Antisecretory Medications Research Articles

Duodenogastric reflux causes growth stimulation of foregut mucosa potentiated by gastric acid blockade.

We investigated whether duodenogastric reflux (DGR) together with gastroesophageal reflux causes growth stimulation of the foregut mucosa and if additional gastric acid suppression enhances the effect of DGR. DGR was induced in rats using a split gastroenterostomy. A cardiomyotomy was performed across the gastroeophageal junction in order to enhance reflux into the esophagus. DGR rats were divided into six subgroups: DGR, DGR + truncal vagotomy, DGR + omeprazole, DGR + gastrin receptor blockade, DGR + omeprazole + gastrin receptor blockade, and DGR + gastrin. Two sham groups, one with and one without omeprazole treatment, served as controls. DGR significantly increased the weight and DNA content of the esophageal and gastric mucosa, which was further enhanced by vagotomy or omeprazole. Histology revealed foveolar hyperplasia in the stomach and esophageal mucosal hyperplasia in these groups. In addition, severe esophagitis was found in the DGR group receiving omeprazole. Omeprazole without DGR had no growth-stimulating effect on the foregut mucosa. DGR-induced growth stimulation was accompanied by hypergastrinemia. Increased growth in the stomach but not the esophagus was inhibited by gastrin receptor blockade. Gastrin administration did not result in enhancement of DGR-induced growth stimulation of the foregut mucosa. It is concluded that DGR, often present in severe reflux esophagitis, causes mucosal growth of the foregut of rats. This trophic response may explain why severe reflux esophagitis is associated with an increased risk of esophageal adenocarcinoma. DGR-induced growth stimulation of the foregut is potentiated by gastric acid suppression, suggesting that chronic antisecretory medication in gastroesophageal reflux may not always be advisable. Omeprazole + DGR caused severe esophageal damage, which may explain why antisecretory medication may fail to heal severe reflux esophagitis.

Gastroesophageal Reflux Disease

To review the management of gastroesophageal reflux disease (GERD) in adults with esophageal complications (esophagitis, stricture, adenocarcinoma, or Barrett metaplasia) or extraesophageal complications (otolaryngological manifestations and asthma). Peer-reviewed publications located via MEDLINE or cross-citation. Emphasis was placed on new developments in diagnosis and therapeutics. Thus, fewer than 10% of identified citations are discussed. Controlled therapeutic trials were emphasized. The validity of pathophysiological observations and uncontrolled trials were critiqued by the author. Esophagitis is typically a chronic, recurring disorder treated with long-term antisecretory therapy, titrated to disease severity. Laparoscopic [correction of Laparascopic] antireflux surgery is an alternative strategy, but neither long-term efficacy data nor an appropriate controlled trial comparing it with proton pump inhibitor therapy exists. The main risk of esophagitis is adenocarcinoma arising from Barrett metaplasia, the incidence of which is increasing. Strong evidence suggests that both reflux-induced asthma and otolaryngological complications (subglottic stenosis, laryngitis, pharyngitis, or cancer) can occur without esophagitis. While the otolaryngological manifestations usually respond to antisecretory medications, reflux-induced asthma responds convincingly only to antireflux surgery. Although esophagitis and GERD symptoms predictably respond to antisecretory medicines, the risk of adenocarcinoma from Barrett metaplasia dictates that if heartburn is refractory to treatment, chronic (>5 years), or accompanied by dysphagia, odynophagia, or bleeding, it should be evaluated by endoscopy. Thereafter, patients with Barrett metaplasia require surveillance endoscopy to control the cancer risk. Reflux-induced asthma remains a vexing problem in the absence of either medical therapy or proven efficacy of a reliable mechanism of prospectively identifying affected patients.

Zollinger-Ellison syndrome. Recognition and management of acid hypersecretion.

