Symposium on Gastroenterology for Internists
Peptic Ulcer A Medical Perspective
Mark L. Chapman, M.D. *
Up until fairly recently it was not unusual for a lecturer in gastroenterology to tell his students, "we know little more than we did one hundred years ago about the cause and treatment of peptic ulcer disease." Actually, there have been notable and significant advances with regard to etiology, pathogenesis, pathophysiology, and biochemistry of this disease, as well as what might prove to be dramatic advances in medical management.
EPIDEMIOLOGY
The "Vanishing" Duodenal Ulcer With the development of clinical and radiologic criteria, it was apparent by the 1940's that a duodenal ulcer was a common disorder in work force males. Ivy37 in 1946 projected that duodenal ulcer was developing in the men in the United States at the rate of 150,000 new cases a year in the population over 30, and possibly 15,000 to 20,000 new cases annually in the group under 30. At this rate, one man in 10 in the United States would harbor an ulcer by age 65. In initial British autopsy studies this figure of 10 per cent was exceeded. In a multicentered autopsy study in England in 1956, reviewed by Mendeloff and Dunn,46 the prevalence rate for active duodenal ulcers in men, including those that were fatal, was about 6 per cent. When a study of the living British population was carried out it was concluded that about 7 per cent of the working population of English men had duodenal ulcers. By the 1960's it was apparent that the peptic ulcer "epidemic" had peaked out in the United States and England about 10 to 20 years ago, and is now declining. The recent incidence of duodenal ulcer in men is 1.0 to "Assistant Clinical Professor of Medicine (Gastroenterology), The Mount Sinai School of Medicine of the City University of New York, New York, New York
Medical Clinics of North America- Vol. 62, No. 1, January 1978
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3.5 cases per 1000 per year; the incidence in women is 25 to 40 per cent of that in men. 45 , 48, 53 The recent incidence of gastric ulcers in men is about 0.5 per 1000 per year; the incidence in women is 60 to 80 per cent of that in men.7, 45, 48, 53
Predisposing Factors PSYCHOLOGICAL FACTORS. There have been numerous observations on the response to emotional stress in subjects with gastric fistula, including hyperemia, hypersecretion,5 and even scattered bleeding points and erosions. 71 Psychological interviews can produce hypersecretion, as well as a conditioned response to both the time of the interview and even the appearance ofthe psychiatrist without the interview,61 Recently, the suggestion of relaxation by hypnosis on basal and betazole-stimulated secretion of acid was found to result in a significant reduction in acid secretion in unstimulated as well as betazole-stimulated subjects, and in a decrease in gastric motility. 58 In 1958 Mirsky reported that he had been able to predict duodenal ulcer development in 10 of 120 army recruits who had psychological tests revealing intense infantile and oral dependent wishes, and high serum pepsinogen. 47 More recently Samloff and Lieberman56 have been able to demonstrate that patients with duodenal ulcers have increased levels of circulating group I pepsinogens. About 64 per cent of patients with duodenal ulcer have circulating pepsinogen concentrations of 175 ng per ml or higher, while only 8 per cent of normal subjects fall into this range. There is also good correlation between maximal acid output and the circulating pepsinogen level. OTHER ENVIRONMENTAL FACTORS. Aspirin. While chronic ingestion of aspirin seems to increase the incidence of gastric ulcer in women, 14 and certainly in experimental studies aspirin disrupts the gastric mucosa both anatomically and physiologically,21 there is no conclusive evidence that it causes duodenal ulcer disease. Corticosteroids. There is no significant correlation between the use of glucocorticoids and the development of peptic ulcer.l3 Other Drugs. There is no conclusive evidence that other antiinflammatory drugs such as butazolidine, indomethacin, or iboprofen produce peptic ulcers; nor do the rauwolffia alkaloids, despite early allusions to this. 14 Alcohol. While alcohol has been alleged to be ulcerogenic, there is no epidemiologic evidence establishing alcohol as a cause of peptic ulcer. 14 Coffee, Cola and Cigarettes. In a retrospective study of male college students, ingestion of coffee, soft drinks (primarily cola), and cigarettes, individually and commutatively, seems to increase the incidence of duodenal ulcer. Drinking milk seems to decrease the risk; whether it is the drug or the psychological status of the user that increases the risk of ulcer is unclear. 51 Smoking does appear to delay healing of gastric ulcers.26 GENETICS. Peptic ulcer occurs 2 to 2% times as frequently among the living siblings of patients with ulcer as among the general
