Peptic ulceration and related disorders

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Peptic ulceration and related disorders

Introduction

Peptic ulcer disease affects the oesophagus, stomach and duodenum. The conditions share the symptom of epigastric pain and the common aetiology of mucosal inflammation associated with gastric acid–pepsin secretions. The most important aetiological factor in gastric and duodenal ulcer disease is chronic mucosal infection with the bacterium Helicobacter pylori. Peptic disorders, together with gallstone disease, are the most common causes of organic upper abdominal pain.

With highly effective pharmacological agents to block acid secretion and more reliable diagnostic, treatment and monitoring techniques such as flexible endoscopy, surgery for peptic ulcer disease has declined by over 90% in developed countries in the last 30 years. Recent antibiotic and other treatments against H. pylori result in permanent cure for many peptic ulcer disorders. Most patients with suspected peptic ulcer disease are treated by family practitioners; the rest are largely managed by gastroenterologists. Only a minority present to surgeons because of failed medical treatment. Rates of emergency complications such as perforation and haemorrhage have remained relatively static but peptic pyloric stenosis has markedly declined as chronic ulceration has become less common. Nevertheless, because of the diagnostic difficulties posed by upper abdominal symptoms, surgeons still manage many patients who turn out to have peptic disorders.

Pathophysiology and epidemiology of peptic disorders

Pathophysiology of peptic ulceration

Inflammation, probably initiated by H. pylori infection and sustained by the combined effect of gastric acid and pepsin on the mucosa, is probably the cause of all peptic disorders of the upper gastrointestinal tract other than reflux oesophagitis. H. pylori is a Gram-negative microaerophilic spiral bacterium which has the ability to colonise the gastric mucosa over a very long period. In many cases, infection appears to have been acquired in childhood, often with poor living conditions in early life. Normally, a dynamic balance is maintained between the inherent protective characteristics of the mucosa (the mucosal barrier) and the irritant effects of acid–pepsin secretions. The delicate balance between the two may be disrupted by diminution of mucosal resistance or excessive acid–pepsin secretion or a combination of both. The mucosal surface may become eroded by direct action of an external agent, e.g. alcohol. Whatever the aetiology, the range of pathological outcomes is similar and is summarised in Figure 21.1.

Fig. 21.1 Pathogenesis of peptic ulceration and its possible outcomes
Note that pain is a common factor in any active ulceration

Outcomes of breaches of the mucosal barrier

When the protective mucosal barrier is breached, the delicate underlying connective tissue is exposed to acid–pepsin attack, exciting an acute inflammatory response. If the protective balance is restored at this early stage, inflammation resolves and epithelium regenerates. Little if any residual damage will result. If the healing balance is not restored, continued acid–pepsin attack on the unprotected submucosa leads to an acute peptic ulcer. This tends to become progressively larger and deeper.

Sometimes the ulcerative process continues virtually unchecked through the full thickness of the gut wall. The ulcer either erodes posterior tissues or perforates so that intestinal contents escape into the peritoneal cavity causing peritonitis. More often, the layer of necrotic slough and acutely inflamed underlying tissue in the ulcer base temporarily resist acid–pepsin attack. This allows granulation tissue to form which initiates the process of fibrous repair. If acid-reducing drugs are used, the ulcer may heal, leaving a small scar with normal overlying mucosa. Usually, however, a tenuous balance is established between resistance and attack, matched by an unstable equilibrium between the rates of repair and tissue destruction. A chronic peptic ulcer then results which may persist for years, its size and symptoms varying as mucosal resistance and exacerbating factors fluctuate.

If local or systemic factors change and swing the balance in favour of repair, the lesion may heal completely. On the mucosal surface, the healed ulcer site is usually puckered by scar contraction in the muscular wall. If scarring occurs in a narrow part of the tract, e.g. the pyloric region, the lumen may stricture, and subsequent acute mucosal inflammation and swelling may precipitate gastric outlet obstruction. If healing does not occur, a chronic ulcer may slowly enlarge and deepen. Continual bleeding from the ulcer may cause chronic anaemia. Ulceration posteriorly may erode into the gastroduodenal artery causing acute major haemorrhage; if the ulcer lies on the anterior wall, it may perforate into the peritoneal cavity.

Epidemiology and aetiology of peptic ulcer disease

The size of the problem

Chronic peptic ulcer disease is very common in developed countries, affecting around 10% of the population at some time in their lives. The incidence of duodenal ulcer has been falling over the last 30 years, probably because of improved living conditions, reduced smoking and good medical therapy. The incidence of gastric ulcer is probably constant, although increasing numbers of cases are revealed as a result of NSAID-provoked haemorrhage.