Zollinger-Ellison syndrome (ZES) should be suspected if a patient has severe peptic ulceration, ulcers and kidney stones, a family history of ulcers or endocrine diseases, watery diarrhoea or malabsorption with or without ulcers, or if hypergastrinaemia is found. Any patient in whom ZES is suspected, and certainly if diagnosed, should be given large doses of antisecretory medication immediately. This should never be stopped except under controlled conditions or unless acid outputs have been reduced surgically. Patients cannot be managed safely without measuring acid outputs. These should be lowered to < 10 mmol/h, or < 5 mmol/h in patients with a previous gastric resection or severe oesophageal disease. Acid secretion can be controlled acutely in 70% of patients with an infusion of ranitidine 1 mg/kg/h, while 4 mg/kg/h will control acid in all. The initial oral dosage of omeprazole or lansoprazole should be 60 mg/day. Doses should then be adjusted daily on the basis of acid outputs. Proton pump inhibitors in a dosage of 60 mg/day will control acid output in most patients and 60 mg every 12 hours will control acid output in all. Doses can then often be slowly and progressively reduced. A parietal cell vagotomy reduces acid secretion and reduces, but does not abolish, the need for antisecretory medication. In patients with multiple endocrine neoplasia type 1 and hyperparathyroidism, a parathyroidectomy that results in normocalcaemia will reduce acid secretion and drug requirements. A total gastrectomy is rarely if ever needed nowadays. Given the high degree of safety of gastric antisecretory medications versus the risks of acid hypersecretion in patients with ZES, the mistakes in management of acid hypersecretion that must be avoided are those of giving insufficient medication and not measuring acid secretory rates.

742 Pathophysiology and therapy of irinotecan (CPT-11) induced delayed onset diarrhea (DD): A prospective assessment

DD is the main toxicity of CPT-11 at the currently recommended dose (RD) of 350 mg/sqm IV (30’) q 3 weeks. In previously treated colorectal cancer patients (pts), we tried to determine the mechanism of DD and assess the efficacy of combined antidiarrheal medication. From Dec 93 until March 95, 24 pts having failed ≥ 1 ≤ 3 lines of 5-FU based treatment, entered a CPT-11 Phase II trial at the above RD. In the first cohort (14 pts), Acetorphan (Acet), a specific enkephalinase inhibitor, was given as 100 mg tid PO after the second loose stool, and supplemented, if DD > 48 hrs, with Loperamide (Lop) 2 mg q 2 hrs PO till 12 hrs after last loose stool. Pts had at baseline and if DD occurred endoscopy, with biopsies for Topo I and CPT-11 assays as well as transit time, stool frequency, weight, culture, electrolytes, osmotic gap, pH, fat and protein excretion, α antitrypsin ( α AT) clearance, D-xylose test; blood tests for VIP, glucagon, somatostatin, gastrin. Twelve/14 pts (first cohort) had CFT-11 DD: 5 responded to Acet alone, and the other 7 responded within 24 hrs to addition of Lop. Transit time normal in 5/7 pts, α AT increased in 4/4 pts. Stools weight >800 gr/day and fecal Na/K increased in 6/6 pts. Osmotic gap small in 3/6 pts. The second cohort (pts 15–25) received simultaneous Acet/Lop after first DD loose stool. Eight/11 pts had DD, and 7/8 had resolution of diarrhea within 12 hrs of treatment start. Available PK's of CPT-11 and SN-38 (active metabolite) show no pharmacodynamic relationship. Results suggest that CPT-11 DD is due to a secretory exudative mechanism, as attested by its response to early simultaneous antisecretory medications.

7 Helicobacter pylori in duodenal and gastric ulcer disease

The decision to treat a patient should in general always be based on potential risk and advantage. Widespread and uncontrolled use of all kinds of anti- H. pylori regimens may promote development of antimicrobial resistant strains. In particular, antimicrobial monotherapy is associated with failure to eradicate H. pylori and induction of resistant strains. Polychemotherapy is much more effective and has a lower risk for development of antimicrobial resistant H. pylori strains but carries the risk of significant drug-related side effects. If the prescribed anti- H. pylori regimen is not effective in at least 80%, or if the patient is not compliant, this type of therapy should not be considered. Also if reinfection is to be expected, the risk may outweigh potential benefits (Graham, 1993). Guidelines published in 1990 by an international working party during the World Congress of Gastroenterology recommended H. pylori eradication only in patients where duodenal ulcer was a serious management problem requiring lifelong maintenance therapy, and in whom complications (bleeding, perforation) had occurred or surgery was considered (Tytgat et al, 1990). Recently less stringent guidelines were recommended. A National Institutes of Health (NIH) Consensus Development Conference has recommended that all patients with gastric or duodenal ulcer who are H. pylori infected should be treated with antimicrobials including patients presenting with an ulcer for the first time. In addition, patients on maintenance antisecretory medication should also be contacted and treated for H. pylori infection (Anonymous, 1994). The ulcer relapse rate during prolonged follow-up after H. pylori eradication is very low. Despite this, it is advised that antisecretory medication is continued after successful H. pylori eradication in patients with previous ulcer complications. In all other patients maintenance antisecretory medication can be stopped after successful eradication. It is not known whether H. pylori eradication lowers the risk of NSAID-induced ulceration or whether the risk of ulcer complications is reduced.

