Peptic ulceration and related disorders

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).

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.

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.

Gastritis: Gastritis appears as widespread reddening of the mucosa. If biliary reflux from the duodenum into the stomach is evident, the condition is sometimes referred to as ‘biliary gastritis’ on the assumption that it is caused by the irritant effect of biliary and pancreatic secretions. Acute gastritis, often caused by alcohol (chronic alcoholism or single alcoholic binges) or aspirin/NSAID ingestion, can cause symptoms of sufficient severity to warrant gastroscopy. The mucosa often exhibits patchy shallow ulceration (erosive gastritis) and is friable and easily traumatised, causing bleeding.

Stress ulcers: Acute ‘stress’ ulcers are single or multiple small discrete superficial lesions that may develop rapidly in seriously ill patients, often in intensive care units. The condition may be a complication of extensive burns, systemic sepsis (possibly via visceral hypoperfusion), multiple trauma, major head injuries, uraemia or terminal illness. Stress ulcers typically present with haemorrhage (haemorrhagic gastritis), which is sometimes catastrophic, and occasionally with perforation. There is minimal mucosal inflammation around the ulcers and the aetiology may be primarily mucosal ischaemia rather than peptic. The risk of this life-threatening complication can be minimised in vulnerable patients by prophylactic treatment with proton pump inhibitors.

Chronic gastric ulceration: Chronic gastric ulcers vary greatly in size but the majority are small (less than 2 cm in diameter). Giant ulcers (up to 10 cm) are occasionally seen in the elderly; if posteriorly situated, they may erode through the stomach wall, obliterating the lesser sac and adhering to the surface of the pancreas. In these cases, the ulcer base or floor is composed of pancreatic tissue and erosion may cause catastrophic haemorrhage.

Benign gastric ulcers are typically regular in outline with a base consisting of white fibrinous slough. The ulcer gives the impression of having been punched out of the gastric wall, and there is no heaping-up of the mucosal margin as seen in malignant ulcers. The surrounding mucosa is surprisingly normal, although there may be radiating folds resulting from chronic fibrotic contractures. The typical endoscopic appearance of a gastric ulcer is shown in Figure 21.5a.

Peptic disorders of the stomach typically cause severe, often disabling, epigastric pain which tends to be exacerbated by food, especially if acidic or spicy. The pain may be so severe that patients lose weight and develop a fear of food. Symptoms tend to persist for weeks or months, fluctuating in intensity and then disappearing completely, only to recur weeks or months later. Symptoms are a poor guide to disease activity or response to treatment. Indeed, major ulcers may be silent. Both can be monitored only by repeated gastroscopy until healing. A rare complication of peptic disease is perforation of a gastric ulcer into the transverse colon. The resulting gastro-colic fistula causes true faecal vomiting.

Duodenitis: Duodenitis, a non-ulcerative form of duodenal inflammation, has a similar endoscopic appearance to gastritis. It is commonly discovered in patients suspected of having duodenal ulceration, and probably represents a mild form of peptic disease.

Chronic duodenal ulceration: Chronic duodenal ulcers almost exclusively occur in the pyloric channel and the first part of the duodenum. The latter area is known endoscopically as the ‘duodenal bulb’ and radiologically as the ‘duodenal cap’. On endoscopy, duodenal ulcers have a range of appearances similar to chronic gastric ulcers. There is usually a single ulcer but two or more ulcers at one time are common (‘kissing ulcers’ occur on opposing walls of the duodenum). Malignancy is very rare in the duodenal bulb, so biopsy of the ulcer for this purpose is seldom necessary; biopsy of the gastric antrum for confirmation of H. pylori infections is, however, indicated. The endoscopic characteristics of a duodenal ulcer are shown in Figure 21.6.

Duodenal ulcer symptoms follow the same general pattern as gastric ulcer but with important exceptions. The pain tends to appear several hours after a meal (‘hunger pain’) and is relieved by eating. A typical history includes episodic early morning waking (often around 2 a.m.) with epigastric pain; this pain is relieved by drinking milk and eating bland foods. Consequently, undiagnosed patients tend to gain weight from the increased intake of food and milk. This is in contrast to the weight loss often associated with gastric ulcer. Symptoms in duodenal ulcer are more useful as a guide to disease activity and response to treatment than in gastric ulcer.