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population. 27 In addition, there is a higher rate of concordance for duodenal ulcer among monozygous (three times as often) than among dizygous male twins. 42 Other evidence for genetic factors influencing the development of duodenal ulcer is the fact that subjects of blood group "0" are about 37 per cent more likely to develop duodenal ulcer than people of other groups and that nonsecretors of blood group substances in their saliva are 50 per cent more prone to develop duodenal ulcer. The genes exert their effects independently.44 Phenyl thiocarbamide taste sensitivity is significantly different from controls in duodenal ulcer,64 and there are even studies that correlate the linear build (low mean weight/statue ratio) with both the incidence and the prognosis of peptic ulcer.16
PATHOGENESIS OF DUODENAL ULCER Increased Capacity to Secrete Acid and Pepsin At autopsy studies the stomachs of patients with duodenal ulcer contain 2 billion parietal cells, which is about twice the normal number. 15 In addition, the maximal secretion of the stomach correlates directly with the number of parietal cells in the stomach. The maximal acid secretion in patients with duodenal ulcer is about 40 mEq per hour, which is about twice normal. 72 However, about 50 per cent of patients with peptic ulcer fall into the normal range, which limits secretory studies as a diagnostic test. 3 There appears to be little correlation between severity of ulcer disease and level of acid hypersecretion, and there is little evidence at present to justify a policy of selective surgery, "tailored" to the level of secretion. 4 Increased Responsiveness of the Stomach to Submaximal Stimulation by Agents Promoting Gastric Secretion The stomach secretes maximally for only a few minutes after each meal. If the stomach of patients with duodenal ulcer is more sensitive to submaximal stimulation one would expect increased levels of secretion during intraprandial periods. Isenberg et al. 39 gave graded submaximal doses of pentagastrin to patients with duodenal ulcer and controls and found that the dose required to produce half-maximal secretion is in duodenal ulcer, only one third that required in normals. Surgical removal of the vagus decreases basal and stimulated secretion. It has long been suspected that increased vagal drive, originating high in the central nervous system, leads to hypersecretion of duodenal ulcer. Unfortunately, vagal drive cannot be measured. Gastrin Gastrin, a potent stimulator of gastric secretion, is a peptide horomone secreted by the G cells in the gastric antrum and to a lesser extent in the duodenum. It is released by vagal stimulation, digested protein in the antruin, and distention of the antrum.
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In 1964 Gregory and Tl'acey35 isolated a pure extract of gastrin from hog gastric mucosa consisting of 17 amino acid residues. Yalow and Berson's immunoreactive fractionation resulted in isolation of a large form of gastrin, "big" gastrin, 73 later found to have 34 amino acid residues (G34) as opposed to the 17 amino acids of Gregory and Tracey's "little gastrin" (G17), which in fact is the C terminal fraction of G34. 36 Other immunoreactive gastrins have been identified, one with 13 amino acid residues (G13), or "mini" gastrin, and a very large molecule, "big-big" gastrin.36 In fasting human serum "big" and "big-big" gastrin predominate,59 perhaps because the half-life is related to the size of the molecule. After stimulation the proportion of G17 increases 65 and thus is important because it is a more potent secretogogue. Although G17 made up only 30 per cent of serum gastrin, it accounted for 70 per cent of its acid stimulatory activity.25 It has been postulated that patients with duodenal ulcer may have relatively greater levels of G17 in the fasting state, although the total serum gastrin is normal and antral gastrin content is normal. However, studies have shown an increase in serum gastrin over control levels after a meal in patients with duodenal ulcer,70 and it has been suggested that there is "autonomy" of gastrin release following ingestion of food in patients with duodenal ulcer, although it certainly does not result from a greater number of G cells. It might result from a defect in the feedback inhibition of the release of gastrin.