Peptic ulceration is less common in developing rural communities, despite a high incidence of H. pylori gastroduodenal infection. This implies that environmental factors associated with Western life are additional aetiological factors in the disease.

Sites of peptic ulceration (see Fig. 21.2)

Stomach and duodenum: The most common sites for chronic peptic ulcers are in the first part of the duodenum (the duodenal bulb) or the gastric antrum, particularly along the lesser curve. A chronic stomal ulcer may also appear at the margin of a surgically created communication between stomach and intestine (gastroenterostomy).

Fig. 21.2 Surgical anatomy of stomach and duodenum showing common sites of peptic ulceration
Acid secretion by the gastric mucosa is controlled by two mechanisms: (a) the vagus nerve stimulates acid secretion by the parietal cells (cholinergic stimulation) and (b) gastrin (produced by the APUD cells in the antrum) promotes secretion of acid and pepsin by the parietal and peptic cells of the fundus and body. The second is mediated via H₂-receptors. (1) Marks the common site for duodenal ulcers which may be anterior or posterior; (2) the common site of lesser curve gastric ulcers; and (3) the site of pyloric channel ulcers

In the rare Zollinger–Ellison syndrome, a gastrin-secreting tumour of pancreatic origin over-stimulates acid–pepsin production and causes severe and widespread peptic ulceration. The ulcers commonly involve stomach and duodenum and extend into the second part of the duodenum or even further distally.

Oesophagus: Peptic inflammation and superficial ulceration may involve the lower oesophagus. It is almost always secondary to acid–pepsin reflux, and is often associated with hiatus hernia. H. pylori infection (see below) is probably not an important factor here. Reflux causes intermittent destruction of the lower oesophageal mucosa by acid or bile (or both), causing linear ulceration and prompting vigorous attempts at healing. One outcome is replacement of the normal squamous epithelium with metaplastic columnar mucosa. This is known as Barrett’s oesophagus and is one of the few known predisposing factors for adenocarcinoma of the lower oesophagus, a condition that has increased by 70% over the last 25 years (see Ch. 22, p. 311). Chronic peptic ulcers, similar to gastroduodenal ulcers, may also develop at the lower end of the oesophagus.

Aetiological factors in peptic disease

H. pylori infection: The importance of H. pylori infection as the main initiating factor in peptic ulceration has finally been universally accepted following the pioneering work of Dr Barry J. Marshall and Dr J. Robin Warren in Perth, Australia in the early 1980s. In a dramatic demonstration of Koch’s postulates, Marshall produced a duodenal ulcer in himself a few days after ingesting cultured H. pylori. The ulcer proved to be H. pylori-positive on biopsy and was cured by anti-Helicobacter antibiotic therapy. The pair won the Nobel Prize in Physiology or Medicine for 2005 for their discovery of the bacterium and its role in gastritis and peptic ulcer disease. Before their work, it had been believed that microorganisms could not live in the highly acid environment of the normal stomach. However, gastric biopsies had frequently shown intramucosal bacteria, which they were eventually able to culture in vitro. These spiral-shaped organisms appear able to penetrate protective surface mucus and then accumulate in the region of intercellular junctions. There they may excite inflammation, stimulating excess acid–pepsin production or compromising normal protective mechanisms.

The jigsaw began to fit together when it was found that peptic ulcers could regularly be successfully treated with a combination of bismuth and antibiotics. Later work showed that H. pylori infection in duodenal ulcer patients was associated with a six-fold increase in gastric acid production which remitted when the infection was eliminated. There is now evidence that H. pylori is sometimes carcinogenic, initiating certain types of gastric lymphoma and some cases of gastric cancer. The broad picture is now evident: H. pylori causes a chronic infection with complications that include gastric and duodenal ulcer, gastric mucosa-associated lymphoma and gastric cancer. Only a small percentage of patients with duodenal or gastric ulcers are H. pylori negative. Tests for H. pylori infection include stool antigen tests, serum anti-H. pylori IgG and hydrogen breath tests. However, the most reliable method of diagnosis is endoscopic biopsies with immediate testing for urease produced by the organism (see below, Fig. 21.7) and histological examination of biopsy specimens.

Further details of this fascinating story remain to be worked out; for example, why not all patients with H. pylori infection develop upper gastrointestinal lesions, and why not all patients with certain gastric cancers have been exposed to H. pylori. There is even speculation that elimination of H. pylori may predispose some patients to gastric cancer.

