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GI Week 1 > Lecture 5: Pathophysiology of Peptic Ulcer Disease and Helicobacter pylori Infection > Flashcards

Lecture 5: Pathophysiology of Peptic Ulcer Disease and Helicobacter pylori Infection Flashcards

1
Q

What are the types of gastric mucosal cells?

A
  1. Parietal cells
    • H+ and IF
  2. G-cells (antrum)
    • gastrin
  3. D-cells (throughout stomach)
    • somatostatin
  4. ECL-cells
    • histamine
  5. Chief Cells
    • pepsinogen
  6. Surface epithelial cells
    • mucus and bicarbonate
  7. Mucus neck cells
    • mucus and bicarbonate
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2
Q

What is the mechanism of H+ production in parietal cells?

A

1) Gastrin
2) histamine (acts through receptor)
3) prostaglandin E (acts through receptor)
4) vagal nerve stimulation
All increase the concentration of protein kinases which increases INTRAcellular concentration of H+ in parietal cells
A H/K ATP-dependent transport at the apical membrane of the parietal cell then secretes H+ while taking in K+

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3
Q

What are the 3 receptors located on the basolateral membrane of the parietal cell?

A
  1. acetylcholine
  2. gastrin
  3. histamine
    Activation of all three receptors = acid production
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4
Q

What does an increase in Ca2+ in parietal cell do?

A

Gastrin and vagal nerve INCREASES Ca2+ which increases protein kinases and H+

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5
Q

What is the mechanism of proton pump inhibitors?

A

They inhibit the H/K ATPase on the apical side of the parietal cell

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6
Q

What is the association between somatostatin and parietal cells?

A

Somatostatin INHIBITS G cell and ECL cell, and thereby inhibit parietal cells H+ productio

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7
Q

What happens when you smell food?

A

You stop somatostatin production
Therefore there is no more feedback inhibition
You make acid in response to food

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8
Q

What is the major stimulus for gastric acid production in the human?

A

Histamine, so gastrin’s main effect is to activate ECL cell

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9
Q

What does Ach do in the stomach?

A
  1. upregulates H+ secretion in parietal cell
  2. upregulates gastrin production in G cell
  3. upregulates histamine production by ECL cell
  4. upregulates somatostatin (which is inhibitory) in D – cell
    Mediator of the cephalic phase of acid secretion
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10
Q

Why is the stomach two organs into one?

A

Top half secretes acid
-accepts food and relaxes
Bottom half controls the production of acid
-grinds food

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11
Q

What are gastric protective mechanisms regulated by?

A

PROSTAGLANDINS
Prostaglandins are PROTECTIVE of stomach
They promote mucus and bicarb production and increase submucosal blood flow

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12
Q

What are the two types of prostaglandins?

A

Cyclooxygenase 1

Cyclooxygenase 2

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13
Q

Why do NSAIDs fuck with stomach lining?

A

Because they inhibit prostaglandins, which are protective of the stomach lining
Less prostaglandins = less bicarbonate in the mucous

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14
Q

What are the aggressive factors that lead to peptic ulcers?

A
  1. acid (“no acid no ulcer”)
  2. NSAIDs
    • inhibition of cyclo-oxygenase/prostaglandins
    • local caustic effect because it is broken down in mucus but this is not as significant
  3. H. pylori
  4. pepsin
  5. bile salts
  6. steroids, smoking, alcohol, caffein
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15
Q

What are the defensive factors that protect against peptic ulcers?

A
  1. mucus/mucosal barrier
  2. bicarb
  3. blood flow
  4. cell regeneration
  5. prostaglandins
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16
Q

What are the key characteristics of mucosal cytoprotection?

A
  1. Mucus acts as a barrier to back-diffusion
  2. Bicarbonate neutralizes protons
  3. Internal buffering mechanisms maintain tissue acid/base neutrality
  4. additional barrier provided by tight junctions
  5. epithelial restitution and mucoid cap formation if injury occurs
  6. Mucosal blood flow delivers oxygen and soluble mediators
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17
Q

Why is it important to have good blood flow to the stomach?