Defective Inhibition of Gastrin Release of gastrin is inhibited by the very acidity it stimulated. Antral acidification is one of the most potent inhibitors of the release of gastrin. The hypothesis that the G cells of patients with duodenal ulcer may not be as sensitive to acid inhibition has been tested by perfusing the stomachs of patients with duodenal ulcer and controls, and simultaneously measuring acid secretion and intragastric pH and serum gastrin; at a pH of 2.5, release of gastrin is almost completely inhibited in normal subjects, but is moderately inhibited in patients with duodenal ulcer.68 Hormonal regulation may be a principal mechanism in inhibition of gastrin. Gastrointestinal polypeptide-secreting cells all originate from the neural crest and possess similar staining characteristics (amino-precursor uptake and decarboxylation) from which the acronymous title APUD has been derived. 52 Four peptides of the secretin family (secretin, glucagon, GIP, and VIP) all inhibit stimulated release of gastrin and acid secretion. 52 Although most studies deal with pharmacologic doses of these polypeptides, and their true physiologic activity with regard to acid secretion is unknown, it is conceivable that a defect in release of some of these pep tides may be responsible for impaired inhibition of gastrin release in duodenal ulcer. Abnormal Gastric Emptying In an elegant study using a standard steak, water, and bread meal, Fordtran32 found that patients with ulcer have markedly increased gastric emptying so that there is a rapid loss of the buffering capacity of the meal.
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In addition there was concomitant increase in acid secretion rate because of the acid-stimulating effect of protein, which was higher in ulcer patients. Fordtran postulated that the rapid buffer emptying, acid hypersecretion, and increased parietal cell responsiveness could all be manifestations of a single underlying abnormality, e.g., increased vagal tone or a defect in hormonal inhibition of gastric motility and secretion by duodenal factors. U sing a peptide meal, Cano and Isenberg8 found that patients with duodenal ulcer have a greatly increased acid load during the second half hour after a meal. Some of the patients had an increased acid load by virtue of rapid emptying of buffer, although the secretory response to a meal remained normal. Duodenal Defense and Acid Neutralization Acid entering the duodenum is neutralized by both pancreatic secretion of bicarbonate and absorption of acid. Patients with duodenal ulcer do not have pancreatic insufficiency. Chapman et al. l1 found that there was decreased gastric permeability to acid in those with duodenal ulcer, with a possible resultant increase in acid load delivered to the duodenum. Mechanisms of resistance of the duodenum remain poorly understood, particularly with reference to blood supply and intrinsic cellular defenses to damage. Naturally Occurring Experiments in Duodenal Ulcer ZOLLINGER-ELLISON SYNDROME. This is now known to be due to a non-beta islet cell tumor of the pancreas which secretes gastrin, although extrapancreatic tumor is occasionally found in the wall of the duodenum and rarely in extragastrointestinallocations. The tumor is malignant 60 per cent of the time and produces fulminant or recurrent ulcer disease, the ulcer being in atypical locations (postbulbar, jejunal) less than 25 per cent of the time. There is concomitant massive hypersecretion of acid, hypergastrinemia, and diarrhea 70 per cent ofthe time. About 20 per cent of the time the syndrome exists with other endocrine adenomas, and sometimes as part of the multiple endocrine neoplasia syndrome (Type I M.E.N.), where other associated adenomas include those of pancreas, pituitary, and adrenal glands. Patients with this disease will have markedly elevated serum gastrin levels and acid hypersecretion. Rarely the disease is due to diffuse 38 hyperplasia of pancreatic islet cells rather than tumor. THE RETAINED ANTRUM. When the antrum is inadvertently left in, after subtotal gastrectomy and gastrojejunostomy, it becomes isolated from the acid stream and release of gastrin is no longer inhibited by low pH leading to hypergastrinemia, hypersecretion, and ulcer.67 HYPERPLASIA OF ANTRAL GASTRIN CELLS. There are some patients with clinical features of the syndrome but in whom there is no islet cell tumor or hyperplasia, but hyperplasia of G cells in the antrum. 34 RENAL DISEASE. While other hypergastrinemic syndromes are due to excessive production of gastrin, elevated serum gastrin in renal failure is due to lack of renal24 inactivation. Although patients with renal