Acid–pepsin production: Parietal cells secrete acid in direct or indirect response to acetylcholine, gastrin and histamine. It is likely that the common mediator is histamine via H₂-receptors. The final common pathway for hydrogen ion secretion is via activation of a specific enzyme, H⁺/K⁺ ATPase, which exchanges hydrogen ions generated in the parietal cell for potassium ions in the gastric lumen using a mechanism known as the proton pump. In duodenal ulceration, the fundamental abnormality appears to be excessive production of acid–pepsin by the stomach, both basal (i.e. overnight) and stimulated. This may be a defensive response to H. pylori infection.

In patients with gastric ulcers, measured acid secretion is either normal or low, and the essential problem seems to be diminished resistance to acid–pepsin attack, probably related to the quantity or quality of mucus produced. Nevertheless, reduction of acid production by medical or surgical means is effective in healing gastric ulcers.

Mucosal resistance: There are several mechanisms which protect the upper gastrointestinal mucosa against autodigestion. Somatostatin and COX1 induced prostaglandins are inhibitors of parietal cell secretion and the latter have other cytoprotective properties. Two forms of mucus, soluble and insoluble, are secreted continuously by gastric and duodenal mucosa; they contain bicarbonate and together maintain the cell surface pH at neutrality.

Non-steroidal anti-inflammatory drugs (NSAIDs) prescribed for arthritic disorders are commonly identified as the causative factor for acute presentations of peptic ulceration. NSAIDs probably have their greatest effect systemically rather than locally, via their blocking effects on prostaglandin production. Indeed, in elderly patients presenting with upper gastrointestinal bleeding or perforation, ulceration may occur after only a few NSAID tablets have been taken or at any time during their use. This risk is not diminished by enteric-coated preparations, nor by administration by routes other than orally, e.g. as suppositories. The risk of NSAID-induced ulceration increases steeply in later life. All NSAIDs have been incriminated and their power to provoke peptic ulceration is in direct proportion to their effectiveness at relieving arthritic symptoms. A history of ‘indigestion’ in patients taking NSAIDs must be taken seriously.

Other mucosal irritants: Aspirin and other NSAIDs are known to induce acute mucosal inflammation directly (acute gastritis). In a susceptible individual, inflammation may persist, resulting in chronic ulceration. Prolonged heavy alcohol intake is also a recognised risk factor. The junction between parietal and antral cells on the lesser curvature of the stomach has been noted to be particularly vulnerable to gastric ulceration, although the reason is not understood. Cigarette smoking is twice as common in patients with chronic peptic ulcer disease as in the general population. Its pathogenic role is attributed to increased vagal activity, and its effect on producing relative gastric mucosal ischaemia. Ceasing smoking greatly assists in the healing of peptic ulcers.

Investigation and clinical features of peptic disorders

Investigation of suspected peptic ulcer disease

The diagnosis and management of peptic disorders relies mainly on flexible endoscopy, which revolutionised the process after its introduction in the late 1960s. Barium meal contrast radiography has largely been superseded by endoscopy.

Endoscopy

Oesophago-gastro-duodenoscopy, also known as OGD or gastroscopy, involves visual examination of the mucosa using a steerable, flexible endoscope. Gastroscopy enables direct and comprehensive examination of the whole of the upper gastrointestinal tract prone to peptic ulcer disease.

In peptic ulcer disease, gastroscopy has definite advantages over contrast radiography, which by its nature can only demonstrate substantial structural abnormalities and then only as two-dimensional images. Benign gastric or oesophageal ulceration can be reliably distinguished from malignancy if endoscopic biopsies are taken from several places around the ulcer edge. In patients with peptic disorders, biopsies of distal gastric mucosa are now taken routinely to investigate H. pylori infection.

In acute upper gastrointestinal haemorrhage, gastroscopy is almost mandatory, as described in Chapter 19. Gastroscopy can identify the site of the bleeding and is particularly useful if gastro-oesophageal varices are suspected to be the source of bleeding but are found not to be. Gastroscopy also allows recognition of features which can help stratify patients into low or high risk of rebleeding and it provides an important means of treating bleeding sites by injection of vasoconstrictors or sclerosants.

Contrast radiology

Contrast radiography of the upper gastrointestinal tract is used largely to determine swallowing function, to define anatomy, particularly with large hiatus hernias, and to give an idea of the effectiveness of gastric emptying. It involves the patient swallowing barium suspension (barium meal). During the investigation, the patient is tilted and rolled in various directions to demonstrate the whole region of interest. Effervescent tablets are given to produce gaseous distension of the stomach and duodenum and spread the contrast in a thin, even layer over the mucosal surface. This standard double contrast technique improves the imaging of mucosal detail.

Presenting features of peptic ulcer disease

The various ways in which peptic inflammation affects the oesophagus, stomach and duodenum are summarised in Table 21.1.

Table 21.1

Clinical consequences of peptic ulcer disease in different anatomical sites

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