Duodenal Ulcer Video (85.2 mb)

4.1 Gastric Ulcer Disease

Acute ulcers may occur in the patient with burns (Curling's ulcer), midbrain disease (Cushing's ulcer) and chronic debilitating disease. ASA-containing analgesics and nonsteroidal anti-inflammatory drugs may also induce acute ulcer bleeding, though the risk of this complication has probably been overstated. There is epidemiologic evidence suggesting that the incidence and behavior of chronic peptic ulcers vary according to the site at which they occur. Therefore, gastric and duodenal ulcers will be considered separately, although the basic defects that cause either type relate to an imbalance of aggressive and protective factors.

Numerous pathophysiologic defects have been identified in gastric ulcer disease (Table 2A). Not all of these factors are present in each patient. These defects include decreased acid secretion, decreased parietal cell mass and back-diffusion of acid. Many patients with chronic gastric ulcers have associated gastritis. There may be increased concentration of bile acids and pancreatic juice in the stomach as a result of duodenogastric reflux. Delayed gastric emptying has also been identified in some patients with gastric ulcers, and this may accentuate the release of gastrin and the secretion of hydrochloric acid. It has yet to be determined whether delayed gastric emptying is the cause or secondary effect of gastric ulcer disease. However, as a result of back-diffusion of acid, the actual concentration of acid in the gastric lumen may be underestimated. Hypergastrinemia and hyperchloremia are not commonly thought to be associated with gastric ulcers. The pressure of the pyloric sphincter may be inappropriately decreased under basal conditions and may fail to respond normally to acid or fat in the duodenum, thereby predisposing to duodenogastric reflux.

A number of pathophysiologic defects have also been identified in some patients with duodenal ulcer disease (Table 2B). These include increased parietal cell mass (leading to increased maximal and peak acid output); increased sensitivity of the parietal cells to gastrin and other secretagogues; increased secretory drive; decreased acid-induced inhibition of meal-stimulated gastrin release; and increased gastric emptying (leading to increased duodenal acid and pepsin loads).

Apart from an increased parietal cell population (and possibly G-cell hyperplasia), the gastric mucosa is histologically normal in duodenal ulcer. By contrast, in gastric ulcer the nonparietal mucosal area is usually increased, especially on the lesser curvature, and there is often some degree of histologically demonstrable gastritis. Biliary reflux through the pylorus is also a common finding in patients with gastric ulcers, and it has been suggested that the combination of bile and acid may be particularly damaging to the mucosa, probably by causing back-diffusion of hydrogen ions into it and thus disrupting intracellular organelles.

Hereditary factors are important in the pathogenesis of peptic ulcer disease, as suggested by a higher prevalence of peptic ulcer disease in certain genetic syndromes. A number of familial aggregations have been noted in patients with peptic ulcer disease. These include hyperpepsinogenemia 1, normal pepsinogenemia 1, antral G-cell hyperfunction, rapid gastric emptying, childhood duodenal ulcer and immunologic forms of peptic ulcer disease. Heredity also plays a role in the development of ulceration and is associated with the syndrome of multiple endocrine adenomatosis 1 (adenomas of the pancreas, pituitary and parathyroid). Parents, siblings and children of ulcer patients are more likely to have peptic ulcer disease than control individuals. There is greater concordance for ulcer disease in identical than in fraternal twins. Hyperpepsinogenemia 1 appears to be an autosomal dominant trait. Families have been described in which a number of physiologic abnormalities associated with the development of ulcer disease have been noted, including increased meal-stimulated gastrin release and altered gastric emptying. There is increasing evidence to suggest that familial peptic ulcer disease is related to Helicobacter pyloric infection amongst family members.

Peptic ulcer disease is thought to occur as a result of an interplay between acid and pepsin. Peptic ulcers occur more commonly in the duodenum and less commonly in the stomach and esophagus. They usually occur near mucosal junctions. Rarely, peptic ulcers occur in the jejunum; this should raise the possibility of the Zollinger-Ellison syndrome. When gastric mucosa is present in a Meckel's diverticulum in the ileum, peptic ulceration and bleeding can occur. The ulceration occurs in the ileum adjacent to the diverticulum.