Control of predisposing or aggravating causes: The patient's history may reveal adverse factors which can be easily eliminated. These are summarised at the start of Box 21.1. Radical dietary modification is unnecessary; patients should merely be advised to avoid food which they find aggravates the symptoms. Spicy or acidic foods are often blamed.

Aspirin and other NSAIDs should be avoided, although this is often difficult in patients with arthritic disorders. The ulcerogenic effect of these drugs is directly proportional to their effectiveness and relates largely to their systemic anti-cyclooxygenase (COX1) activity, an agent protective of gastro-duodenal mucosa. There is therefore little to be gained from changing drugs within the group or by using them in enteric-coated or suppository form. If NSAIDs cannot be avoided in patients with a predisposition to peptic ulceration, concurrent use of cytoprotective drugs may be indicated.

Patients with oesophageal reflux, especially if associated with hiatus hernia, can minimise the damage by simple mechanical measures such as losing weight, elevating the head end of the bed and being aware of posture in daily activities.

Elimination of proven H. pylori infection: Once H. pylori has been confirmed, treatment involves a course of acid inhibition combined with antibiotic treatment. Eradication usually produces long-term ulcer remission, and H. pylori reinfection is rare. A triple regimen including a proton pump inhibitor (e.g. omeprazole) and two antibiotics (clarithromycin plus either amoxicillin or metronidazole) given for 1 week eliminates Helicobacter in over 90% of cases, although increasingly strains of H. pylori are demonstrating antibiotic resistance and local antibiotic protocols should be followed. Longer courses give potentially higher elimination rates but produce more side-effects and lower compliance. Confirmation of eradication can be achieved by re-endoscopy and rapid urease testing (Fig. 21.7), or by breath testing.

Diminishing of irritant effects of acid–pepsin: An array of proprietary antacid preparations is available over the counter and on prescription. When used assiduously, they promote ulcer healing almost as effectively as any other drug, although more slowly. They all utilise a few main active ingredients. Sodium bicarbonate offers rapid but temporary relief of symptoms, while magnesium trisilicate or aluminium hydroxide promotes ulcer healing. Some of these agents, however, interfere with proton pump inhibitors. Colloidal bismuth compounds have been in use for many years. They have an antacid action and have been found to be active against H. pylori.

Alginate preparations form a foamy layer on the surface of gastric contents, coating the upper stomach and lower oesophagus and protecting it from oesophageal reflux.

Administration of mucosal protective agents: Sucralfate is a complex of aluminium hydroxide and sulphated sucrose that is minimally absorbed from the gastrointestinal tract. It is believed to act by binding to denuded areas of mucosa and protecting them from acid–pepsin attack. It has been shown to be as effective as H₂-blockers in providing symptom relief and healing when given in the dose of 2 g twice daily. It does not interfere with other drugs and is safe in pregnancy. It is also effective for preventing stress ulcers in seriously ill patients.

Reduction of acid secretion: Acid secretion by the gastric mucosa is normally controlled by two mechanisms:

From this, two practical methods have been found to reduce acid secretion: drugs which selectively block H₂-receptors or the proton pump mechanism (described earlier), and surgical division of the vagus nerve.

H₂-receptor blockade and proton pump antagonists: H₂-receptor blocking drugs were developed in the 1970s and were the first ‘medical’ revolution in the management of peptic disorders. Cimetidine was the first but was joined by ranitidine, which has a few minor advantages but is no more effective for healing ulcers. H₂-receptor antagonists are highly effective in reducing gastric acid secretion. Symptomatic response is rapid, usually within a day or two, and healing follows within a few weeks in 70–90% of cases. Recurrence rates, however, are high even with maintenance therapy, with 50–75% of patients developing further symptoms within 2 years.

A newer group of drugs, the substituted benzimidazoles, are extremely potent and reduce acid production to near zero by direct inhibition of the proton pump. Omeprazole and other variants are now often the first line treatment for most peptic ulcer disorders. In all cases where H. pylori infection is present, the use of these drugs must be combined with eradication antibiotic therapy.

Vagotomy: Vagotomy was first performed in the 1920s and popularised by Dragstedt from 1943. It gradually superseded classic partial gastrectomy as the surgical treatment of choice for chronic duodenal ulcer. The vagotomy operations illustrated in Figure 21.8 are now only of historical interest. The simplest involved dividing the anterior and posterior vagal trunks close to the abdominal oesophagus just below the diaphragm (truncal vagotomy). The operation is effective in promoting ulcer healing but paralyses gastric motility and slows pyloric emptying. A surgical drainage procedure, usually pyloroplasty (‘V & P’), or less commonly gastro-jejunostomy, was therefore a necessary part of the operation.

