnerable to acid
Lack of neutralising effects of food in the stomach, no urea produced to be broken down, neutralisation reacts occur.

Question 54

What are some risk factors for h.pylori infection?

Answer 54

Crowded areas
Poor hygiene /sanitation
Contaminated water supply
Living in close contact to someone with h.pylori

Question 55

What lifestyle factors can increase risk of peptic ulcers?

Answer 55

Smoking
Alcohol
Caffeine

Question 56

What are the expected follow ups and outcomes from a h.pylori infection?

Answer 56

Advised to avoid NSAID use, recommend paracetamol over ibuprofen, is NSAID is required reduce dosage and time span and given with a PPI.

Should return 6-8 weeks after eradication treatment started to retest for H.pylori and review symptoms

Question 57

Why is the duodenal prone to ulceration?

Answer 57

Under normal physiological conditions the duodenum is exposed to reduce concentrations and quantity of stomach acid than the stomach, therefore the duodenum has a reduced mucin covering meaning it is easier to dissolve so epithelial cells are more likely to be exposed to damage.

Question 58

What are the histological changes in the stomach lining when a peptic ulcer forms?

Answer 58

Lack of debris in ulcer - due to mechanical digestion, churning motion of the stomach
Acute and chronic inflammation features simultaneously.
Leukocytes - mainly neutrophils (purple colour in epithelium)
Granulation tissue - thin-walled capillaries, fibroblasts and leukocytes
Coagulation necrosis
Fibrosis - thicker pink collagen deposits, typically at the bottom of the ulcer

Question 59

What are the gross pathophysiological features of a peptic ulcer?

Answer 59

Range from mm to centimeters in size. Must be bigger than 5mm in diameter.
Acute ulcers tend to have regular borders, chronic ulcers have elevated borders due to chronic inflammation
Depressed base, sharply punched out look
Clean base - no debris.

Question 60

What part of the stomach has H.pylori likely colonised why?

Answer 60

Antrum - higher pH than rest of stomach due to lower concentration of parietal cells
Lesser curvature - covered in less mucin and bicarbonate than the greater curvature

Question 61

Describe the process of healing at a site of ulceration?

Answer 61

Damaging stimuli removed
H.pylori infection resolves - resolution of inflammation, turn off effect phenotypes, activation of regulatory cells, creation of memory cells and the transition from M1 macrophages to M2 macrophages
M2 macrophages will secrete VEGFs and MMPs. VEGFs act on endothelial cells to stimulate angiogenesis (forming new blood vessels from old) and encourage the migration and proliferation of fibroblasts.
This results in granulation tissue formation - thin-walled capillaries surrounded by primitive fibroblasts secreting ECM components and collagen.
More growth factors will act on the epithelial cells to encourage them to proliferate across the top forming a cap as the epithelial layer is returned.
MMPs will degrade the ECM allowing it to be reformed, fibrin will be replaced by type 3 collagen then type 1 collagen, improving the tensile strength.
In areas of less severe damage where the structure of the ECM remains in tact, regeneration will occur as cells proliferate to replace lost cells
In areas of severe damage to cells so loose proliferative capacity of loss of ECM structure, fibrosis occurs in which there is an increase in collagen and loss of function.

Question 62

How does smoking increase the risk of peptic ulcers?

Answer 62

2x increase in risk
Reduces salivary secretion of EGF and reduces mucosal blood flow - impairs healing
Decreases PGE2 release - decrease mucus and bicarbonate secretion, increased histamine secretion (leading to increased activity of the proton pump)

Question 63

How does caffeine lead to an increased risk of a peptic ulcer?

Answer 63

Acts on type 2 bitter taste receptors - Stimulates gastrin release - increasing acid secretion
Exaggerates gastritis

Question 64

How does alcohol increase the risk of peptic ulcer?

Answer 64

Excessive consumption causes alcoholic gastritis - increased gastrin
Indirect damage to epithelial cells through inflammation - contribute to erosion of mucusa