When considering the pathogenesis of any disease, we need to examine environmental factors, hereditary associations and pathophysiologic abnormalities. Environmental factors (Table 3) that have been examined include drugs, smoking, alcohol, caffeine-containing beverages and stress. Nonsteroidal anti-inflammatory agents such as ASA are thought to cause ulceration, mostly as a result of damage to the protected mucosal barrier. Smoking is associated with a higher prevalence of peptic ulcer disease and may be associated with impaired healing of duodenal and gastric ulcer disease. Also, death rates from peptic ulcer disease are higher in individuals who smoke. Alcohol and caffeine-containing beverages may affect acid secretion, and have been considered in the pathogenesis of peptic ulcer disease. However, it is fair to say that the role of coffee, alcohol, nonsteroidal anti-inflammatory agents and corticosteroids in the pathogenesis of peptic ulcer disease remains unclear.

Both patients and physicians often express the concern that "stress" is important in the initiation or perpetuation of peptic ulcer disease. Some patients with duodenal ulcer disease may have an exaggerated sense of self-sufficiency and demonstrate overambitiousness and aggressiveness. Some psychiatric views suggest that these attitudes represent a defense against an awareness of dependency. It is possible but unproven that patients exposed to excess stress may have more frequent ulceration, may be more sensitive to the symptoms of peptic ulcer disease, and may be more likely to develop perforations.

Recent studies from Israel and the United States have identified a number of predictors of duodenal ulcer disease in men. These are psychosocial and biological. The important psychosocial factors include anxiety - stress, brooding (i.e., difficulty coping and difficulty expressing emotions) and inadequate caring, particularly lack of family support. Biological factors include age, lower blood pressure, use of cigarettes and leanness.

At a molecular level, the pathogenesis of ulcer disease is believed to reflect an imbalance between increased aggressive factors and decreased protective factors. In considering the possible aggressive factors, we need to briefly review the normal mechanism of acid secretion. Acid secretion is divided into the cephalic, gastric and intestinal phases. As a result of vagal stimulation arising from the sight, smell, taste or thought of food, acetylcholine is released and acts on the parietal cells to produce acid. In addition, vagal afferents stimulate the antral G cells to release gastrin. Food in the stomach gives rise to antral distention, and this along with peptide breakdown products stimulates the antral G cells to produce gastrin. The gastrin and acetylcholine act directly on the parietal cells or the mast cells. The mast cells in turn release histamine, which stimulates gastric acid secretion.

Once acid secretion has been initiated, how is further acid secretion limited? Clearly, there will be loss of vagal stimulation, loss of antral distention and loss of stimulated release of gastrin as food is virtually digested and emptied from the stomach into the duodenum. Also, the acid released from the parietal cells acidifies the antrum and thereby inhibits the further release of gastrin. The presence of food in the intestine further stimulates the release of a number of gastrointestinal hormones (including secretin, somatostatin, GIP and VIP) that inhibit the secretion of acid by parietal cells.

In health, a basal acid output obtained under unstimulated conditions is 5-10 mmol/hr. Following the administration of 6 mg/kg of pentagastrin, the parietal cell mass will be stimulated to produce hydrochloric acid. The maximal acid output will be less than 35 mmol/hr, and the peak acid output will be less than 60 mmol/hr. In health, the ratio of basal to maximum acid output or basal to peak acid output will be less than 0.25. The peak or maximum acid output reflects the parietal cell mass, whereas the ratio of BAO/PAO reflects the parietal cell function under basal conditions.

In disease, acid secretion may change. With gastric atrophy, both the basal and stimulated acid outputs are reduced. Peak acid output is increased in approximately one-half of patients with duodenal ulcer disease, whereas in patients with the Zollinger-Ellison syndrome, the major change is in the increased basal acid output. In patients with gastric ulcers, basal and peak acid output are usually normal or reduced. It must be stressed that this represents the acid measured in the gastric lumen and does not necessarily reflect the acid-secreting ability of the parietal cells in patients with gastric ulcer disease. That is, as a result of associated gastritis and back-diffusion of acid, these patients may secrete normal amounts of acid, which then diffuse back into the parietal cell. Therefore, the amount of acid measured in the gastric lumen would be normal or reduced.

