The oesophagus in health and disease

The normal oesophagus effortlessly transfers food and drink from the benign environment of the mouth through the gate of the lower oesophageal sphincter into the harsh acidic environment of the stomach. Transient gastro-oesophageal reflux occurs in almost everybody and it is only when episodes become frequent, with prolonged exposure of the oesophageal mucosa to acid and pepsin, that problems develop.

The physiological lower oesophageal sphincter (LOS), normally located at the gastro-oesophageal junction at the level of the diaphragm, allows solid and liquid boluses to pass into the stomach while preventing acidic gastric contents refluxing into the oesophagus. Intrinsic tonic contraction of the LOS is interrupted by normal transient lower oesophageal relaxation as well as coordinated relaxation when swallowing is initiated. Numerous neurohumoral intermediaries are involved in these processes, including parasympathetic efferents, acetylcholine (Ach), γ-aminobutyric acid (GABA) and glutamate. The integrity of the sphincter can be compromised by the presence of a hiatus hernia, which disrupts its anatomical and physiological components.

Excessive or inappropriate relaxation of the LOS results in gastro-oesophageal reflux disease, oesophagitis and oesophageal ulceration, stricturing resulting in mechanical obstruction and sometimes a secondary oesophageal dysmotility and spasm. Reduced oesophageal clearance of acid may also contribute. In susceptible individuals, acid reflux triggers columnar metaplasia of the native squamous epithelium (also known as Barrett’s oesophagus). This is a pre-malignant condition for oesophageal adenocarcinoma.

Oesophageal dysmotility tends to produce symptoms of dysphagia to both solids and liquids, as opposed to mechanical obstruction which results in dysphagia to solids unless very advanced. A high sphincter tone and uncoordinated oesophageal contractions can cause dysphagia and pain. Achalasia is a motility disorder of unknown aetiology characterised by oesophageal hypomotility, a hypertonic LOS and a failure of relaxation of the LOS.

Gastric acid secretion and mucosal protection

In the normal upper GI tract, the destructive effects of gastric hydrochloric acid are balanced by a variety of mucosal protective mechanisms. Duodenal and gastric ulceration results from an imbalance between these two opposing forces. Helicobacter pylori infection and use of non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in upsetting this fine balance. Other digestive enzymes such as pepsinogen/pepsin also contribute to the gastric phase of digestion but are qualitatively of less importance.

Gastric acid secretion

Acid secretion by parietal cells in the gastric mucosa is regulated by four main neurohumoral mediators.

Mucosal protective mechanisms

Mucus and bicarbonate is secreted by cells in the gastric and duodenal mucosa and provides a protective relatively alkaline physical barrier against the otherwise destructive intragastric environment. Secretion is promoted by prostaglandins, which also inhibit gastric acid secretion. Numerous lifestyle factors adversely affect the mucosal barrier, including smoking and alcohol.

Helicobacter pylori (H. pylori): an occasionally silent killer

It is now known that a large majority of benign gastric and duodenal ulceration is due to H. pylori infection (following Marshall and Warren’s Nobel prize-winning experiments ¹^,²); most of the remainder can be attributed to NSAID use. Colonisation of the stomach with H. pylori is seen in virtually all patients with a duodenal ulcer and in 70–80% of those with gastric ulcers. H. pylori appears to stimulate increased acid secretion. All patients colonised with H. pylori develop gastritis, but only about 20% have ulcers or other lesions. As yet incompletely understood host factors and differences in strain of the organism are likely to explain this discrepancy.

H. pylori infection is carcinogenic and is the leading cause of gastric carcinoma. It is also highly associated with gastric MALT lymphoma. Eradication of the organism can lead to regression and even resolution of this latter malignancy.

Somewhat counterintuitively, H. pylori infection is not a cause of acid reflux disease, and in fact its eradication may precipitate or exacerbate acid reflux. Indeed, the recent surge in oeosphageal adenocarcinoma incidence in the West has been blamed by many on the now commonplace practice of searching for and eradicating H. pylori, although this has conversely resulted in a fall in the incidence of gastric cancer.

NSAIDs: enemies of the gut

Some 500 million prescriptions for NSAIDs are written each year in the UK, and 10–15% of patients develop dyspepsia while taking these drugs. Gastric erosions develop in up to 80%, but these are usually self-limiting. Gastric or duodenal ulcers occur in 1–5%. The incidence increases sharply with age in those over 60 years, and the risk of ulcers and their complications is doubled in patients aged more than 75 years and those with cardiac failure or a history of peptic ulceration or bleeding. All NSAIDs are ulcerogenic, but ibuprofen is less prone to cause these problems than other non-selective NSAIDs.

NSAIDs are weak organic acids and the acid milieu of the stomach facilitates their non-ionic diffusion into gastric mucosal cells. Here the neutral intracellular pH causes the drugs to become ionised and trapped in the mucosa because they cannot diffuse out in this form.

Aspirin and the other NSAIDs inhibit cyclo-oxygenase (COX) (see Ch. 16). In the stomach, the constitutively expressed COX-1 isoform is responsible for the production of the gastroprotective prostaglandins E2 and I2 (see above). Inhibition of the inducible COX-2 isoform (which is normally up-regulated in activated inflammatory cells) is responsible for NSAIDs’ anti-inflammatory properties. Most NSAIDs inhibit both isoforms unselectively, so the beneficial anti-inflammatory effect is offset by the potential for mucosal injury by depletion of protective prostaglandins. Aspirin is particularly potent in this respect, perhaps because it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent.

Selective COX-2 inhibitors represent an attempt to provide beneficial anti-inflammatory effects without promoting ulceration. Unfortunately, there is evidence that unopposed COX-2 inhibition results in an increased risk of thrombotic events (including myocardial infarction and stroke); the UK Committee on Safety of Medicines therefore counsels against their use in preference to non-selective NSAIDs in the absence of a compelling indication, and cardiovascular risk should be assessed.