Lecture 2 - Peptic Ulcer Disease and GORD Flashcards
What percentage of the population suffer from dyspepsia anually?
40%
leads to primary care consultation in 5% and endoscopy in 1%
Of those who undergo endoscopy what percentage have GORD and PUD?
40% have GORD
13% havd PUD
What is dyspepsia?
A group of symptoms that alert doctors to consider disease of the upper GI tract
Dyspepsia itself is not a diagnosis
What are the symptoms of dyspepsia?
Upper abdominal pain or discomfort, heartburn, gastric reflux, nausea or voiting
What is GORD?
Gastro-oesophageal reflux disease
refers to endoscopically determines oesophagitis or endoscopy-negative reflux disease
What % of GORD and PUD sufferers self medicate?
50%
What percentage have cancer?
2% have gastric cancer
1% have oesophageal cancer
What are peptic ulcers?
Sores that develop in the lining of the stomach, lower oesophagus or small intestine
How much more frequent are duodenal ulcers than gastric ulcers?
10 times more frequent
What causes bleeding into the GI lumen?
damage to the blood vessels in tissues underlying the ulcer
What is a perforated ulcer?
When the ulcer penetrates the entire wall, resulting in leakage of the luminal content into the abdominal cavity
needs to be treated immediately - patient can die from infection
what % of patients with peptic ulcers suffer a perforation?
5-10%
this is higher in men than woman
What is the first sign of a perforated ulcer?
Sudden, intense, steady abdominal pain
How many patients die from perforated ulcer?
15%
Why do patients die from a perforated ulcer?
It enables the bacteria that live in your stomach to escape and infect the lining of the abdomen (peritoneum)
this is known as peritonitis
What happens in peritonitis?
the infection can rapidly spread in the blood (sepsis) before spreading to other organs
this carries the risk of organ failure and can be fatal if lest untreated
How does the mucosa protect the stomach from being digested?
The surface of the mucosa is lined with cells that secrete alkaline mucus that forms a thin layer over the luminal surface
both the protein content and its alkalinity neutralize H+ in the immediate area of the epithelium
What does the alkaline mucus form?
a chemical barrier between the highly acidic contents of the lumen and the cell surface
What do the tight junctions between epithelial cells do?
Limit the diffusion of H+ into the underlying tissue
How often are damaged epithelial cells replaced?
Every few days by new cells arising by the division of cells within gastric pits
What does peptic ulcer mean?
Ulcer of the stomach or duodenum
What does ulcer formation involve?
breaking down the mucosal barrier and exposing the uderlying tissue to the corrosive action of acid and pepsin
What are the characteristics of a peptic ulcer?
Epigastric pain that is relieved by antacids, nocturnal pain and vomiting
Who is peptic ulcer disease more common in?
Men and in smokers
there is often a family history of the disease
people who use NSAIDs or have a heavy alcohol intake
What ulceration are woman more likely to have?
Gastric rather than duodenal ulceration
What are gastric ulcers associated with?
the breakdown of the protective functions of the gastric mucosa, in association with normal or reduced acid secretion
What is duodenal ulceration accompanied by?
Excess acid secretion
What does the aetiology of PUD include
H. pylori, NSAIDs, pepsin, smoking, alcohol, bile acids, steroids, stress, changes in gastrin mucin consistency
What do the defence mechanisms include?
mucus, bicarbonate, mucosal blood flow and prostaglandins, cellular resitution and epithelial renewal
What can alter the mucosal defence?
NSAIDs, H. pylori infection, alcohol, bile salts, acid and pepsin
How do the factors alter the mucosal defence?
by allowing back diffusion of hydrogen ions and subsequent epithelial cell injury
When was H. pylori linked to gastritis?
First in 1983
Since then, further study has revealed it is a major part of the triad which includes acid and pepsin that contributed to primary peptic ulcer disease
What type of bacteria is H. pylori?
Gram negative
What is duodenal ulceration?
A relapsing disorder, even after successful healing
What will a proportion of patients presenting with ulcer symptoms have?
gastric cancer, especially those over the age of 45
Why is investigation by endoscopy important in those above 45?
early drug treatment can produce symptomatic improvements in patients with early gastric cancer
What are peptic ulcers specifically?
defects in the gastric or duodenal mucosa that extend through the muscularis mucosa
What do epithelial cells of the stomach secrete?
Mucus in response to irritation and as a result of cholinergic stimulation
What does the superficial proportion of the gastric and duodenal mucosa exist as?