Gastrin, histamine, acetylcholine and unspecified inhibitors influence the gastric secretory drive. Gastrin concentrations may be increased physiologically following food intake, with an increase of less than 100% above basal or fasting values. Secretory drive may be increased in the Zollinger-Ellison syndrome, G-cell hyperplasia or retained antrum. In the short bowel syndrome, temporary gastric hypersecretion may occur. The pathogenesis of this abnormality is unknown, and may relate to the loss of gastrin inhibitory factor in the small bowel. Gastrin levels are commonly increased in renal failure and pernicious anemia, and more rarely in diabetes mellitus and rheumatoid arthritis. In the latter two conditions, it is presumed that the gastrin levels are increased as a result of hypochlorhydria.

Once the stimulants of acid secretion (gastrin and acetylcholine) have been released, parietal cells are stimulated to secrete acid. The receptor for acetylcholine and gastrin may be on the mast cells, which are then stimulated to release histamine, which acts directly on the parietal cells to produce acid. Alternatively, there may be three separate receptors on the parietal cell: those for gastrin, acetylcholine and histamine. The histamine acts on adenylate cyclase in the parietal cell membrane to increase the production of cyclic AMP. In the presence of calcium, a protein kinase is stimulated, which then acts on the H⁺/K⁺-ATPase to secrete hydrochloric acid. This H⁺/K⁺-ATPase is known as the "proton pump." It represents the final common pathway for hydrogen ion secretion. Acetylcholine may act on the mast cells to release histamine, but may also act on the parietal cells to increase the influx of calcium ions, which then stimulate the protein kinase. The intracellular mechanism of gastric-mediated acid secretion is not known, although gastrin may stimulate the mast cells to release histamine, which further stimulates acid secretion.

This discussion of the mechanism of acid secretion provides the basis for understanding the pathogenesis of peptic ulcer disease. The parietal cell mass may be increased, and this may be reflected by an increase in the peak acid output or in serum pepsinogen 1. Secretory drive may be increased, and this is reflected by an increase in the ratio of BAO/PAO. Stimulated secretion is abnormal, as reflected by an increased parietal cell sensitivity to gastrin and possibly to histamine. Finally, the acid load in the duodenum is increased (as a result of increased acid secretion, as well as an increased rate of gastric emptying) in duodenal ulcer disease.

Radiology for the diagnosis of peptic ulcer disease is being increasingly replaced by upper gastrointestinal endoscopy (esophagogastroduodenoscopy, or EGD). A chronic lesser-curve ulcer is usually seen as a distinct niche or pocket of barium projecting out from the line of the barium-filled stomach. The crater has a clean, smooth outline, and often its upper part contains a fluid level between the barium below and gastric juice or gas above. A posterior-wall gastric ulcer is often best seen en face as a barium-filled niche after a small amount of the barium suspension has been drunk, and when the abdomen has been compressed. A spastic notch on the greater curvature opposite the ulcer is a common feature of chronic gastric ulcer. Occasionally, a gross horizontal fibrous contracture in association with long-standing ulceration can cause a permanent hourglass constriction, or the lesser curvature can shorten longitudinally. Antral or prepyloric ulcers present special diagnostic difficulties to the radiologist, because the associated spasm or inflammatory swelling cannot always be distinguished from the appearance of gastric cancer. Greater-curvature ulceration is uncommon, and is seldom malignant. Lesser-curvature ulcers above the angulus can usually confidently be separated from malignant disease by their regularity and relative absence of mucosal distortion within the line of the barium-filled viscus (except by the classical appearances of fibrous contracture). The size of a gastric ulcer is not a guide to the presence of malignancy or to the severity of symptoms; furthermore, large gastric ulcers often respond better to medical treatment than small ones (Figure 4A, Figure 4B).

The radiologic diagnosis of duodenal ulcer is complicated by the problem of distinguishing simple deformity (scarring) in the duodenal bulb (due to previous and now healed ulceration) from deformity with active ulceration. Ulceration in an undeformed cap is relatively uncommon. It may be seen either as a niche in profile on one border of the bulb (Figure 5A, Figure 5B) or en face through the bulb when the bulb contains a small quantity of barium suspension and is compressed or examined in air contrast films (e.g., in a posterior view with the patient lying slightly on the left side). Scarring of the bulb can induce a number of deformities, such as trefoil deformity following ulceration at the base of the bulb, and pseudodiverticulum formation. A minority of ulcers occur in the immediate postbulbar region of the duodenum. Close attention to this region is needed if they are to be found.

