Gastric Acid Secretion: Disorders Flashcards
What is GIT involved in?
What can malformation of GIT lead to?
GIT is involved in absorption of nutrients, salts, water and elimination of undigested waste.
Malformation of GIT can lead to a decreased nutrient status/malnutrition.
Mechanism of peptic ulcer
2 mechanisms for peptic ulcer?
which sites are commonly affected by uclers? which areas arer particulary vunerable?
- There is breakage of mucosal barrier, then if there is an imbalance between the protective factors and damaging factors (HCl) it can cause damage
- Exposure of tissues to the erosive effects of HCl //pepsin
But some sufferers can have normal or even subnormal levels of acid secretion
- 10% of the population are affected by ulcers, sites commonly effected are the oesophagus, stomach and duodenum
o Areas usually exposed to HCl and pepsin, especially duodenum as it’s not as well protected and the food going here is very acidic.
factors responsible for gastric acid secretion
- Histamine
- Ach
- Gastrin
- Alcohol, smoking, caffeine, NSAIDs
Stress may also play a role, possibly aggravating existing ulcers.
Bile acids are also irritants and genetics may play a part in ulcer formation.
What are factors predisposing to peptic ulceration?
what is a major risk factor?
what can impair the mucosal defence mechanism?
how can nsaids impair the mucosal defence mechanism?
o Gastric and duodenal infection with H. pylori is a major risk factor
o Peptic ulcers can be acquired in childhood
Environmental and host factors can determine the distribution and colonisation of H.pylori in the stomach.
So smoking, genetic factors, stress can all promote acid/pepsin secretion which impairs the mucosal defence mechanisms leading to a peptic ulcers.
NSAIDs also impair the mucosal defence mechanisms by removing PGE2 (gastro-protective effects, increase mucus secretion and bicarb secretion) and thromboxane A2 (involved in healing).
Do HCl and pepsin serve any useful purposes?
3 roles of HCL and pepsin
5 other factors that prevent infection of gastric mucosa?
o They help kill aerobic microorganisms and reduce risk of infection of the gastric mucosa
o Plays a role in pepsinogen activation
o Stimulate release of bile and pancreatic juice release
Other factors that prevent infection of gastric mucosa are the mucus production, the peristalsis/fluid movement, having a seamless epithelium with tight junctions, a fast cell turnover and IgA secretion at the mucosal surfaces.
Very importantly we also have Peyer’s patches
Protective Factors that Prevent Autodigestion of the Stomach
5 factors that prevent this?
what protects the stomach from the low pH in general?
The gut is exposed to a very hostile environment, the gastric juices contain about 150mM HCl as well as the presence of pepsin.
The protective mechanisms include:
- Secretion of an alkaline mucus and HCO3-
- The protein content of food
- Presence of tight junctions
- Replacement of damaged cells within the gastric pits
- Prostaglandins (E and I) which inhibit acid secretion and enhance blood flow
The mucus layer protects the gastric mucosa from the low pH
H. Pylori and Peptic Ulcer
what ype of bacteria is H. Pylori?
what does it do in the stomach?
what virulence factors allow it to survive and infect stomach? urease? CagA? VacA?
what outer membrane proteins help the bacteria?
what enzymes does the bacteria use and effect of this?
effect of h.pylori on d and g cells? effects on other cells?
H. Pylori is a gram negative spiral shaped aerobic bacterium. It penetrates the gastric mucosa/mucus (as able to survive under the harsh conditions of the stomach).
H. Pylori is highly pathogenic with many virulence factors
Virulence factors of H.Pylori include its motility, it can move (by a corkscrew movement) through the mucus and down close to the epithelium where the pH is around 7.
It also produces urease, which converts urea -> ammonia which buffers gastric acid and produces CO2, this helps it survive the hostile environment.
Other important virulence factors include:
- Cytotoxin-associated antigen (CagA), this inserts pathogenicity islands inside the host and this confers ulcer-forming potential (cause apoptosis of cells and affect tight junctions)
- Vacuolating toxin A (VacA) this alters the trafficking of intracellular proteins in gastric mucosal cells
These also alter immune cells like T-cells and macrophages
A large number of outer membrane proteins such as adhesins (BabA), phospholipases, porins, iron transporters and flagellum- associate proteins. These all help the bacteria.
Bacteria also use enzyme called mucinase, this enzyme degrades the mucus membrane overlying the epithelial cells.
H. pylori infection dysregulates gastrin secretion and decreases D//G cells (but decreases D cells more). It can also cause problems with the neutrophils and macrophages leading them to not function properly.
H. Pylori and Mucosal Damage
where does the H. Pylori go? what does it do there? what effect does this have and why is it useful for H. Pylori? how can this effect be exacerbated?
summary
what leads to mucosal breakdown?
aggravators of peptic ulcer?
what interferes with epithelial protection?
The H. pylori bores its way through the mucosa and then attaches to the epithelium using some of the virulence factors previously spoken about.
While there it releases ureases to convert urea -> ammonia which neutralises any acidity that is in this area or being secreted.
Therefore, any bacteria around can come and survive nicely in this area. The epithelium is red in the picture because it starts bleeding and being inflamed due to HCl//pepsin exposure and toxins. Inflammatory cells turn up and their effects can be damaging.