Gastric ulcers differ from duodenal ulcers evaluation of basal acid output

Patients with pyloric channel and prepyloric gastric ulcers are often considered to have an ulcer diathesis similar to patients with duodenal ulcers, while patients with more proximal gastric ulcers (ie, fundus, body, antrum) are excluded. To evaluate possible differences in basal acid outputs with regard to gastric ulcer location, basal acid outputs were determined by nasogastric suction in 80 patients with endoscopically documented benign active gastric ulcers. The results were compared to 65 normal subjects and 155 patients with endoscopically documented duodenal ulcers. There were no significant differences in basal acid outputs among the 80 patients with gastric ulcers with regard to location (ie, fundus-body, antrum, prepyloric, channel), and no significant differences compared to the 65 normal subjects. However, basal acid output for the 155 patients with duodenal ulcers was significantly different from the 80 patients with gastric ulcers (P < 0.05) and the 65 normal subjects (P < 0.05). Basal acid outputs tended to be higher and there was more gastric acid hypersecretion when gastric ulcers were located near the pylorus. However, irrespective of gastric ulcer location, basal acid outputs were higher in patients with duodenal ulcers. Seventy-one of the 80 patients with gastric ulcers were treated for eight weeks with standard doses of antisecretory medications, and endoscopic healing or nonhealing was documented. In 60 patients their gastric ulcers completely healed, while 11 patients had nonhealed gastric ulcers. There were no significant differences between the two groups with regard to gender, mean age, or basal acid output.(ABSTRACT TRUNCATED AT 250 WORDS)

Review article: the management of Zollinger-Ellison syndrome.

Awareness of the sometimes subtle features of Zollinger-Ellison syndrome is important in order not to miss the diagnosis. Immediately after initial diagnostic tests, the patient should be given antisecretory medication, while tests for the type of Zollinger-Ellison syndrome and tumour extent can be delayed. Acid output should be decreased to < 10 mmol/h to control symptoms and prevent complications. Histamine H2-antagonists remain the best available intravenous therapy but omeprazole is the most effective long-term oral therapy and has proved to be safe in nearly 10 years of continuous use. The management of the gastrinoma has changed in recent years since the discovery that the majority of gastrinomas arise outside the pancreas. Exploratory surgery with tumour resection is the treatment of choice in sporadic Zollinger-Ellison syndrome but there are few indications for surgery in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type-1. None of the available therapies for metastatic gastrinoma is very effective.

Definition for idiopathic gastric acid hypersecretion

Zollinger-Ellison syndrome and other gastric acid hypersecretory states in which a specific etiology is identified are defined as a basal acid output of greater than 15.0 meq/hr. To determine the level of basal acid output that defines idiopathic gastric hypersecretion, basal acid outputs were investigated in normal subjects and patients with duodenal ulcers, and functional and statistical definitions for idiopathic gastric acid hypersecretion were developed. Sixty-five normal subjects were evaluated to define idiopathic gastric acid hypersecretion on a statistical basis, and 22 patients with refractory duodenal ulcers were evaluated to define idiopathic gastric acid hypersecretion on a functional basis. Mean basal acid output for the 65 normal subjects was 3.0 +/- 2.7 meq/hr. Even though the mean basal acid output for the group of 28 normal male subjects was slightly higher than for the group of 37 normal female subjects, the groups were not significantly different. The 95% confidence interval around the mean basal acid output for all normal subjects was 2.4-3.7 meq/hr, with little difference between the male and female groups. The mean basal acid output plus two standard deviations and the mean basal acid output plus three standard deviations for the 65 normal subjects were 8.4 meq/hr and 11.1 meq/hr, respectively. Of 109 patients with active duodenal ulcers treated for eight weeks with standard doses of antisecretory medication, 22 showed no healing as documented by endoscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Observations on a proposed measure of genotoxicity in rat gastric mucosa