Modern fiberoptic instruments used in endoscopic examination have greatly increased its safety and diagnostic range, and the patient's comfort. The available instruments are either end- or side-viewing. The former are good general-purpose instruments that allow an adequate view of the esophagus, stomach and upper duodenum. Distal duodenal lesions can be viewed using an enteroscope or pediatric colonoscope through the upper gastrointestinal tract.

Medications used in the treatment of peptic ulcer disease can be classified into those that inhibit or neutralize acid secretion and those that are cytoprotective (Figure 6). Acid that has already been secreted can be neutralized with antacids, or the synthesis of acid can be inhibited by the use of H₂ blockers (such as ranitidine and cimetidine), anticholinergics (such as pirenzepine) or antigastrin agents (such as proglumide). The cytoprotective agents include licorice extracts, sucralfate and prostaglandins. Recent attention has turned to combining various therapeutic agents with antibiotic therapy to treat both the peptic ulcer and the Helicobacter pylori-associated gastritis in an attempt to prevent ulcer recurrence (see Section 8.2.3 for a further discussion).

The medications that inhibit acid secretion act either on the three receptors on the parietal cell or on the acid pump. These include H₂-receptor antagonists (cimetidine and ranitidine), muscarinic-receptor antagonists (pirenzepine, propantheline), gastrin-receptor antagonists (proglumide) and H⁺/K⁺-ATPase inhibitors (omeprazole).

Cimetidine is structurally similar to histamine, with an imidazole ring. The side structure of ranitidine is vaguely similar to that of cimetidine, but there is a furan rather than an imidazole ring. This difference in ring structure may account for the differences in side effects of these two H₂-receptor antagonists. Many side effects have been ascribed to H₂ blockers (Table 4). It must be stressed, however, that these side effects are rare with H₂ blockers. Cimetidine is metabolized by the cytochrome P-450 system, as are a number of cardiovascular, anorexic, CNS, analgesic and anesthetic medications. Those in common use include diazepam, warfarin, theophylline, propranolol, phenytoin and lidocaine. As a result of this interaction, patients receiving cimetidine must have a reduction in the dose of any medication that is also metabolized by the cytochrome P-450 system. Ranitidine is not metabolized to the same degree by this hepatic oxidative system; therefore no adjustment in the dosage of other medications is necessary in patients on this H₂-receptor antagonist. Furthermore, antiandrogenic effects, particularly gynecomastia, are exceedingly rare in patients taking ranitidine.

A number of tricyclic agents are available to reduce acid secretion. The tricyclic antidepressants have been shown to be modestly useful in the treatment of acid-peptic disorders. The non-antidepressant tricyclic agent pirenzepine is efficacious in the healing of duodenal ulcer disease when given in a dose of 50 mg b.i.d., but this dose is associated with prevalent side effects (including bradycardia, dry mouth and difficulty in focusing the eyes). Because of its anticholinergic effects, this medication is contraindicated in patients with glaucoma or with GI or genitourinary obstruction. The tricyclic agents are generally not considered to be the first line of therapy.

Omeprazole is the first agent of a class of substituted benzimidazoles that are able to specifically block the H⁺/K⁺-ATPase enzyme that is unique to the secretory canaliculus for the parietal cell. Inhibition of this final common pathway of gastric acid secretion is able to abolish the secretory response to all known secretagogues. Omeprazole is a weak base absorbed from the proximal small intestine at the highly acidic compartment of the secretory canaliculus, leading to activation of a sulfoxide metabolite, which is either rapidly inactivated or binds to the H⁺/K⁺-ATPase enzyme. Binding to the H⁺/K⁺-ATPase inactivates the enzyme and profoundly inhibits gastric acid secretion. Omeprazole will act in the stimulated parietal cell only when the drug can be trapped and converted to its active form in the highly acidic compartment. Peak absorption occurs 3 to 4 hours after oral administration, and the plasma levels are undetectable by about 11 hours after a single dose of the drug. The bioavailability of omeprazole increases with repeated doses up to about four days, probably as a result of increasing drug absorption as intragastric acidity decreases. Gastric acid inhibition approaches 98% following omeprazole 30 mg daily for one week.

The powerful antisecretory effects of omeprazole result in an elevation of serum gastrin concentrations, which in humans appear to be related to the degree of acid suppression. However, toxicologic studies in the rat in which massive doses of omeprazole have been used have shown markedly elevated gastrin levels associated with ECL-cell hyperplasia and gastric carcinoid tumors, which have been found after long-term treatment. Omeprazole at present is approved for short-term clinical use. It is an effective agent in the treatment of peptic ulcer disease and reflux esophagitis. Omeprazole inhibits the hepatic microsomal P-450 mono-oxygenase system, and the plasma half-life of drugs metabolized by this route may be extended.