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failure have a high incidence of peptic ulcer, no correlation between serum gastrin, gastric secretion, and peptic ulcer in renal failure has been demonstrated. THERAPY. It is very rare to find a solitary nonmetastasizing pancreatic turn or in the Zollinger-Ellison syndrome so that surgical treatment is total gastrectomy. 38 DIFFERENTIATING HYPERGASTRINEMIC STATES. "OXO" meat broth will produce a significant rise in serum gastrin in antral hyperplasia but not in the Zollinger-Ellison syndrome. 67 The hypergastrinemic response to an infusion of serum calcium in Zollinger-Ellison is more than double that seen in patients with duodenal ulcer. 54 After stimulation with secretin, patients with retained antrum and G cell hyperplasia of the antrum usually have a decreased serum gastrin level, while in gastrinoma there is a doubling of basal gastrin. 62
PATHOGENESIS OF GASTRIC ULCER The concept that all gastric ulcers are due to poor gastric emptying, secondary to pyloric stenosis, with distention of antrum, excessive release of gastrin, and ulcer production, 29 is highly unlikely. Patients with gastric ulcer have normal emptying and low acid secretion, and those with low acid secretion have high serum gastrin because there is less acid to inhibit antral gastrin release. Gastric ulcers may be due to an abnormality in the gastric mucosa. Breaking the Gastric Mucosal Barrier It is now well documented that the gastric surface epithelium is relatively impermeable to certain ions. In the oxyntic gland area, this barrier to ionic migration markedly restricts the rate of back diffusion of hydrogen ion from the gastric lumen to blood, and there is concomitant limitation of sodium ion movement in the opposite direction. 22 In the pyloric gland area, there is greater net flux across the mucosa of hydrogen, sodium, and potassium ions than in the oxyntic gland area, but it still offers a significant barrier to their free diffusion. This is referred to as the gastric mucosal barrier. The remarkable resistance of the normal gastric mucosa to damage by hydrogen ions appears to be related to this impermeability to ions. Davenport and his colleagues have found that non-ionized and fatsoluble substances such as acetic acid, propionic acid, acetylsalicylic acid, ethanol, and eugenol, when applied to mucosa of the oxyntic gland area, result in increased transmucosal flux of hydrogen, sodium, and potassium ions. Similar changes were noted with dog bile, sodium, taurocholate, deacyl sulfate, urea lysolecithin, digitonin, and phospholipase A.17-20 It was found that human bile disrupted the gastric mucosal barrier in both oxyntic and pyloric gland area pouches 69 and in the human stomach. 40 The increased rate of penetration of hydrogen ion into the mucosa with impaired barrier function has been thought to cause bleeding and
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ulceration via the mechanism of local histamine release with vasodilation, tissue damage, and bulk flow of intestinal fluid. Pyloric Sphincter Incompetence and Dysfunction and Gastric Ulcer GASTRITIS. Attempts have been made to study the behavior of the gastric mucosal barrier in normal and abnormal human stomachs. These studies, which utilized instilled acid loads and glycine buffers after stimulation with pentagastrin, found that some patients with gastric ulcer and atrophic gastritis absorbed more hydrogen ion through the mucosa and put out more sodium ion into the lumen than normal control subjects. lO • 11 Schrager et al. 57 have demonstrated that diffuse inflammatory and epithelial changes are nearly always present in the mucosa of patients with gastric ulcer. These changes are severe and are limited, for the most part, to the pyloric gland area mucosa. They are present in areas remote from the ulceration itself and may persist after the ulcer is healed. Nearly all gastric ulcers occur in the pyloric gland area mucosa (or at least the "alkaline area of mucosa") and the pyloric gland area may occupy an unusually large proportion of the total gastric lining in the gastric ulcer disease. 