Current methods for the study of the toxicological effects of antisecretory medications on the gastric mucosa possess disadvantages or limitations. A novel assay has been proposed to assess gastric mucosal genotoxicity in which the proton-pump inhibitor omeprazole has been reported to induce direct damage to cellular DNA, raising questions about the safety of this drug. To define the applicability of this proposed measure of genotoxicity and to examine the effects of omeprazole in this assay, control agents, known carcinogens, and omeprazole in various doses and formulations were administered to rats by gavage, followed by [3H]thymidine labeling of DNA in vivo approximately 14 hours later. The incorporation of the [3H]thymidine label into DNA of gastric mucosal cells liberated by limited pronase digestion was in close agreement with published results for negative and positive controls. Omeprazole, administered in doses ranging from 10 mg/kg to 300 mg/kg, did not increase [3H]thymidine incorporation into cellular DNA in this assay. The gastric carcinogen 1-methyl-2-nitro-1-nitrosoguanidine at 20 and 50 mg/kg increased [3H]thymidine incorporation. Pretreatment in vivo with hydroxyurea before [3H]thymidine labeling to inhibit replicative DNA synthesis suppressed [3H]thymidine incorporation more than 97% in negative controls and MNNG and more than 93% in omeprazole treatments. This indicates that replicative DNA synthesis was almost totally responsible for the [3H]thymidine incorporation and the contribution of unscheduled DNA synthesis to the total [3H]thymidine incorporation is minor. Flow cytometric analysis of the cell cycle of the gastric mucosal cells liberated by the limited pronase digestion indicated significant contamination of the preparation with dividing cells (4% in negative controls and 14% in MNNG-treated positive controls). These findings indicate that the proposed screening assay for genotoxicity in rat gastric mucosa is not a reliable measure of unscheduled DNA synthesis in its present form, and conclusions about genotoxic effects of any drug using this assay as initially proposed appear questionable.

Proton-pump inhibition for acid-related disease.

Omeprazole and lansoprazole are the forerunners of a group of substituted benzimidazole compounds that block the gastric proton pump. These drugs exert a potent antisecretory effect by blocking the final common pathway of acid secretion. Prolonged, potent reduction of acid secretion using omeprazole has resulted in significant therapeutic advantage over existing antisecretory medication, such as H2 receptor antagonists (H2RAs). Research experience with lansoprazole indicates that it has treatment properties for acid-related disease that are similar to those of omeprazole. Omeprazole has been used successfully in the treatment of reflux esophagitis and the Zollinger-Ellison syndrome in the United States over the past year and has received approval recently as first-line therapy for duodenal ulcer disease. Research involving more than 20,000 individuals, postmarketing surveillance studies, and thorough safety studies in man and animals have shown omeprazole to be well tolerated, with an incidence and spectrum of adverse events in clinical trials similar to those observed with H2RAs.

Role of acid suppressants in patients with Zollinger–Ellison Syndrome

Virtually all symptoms in patients with Zollinger-Ellison syndrome are due to acid hypersecretion, thus the control of acid secretion is the first and most important step in the management of patients with this syndrome. Antisecretory medication is prescribed as soon as the diagnosis of Zollinger-Ellison syndrome is made, as patients may bleed or perforate with little warning. Acid output is reduced to less than 10 mmol/h to heal mucosal lesions, but in patients with a Billroth I or II gastrectomy and those with severe oesophagitis and stricture formation, acid output is reduced to less than 5 or less than 1 mmol/h. Acid output and not symptomatic response is a reliable guide of the adequacy of therapy. In sufficient doses, all H2-receptor antagonists are useful; however, side effects associated with cimetidine therapy limit its use. The ratio of potencies of cimetidine:ranitidine:famotidine is 1:4:32. Ranitidine given as a 50-mg intravenous bolus, followed by a continuous infusion of 0.5 mg.kg/h, controls acid hypersecretion acutely in patients with Zollinger-Ellison syndrome. Acid output is checked after 4 h, and the dose increased until acid output is less than 10 mmol/h. In 70% of patients with Zollinger-Ellison syndrome, 1 mg.kg/h reduces acid output to less than 10 mmol/h; however, doses up to 4 mg.kg/h have been used. When patients are switched to oral ranitidine, a useful dosage conversion is to administer 1.5 times the total daily intravenous dose in four equal doses every 6 h. Four doses of oral drug are given before the infusion is stopped. Six hours after the first/last oral dose, acid output is checked. In our patients, the mean dose of ranitidine was 2100 mg/day (range, 450-9200 mg/day). No serious toxicity was observed. Omeprazole, which has a long duration of action and is a potent inhibitor of gastric acid secretion, has simplified management. Once-daily dosing is sufficient in most patients, and a reasonable starting dose is 60 mg daily. The dose may be increased to 120 mg once daily; if this dosage fails to control acid secretion, 60 mg is administered every 12 h. In our studies, the median dose was 90 mg/day (range, 20-120 mg/day). Omeprazole was more effective than H2-receptor antagonists in providing symptom relief and mucosal healing and did not cause significant toxicity. In particular, no gastric carcinoid tumours developed during four years of use. Omeprazole is, therefore, the treatment of choice for control of acid secretion in patients with Zollinger-Ellison syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Reflux esophagitis in patients with Zollinger-Ellison syndrome