The form of a gel layer, which is impermeable to acid and pepsin
what do other gastric and duodenal cells secrete
bicarbonate, which aids in buffering acid that lies near the mucosa
what do prostaglandins do?
Prostaglandins of the E type, have an important protective role, because PGE increases the production of both bicarbonate and the mucous layer
what are the 2 most important factors disrupting the balance between acid/pepsin attack
H. pylori and NSAIDs
What does H. pylori cause?
stimulates increased gastrin release and thereby increases acid secretion
it also causes direct damage to the mucosa, further disrupting the physiological balance
what do NSAIDs do?
impair the mucosal resistant, but do not alter acid secretion
patients taking NSAIDs do not produce prostaglandins
What % of peptic ulcers are caused by infection with H pylori or NSAID use
90%
What does inhibition of prostaglandin synthesis lead to?
a decrease in epithelial mucus, bicarbonate secretion, mucosal blood flow, epithelial proliferation and mucosal resistance to injury
What does lower mucosal resistance increase?
the incidence of injury by endogenous factors such as acid, pepsin and bile salts
as well as exogenous factors such as NSAIDs
How do NSAIDs cause peptic ulcer disease?
they disrupt the mucosal permeability barrier, rendering the mucosa vulnerable to injury
as many as 30% of adults taking NSAIDs have GI adverse effects
How does smoking affected PUD?
smoking is harmful to the gastroduodenal mucosa and H pylori infiltration is denser in the gastric antrum of smokers
cigarette smoke may increase susceptibility, diminish the gastric mucosal defensive factors or provide a more favourable milieu for H pylori infection
How does alcohol affect PUD?
ethanol is known to cause gastric mucosal irritation and nonspecific gastritis
evidence that consumption of alcohol is a risk factor for duodenal ulcer is inconclusive
What stressful conditions may cause PUD?
burns, CNS trauma, surgery, and severe medical illness
What increases the risk for secondary (stress) ulceration?
serious systemic illness, sepsis, hypotension, respiratory failure and multiple traumatic injuries
What can stress do once an ulcer is formed?
Emotional stress can aggravate the condition by increases acid secretion and also decreasing appetite and food intake
What are the causes of PUD
H. pylori infection, drugs (NSAID use), lifestyle factors (smoking, drinking), severe physiological stress, hypersecretory states (uncommon), genetic factors
What happens to basal acid output and maximal acid output in patients with duodenal ulcers?
In up to 1/3 of these patients, these are increased
How many patients have a family history of duodenal ulcers?
20% of patients have family history
What do the genetic factors relate to?
The production of mucin
what are the symptoms of a peptic ulcer?
Abdominal discomfort, pain or nausea
pain is located in the epigastrum and usually does not radiate
pain may be describes as burning, gnawing or hunger pains
classically gastric ulcer pain is aggravated by meals whereas duodenal ulcer is relived
what does pain radiating in the back suggest?
that an ulcer has penetrated posteriorly or the pain may be pancreatic in origin
what does pain radiating in the right upper quadrant suggest
disease of the gallbladder or bile ducts
how is the pain of peptic ulcer described
as burning or hunger pains slowly building up for 1-2 hours then gradually decreasing
antacids may provide temporary relief
why do patients with gastric ulcers present with weight loss?
because the pain is aggravated by meals so they avoid food
What alarm features warrant prompt gastroenterology referral?
bleeding, anaemia, early satiety, unexplained weight loss, progressive dysphagia or odynophagia, recurrent vomiting, family history of GI cancer
what does documentation of PUD depend on
radiographic and endoscopic confirmation
an upper GI series is not as sensitive as endoscopy for establishing a diagnosis of small ulcers (< 0.5cm)
Diagnosis of an ulcer
endoscopy is not required unless the patient is present for the first time above the age of 55 or there are warning signs
What happens with people with dyspepsia with significant, acute GI bleeding?
they are referred immediately to a specialist
What is an endoscope?
a device used to diagnose gastric or duodenal ulcers, this uses fibre optic technology to visualise the mucosa
What is a biopsy?
samples of the tissue taken during the procedure
How big are ulcers?
usually range between 3mm and several centimeters in diameter
When are X-rays good
when the ulcer is large and can be seen
what % of individuals are infected with H pylori
40%
only some will develop disease
how many patients with ulcers is H pylori seen in
95% of patients with gastric ulcer and 80% of those with duodenal
Who won the Noble Prize for role of H pylori in gastritis?
