Physiology of Gastric Acid Secretion and Acid Peptic Disorder/Peptic Ulcer Disease Flashcards
1
Q
Does not being able to make acid in the stomach affect quality of life?
A
Not as much in developed world b/c food is free of most organisms
2
Q
What product is produced by the cell? Parietal cells
A
acid and intrinsic factor
3
Q
What product is produced by the cell? G-cells (antrum)
A
gastrin
4
Q
What product is produced by the cell? D-cells
A
somatostatin
5
Q
What product is produced by the cell? ECL cells (enterochromaffin-like cells)
A
histamine
6
Q
What product is produced by the cell? Chief cells
A
pepsinogen
7
Q
What product is produced by the cell? surface epithelial cells
A
mucus and bicarbonate
8
Q
What product is produced by the cell? mucus neck cells
A
mucus and bicarbonate
9
Q
On which surface of the parietal cell do signals result in second messenger activation?
A
basal surface
10
Q
What is the final step in acid production at the level of the parietal cell?
A
proton pump on lumenal side of parietal cell
11
Q
What inhibitory signals act on parietal cells?
A
somatostatin and prostaglandin E (Gi)
12
Q
What excitatory signals act on parietal cells?
A
- vagus nerve acetylcholine works on ECL cells to produce histamine that acts on H2 receptors on the parietal cell (Gs)
- vagal acetylcholine acts directly on the parietal cell
- gastrin acts on ECL cells to produce histamine that acts on H2 receptors on the parietal cell (Gs)
- gastrin acts directly on the parietal cell
13
Q
What two second messenger signaling pathways work within the parietal cell?
A
cAMP (histamine signal) and IP 3(gastrin and vagal signals)
14
Q
Parietal cellular target for: atropine
A
vagal nerve stimulus
15
Q
Parietal cellular target for: H2 receptor antagonists
A
H2 receptor
16
Q
Parietal cellular target for: proglumide
A
gastrin recepptor
17
Q
Parietal cellular target for: PPI
A
H+/K+ Atpase (proton pump)
18
Q
What is the minor component of acid production stimulus?
A
neurocrine stimulus (seeing food/smelling food) –> 10-15% of acid production
19
Q
Major pathway for acid production?
A
consumption of food –> distention of stomach –> inhibits somatostatin production –> allows gastrin dominance on acid secretion
20
Q
How does acid production get shut off in stomach?
A
As stomach pH drops, D cells get switched on –> drives inhibition of gastrin and ECL production
21
Q
How is the pH at the lining of the stomach maintained at 7?
A
bicarbonate secretion around mucus layer protects against back/auto-digestion of stomach
22
Q
How does acid peptic disease occur if there is mucosal protection of stomach?
A
If the pH drops low enough, pepsinogen turns into pepsin which can autodigest the stomach
23
Q
5 protective features that prevent autodigestion of the stomach
A
- thick mucus layer, 2. pH gradient, 3. bicarbonate secretion, 4. good mucosal blood flow to support epithelial growth, 5. prostaglandin production (COX 1 and 2)
24
Q
What prostaglandin is constitutively expressed?
A
COX1
25
What prostaglandin is induced by inflammation?
COX2
26
Why do NSAIDs reduce mucosal cytoprotection and what is the consequence?