The incidence of ulcers of the stomach and duodenum and their response to medical therapy, in patients with Zollinger-Ellison syndrome is well described. However, reflux esophagitis is less well recognized. In this study we determined the frequency of reflux esophagitis in 122 patients with Zollinger-Ellison syndrome and examined their response to medical therapy. Esophageal symptoms, endoscopic abnormalities, or both were present in 61% of patients. Forty-five percent of patients had esophageal symptoms consisting of heartburn, dysphagia, or both. Forty-three percent of patients had endoscopic abnormalities of the esophagus, and 23% demonstrated moderate or severe disease. When sufficient antisecretory medication was administered to lower gastric acid secretion to < 10 mEq/h in the last hour before the next dose of drug, 67% of the patients with reflux esophagitis responded with complete disappearance of symptoms and normalization of the endoscopic abnormalities. The other 33% of patients required an increase in medication to lower acid output to < 5 mEq/h in 7% and < 1 mEq/h in the other 26% to resolve symptoms and signs completely. We conclude that reflux esophagitis occurs in the majority of patients with Zollinger-Ellison syndrome and responds well to medical therapy, although one third of patients require intensive antisecretory medication.

Gastrinoma Excision for Cure

The role of surgery in the treatment of gastrinoma is unclear. The purpose of this study was to determine prospectively the surgical cure rate using a controlled clinical trial. Eleven patients who fit the entry criteria underwent abdominal exploration and attempted tumor resection for cure. A historical control group was used for comparison. Cure was defined as: (1) normal serum gastrin level, (2) no response to intravenous secretin, (3) no symptoms when antisecretory medications are stopped, and (4) no tumor recurrence on follow-up examination. Tumors found in both groups tended to be small (1.5 cm vs. 2.2 cm), multiple (71% vs. 40%), and in lymph nodes (70% vs. 70%). All tumors identified were located anatomically within the gastrinoma triangle. Tumors were found in 10 of 11 patients (91%) in the study group, and significantly more patients had their tumors excised for cure as compared to controls (82% vs. 27%, p less than 0.05). The current prospective cure rate for gastrinoma is higher than previously appreciated and tumors within lymph nodes do not preclude curative resection.

Refractory duodenal ulcers (nonhealing duodenal ulcers with standard doses of antisecretory medication).

To evaluate possible differences between patients with refractory duodenal ulcers and those with duodenal ulcers that respond to standard doses of antisecretory medications, we determined basal acid outputs by nasogastric suction and daily smoking histories in 75 patients with endoscopically documented active duodenal ulcers. Patients were treated for at least eight weeks with standard doses of antisecretory medications and endoscopic healing or nonhealing was documented. Fifty-five patients that had complete healing of their duodenal ulcers had a mean basal acid output of 6.6 +/- 5.3 meq/hr, and 18/55 had daily cigarette smoking histories, whereas 20 patients that had nonhealing duodenal ulcers had a mean basal acid output of 20.0 +/- 9.6 meq/hr, and 8/20 had daily cigarette smoking histories. There were no significant differences between the two groups with regard to age, duodenal ulcer size, or cigarette smoking history. However, there were significant differences in male-female ratio (P less than 0.02) and in mean basal acid output (P less than 0.001), and all patients with nonhealing duodenal ulcers had basal acid outputs of greater than 10.0 meq/hr. Patients with nonhealing duodenal ulcers were treated with increased doses of ranitidine, mean 675 mg/day (range 600-1200 mg/day), and all had complete healing endoscopically documented. These results indicate that patients treated with standard doses of antisecretory medications with nonhealing duodenal ulcers have increased basal acid outputs of greater than 10.0 meq/hr, and the duodenal ulcers heal with increased doses of antisecretory medication.