Attempts to reduce the gastric emptying complications of truncal vagotomy led to operations designed to preserve the innervation of the distal antrum and pylorus whilst denervating the proximal acid-secreting portion of the stomach. Highly selective vagotomy preserved the nerves of Latarjet and avoided the need for a gastric drainage procedure. Early postoperative side-effects were fewer but ulcer recurrence rates were higher than for truncal vagotomy.

Surgical removal of intractable ulcers and gastrin-secreting tissue: Partial gastrectomy was occasionally used for patients where medical management had failed to heal a benign gastric ulcer or to treat repeated recurrences. The operation had the dual role of removing the ulcer and the gastrin-secreting mucosa. The classic gastrectomy for chronic gastric ulcer was known as the Billroth I type (Billroth, 1881) and involved removing the distal two-thirds of the stomach. The gastric remnant was then anastomosed to the first part of the duodenum (see Fig. 21.9).

The standard partial gastrectomy for duodenal ulcers was a Polya-type gastrectomy (Polya, 1911), also involving resection of the distal two-thirds of the stomach but anastomosing the cut end of the stomach to the side of a loop of proximal jejunum (gastro-jejunostomy). This is also known as a Billroth II operation. The cut end of the duodenum (duodenal stump) was closed and the ulcer left in situ to heal (see Fig. 21.9). Numerous variations on gastrectomy have been described over the years, but the essential difference is whether the gastric remnant is anastomosed to the duodenum (Billroth I-type) or to a jejunal loop (Polya-type).

In general, partial gastrectomy was highly effective in relieving symptoms and preventing recurrence of peptic disease, but long-term side-effects were a serious problem affecting 30–40% of patients.

Complications and side-effects of partial gastrectomy: The main complications of partial gastrectomy occur in the long term and may not become manifest for years (see Box 21.2). Recurrent ulceration after partial gastrectomy was rare and occurred in the gastric remnant or at the stomal margin. The usual reason was that insufficient stomach had been removed, but occasionally malignant change was responsible (3% risk over 15 years). Abnormally high acid production was another cause, sometimes due to Zollinger–Ellison syndrome or hyperparathyroidism.

Correction of secondary anatomical problems: The main anatomical problems secondary to peptic disease are oesophageal stricture and pyloric stenosis.

Oesophageal strictures can usually be managed by periodic dilatation and medical or surgical treatment of the underlying cause. With the patient intravenously sedated, a guide-wire is inserted across the stricture endoscopically, and then metal, plastic or balloon dilators are inserted over it. Occasionally, reflux continues to cause damage and stricturing; it may then become necessary to perform anti-reflux surgery.

Clinical presentation of perforated peptic ulcer: Perforation of a gastric or duodenal ulcer usually presents as a sudden onset of epigastric pain, rapidly spreading to the whole abdomen. The pain is continuous and is aggravated by moving about. Paradoxically, there may be vomiting of brownish or even blood-stained fluid. On examination, the patient is in obvious pain but is not shocked or toxic.

There is generalised involuntary abdominal guarding, which in younger patients is so tense as to be described as ‘board-like rigidity’, although this may be absent in the elderly. There is also generalised abdominal tenderness but this may be difficult to detect because of guarding. After several hours, abdominal wall rigidity tends to relax although tenderness remains. Peptic ulcer perforation initially causes a chemical, as opposed to bacterial, peritonitis, unlike more distal bowel perforations. This explains the lack of general toxicity in the early stages. If untreated for more than 24 hours, secondary infection may take place and systemic signs appear.

If posterior wall gastric ulcers perforate, they leak gastric contents into the lesser sac, which tends to confine the peritonitis. These patients thus present with less marked symptoms.

Diagnosis of perforated peptic ulcer: Diagnosis of an upper gastrointestinal perforation can usually be made from the symptoms and signs alone. A plain erect radiograph of the chest often reveals gas under the diaphragm, confirming the perforation of a hollow viscus but not its origin. This radiographic evidence of perforation, however, is not always present. If perforation is suspected but the signs are equivocal, an abdominal radiograph may be taken after the patient has swallowed 25 ml of water-soluble contrast; this may confirm the leakage. Diagnostic gastroscopy is contraindicated because the stomach must be inflated during this examination and air and gastric contents would erupt into the peritoneal cavity. CT scanning is commonly used and reveals free gas within the abdomen together with free fluid, although again the origin may not be clear. Laparoscopy is increasingly used to diagnose perforated ulcers.

