FRS 1. Oesophageal anatomy, physiology, and pharmacology. Acid secretion Flashcards
Describe the structure of the oesophagus
Muscular tube
~ 25cm long (depends on height of person)
3 regions along its length:
o cervical
o thoracic – suprasternal notch to diaphragm
o abdominal – last few cm
Bordered by upper and lower oesophageal sphincters
What are the layers of the oesophagus?
- mucosa
- submucosa
- muscularis - inner circular/outer longitudinal
- adventitia - loosely packed connective tissue
Describe the mucosa of the oesophagus
- nonketatinised stratified squamous epithelium
- pH 7
- adapted for shear stress (stratified), not for acidic environments
Describe the lower oesophageal sphincter
LES is a physiological sphincter internal sphincter, not a visible narrowing but maintains tone to make
sure pressure is 10-15 mmHg higher than surrounding
External sphincter of diagram
LES (intrinsic and diaphragm) prevents acid from refluxing into the oesophagus
The angle of the entry of the oesophagus into the stomach also plays a role in preventing reflux
What are the factors that prevent reflux?
Intrinsic sphincter tone
Extrinsic sphincter (pinch of crural diaphragm)
Intra-abdominal length of oesophagus
Angle of His/Flap Valve
Secondary pesistalsis/swallowed bicarbonate
What is the angle of his/ flap valve?
o acuteanglecreated between the cardia at the entrance to the
stomach, and the oesophagus.
o Forms a valve, preventing reflux
What is secondary pesistalsis/swallowed bicarbonate
If acid comes up into the oesophagus, secondary peristalsis clears it from the oesophagus
What is reflux a consequence of?
o Increased stress on the barrier
o Malfunction of the barrier
What are the causes of barrier malfunction in reflux?
Impaired Defences
o Hiatus hernia
o Transient lower oesophageal relaxations (TLOSRs) -
burping
o Low sphincter pressure – caused by e.g. smoking
o Impaired oesophageal clearance – oesophageal
dysmotility
What are the causes of stress on barrier in reflux?
o Increased intra-abdominal pressure - Hiatus hernia,
obesity (chronic pressure weakens barrier)
o Reduced gastric emptying
What is a hiatus hernia
Protrusion of part of the stomach through the diaphragmatic hiatus and into the chest
Affects about 20% of population
What are the two types of hiatus hernia?
Sliding (80%): gastro-oesophageal junction slides through hiatus
Rolling: fundus of stomach protrudes through hiatus alongside GOJ
o Does not predispose to reflux
What is reflux?
retrograde passage of acidic gastric contents into oesophagus
What is GORD?
symptoms due to reflux sufficient to impair quality of life or cause complications
o Heartburn
o Regurgitation
o Epigastric pain (dyspepsia)
o Nausea
o (Extra-oesophageal symptoms: non-cardiac chest pain, pharyngeal symptoms, wheeze)
What is the mechanism of swallowing?
Complex reflex
Food bolus pushed up against soft palate and into pharynx
UES relaxes, respiration pauses, glottis closed
Primary peristaltic wave propels bolus towards stomach.
LOS opens at initiation of swallow
Secondary peristalsis occurs locally in response to distension
What is dysphagia?
Symptom of difficulty in swallowing
What are the structural causes of dysphagia
Intrinsic lesion:
Foreign body
Stricture – Benign/Malignant
Rings/webs
Extrinsic causes
Lymph nodes
Goitre
Enlarged LA
What are the functional causes of dysphagia?
Motility Disorders:
Achalasia
Oesophageal spasm
Neuromuscular Disorders:
Cerebrovascular Disease
Bulbar palsy
What are the complications of chronic acid reflux
- oesophagitis
- peptic stricture
- barret’s oesophagus
- oesophageal cancer
What is oesophagitis?
inflammation of squamous mucosa secondary to acid damage. Can cause strictures
What is a peptic stricture
narrowing or tightening of the oesophagus that causes swallowing difficulties.
o Complication of untreated chronic oesophagitis, causes dysphagia
What is Barret’s oesophagus
metaplasia in the cells of the lower portion of theoesophagus
o Characterised by replacement of the normalstratified squamous epitheliumlining of the
oesophagus by simple columnar epithelium withgoblet cells(which are usually found lower in
thegastrointestinal tract).
o Columnar transformation of squamous mucosa (squamous columnar) is caused by chronic
acid damage
o Pre-cancerous condition. Patients should be monitored regularly for dysplasia
Describe oesophageal cancer
accumulating cellular genetic changes causing dysplasia and ultimately cancer
What are the treatment options for GORD?