A

To replace the damaged cells and to heal shit that may be damaged by the acid
Ischemia of stomach is very uncommon

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18
Q

What are the similarities/differences of gastric and duodenal ulcers?

A

Onset of gastric ulcers are after meals whereas duodenal ulcer feels pain 1-3 after meals
Duodenal ulcers are PINPOINT
Gastric ulcers are DIFFUSE and lead to weight loss, nausea and vomiting

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19
Q

What is the location of gastric ulcers?

A

The antrum (where acid is regulated)

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20
Q

What is the location of duodenal ulcers?

A

Duodenal bulb

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21
Q

What is the duodenal bulb?

A

The portion of the duodenum closest to the stomach

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22
Q

What are the peptic ulcer trends in the USA?

A

Uncomplicated ulcers are declining because of PPI and histamine antagonist use
Disappearance of H. pylori

23
Q

What is the pathophysiology of the peptic ulcer disease?

A

Aspirin alters mucosal defense mechanisms
Hypersecretory states increases acid
H pylori fucks with both defense and acid production

24
Q

What is Zollinger Ellisone Syndrome (ZES)?

A

An example of hypergastrinemia that leads to hypersecretion of acid
A non-beta islet cell tumor that secretes GASTRIN
Gastric acid hypersecretion
Fulminant peptic ulcer disease
Gastrinoma cells are not inhibited by somatostatin

25
Q

What do you need to measure to determine the cause of peptic ulcer?

A

Gastrin levels AND acid levels

Because you can have high gastrin and low acid if the parietal cells are fucked up

26
Q

What is INAPPROPRIATE hypergastrinemia?

A

Hypergastrinemia in presence of gastric acid production

Example: ZES

27
Q

What is appropriate hypergastrinemia?

A

Occurs as a normal physiologic response in situations such as atrophic gastritis, pernicious anemia, etc.

28
Q

What is pernicious anemia?

A

Megaloblastic anemia
Loss of gastric parietal cells which secrete intrinsic factor
Intrinsic factor is important for absorption of vitamin B12 in the ileum

29
Q

How does destruction of parietal cells (atrophic gastritis) lead to pernicious anemia?

A

Because parietal cells secrete intrinsic factor and intrinsic factor is necessary to absorb vitamin B12 in the ileum
Vitamin B12 deficiency leads to megaloblastic anemia
-vitamin B12 is needed for purine and thymidylate synthesis
-no vit b12 = no nucleotides for DNA replication = inhibition of DNA replication in RBCs

30
Q

What are the two types of Zollinger Ellison syndrome (ZES)?

A
  1. sporadic

2. MEN-1 syndrome

31
Q

What are the characteristics of MEN-1 syndrome with ZES?

A 
Multiple endocrine neoplasia syndrome type 1
Autosomal dominant
3 P’s
	i. Parathyroid hyperplasia
	ii. Pituitary adenomas
	iii. Entero-Pancreatic tumors
32
Q

What are the 3 P’s of MEN-1?

A

i. Parathyroid hyperplasia
ii. Pituitary adenomas
iii. Entero-Pancreatic tumors

33
Q

What are the two processes in ZES?

A
  1. hormonal syndrome due to uncontrolled gastrin disease

2. Enteropancreatic neuroendocrine tumor with a potential for neoplastic growth

34
Q

What are the presenting symptoms of ZES?

A

Similar to gastric acid hypersecretion

  1. abdominal pain
  2. pain and diarrehea
  3. heartburn
  4. initial perforation
35
Q

Aside from ZES, what else causes hypersecretion?

A

Idiopathic hypersecretion
Increased parietal cell mass
Increased meal stimulated acid output

36
Q

What are the differences in parietal cell mass in duodenal vs. gastric ulcer?

A

Duodenal ulcers are caused by increased NUMBER of parietal cells
Gastric ulcers are caused by increased SECRETION of acid

37
Q

What does H. pylori make? Significance?