50 BILE REFLUX AND PYLORIC DYSFUNCTION. Beaumont,5 from his study of Alexis St. Martin in 1833, stated that "Bile is never found in the gastric lumen in a state of health." Increased bile acid reflux in patients with gastric ulcer has been demonstrated via many techniques. It is possible that excessive bile reflux from duodenum into stomach, in the presence of acid secretion, might lead to damage of the gastric mucosal barrier and to chronic inflammatory and metaplastic changes seen in human gastric ulcer and ultimately to chronic peptic ulcer itself. While some investigators report no evidence of a pyloric sphincter or high pressure zone,43 Valenzuela et al. 63 report that patients with gastric ulcer have a lower basal sphincter pressure than normal individuals or patients with duodenal ulcer. Fisher and Cohen30 reported that in patients with gastric ulcer, pyloric sphincter pressure did not increase in response to secretin, cholecystokinin, intraduodenal amino acids, or fat. Cigarette smoking, which has been shown to increase bile reflux, decreases resting sphincter pressure. 63
THERAPY The goals of therapy in peptic ulcer are to relieve pain, promote healing, and prevent complications. Diet At least five studies 66 since 1942 have demonstrated that slightly modified or regular diets produce radiologic evidence of healing as well as relief of symptoms, just as effectively as the strict or bland "peptic ulcer diet." Frequent feedings are stimulants of acid secretion. Milk, which only transiently neutralizes gastric acid, also stimulates acid secretion
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and is followed by a rise in gastric acidity.31 No studies show that frequent feedings or milk are effective forms oftherapy. Despite this, a bland diet was used for in-hospital therapy in 77 per cent of hospitals in a recent survey, and frequent milk in over 50 per cent. 66
Antacids Antacids have been used in the past occasionally as part of a regular progr'am for treatment of ulcer, and more frequently on an as needed basis for relief of ulcer pain. Few gastroenterologists will deny that antacids relieve pain, and early uncontrolled studies reported relief of pain in 80 per cent of subjects. There are, however, studies where introduction of acid failed to produce pain and at least one study where ulcer pain was relieved with 200 ml of 0.1 N hydrochloric acid in 18 of 42 subjects. 4 In a recent double-blind controlled study, antacid and placebo produced similar relief of pain in patients with duodenal ulcer. 60 Despite this disquieting information, there is certainly a physiologic rationale for the use of antacids. Peptic ulcer does not develop in the absence of acid and the activity of pepsin decreases with decrease in acidity. Experimental ulcer formation is inhibited by antacids, and acidreducing operations cure peptic ulcer. Although it is relatively impossible to maintain an intragastric pH above 3.5, the average level of maximal activity of pepsins, one must remember that pH changes logarithmically, and changes at very low levels do not accurately reflect neutralization; e.g., a change in pH from 1.3 to 1.6 represents 50 per cent neutralization, from 1.3 to 2.3, 90 per cent, and from 1.3 to 3.3, 99 per cent. Minor changes in pH make major changes in the amount of hydrogen ion available for mucosal damage. PHARMACOLOGY. Antacids act either by chemical neutralization (sodium bicarbonate, calcium carbonate, or magnesium hydroxide) or by absorption (aluminum hydroxide gels). Fordtran31 has shown that in the fasting state, antacids have only a transient intragastric buffering effect of 15 to 20 minutes. The optimally effective dose is that given 1 hour after a meal, as they then have a prolonged effect of some 3 to 4 hours. Another dose some 3 hours after a meal will continue to prolong the buffering effect. A recent report has demonstrated promotion of ulcer healing using this regimen. The in vitro and in vivo buffering effects of antacids vary, some being very potent and others much weaker, so one should be familiar with potency. Optimal buffering differs in different patients. The hypersecretor (MAO of greater than 25 mEq per hour) requires about 80 to 160 mEq of buffer (equivalent to 30 to 60 cc of Mylanta or Maalox) and in the hypersecretor, such as the patient with gastric ulcer, 40 to 80 mEq of buffer (15 to 30 cc of Mylanta or Maalox) will suffice. Since magnesium can produce diarrhea, the antacids containing magnesium can be alternated with equivalent amounts of aluminium hydroxide gel (40 to 80 cc in hypersecretors), which is constipating. 3 ! The calcium carbonate antacids, which are very potent, are now in disfavor because calcium is absorbed in acid milieu and can produce an increase in serum gastrin and acid secretion. There is evidence that there can be significant hypercalcemia and impaired renal function as well as increased ulcer pain and delay in healing with their use.