- lifestyle changes
- pharmacotherapy
- surgical management
Describe the lifestyle changes adopted in the management of GORD
Weight loss
Elevate head of bed at night
Avoid precipitants, e.g. coffee, chocolate, tomatoes, alcohol,and fatty
or spicy food
What are the pharmacotherapy options in the treatment of GORD
- PPIs
- H2 receptor antagonsists
- antacids
- alginates
- mucosal agents
- prokinetics
What are PPIs?
Proton-pump inhibitors (mainstay oftherapy)
What is the mechanism of action of PPIs?
Accumulate selectively in the canaliculi of the parietal cells
Undergo an acid-catalysed rearrangement to the active drug
This cationic sulfenamide binds irreversibly with sulphydryl groups on the proton pump causing inhibition
Irreversible inhibition leads to longer duration of action compared to H2RAs
What are the side effects of PPIs?
o Diarrhoea (esp. Lansoprazole) o Rash o Headache o Infections – C. diff o Interact with cytochrome P450 - Clopidogrel (?Pantoprazole) o Long-term use - ?GNETs
What is the mechanism of action of H2 receptor antagonists?
Competitively block histamine receptors on the
parietal cell
What are the side effects of H2 receptor antagonists?
o Diarrhoea o Deranged LFTs o Headache o Dizziness o Fatigue o Rash
Tachyphylaxis
Tachyphylaxis:
a rapid decrease in the response to a drug due to previous (long term) exposure to that
drug
List examples of H2 receptor antagonists
o Cimetidine
o Ranitidine
o Famotidine
o Nizatidine
What is the mechanism of action of antacids
o Raise the pH of gastric secretions
o Decrease pepsin activity
o Some bind bile acids
o Duration of action depends on rate of gastric emptying
What are antacids?
predominantly aluminium and magnesium salts => neutralise the effects of stomach acid
What are the side effects of antacids?
o Al salts – constipation
o Mg salts – diarrhoea
o Some formulations have high Na levels – avoid in cardiac/renal disease
o Interact with tetracyclines, digoxin, iron, prednisilone.
What are alginates?
Giant Pacific Kelp - Macrocystis pyrifera
o Algin extracted
Sodium alginate used in treatment of GORD
Mixture of polyurionic acids
Added to antacid preparations as foaming agents
Layer of foam on stomach contents – mechanical barrier to reflux.
Name examples of prokinetics and how they work
Metoclopramide/domperidone
Both increase gastric emptying and increase LOS pressure
Metoclopramide also acts on cholinergic systems in GI tract to increase ACh release
Useful GORD and functional dyspepsia
o Early satiety, belching, nausea +/or bloating
What are the side effects of domperidone?
drowsiness, diarrhoea, hyperprolactinaemia
Give an example of a mucosal agent and how it works
Complex sucrose polymer, cytoprotective agent
o sucrose sulfate-aluminium complex
o Binds to the ulcer, creating a physical barrier that protects the gastrointestinal tract from
stomach acid and prevents the degradation of mucus
o Anionic sulphate binds to positively charged glycoproteins in ulcer
Forms a ‘paste’, impeding diffusion of acid and acting as buffer for 6-8 hours
Describe the surgical management of GORD
Repair of hiatal hernia, if one is present.
o Involves tightening the opening in the diaphragm with stitches
Laparoscopic Nissen fundoplication
o Wrapping the fundus of the stomach around the end of the
oesophagus with stitches.
o The stitches create pressure at the end of the oesophagus,
reinforcing the lower oesophageal sphincter
o This helps prevent stomach acid and food from flowing up from
the stomach into the oesophagus.