They block both COX1 and COX2 and can result in peptic ulcer disease
27
Aggressive factors in PUD (3)
acid, pepsin, bile salt
28
"no acid, no ulcer"
cannot have ulcers without acid --> may otherwise have atrophic gastritis
29
Effect of NSAIDs on the stomach
local caustic effect + COX inhibition
30
The major cause of gastric cancer
H pylori --> decreased mucosal protection and increased acid output
31
Two types of ulcers
duodenal and gastric ulcers
32
What kind of ulcer? pinpoint, epigastric burning pain
duodenal ulcer
33
What kind of ulcer? 1-3 hours after meals, empty stomach, relieved by foods or antacids
duodenal ulcer
34
What kind of ulcer? nausea, vomiting, diffuse epigastric pain, weight loss
gastric ulcer
35
What kind of ulcer? onset immediately after meals, aggravated by food
gastric ulcer
36
What kind of ulcer? location at the duodenal bulb
duodenal ulcer
37
What kind of ulcer? location at the antrum
gastric ulcer
38
What kind of ulcer? normal/high gastric acid production
duodenal ulcer
39
What kind of ulcer? normal/low gastric acid production
gastric ulcer
40
Uncomplicated ulcers are increasing/decreasing in incidence/prevalence
decreasing in us b/c of PPIs and histamin antagonist use, disappearance of H. pylori, judicious use of NSAIDs and introduction of coxibs/selectives, better management of ICU patients
41
Bleeding ulcers are increasing/decreasing in incidence/prevalence
prevalence is unchanged resulting in increasing proportion overall
42
Etiologies of PUD that reduce mucosal defense (2)
Aspirin/NSAIDs and H pylori gastritis
43
Etiologies of PUD that increase acid/pepsin (2)
H pylori gastritis and hypersecretory states
44
Zollinger Ellison Syndrome
non-beta islet cell tumor that hypersecretes gastric acid w/the loss of paracrine somatostatin secretion leading to fulminant PUD
45
Pathophysiology of ZES
tumor produces gastrin --> blood stream --> drives ECL and stomach to make acid/histamine --> reduce pH --> switch on D cells locally but no paracrine function of somatostatin --> no feedback inhibition
46
Can a local somatostatin analog turn off hypersecretion of acid?
No --> need a systemic one like octreotide
47
Hallmark of ZES and diagnostic criteria
hypergastrinemia --> elevated acid output AND serum gastrin (these measurements have no value on their own; they have to exist together)
48
What is appropriate hypergastrinemia?
There are no parietal cells --> pH increases --> somatostatin switches off --> gastrin goes sky high to try to make acid --> hypergastrinemia without hyperacidemia (e.g. atrophic gastritis)
49
Diff Dx of appropriate hypergastrinemia
drugs (H2RA and PPI), atrophic gastritis, H. pylori pangastritis, chronic renal failure, vagotomy
50
Diff Dx of inappropriate hypergastrinemia
ZES (sporadic or MEN1), retained antrum syndrome, antral predonominant H.pylori infection with G cell hyperplasia, massive intestinal resection (temporary), gastric outlet obstruction (reversible)
51
Genetics of MEN1
two hit Rb hypothesis + autosomal dominant --> cloning of 11q13 resulting in increased Menin
52
Clinical presentations of MEN1
parathryoid hyperplasia (early), pituitary adenomas, entero-pancreatic tumors +/- lipomas, adrenal hyperplasia, etc.
53
BAO
how much basal acid do you make in an hour --> calculated by titration --> concentration is irrelevant, absolute amount is key
54
MAO
maximal acid output or BAO after pentagastrin stimulation
55
PAO
peak acid output --> alternate measure of stimulated acid secretion
56
Control acid output
BAO in the presence of therapy (efficacy of Rx)
57
Two processes in ZES
hormonal syndrome due to uncontrolled gastrin release + enteropancreatic neuroendocrine tumor with a potential for neoplastic growth
58
Features of patient with ZES
duodenal ulcer (multiple or recurrent) w/ acid hypersecretion leading to diarrhea + not on NSAIDs + no H. pylori +/- MEN1
59
Clinical presentation of ZES
abdominal pain, diarrhea, heartburn, initial perforation
60
Idiopathic hypersecretion gastric analysis
BAO and MAO increased, increased parietal cell mass, increased meal-stimulated acid output, increased 24 hour secretory profile
61
Acid response in duodenal ulcers
higher basal acid and higher meal-stimulated acid too
62
4 possible causes for gastric hypersecretion in duodenal ulcers
1. increased parietal cell sensitivity to gastrin secretagogues
2. basal or meal-stimulated hypergastrinemia
3. abnormality of inhibition (e.g. somatostatin deficiency)
4. decreased bicarbonate secretion
* usually always due to H. pylori
63
How does H pylori affect the gut
secreates urease to neutralize local pH via production of ammonium --> attaches to host epithelium --> gastric acid secretion modified to permit maximal survival and induces inflammation to permit nutrition
* non invasively evades host immune response
64
Cohort effect
there is higher transmission of bugs like H pylori within an age cohort --> that group of people eventually age out of the population together --> leads to multimodal distribution of infection across the population
65
H. pylori mode of transmission
person-to person
66
Function of flagellae and spiral morphology of H pylori
penetration of mucus layer
67
Does H pylori invade the mucosa
no
68
3 ways H pylori affect acid secretion
antral predominant infection, asymptomatic chronic infection, pangastritis (with GU, cancer, lymphoma)
69
The gastrin hypothesis
antral H pylori infection inhibits somatostatin production leading to unopposed gastrin release --> basal and meal hypergastrinemia lead to inappropriate hypersecretion of gastric acid --> consequent duodenal gastric metaplasia permits colonization in duodenal bulb --> local defenses are undermined + acid hypersecretion results in duodenal ulceration
70
What is the spectrum of H. pylori infection?