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The other antacids also have complications, which include diarrhea with magnesium, magnesium toxicity in renal failure, and constipation and hypophosphatemia with the aluminum hydroxide gels. The tablet form of antacid is not as effective as the liquid form. Antisecretory Drugs ANTICHOLINERGICS. Anticholinergic drugs can inhibit secretion by 30 to 50 per cent at 1 to 2 hours after oral administration with the effect lasting 4 to 5 hours. They are therefore prescribed 1 hour before each meal and at bedtime. 31 The effective dose level varies in different patients, and all the anticholinergics produce side-effects. Use is prohibited in glaucoma, urinary retention, gastric retention, and sometimes in arrhythmias. The side-effects almost obviate performing double blind control studies and to say the least there is a great deal of data, mostly conflicting, concerning efficacy in relief of pain as well as promotion of healing and prevention of complications. From a purely physiologic point of view, their use in patients with duodenal ulcer might be justified. HISTAMINE (H 2) ANTAGONISTS. Conventional antihistamines will antagonize the action of histamine on smooth muscle in the gut and bronchus, but not the stimulation of gastric secretion, the former being mediated by Hi receptors. 1 Black et al. 6 described the properties of an H2 receptor antagonist, burimamide. These properties include inhibition of secretion induced by histamine, pentagastrin, and insulin hypoglycemia. A more potent oral compound was introduced, metiamide, which profoundly decreased nocturnal acid secretion and meal-stimulated secretion up to 80 per cent in both normal individuals and those with duodenal ulcer.6 In a multicenter double-blind trial in 68 patients with endoscopically proven duodenal ulcer,' healing was significantly greater in the patients receiving metiamide (67 per cent) compared with those receiving placebo (25 per cent). Transient granulocytopenia occurred in 7 patients receiving the drug, and was readily reversible in 6, but 1 died. The toxicity was thought to be due to thiourea moiety in the molecule. 9 Cimetadine which substitutes a cyanoguanidine for the thiourea is as potent as metiamide and diminishes 24 hour intragastric hydrogen ion concentration when given in four 300 to 400 mg divided oral doses. After 6 weeks of continuous treatment with cimetadine the effect of the drug on basal and pentagastrin-induced secretion is not diminished. There is permanent inhibition while the patient is on the drug, with rapid return of secretion when off the drug. Six week double blind endoscopic studies have shown complete healing in 80 to 90 per cent of patients with duodenal ulcer, a significant difference when compared to placebo-treated controls.2 There have also been reports that treatment results in some rapid healing of gastric ulcers.49 It is highly effective in controlling the Zollinger-Ellison syndrome medically49 lPld its role in the treatment of gastrointestinal hemorrhage, erosive gastritis and reflux esophagitis appears promising in early trials. The H2 receptor antagonists have raised intriguing questions about the role of histamine in the control of gastric secretion. There is still
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debate as to whether histamine serves as the final common pathway in the mediation of secretion or whether the effects can be explained by some form of interaction between the parietal cell receptors. Although it appears that the drug will prove valuable during acute exacerbations of duodenal ulcer, it remains to be seen whether or not chronic administration is safe, before there is a major effect on the role of surgery in management of the disease. PROSTAGLANDINS. The prostaglandins are naturally occurring unsaturated hydroxy fatty acids which may play a role as messengers in enzyme activated effector organs, and inhibit adenyl cyclase release or action, leading to accumulation of cyclic AMP which has been shown in some studies to inhibit gastric secretion. Prostaglandin E 2, which is present in human gastric mucosa and is rapidly inactivated, is effective only in large doses via intravenous administration. 49 The synthetic analogue (methylesters), such as 15 (R) 15-methyl prostaglandin E2 methylester, is not rapidly inactivated and is an extremely potent inhibitor of acid secretion when administered orally, and 16,16 dimethyl prostaglandin E2 caused about 80 per cent inhibition of pentagastrin-stimulated acid secretion. 49 The adverse side-effect is diarrhea, but good inhibition can be obtained without the diarrheogenic effects. Early clinical trials have shown beneficial effect in healing of gastric ulcers.33
Mucosal Protective Agents Carbenoxolone sodium, a triterpene derived from glycyrrhizic acid after extraction from licorice roots, has been shown in numerous studies to increase the gastric ulcer healing rate in ambulant working patients. 28 The drug appears to have a manifold action, decreasing the rate of extrusion of epithelial cells and enhancing intracellular and surface production of mucin. Evidently mucosal contact is necessary and therefore it has been used in capsule form with regard to duodenal ulcer (Duogastrone). Double-blind controlled studies have shown improvement in rate of healing and symptoms; however, some studies do not report a beneficial response. 12 ,23 Carbenoxolone resembles aldosterone and side-effects include hypokalemia, fluid retention, and hypertension. COLLOIDAL BISMUTH. This has been thought to produce an adherent and impervious bismuth protein complex on the ulcer surface, insulating it against digestion. De-Nol (colloidal tripotassium dicitrate bismutrate) has been found in a randomized double-blind study to promote healing of gastric and duodenal ulcers. 55
Summary A host of other drugs are in the process being tested, but lack of studies make their mention superfluous. It remains to be seen whether any drug will materially affect the long term course of peptic ulcer and militate against complications requiring surgical intervention.