Medical management of patients with Zollinger-Ellison syndrome who have had previous gastric surgery: A prospective study

We examined prospectively the criteria for medical management in 16 patients with Zollinger-Ellison syndrome who had had previous gastric surgery. Each patient received sufficient antisecretory medication to lower gastric acid output to <10 mEq/h during the last hour before the next dose of drug. The 7 patients with a vagotomy but no gastric resection were symptom-free and had no mucosal disease. Of 9 patients with a partial gastrectomy, 7 had mucosal disease, with or without symptoms, and 6 of the 7 patients had acid outputs of 5–10 mEq/h. In these patients, antisecretory medication was increased to reduce output to <5 mEq/h and symptoms and mucosal abnormalities resolved in each patient. Patients with Zollinger-Ellison syndrome and a vagotomy can be treated safely by reducing acid secretion to <10 mEq/h, but in patients with a partial gastrectomy, acid secretion must be reduced to <5 mEq/h, and adequacy of therapy must be checked further by endoscopy.

Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome, and multiple endocrine neoplasia type I: a prospective study.

This study evaluates prospectively the effect of parathyroidectomy on basal acid output (BAO), maximal acid output (MAO), fasting serum gastrin, secretin-stimulated serum gastrin, and sensitivity to antisecretory medication in 10 consecutive patients with primary hyperparathyroidism (PHP), Zollinger-Ellison syndrome (ZES), and multiple endocrine neoplasia type I (MEN-I). After parathyroidectomy, 9 of 10 patients remained normocalcemic, and each had a lower BAO; 6 of 9 no longer had gastric acid hypersecretion (less than 15 mEq/hr). Seven of 9 normocalcemic patients had a lower MAO, and a decrease in fasting serum gastrin. Two patients showed no evidence of ZES, a normal BAO, normal fasting serum gastrin concentration, and a negative secretin response after parathyroidectomy. Parathyroidectomy also reduced the dose of histamine H2-receptor antagonist required to control gastric acid secretion in 60% of patients. After successful parathyroidectomy three patients were studied for drug sensitivity, and each had greater acid inhibition with a given dose of histamine H2-receptor antagonist than preoperatively. One patient remained hypercalcemic after surgery and had no change in BAO, MAO, or gastrin. All patients with postoperative normocalcemia will have a lower BAO, 80% a lower MAO, 80% a decreased fasting serum gastrin, and 33% a negative secretin test. Antisecretory medication dose can be reduced because patients have reduced BAO and increased sensitivity to histamine H2-receptor antagonist. The study supports parathyroidectomy as the initial surgical procedure of choice in patients with PHP, ZES, and MEN-I.

Aggressive Resection of Metastatic Disease in Selected Patients with Malignant Gastrinoma

Fifteen patients with Zollinger-Ellison syndrome followed at the National Institutes of Health with extensive metastatic disease had an actuarial 5-year survival of 20%. Therefore, in 1982 a prospective study to examine the effect and feasibility of removing all gross tumor in selected patients with extensive metastatic disease was instituted. Five patients with extensive metastatic gastrinoma confined to the abdomen in whom imaging studies suggested the possibility of complete surgical resection were entered into this study and underwent attempted complete surgical resection and chemotherapy with streptozotocin, doxorubicin, and 5-fluorouracil. Median follow-up was 24 months. Surgical resection of all gastrinoma was possible in 4/5 patients attempted. In one patient in whom all gross disease could not be resected, the residual tumor progressed and the patient died 19 months after operation. All four patients with all disease resected appeared to benefit since all of them had a significant reduction in antisecretory medications and are enjoying normal activity and work. Three patients have had no detectable tumor on follow-up, and two of these patients are clinically and biochemically "cured" with normal fasting gastrin levels and negative provocative gastrin tests at 14 and 32 months. Therefore, aggressive resection of metastatic disease in selected patients with malignant gastrinoma is recommended.