Dr. Barry Marshall and Dr. Robin Warren
What does H pylori survive in
a microaerophil
Where does H pylori infect
the lower part of the stomach, the antrum
what does H pylori cause
inflammation of the gastric mucosa (gastritis)
it is often asymptomatic
What MAY H pylori result in
weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression
resides mainly within the gastric mucus and has a high activity of the enzyme urease which enables it to colonise in the stomach
how does H pylori avoid the acidic interior of the stomach
H pylori uses its flagella to burrow into the mucus lining of the stomach to reach the epithelial cells underneath where the pH is more neutral
H pylori is able to sense the pH gradient in the mucus and move towards the less acidic region (chemotaxis)
what does this movement to the more neutral environment do?
keeps the bacteria from being swept away into the lumen with the bacterias mucus environment, which is constantly moving from its site of creation at the epithelium to its dissolution at the lumen surface
Where is H pylori found?
in the mucus, on the inner surface of the epithelium and occasionally inside the epithelial cells themselves
how does H pylori adhere to cells?
by producing adhesions, which bind to lipids and carbs in the epithelial cell membrane
What does BabA bind to?
the Lewis b antigen displayed on surface of stomach epithelial cells
What does SabA bind to?
Increased levels of sialyl-Lewis x antigen expressed on gastric mucosa
How else does H pylori avoid areas of low pH
it neutralises the acid in its environment by producing large amounts of urease, which breaks down the urea present in the stomach to CO2 and ammonia, the ammonia (which is basic) neutralises the stomach acid
What does serologic evaluation do?
Looks for the presence of h pylori antibodies
this may reflect previous exposure to the antigen but not indicate present, active infection
What are the invasive diagnostic techniques
gastric endoscopy and tissue biopsy
What are the non-invasive techniques
serum, breath tests and stool samples
What is the urea breath test?
is it based on the ability of H pylori to break down urea into CO2 and ammonia
the CO2 is absorbed from the stomach and eliminated in the breath
How is the urea breath test carried out
Patients swallow a capsule containing urea and if H pylori is present in the stomach the urea is broken up and turned into CO2, the CO2 is then absorbed across the lining of the stomach ad into the blood, it then travels to the lungs where it is excreted in the breath
samples of exhaled breath are collected and the isotopic carbon in the exhaled CO2 is measured
If the isotope of carbon is present?
it means H pylori is present in the stomach, if it is not found it means H pylori is not present
What happens to the test once H pylori is treated?
the test changes from positive to negative
it provides evidence of the infection being present
it has high sensitivity and specificity
Blood tests?
commonly used and if the patient has been infected they will have H pylori antibodies in the blood
it does not tell you if H pylori is present in the stomach
Stool antigen test?
an enzyme immunoassay designed to detect H pylori in faecal specimens by measuring H pylori antigen released from organisms lining the stomach wall
it is an accurate tool to diagnose active H pylori infection and to establish eradication of the organism following treatment
What is the most accurate non-invasive test?
faecal antigen is more accurate than antibody testing and less expensive that urea breath testing
What happens if H pylori is not eradicated?
about 80% of gastric and duodenal ulcers will reoccur within a year
if H pylori is eradicated the recurrence rate is low
what does the body of the stomach secrete?
mucus pepsinogen and HCl
it is thinned wall
what does the antrum of the stomach secrete?
mucus pepsinogen and gastrin
What is the antrum?
the lower portion of the stomach
it has a thick layer of smooth muscle and is responsible for mixing and grinding the stomach contents
What do the glands in the antrum secrete?
they contain endocrine cells that secrete gastrin
What do the opening of the gastric glands secrete?
Mucus
lining the wals of the glands are parietal cells, which secrete acid and intrinsic factor an chief cells which secrete pepsinogeen
What are the unique invaginations?
an infolding of the outer layer of cells of a organism or part of an organism so as to form a pocket in the surface
What do the invaginations of the luminal membranes do?
they increase the surface area for secretion, thereby maximising the secretion into the lumen of the stomach
called canaliculi
What else do the gastrin glands of the antrum contain?
Enterochromaffin-like cells
and endocrine D cells
What do enterochromaffin like cells release?
Histamine
What do endocrine D cells secrete?
Somatostatin
these are located in and around the glands in the antral region
What do histamine and somatostatin have roles in?