What are the red flag symptoms of dyspepsia
Iron deficiency anaemia (may indicate bleeding)
Unintentional weight loss
Dysphagia
Persistent vomiting
Epigastric mass
>55 with unexplained and persistent dyspepsia
Describe atrophic gastritis
- chronic inflammation of fundic glands
- parietal cell atrophy
- resulting in reduced acid secretion (hypochlorhydria or achlorhydria)
- => increased gastrin production
Describe endoscopy as an investigation of oesophageal disorders
Can be performed with topical anaesthesia or conscious sedation
Direct visualisation of upper GI tract to d2
Diagnosis of structural and mucosal abnormalities, e.g. Hiatus hernia, tumours, Barrett’s oesophagus
Allows mucosal biopsy
Therapeutic intervention
Complications
What is Radio frequency ablation?
Used to remove tissue affected by Barrett’s oesophagus
Endoscopic technique in which diseased tissue is exposed to heat energy and destroyed
What is the gold standardfor diagnosis ofgastroesophageal reflux disease?
Oesophageal pH monitoring
What is Oesophageal pH monitoring
Provides direct physiologic measurement of acid in theoesophagus and is the most objective method to
o document reflux disease
o assess the severity of the disease
o monitor the response of the disease to medical or surgical treatment
How is an oesophageal pH monitoring test performed?
the sensor is placed 5cm above upper border of thelower oesophageal sphincter (LOS) determined byoesophageal manometry.
To measure proximal oesophageal acid exposure the second sensor is placed 1-5 below the lower border of theupper oesophageal sphincter(UOS).
Oesophageal pH monitoring is performed for 24 or 48 hours and at the end of recording, a patients tracing is analysed and the results are expressed using six standard components.
Of these 6 parameters, a pH score calleda DeMeester Scoreis been calculated
o This is a global measure of oesophageal acid exposure.
o A Demeester score > 14.72 indicates reflux.
How is a reflux episode defined in oesophageal pH monitoring?
A reflux episode is defined as oesophageal pH drop below 4
o pH below 4 is damaging because pepsin is active at pH 4
What constitutes a normal and abnormal result on oesophageal pH monitoring
Normal pH trace would show relatively constant pH around 7 with a few short dips in the day
Abnormal:
o Episodes of change in pH are more frequent and more prolonged
What is the benefit of high resolution manometry?
Allows recording of pressures within the oesophagus and proximal
stomach.
Oesophageal manometry measures the rhythmic muscle contractions
that occur in your oesophagus when you swallow assesses motility
Oesophageal manometry also measures the coordination and force
exerted by the muscles of your oesophagus
How is high resolution manometry performed?
Catheter inserted through nose with local anaesthetic spray.
Display showing pressures as colour plot or lines
Diagnosis of motility disorders eg oesophageal spasm,
How is Radio frequency ablation performed?
An electrode mounted on a balloon catheter or an endoscope is used to deliver heat energy directly to
the diseased lining of the oesophagus
Tissue sloughs off over 48 to72 hours following the procedure.
Over a period of six to eight weeks, this tissue is replaced by normal (squamous) lining
What is Melena
(Black blood) = partially digested, therefore it must originate from the upper GI tract and have
been mixed with acid
How does the functional anatomy differ in different regions of the stomach
o Gastric body contains oxyntic glands
Contains parietal cells that secrete HCl and INTRINSIC FACTOR
o Gastric antrum contains pyloric glands
Contain G cells that secrete GASTRIN
What are the key actors of gastric secretion?
Acetylcholine (neuronal – parasympathetic)
Gastrin (G cell – endocrine)
Histamine (ECL cell – paracrine)
Somatostatin (D cell – endocrine)
Describe the processes during the cephalic phase
ACh acts on parietal cells
ACh acts on G cells to increase gastrin secretion this increases acid production by stimulating parietal
cell via CCK2
o Stimulates ECL cells to secrete histamine these act on H2 receptors on parietal cells,
increasing acid secretion
ACh inhibits D cells, inhibiting somatostatin production (inhibits the inhibitor)
Describe the processes during the gastric phase
When food is ingested, proteins in food buffer acid, increasing the pH in the stomach
Gastrin is produced in response to elevated pH, stimulating increased acid production
More acid is produced in response
Describe the processes during the intestinal phase
When food leaves the stomach, gastric pH drops
D cells secrete somatostatin in response, which inhibits acid production
Acid secretion falls
What are the functions of gastric acid?
