Medical Management versus Operation

Optimum treatment recommendations for patients with Z-E syndrome have undergone continuing change during the 40 years since Zollinger and Ellison reported on their first two patients, both of whom required a TG to control the complications of recurring peptic ulcer disease. These changes in Z-E syndrome management have come with a better understanding of the natural history and pathophysiology of Z-E syndrome, the RIA for gastrin, new imaging technologies that preoperatively and intraoperatively localize gastrinomas, and, perhaps most important, new drugs that inhibit gastric acid secretion.88

Medical Management

Inhibition of gastric acid secretion in many Z-E syndrome patients was made possible with the introduction of the H2 receptor antagonist cimetidine.18 Previously, TG had been necessary to achieve long-term survival of patients with Z-E syndrome. After cimetidine became available in 1977, some argued for medical management alone, claiming that the mortality for TG was inordinately high and finding and removing all gastrinoma tissue were unlikely.89 However, there were failures of medical management and antiandrogen side effects at high cimetidine doses (>4.8 g/day), such as breast tenderness, gynecomastia, and impotence in men, which continued to fuel the controversy. Some surgeons still favored TG when not all tumor could be removed.21 The introduction of two new H2 blockers, ranitidine and famotidine, which inhibited gastric acid secretion more effectively and did not have antiandrogen side effects, made medical therapy even more attractive.

Then another important advance in medical therapy came with the advent of a new class of antisecretory drugs: the substituted benzimidazoles (omeprazole).49,90 The mechanism of action of these drugs is different from that of the H2 receptor antagonists in that they bind to a unique enzyme responsible for acid secretion at the apical (luminal) aspect of the gastric parietal cell: the hydrogen-potassium adenosine triphosphatase proton pump enzyme. In most Z-E syndrome patients, gastric acid hypersecretion can be treated effectively with a once-daily dose of omeprazole, although about 10% to 25% of patients require a dose every 12 hours.50,53 Tachyphylaxis does not occur, and the dose can be decreased over time in some patients. The Z-E syndrome patient must continue to take omeprazole indefinitely unless cured surgically. Repeated gastroduodenal endoscopy is necessary to evaluate the dose of antisecretory medication adequately.33,54 There has been concern that long-term complete acid inhibition with achlorhydria might increase the risk of gastric carcinoids because these tumors can be so induced in rats.91 However, studies report that in Z-E syndrome patients there is no increase in occurrence of gastric carcinoids as a result of omeprazole.49

Omeprazole is now the drug of choice for long-term antisecretory therapy in Z-E syndrome patients because of its potency, long duration of action, and ease of use. Long-term prospective studies of antisecretory therapy for the Z-E syndrome by the group at the NIH outline the most effective methods to control gastric acid hypersecretion.49,50

Operative Management: Sporadic Gastrinoma

Laparotomy is now recommended for most patients with evidence of gastrinoma (sporadic type) to define the extent of disease and then to achieve curative resection when possible. The rationale for this approach is based on several factors. First, although gastrinomas may have histologic characteristics that appear benign, most have malignant potential, and, although frequently indolent in nature, these tumors can grow, metastasize, and cause death. Second, using improved preoperative imaging modalities and aggressive exploratory techniques to find the tumor, modern studies suggest that 20% to 50% of Z-E syndrome patients may be cured by early exploration and excision of the gastrinoma.92*96 Early laparotomy and tumor extirpation, even with incomplete excision of all gastrinoma tissue, appears to alter favorably the natural history of this syndrome.96"98

Operative Management: Familial Gastrinoma

Controversy continues among Z-E watchers regarding the advisability of early operation for the MEN 1 patient with hypergastrinemia. Most MEN 1 patients present with primary hyperparathyroidism before there is evidence of a gastrinoma, and it is agreed that parathyroidectomy should be performed before a laparotomy to explore for gastrinoma because gastric acid hypersecretion and serum gastrin are often reduced when parathyroidectomy returns serum calcium to normal. The controversy centers on the question of whether to explore the young, asymptomatic, hypergastrinemic

MEN 1 patient (acid secretion controlled) early or to wait until a gastrinoma can be seen on an imaging study.22,99 Surgeons from Ohio State University, NIH, Mayo Clinic, and Paris reported few, if any, cures after exploration for gastrinoma in MEN 1 patients.26,27,100,101 A cure is defined by the return of serum gastrin to normal after removing one or more gastrinomas.

Gastrinomas in MEN 1 patients are invariably multiple and usually not large enough to be localized preoperatively, so one is less likely to find and remove all gastrinoma tissue than when one is operating for gastrinoma of the sporadic type.102,103 For these reasons, some authorities recommend antisecretory therapy without surgery for the patient with familial gastrinoma unless tumor can be identified on localizing studies.27,100,101,104 However, Thompson's group at the University of Michigan suggested that some MEN 1 patients with gastrinomas can be cured if PVS is used to regionalize the location of the gastrinomas.22,79,99 The NIH group105 also used the preoperative PVS technique but failed to cure any patient even though each patient had an islet cell tumor removed from the exact area of the pancreas implicated by PVS. This topic of familial gastrinoma in the MEN 1 syndrome is discussed in more detail in Chapter 76.

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