Regulating acid secretion by the stomach
What drugs are used to treat PUD?
antacids, antisecretory agents, raising gastric pH (above 3) for a few hours per day, pharmacological treatments, eradication of H pylori
What are antacids?
they are weak alkalis so they partly neutralise free acids in the stomach
they also stimulate mucosal repair mechanisms around ulcers, possibly by stimulating prostaglandin release
What are antacids mainly used for?
Symptomatic relief in patients with PUD and GORD and non-ulcer dyspepsia
What are antisecretory agents?
Drugs that inhibit gastric acid secretion
How long must gastric pH be raised for to promote rapid healing?
For a minimum of 18-20 hours per day
Raising gastric pH?
Need to raise it to more than 3 to promote healing and the duration of acid suppression will determine the rate of healing
Name histamine receptor antagonists
cimetidine, ranitidine, nizatidine, famotidine
How do H2 receptor antagonists work?
they are competitive antagonists for histamine at the H2 receptor found on parietal cells
by competing with histamine at the receptor, these drugs reduce acid secretion by the parietal cells
When are H2 receptor antagonists best at reducing acid secretion?
At night and in the fasting state
How effective are H2 receptor antagonists?
Bring about a 50% decrease in acid secretion for 10 hours, they are given twice daily
relapse is common after treatment
How quickly can H2 antagonists heal duodenal ulcers?
~75-80% within 4 weeks of treatment and increases to ~90% by 8 weeks
How quickly can H2 antagonists heal gastric ulcers?
It is slower, ~80% should heal by 8 weaks, this should be documented endoscopically
Can H2 antagonists be used long term?
They can be continued as long term maintenance therapy however the role of these has been reduced since the important of H pylori infection has become appreciated
Adverse effects of H2 antagonists?
diarrhoea, headache, confusion in elderly, gynaecomastia with cimetidine
What is cimetidine?
A weak anti-androgenic (blocks the effect of dihydrotestosterone) in humans
What does cimetidine inhibit?
cytochrome P450 system and has potential interactions with warfarin, phenytoin and theophylline as the half-lives of these drugs will be prolonged
What has occurred after IV injections of H2 antagonists?
Some potentially serious cardiac dysrythmias
Name some proton pump inhibitors
omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole
How do PPI’s work?
they are irreversible inhibitors of the H+/K+ATPase pump and almost completely block acid secretion
What does return of acid after PPI’s depend upon?
synthesis of new enzymes
How do PPI’s bond to the pump?
they bind covalently via a disulphide bond thereby irreversibly inhibiting the proton pump
When are PPI’s most effective?
when taken around meal times
How effective are PPI’s?
Acid secretion is inhibited by ~90% for 24 hours after a single dose
Adverse effects of PPI’s?
GI upset (epigastric discomfort, nausea, vomiting, diarrhoea), headache, skin rashes
What is an adverse effect of omeprazole?
it has both stimulant and inhibitory effect on CYP450 system
What does omeprazole reduce?
the elimination of diazepam, phenytoin and warfarin through inhibition of their heptatic metabolism
What may long term use of PPI’s cause?
gastric atrophy or gastric cancers
this is due to substantial reduction of gastric acid and associated rise in gasrin secretion
What else do PPI’s have a modest suppressant effect on?
H pylori
What do patients with PUD testing +ve for H pylori infected get treated with?
Triple therapy - 7 day twice daily course of treatment
PPI, amoxicillin, either clarithromycin or metronidazole
What is used as treatment in patients allergic to penicillin?
PPI, clarithromycin and metronidazole
7 day, twice daily
What is recognised as an important factor in the failure to treat H pylori?
resistance to clarithromycin and metronidazole
What are cytoprotective agents?
prostaglandin analogue (misoprostol), methyl analogue of prostaglandin E1, enhanced duodenal bicarbonate secretion, weak inhibition of gastric acid secretion, through activation of prostaglandin receptor on parietal cells, increased mucosal blood flow
When can cytoprotective agents not be used?
In pregnancy - potential uterine stimulant and may induce aborption
What is misoprostol?
A synthetic prostaglandin E analogue, which has an inhibitory effect on acid secretion and also enhances the secretion of bicarbonate, thus providing some additional protective properties
What can misoprostol be used for?
To heal ulcers but is more commonly used prophylactically to prevent NSAID induced ulceration
What happens in patients with an ulcer caused by NSAID?
the NSAID should be discontinued and patient given a H2 receptor antagonist
if the NSAID must be continues they should be given a PPI
What does blood flow contribute to?