```
basically anything:
chronic gastritis
duodenal ulcers (90%)
gastric ulcers (70%)
gastric metaplasia/dysplasia/cancer
maltoma
non-ulcer dyspepsia
```
71
T/F all H pylori sequelae begin with an acute infection
T --> acute infection followed by superficial gastritis is the starting point for any hyper or hypo secretory state
72
H pylori pangastritis features
Hyposecretory state with chronic atrophic gastritis (leading to gastric ulcers or cancers) or lymphocytic predominance leading to maltomas
73
H pylori antral predominance features
Hypersecretory state with propensity for duodenal ulcers
74
Are distal or proximal stomach cancers associated with H. pylori?
both are but distal corpus/antral cancers are more associated than cardia/GEJ cancers
75
Host factors in H. pylori that lead to increased pathogenicity
of lymphocytes, macrophages, PMNs, quantity of IL1, IL8, TNFalpha, genetic HLA loci, hypergastrinemia
76
Bacterial factors in H. pylori that lead to increased pathogenicity
virulence factors: Vac A, Cag A, Ice A, etc.
77
Environmental factors in H. pylori that lead to increased pathogenicity
nitroso compounds, salt, smoking, vitamin C
78
CagA
gene that forms a pathogenicity island present in 50-60% of all Hpylori isolates --> marker of virulence --> CagA+ organisms are associated with increased cytokine release and increased inflammation and are closely related to gastric cancer
79
IL polymorphism
IL1beta polymorphisms are proinflammatory run in families
80
Are H pylori present once gastric atrophy turns to metaplasia --> dysplasia --> cancer?
no --> they are gone at this point
81
Corpus gastritis
precursor to hypochlohydria and gastric atrophy (along the timeline to cancer) and results from Hpylori gastritis, proinflammatory phenotype, and CagA+ features
82
What are the effects of NSAIDs on the GI system?
topical effects that are direct/indirect and cause GI erosions + systemic PG inhibition/antiplatelet effects
83
What is the function of constitutive Cox1 on the GI system?
protection of gastric mucosa and hemostasis
84
What is the function of inducible Cox2 on the GI system?
mediate inflammation/gastritis
85
What Cox system does H pylori infection upregulate?
Cox2 inflammation
86
What kind of Cox would the ideal NSAID inhibit?
Cox2
87
In the absence of a Cox2 selective inhibitor, how can you prevent ulceration in NSAID-using patients?
use omeprazole or misoprostol (PPI or synthetic prostaglandins) to restore prostglandins that are missing due to Cox 1/2 dual inhibition
88
Does H pylori affect Cox1?
not really
89
T/F NSAIDS and H. pylori together increase the risk of ulcers
yes --> additive effect
90
Curling's ulcers are due to ___
burns
91
Cushing's ulcers are due to ____
head injury
92
dyspepsia
ulcer like pain in the absence of ulcers: GERD, gallstones, pancreatitis, pneumonia, PE, MI, AAA