Another therapeutic approach to the patient with peptic ulcer disease, based on different pathophysiologic mechanisms, includes the use of drugs that enhance mucosal defense. Colloidal bismuth compounds (e.g., tripotassium dicitrato bismuthate [De Nol®]) are used in the United Kingdom to treat peptic ulcer disease. Licorice extracts have been used for many years for the treatment of peptic ulcer disease, but the active agent, carbenoxolone, is unfortunately associated with significant aldosterone-like side effects and this compound has not gained wide acceptance. We have already considered the potential application of prostaglandins for the treatment of gastric and duodenal ulcer disease; current clinical studies have shown that methylated prostaglandins E₂ given by mouth may be as effective as H₂-receptor antagonists in the rapid healing of peptic ulcers.

It is likely that in the future, prostaglandins will become the drug of choice for the treatment of gastritis and gastric ulcer. Since the side effects from these medications are few, prostaglandins may in time replace H₂-receptor antagonists or sucralfate in the treatment of peptic ulcer disease. Because of their frequent side effects, anticholinergics are generally avoided except in the patient with nighttime pain despite maximal doses of H₂-receptor antagonists. Depression, both overt and masked, occurs in patients with peptic ulcer disease. These individuals may improve with an antidepressant; trimipramine has been shown to accelerate the healing of duodenal ulcer disease.

What therapeutic recommendations can be made? The proportion of patients whose ulcers heal after six weeks of cimetidine, ranitidine, sucralfate or prostaglandin is comparable. Recommendations must therefore be made on other factors, including convenience, side effects, cost and maintenance of healing. Liquid antacids are inconvenient to take, and patient compliance is poor. Side effects from the anticholinergics are frequent, and cimetidine should be avoided in the older patient or in the individual taking multiple drugs. A therapeutic dose of each of these agents - that is, a dose necessary to obtain ulcer healing - is comparable and expensive (about $60 to heal an ulcer).

Peptic ulcer disease has a natural history of recurrence. Once an ulcer has healed, there is a 75% chance that the ulcer will recur in 12 months; 50% will be symptomatic, whereas 25% will be asymptomatic. If patients are maintained on low-dose H₂-receptor antagonists, then only 25% of the patients will have an ulcer recurrence in 12 months. There is no widely accepted practice advised for maintenance therapy. The general rule of thumb would be to advise maintenance therapy for the patient with severe aggressive recurrent ulcer disease.

More recently, attention has turned to the role of Helicobacter pylori in ulcer recurrence. In particular, Helicobacter pylori is associated with an antral gastritis seen in 95% of duodenal ulcer patients. Eradication of Helicobacter pylori infection associated with duodenal ulcer disease through antibiotic therapy may eliminate ulcer recurrence (see Section 8.2.3).

If the ulcer fails to heal with medical therapy, the patient may have taken inadequate doses of medication for an inadequate duration, or the medication may have been taken improperly. For example, an antacid must be taken one and three hours after meals; sucralfate must be taken one hour before meals and concurrent antisecretory therapy and antacid use must be avoided; and H₂- receptor antagonists must be taken with meals. The possibility of malabsorption of the medication must be considered. An ulcer complicated by penetration or pancreatitis may be associated with continued symptoms. The continuation of the environmental factors responsible for the initial development of the ulcer may be responsible for lack of healing. The adequacy of the diagnosis must be questioned, and it is for this reason that endoscopy is generally recommended for the proper diagnosis of peptic ulcer disease. Finally, concurrent infection of the stomach or duodenum with Helicobacter pylori may be a factor in a resistant ulcer (see Section 8.2.3).

An additional cause of failure of medical therapy and failure of ulcer healing is the presence of a hypersecretory state, possibly due to hypergastrinemia. It is disputed whether G-cell hyperplasia occurs in patients with duodenal ulcer disease. Clearly, however, a small proportion of patients with ulcer disease would have a hypersecretory state due to the presence of a gastrinoma (which will lead to basal and/or stimulated hypergastrinemia). Other conditions leading to basal hypergastrinemia include retained antrum, pyloric obstruction, pernicious anemia, hypercalcemia, renal failure, massive small bowel resection and portacaval anastomoses (Table 5). Peptic ulcer disease does not occur in patients with pernicious anemia, because they lack parietal cells. However, these other conditions associated with basal hypergastrinemia may also be associated with hyperchlorhydria and associated peptic ulcer disease. It is unclear whether hypergastrinemia also occurs in patients with diabetes mellitus or rheumatoid arthritis.