A

Makes urease

Urease neutralizes local pH (ammonium)

38
Q

What are the key characteristics of H. pylori?

A
  1. secretes urease
  2. attaches to host epithelium directly
  3. gastric acid secretion is modified to permit maximal survival
  4. induces inflammation to permit nutrition
  5. evades host immune response
39
Q

What is the pathophysiology of H. pylori gastritis?

A
  1. person-to-person transmission
  2. Urease permits a non-acidic microenvironment in the gastric lumen!
  3. flagellae and spiral morphology permit penetration of mucus layer
  4. enzyme products (protease and phospholipase) permit disruption of the mucosal barrier
  5. Adherence factors permit attachment to surface mucus cells exclusively
    H pylori doesn’t invade gastric mucosa but it does reduce mucosal defences
40
Q

What is the significance of urease?

A

Produced by H. pylori

Permits a non-acidic microenvironment

41
Q

How does H. pylori affect acid secretion?

A
  1. can lead to HYPERacid secretion (antral predominant infection and duodenal ulcer)
  2. can lead to asymptomatic chronic infection which is characterized by normal to low acid output
  3. can lead to HYPO acid output that presents as pangastritis, GU, cancer, lymphoma
    • low acid ouput leads to HYPERGASTRINEMIA!!!!
42
Q

What is the gastrin hypothesis for DU?

A
  1. antral h. pylori infection inhibits somatostatin production leading to unopposed gastrin release
  2. basal and meal-stimulated hypergastrinemia lead to inappropriate gastric acid hypersecretion
  3. duodenal gastric metaplasia permits colonization in duodenal bulb
  4. local defenses are undermined PLUS acid hypersecretion results in duodenal ulceration
43
Q

How do you get hypersecretion with H. pylori infection?

A

Can only happen if h. pylori is predominantly in the ANTRUM!!

44
Q

What is the association of H. pylori and gastric cancer?

A

More H. pylori = gastric cancer in the DISTAL end of stomach (corpus and antrum?)
Proximal (cardia and GE junction) cancers are not as strongly associated
Also associated with Maltoma’s

45
Q

How does H. pylori lead to gastric cancer?

A
  1. host factors
    -cytokines, hypergastrinemia
  2. bacterial factors
    -virulence factors like Cag A, Vac A
  3. Environmental factors
    -smoking
    -vitamin C
    All three combined leads to gastric cancer
46
Q

What is the pathogenesis of NSAID induced GI complications?

A

Dual-injury hypothesis
Systemic = PG inhibition
Topical effects = breakdown

47
Q

What is the significance of arachidonic acid?

A

It is a reactant that is necessary for prostaglandin formation and leukotriene formation

48
Q

What is the role of Cox-1 and 2?

A

They are ENZYMES that convert arachidonic acid to prostaglandins

49
Q

What is the difference between Cox-1 and Cox-2?

A

Cox-1 is constitutive (so always there)

Cox-2 is induced by inflammation

50
Q

What are the mechanisms of NSAID-induced mucosal injury?

A
  1. decreased prostaglandin synthesis
  2. altered mucus
  3. decrease HCO3- and blood flow
  4. direct epithelial injury
  5. acid back-diffusion
51
Q

What is important about misoprostol?

A

Synthetic prostaglandin

Used to offset effect of NSAIDS

52
Q

What is the association between H.pylori and Cox1?

A

H. pylori increase Cox2

So H pylori + NSAiD leads to a lot more peptic ulcers

53
Q

What is the ideal NSAID?

A

The one that is Cox2 selective so that you still have prostaglandin effect in stomach
What does COX-2 do to the stomach?
Mediates inflammation in the stomach so causes gastritis

54
Q

What is non-ulcer dyspepsia? Significance?

A

Patients with typical ulcer pain but in whom no ulcers can be found
Could be on spectrum with IBD but little is known about this shit
Significant because it mimics acid-peptic disease even though there is no evidence of mucosal damage

GI Week 1 (6 decks)

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