Short summary
- Increased gastric acid secretions (HCl and pepsin) can lead to mucosal breakdown
- Aggravators of peptic ulcer: NSAIDs, smoking, spicy foods, H. pylori etc.
- H. pylori ureases, proteases and mucinases interfere with epithelial protection
Peptic ulcers tend to be common in a number of places and in certain conditions
4 locations?
why is gastroenterostomy an issue?
- Duodenal cap (as exposed to lots of acidic chyme)
- Stomach, at the junction of the antrum and body
- Distal oesophagus especially Barrett’s oesophagus
- Meckel’s diverticulum (cells here are thinner)
- After gastroenterostomy (weight loss, recurrent pains, ulcers) as gut designed so that when food leaves the stomach and enters the duodenum the secretions of bile and from pancreas can go there and neutralise.
o But if you change this, it can result in longer time the acidic products go without being neutralised.
A suspected peptic ulcer must be investigated and there are a number of diagnostic tests that we can do
- Endoscopy (oesophagogastroduodenoscopy, EGD)
- Histological examination of an EGD biopsy
o Test for the presence of H. pylori - Stool antigen test
- Evaluate urease activity
- Urea breathe test (can measure C14 isotope in CO2 exhaled after given a urea tablet that contains C14 so can collect the gas and see how much is being produced, this could indicate H. pylori if there are high levels)
Symptoms of peptic ulcer
4 common symptoms to look out for?
age common in?
where is there a high incidenrt rate and why?
what is a risk factor for gastric cancer?
o Anaemia
o Black, tarry stools
o Chest discomfort, weight loss
o Vomiting
Peptic ulcers are asymptomatic in over 80% of people, so they may just go to the chemist. There is a low incidence of peptic ulcers in the young, but it is more common in over 50s.
There is a 90% incidence in developing countries due to high infection rate with H. pylori
Inflammation plays a key role in the disease process. The presence of H. pylori is also a risk factor for gastric cancer, so its eradication can reduce the risk.
Chronic peptic ulcers
where do they occur?
causes?
outcome/treatment?
Chronic peptic ulcers are common, these tend to occur in the upper GIT, the main culprits of this are
- Hyperacidity
- Reflux of duodenal contents
- H. pylori
- NSAIDs
- Genetic factors
- Sex, being male
In terms of outcome, if we treat we can get complete healing with replacement of tissue and possibly scarring.
Acute peptic ulcers
how frequent?
where do they develop?
what else can cause these ulcers?
3 outcomes of this ulcer
Less frequent, these develop from areas of corrosive gastritis (oesophagus, stomach, proximal duodenum), or severe stress or shock (such as burns, trauma).
Acute hypoxia of the surface epithelium may also cause acute ulcers (ischaemia of the gastric mucosa).
Outcomes:
- Severe bleeding
- Complete healing
- Chronic peptic ulcer.
Complications of Peptic ulcers
- Haemorrhage (GI bleeding)
- Perforation (peritonitis) and penetration causing leakage of luminal contents
- Narrowing of pyloric canal due to strictures
o Stricture would lead to pyloric stenosis - Malignant changes become 3-6x more likely with H. pylori infection
Anti – Secretory Agents: H2 receptor Antagonists
what does histamine do? what do H2 receptor antagonist do? so what is the effect of this? name a few antagonists
2 clinical uses for these antagonists
what is their mechanism fo action and where?
how can you get a relapse of the ulcer?
3 main side effects of these drugs?
what does cimetidine effect? effect of this?
H2 (histamine) receptor antagonists e.g. cimetidine, ranitidine, famotidine, nizartidine.
H2 receptor antagonists block the histamine receptor. Histamine promotes acid release, so if we block it with an agent, we will inhibit stimulation of gastric acid release.
Clinical uses of H2 receptor antagonists
o Peptic ulcer
o Reflux oesophagitis
Their mechanism of action is that they inhibit action of H2 receptors on parietal cells, this reduces gastric secretion -> reduce pepsin secretion (which has acidic properties).
As well as inhibiting histamine, it also inhibits Ach and gastrin stimulated acid secretion. This is useful because these mediators, histamine, Ach and gastrin can synergise to promote acid secretion, but if we take H2 receptor antagonists we can block acid secretion mediated by all of these.
It can decrease basal and food-stimulated acid secretion by 90%
The clinical trials on H2 receptor antagonists suggest they promote healing of duodenal ulcers but if you stop treatment you get a relapse because it is not solving the root cause of the problem.
There are a variety of unwanted side effects someone may experience especially if they are taking the drug over a long time.
o These are generally rare, but include diarrhoea, muscle cramps, transient rashes, hypergastrinaemia.
o As H2 antagonist may block D-cells -> somatostatin would decrease, this would make the problem worse, but this is in extreme case.
o Cimetidine may cause gynaecomastia in men (and decrease sexual function, but rare).
Cimetidine also inhibits P450 enzymes, which will decrease metabolism of a number of drugs that are metabolised by P450 enzymes.
• This means if you took these drugs you would be increasing the plasma levels of these drugs e.g. anticoagulants, tricyclic antidepressants.
So, the consequences of taking cimetidine with anticoagulants/anti-depressants can be quite profound (e.g. bleeding) so we need to alter dosages.