Protection by supplying the mucosa with oxygen and bicarbonate and by removing H+ and toxic agents diffusing from the lumen into the mucosa
What is Zollonger-Ellison syndome?
A rare disorder that can cause gastric or duodenal ulcers (usually multiple) as well as in the jejunum
What does Zollonger-Ellison syndrome cause?
massive gastric acid hyper-secretion due to gastrin secreting tumour in the pancreas or duodenum (gastrinoma) that stimulates acid secretion in the stomach
When would you consider ZES?
if the patient has severe peptic ulceration, kidney stones, watery diarrhoea or malabsorption
What can ZES be associated with?
multiple endocrine neoplasia type I, which occurs earlier tan isolated ZES
What are patients with ZES likely to have?
Intractable ulcer disease
What are patients with ZES serum gastrin levels?
usually have fasting serum gastrin levels of more than 200pg/ml and basal gastric acid hyper-secretion of more than 15mEg/h
What must treatment of ZES do?
control the hyper-secretion and the gastrinoma
What is the prevalence of GORD in the uk?
~20% of people in the UK experience symptoms once a week
What is the increase of GORD due to?
Multi-factorial, though increasing obesity is an important factor
What is acid secretion like in GORD?
most patients secrete a normal amount of acid, however they have an incompetent lower oesophageal sphincter that relaxes inappropriately at times other than swallowing
What does the incompetent oesophageal sphincter allow?
excessive reflux of gastric contents, containing acid and pepsin, and bile acids into the oesophagus
What is the tendency for reflux exacerbated by?
Hiatus hernia is present, since this further diminishes the barrier to reflux
What are the symptoms of GORD?
retrosternal burning because the acidic material remains in contact with the mucosa for prolonged periods as a result of impaired physiological clearance mechanisms
Drugs for treating GORD?
antacids and antacid/alginate combinations
drugs that inhibit gastric secretion (H2 antagonists and PPIs
drugs that act on oesophageal and/or gastric motility
What happens when antacids are combined with alginates?
the alginate provides a protective coating to the lower oesophagus, reducing mucosal contact with the refluxed contents
H2 antagonist use in GORD?
not particularly effective in the management of GORD, to be effective in GORD they need to be given at much higher doses than in PUD
PPI use in GORD?
shown superior results compared to H2 antagonists in controlling symptoms and healing the oesophagitis
Relapse in GORD?
relapse after treatment is common as GORD is a chronic condition and most patients require long-term treatment
most patients, especially with severe GORD require long term treatment with a PPI
patients with mild GORD may obtain sufficient symptoms relief from an antacid or H2 antagonist taken as required
Drugs that increase gastric motility?
have some efficacy in patients with mild GORD because they have a weak tonic effect on the lower oesophageal sphincter and may also improve oesphageal clearance and gastric emptying
Most frequent treatment for GORD?
PPIs
When is surgery used for GORD?
in patients with severe, difficult to control GORD symptoms
may also be considered for people who have complications or scar tissue in the oesophagus
people who do not want to take medications for a long time
How is surgery done for GORD?
using camera guided instruments
laparoscopic surgery requires smaller incisions than conventional surgery
Nissen fundoplication?
excess stomach tissue is folded around the oesophagus and sewn in place
this holds extra pressure around the weakened oesophageal sphincter
What is Barrett’s oesophagus?
an abnormal change in the cells of the lower portion of the oesophagus
the replacement of normal stratified squamous epithelium lining of the oesophagus by simple columnar epithelium with goblet cells (usually found in the lower GI tract where they secrete mucus)
When is Barrett’s oesophagus commonly diagnosed?
in patients with long term GORD
Diagnosis of barrett’s oesophagus?
rests upon seeing a pink oesophageal lining that extends a short distance up the oesophagus from the gastro-oesophageal junction
finding intestinal type cells (goblet cells) on the biopsy of the lining
Symptoms of Barrett’s oesophagus?
most patients complain of heartburn pain, indigestion, blood in vomit or stool, difficulty swallowing solid foods or nocturnal regurgitation
Treatment of Barrett’s oesophagus?
H2 antagonists and PPIs
controls symptoms but does not result in regression of Barrett’s oesophagus
What is Barrett’s oesophagus associated with?
Increased risk of developing oesophageal cancer
Can lead to oesophageal adenocarcinoma (>85% mortality)
important to have checkups for precancerous cells and if they are discovered, they can be treated to prevent cancer