Surgical management of peptic perforation: Emergency surgery is indicated in nearly all cases of upper gastrointestinal perforation. The patient is first resuscitated and a nasogastric tube inserted. The operation is most commonly performed at laparotomy, but laparoscopic management of perforated duodenal ulcers is now well established with equally good results. The principles are similar in either case. At surgery, the abdomen is inspected and the diagnosis confirmed. ‘Peritoneal toilet’ is performed to remove fluid and food contaminating the peritoneal cavity. A perforated duodenal ulcer is usually obvious as a punched-out hole near the pylorus. An anterior gastric perforation is also obvious, but a posterior gastric ulcer is not visible unless the lesser sac is opened, usually along the greater curve.

In duodenal perforation, simple closure of the perforation by suturing a vascularised flap of omentum over the defect is the treatment of choice. This should be followed by Helicobacter eradication therapy as 90% of duodenal ulcers are associated with H. pylori infection.

In perforated gastric ulcer, the classic operation was Billroth I gastrectomy, including the whole ulcer in the resection. However, local excision of the ulcer and simple closure are safely employed, provided the ulcer is believed to be benign. In any case, the ulcer edge must be biopsied in several places to be certain.

Conservative management of perforated duodenal ulcer: If an elderly, unfit patient presents late with a perforated duodenal ulcer, many surgeons treat this conservatively. This involves nasogastric aspiration, intravenous fluids, gastric acid suppression and antibiotics. Many of these patients who might otherwise have succumbed with major surgery recover satisfactorily.

Clinical features of pyloric stenosis: These patients rarely give any history of peptic ulcer pain but tend to present with a short history (a few weeks at most) of episodic and sometimes projectile vomiting. This is unrelated to eating, and the vomitus typically contains foul-smelling semi-digested food eaten a day or more previously. It does not contain green bile. Often patients do not seek medical advice until they have become severely dehydrated with gross electrolyte disturbance.

On clinical examination, undernourishment, dehydration, constipation, weakness and weight loss may dominate the picture. Because the stomach is full of residual fluid and food, shaking the patient's abdomen from side to side produces an audible succussion splash. Gastric peristalsis may be visible in longstanding cases and a dilated stomach full of residual food may be palpable. On plain abdominal X-ray, it may be possible to see the grossly dilated stomach filled with mottled food material.

Several gastric washouts using a large-bore oral tube may be necessary to clear the gastric residue before endoscopy or barium meal is attempted.

The differential diagnosis of gastric outflow obstruction also includes carcinoma of the head of the pancreas (with or without obstructive jaundice) and, rarely, chronic pancreatitis.

Biochemical abnormalities in pyloric stenosis: The biochemical disturbances in these patients are complex and depend on the volume and composition of fluid lost by vomiting and on the body's compensatory mechanisms. Hydrogen and chloride are the principal ions lost in the vomitus. In response, the kidney conserves hydrogen ions by exchanging them for sodium ions (and some potassium ions), which are necessarily lost in the urine. The kidney also conserves chloride ions by exchanging them for bicarbonate ions. The net result may be a profound depletion of total body sodium (which is not accurately reflected in the plasma sodium level), profound hypochloraemia and profound metabolic alkalosis (hypochloraemic alkalosis). The plasma urea level is often high as a result of dehydration. Finally, the proportion of ionised calcium in the serum may fall as a result of the alkalosis, inducing tetany.

Management of pyloric stenosis: The first management priority in gastric outlet obstruction is resuscitation. Fluid and electrolyte deficiencies are corrected by infusion of physiological saline with added potassium chloride. The volume required often amounts to 10 litres or more. Rehydration will usually return the blood urea level to normal but may unmask anaemia serious enough to require blood transfusion.

Often the obstruction has a significant inflammatory element, and acid suppression and Helicobacter eradication will produce a significant clinical response. If these fail or malignancy is suspected, endoscopy should be repeated and careful balloon dilation of the stenosis may achieve the desired result. If the obstruction persists, operative treatment may then become necessary in the form of either a gastro-jejunostomy to bypass the obstruction, or more rarely a partial gastrectomy.