Kills bacteria
Denatures proteins
Aids in absorption of iron, vitamin B12 and calcium
o Calcium is oxidised from Ca 2+ to Ca 3+ to assist in absorption
What does gastric mucous production depend on?
prostaglandins
How are prostaglandins produced?
Arachidonic acid pathway
o AA is broken down into prostaglandins by COX-1 (constitutive)
o COX-2 (inducible) is responsible for inflammatory effects
PGI 2 and PGE
Why do NSAIDs causes peptic ulceration?
NSAIDs cause peptic ulceration because they are non-selective COX inhibitors
However, selective COX-2 inhibitors have been unsuccessful and were withdrawn from the market
because of cardiovascular toxicity
How does peptic ulcer disease occur?
imbalance between attack (acid) and defence
What are the hypersecretory causes of peptic ulcer disease?
o Zollinger Ellison Syndrome (gastrin producing tumour)
Can be controlled with antisecretory drugs
o Helicobacter pylori antral gastritis
What are the defence-reducing causes of peptic ulcer disease
o NSAIDs
o “Stress” ulceration (e.g. following major trauma or burns)
less COX-1 action because of excessvie COX-2 action
reduced by nasogastric feeding and antisecretory drugs
o H pylori infection corpus/pan gastritis
What are the complications of peptic ulcer disease?
Erosion into blood vessel
Perforated peptic ulcer erosion through outside wall of stomach or duodenum causes acute leak of
gastric contents or air into peritonitis
o Acute pan-abdominal pain
Anaemia – tired and breathless, pale conjunctiva
What is the link between h. pylori and peptic ulcer disease
High urease activity => catalyses the reaction between urea and water to form ammonia
What are the reasons of decline in h. pylori causing peptic ulcer disease?
o Now mostly colonises the antrum and not the body
o This decreases somatostatin production, increases gastrin production increased overall acid
secretion (hypersecretion)
o Mucous protection layer is less effective
o Prone to duodenal ulcers and ulcers in the pre-pyloric region
o Slight protective effect against gastric and duodenal cancers
o Treat, usually no need for repeat endoscopies
What causes and what is the consequences of Acid hyposecretion?
dominates in the East (Japan etc.)
o Pan gastritis
o Parietal cells and oxyntic glands are inflamed =>decreased acid production
o Inflammation wears away the gastric defence, leaving people at risk of ulcers and gastric cancer
o Stomach becomes colonised by other bacteria (due to hyposecretion of acid)
o Repeat endoscopies
How is H. pylori tested for?
- blood test
- stool test
- breath test
- endoscopy
What is the use of blood test in H. pylori testing
serology for h pylori antibodies
NB: will always be positive even after infection has cleared. Therefore useful for primary investigation
only, not follow-up after treatment
How are stool tests used in H. pylori testing
test for bacteria antigen
How is breath tested for H. pylori
– urea breath test
- patient given urea that is labelled with C 13 /C 14
- then asked to breathe out into bag to determine how much of the exhaled carbon is labelled
- no helicobacter, urea will be absorbed and urinated out, only C 12 in breath test
- positive test will show heavier carbon isotope in exhaled air
How is H. pylori identified on endoscopy
test urease activity on gastric biopsy, or microscopic analysis (histological biopsy)
- rapid urease test (contains pH indicator). Production of ammonia changes colour from yellow to red
How are PPIs uptaken in the body?
The low pH in the stomach converts all of the PPI to the ionised form, which cannot be absorbed. It
therefore has to be packaged in enteric coating
It is absorbed in the small intestine and is transported to parietal cells
o Here is becomes ionised and is trapped within the parietal cells
o PPI forms an unbreakable disulphide bond with the proton pump, blocking it
What is the reason behin reducing pH in ulcer treatment
Can’t heal an ulcer/eradicate H pylori without reducing acid secretion
The pH need to be > 4 for extended period of time to allow for the stomach/duodenum to heal