For the complications of hemorrhage, obstruction, perforation or intractability, surgery will be necessary. There is no consensus regarding the procedure of choice, but generally some form of vagotomy (e.g., truncal, selective or parietal cell) with a drainage procedure (pyloroplasty or antrectomy) is advised.

In general, a vagotomy is performed with a gastric draining procedure (pyloroplasty/gastroenterostomy) and/or a gastric resection to avoid gastric stasis (Figure 7). Three forms of vagotomy are in vogue: truncal, selective and parietal cell. A Billroth I or Billroth II anastomosis may also be performed, particularly when the antrum or portions of the body of the stomach are resected. A drainage procedure is needed to avoid the gastric atony resulting from the vagotomy and associated delayed gastric emptying.

The Zollinger-Ellison (ZE) syndrome is characterized by autonomous gastrin production by an adenoma or adenocarcinoma of the pancreas or duodenum. Patients may present either with severe acute ulcer disease or recurrent ulcer disease; the ulcers will often occur in unusual sites and be associated with diarrhea. The Zollinger-Ellison syndrome is distinguished from peptic ulcer disease by the demonstration of fasting hypergastrinemia. There are many causes of fasting hypergastrinemia (gastritis, vagotomy and pyloroplasty, the short bowel syndrome, rheumatoid arthritis, retained antrum, G-cell hyperplasia), but only two conditions - atrophic gastritis and renal failure - are associated with gastrin levels increased several times above the upper limit of the normal range. However, in a patient with peptic ulcer disease and hypergastrinemia, it is important to exclude the Zollinger-Ellison syndrome. Gastric analysis may be helpful: the finding of a dramatically increased basal output relative to a modestly increased maximal acid output (i.e., BAO/MAO greater than 0.6) is suggestive of this syndrome. Ingestion of a protein-containing meal normally produces a doubling of the gastrin concentration (a.c. versus p.c.), but an exaggerated response is seen in G-cell hyperplasia rather than in gastrinoma syndrome. Infusion of calcium intravenously results in an increase in gastrin concentration in normal individuals and an exaggeration of this response in patients with the Zollinger-Ellison syndrome. However, the most useful diagnostic test is the secretin infusion. In normal individuals or those with G-cell hyperplasia, injection of secretin results in a rapid decline in plasma gastrin concentrations, whereas in patients with the Zollinger-Ellison syndrome, the gastrin concentration will increase in response to secretin.

The Zollinger-Ellison syndrome arises from a gastrinoma, a tumor in the pancreas. This may be a localized or diffuse tumor. The presence of hypergastrinemia leads to hypersecretion; while the maximal acid output may be increased, the major defect is basal hypergastrinemia and a marked increase in the basal acid output. The patient will have aggressive peptic ulcer disease with ulceration in unusual sites, or multiple ulcers that fail to heal on medical therapy. Hypertrophic gastric folds and diarrhea may be prominent features (see Section 6.5). The presence of a gastrinoma should be suspected from the history, and confirmed with provocative tests. A protein meal will increase the serum gastrin concentration in patients with G-cell hyperplasia; a calcium infusion will markedly increase the gastrin concentration in patients with gastrinoma, and have a lesser effect in normal patients and patients with G-cell hyperplasia. The best test to diagnose a gastrinoma is a secretin test in which the basal gastrin concentration increases dramatically, in contrast to the reduction in gastrin concentration that occurs following secretin infusion in patients with G-cell hyperplasia or a normal stomach. A CT scan or an angiogram may be useful in identifying the gastrinoma, although these tumors are often small and difficult to identify. A laparotomy will be necessary to determine whether there is a localized tumor. Since one-half of these tumors are malignant, it is worthwhile to undertake surgery in the hope that resection of the tumor will produce a cure.

If the high dose of H₂-receptor antagonists does not sufficiently relieve the patient's pain, then nighttime anticholinergics can be used. A trial of parietal cell vagotomy is under way, but this is not yet accepted therapy.