The pathophysiology of peptic ulcer disease.

Heterogeneity is the most important consideration in the pathophysiology of peptic ulcer disease. Acute ulcers and erosions present clinically with gastrointestinal bleeding or perforation. If they heal there is no predictable recurrence. Factors concerned with mucosal defense are relatively more important than aggressive factors such as acid and pepsin. Local ischemia is the earliest recognizable gross lesion. The gastric mucosa is at least as vulnerable as the duodenal mucosa and probably more so. Most drug-induced ulcers occur in the stomach. Chronic or recurrent true peptic ulcers (penetrating the muscularis mucosae) usually present with abdominal pain. Many duodenal ulcer patients report that the pain occurs when the stomach is empty or is relieved by food, and follows a pattern of relatively long periods of freedom from symptoms between recurrences. Approximately 50% of patients experience a recurrence within a year if anti-ulcer medication is stopped. In most western countries recurrent duodenal ulcer is more common than gastric ulcer. Peptic ulcer disease is also more common in men. Recent evidence indicates genetic and familial factors in duodenal ulcer and increased acid-pepsin secretion in response to a variety of stimuli. However, it is also becoming clear that of all the abnormal functions noted, few are present in all subjects and many are clustered in subgroups. In chronic gastric ulcer of the corpus, defective defense mechanisms, such as duodenogastric reflux and atrophic gastritis, seem to be more important than aggressive factors. Nevertheless, antisecretory medications accelerate the healing of such ulcers. It remains to be seen whether prostaglandins, mucus secretion, or gastric mucosal blood flow are impaired in chronic ulcer disease.

Liaison psychiatry: A gastroenterologist's perspective

48 Dr. Cooper is associale clinical professor of medicine al Ihe Georgelown Universily School of Medicine. and chief. seclion ofgaslroenlerology. al The Fairfax Hospilal. Falls Church. Va. Reprinl requesls 10 him allhe Hospilal. 3300 Gallows Road. Falls Church. VA 22046. To a gastroenterologist active in both clinical practice and medical education, it is apparent that an effective psychiatric liaison service is a very valuable resource in the management of complex illnesses with significant psychosomatic or psychiatric components. The psychiatric liaison physician can provide the practicing gastroenterologist with a framework for understanding a patient's personality structure. This enhances integration of the psychological aspects of care into the patient's overall medical management. In addition to educating the gastroenterologist about the features and dosage of specific psychopharmacologic agents, appropriate therapies such as individual or group psychotherapy, biofeedback, or other behavioral techniques can be offered. These therapies will often reduce length of hospital stay and avoid unnecessary delay and expense in dealing with complex emotional illnesses. The psychiatric liaison service may be helpful in a variety of specific gastroenterologic conditions, among them irritable bowel syndrome, anorexia nervosa, peptic ulcer disease, inflammatory bowel disease, morbid obesity, and acute and chronic liver disease including alcoholism. Individuals requiring ileostomy or extensive cancer surgery are also at high risk for emotional difficulties. In addition, the liaison psychiatrist may uncover previously undetected psychiatric iIlnesses such as anxiety neuroses, depression, conversion phenomena, and paranoid psychoses. An effective example of collaboration with a psychiatric liaison service has been our work with individuals with irritable bowel syndrome. Conjoint group sessions were developed, utilizing a gastroenterologist and psychiatrist as coleaders. These sessions included education about the nature of irritable bowel syndrome and its management, and strategies to modify stressors that serve to aggravate the condition.' Supportive psychotherapy complemented the formal didactic aspects of the group treatment. Symptomatic improvement occurred in the majority of individuals with this syndrome. The gastroenterologist is frequently the first individual to evaluate a patient with anorexia nervosa. Correction of malnutrition and reversal of progressive physiologic degeneration can only be accomplished within a setting of psychological management, initiaIly using behavioral principles and foIlowed by psychodynamic treatment. Conjoint work with psychiatric consultants is essential to provide such a treatment approach. Peptic ulcer disease is the prototype of a psychosomatic illness. Although it can usually be managed by an individual physician with antisecretory medication, antacids, diet, and reassurance, certain patients need more extensive psycho(conlinued on page 50)