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REFERENCES 1. Ash, A. S. F., and Schild, H. D.: Receptors mediating some actions of histamine. Brit. J. Pharmacol., 27:427-439, 1976. 2. Bank, S., Barbezat, G. 0., Novis, B. H., et al.: Histamine H 2-receptor anagonists in the treatment of duodenal ulcer. South Afr. Med. J., 50:1781-1785, 1976. 3. Baron, J. H.: Gastric function tests. In Wastell, C., ed.: Chronic Duodenal Ulcer. London, Butterworths, 1972, pp. 82-114. 4. Baron, J. H.: The clinical application of gastric secretion measurements. Clin. Gastroenterol., 1 :293-314, 1973. 5. Beaumont, W.: Experiments on the physiology of digestion. Plattsburg, Alien, 1833. 6. Black, J. W., Duncan, W. M., Durant, C. J., et al.: Definition and antagonism of histamine H 2-receptors. Nature (Lond.)' 236:355-390, 1972. 7. Bonnevie, 0.: The incidence of gastric ulcer in Copenhagen. Scand. J. Gastroenterol., 10:385-393, 1975. 8. Cano, R., and Isenberg, S. L.: Demonstration of increased duodenal acid load in duodenal ulcer patients (abstract). Clin. Res., 23 :97, 1975. 9. Carter, D. C.: Inhibitors of gastric secretion: current progress. Brit. J. Surg., 63:788-792, 1976. 10. Chapman, M. L., Werther, J. L., and Janowitz, H. D.: Response of the normal and pathologic human gastric mucosa to an instilled acid load. Gastroenterology, 55:344353,1968. 11. Chapman, M. L., Werther, J., Rudick, J., et al.: Pentagastrin infusion-glycine instillation as a measure of acid absorption in the human stomach: Comparison to an instilled acid load. Gastroenterology, 63:962-974, 1972. 12. Cliff, J. M., and Milton-Thompson, G. J.: A double blind trial of carbenoxolone sodium capsules in the treatment of duodenal ulcer. Gut, 11: 167-1 70, 1970. 13. Conn, H., and Blitzer, B.: Non-association of adenocorticoid therapy and peptic ulcer. New Eng. J. Med., 294:473-479, 1976. 14. Cooke, A. R.: Drugs and peptic ulceration. In Sleisenger, M. H., and Fordtran, J. S., Gastrointestinal Disease. Philadelphia, W. B. Saunders Co., 1973, pp. 642-656. 15. Cox, A. J.: Stomach size and its relation to chronic peptic ulcer. Arch. Pathol., 54 :407-422, 1952. 16. Damon, A., and Polednok, A. P.: Constitution, genetics and body form in peptic ulcer; a review. J. Chron. Dis., 20:787-802, 1967. 17. Davenport, H. W.: Destruction of the gastric mucosal barrier by detergents and urea. Gastroenterology, 49:189-196, 1965. 18. Davenport, H. W.: Effect oflysolecithin, digitonin, and phospholipase A upon the dog's gastric mucosal barrier. Gastroenterology, 59:505-509, 1970. 19. Davenport, H. W.: Fluid produced by the gastric mucosa during damage by acetic and salicylic acids. Gastroenterology, 50:487-499, 1965. 20. Davenport, H. W.: Gastric mucosal injury by fatty and acetylsalicylic acids. Gastroenterology, 46:245-253, 1964. 21. Davenport, H. W.: Potassium fluxes across the resting and stimulated gastric mucosa: injury by salicylic and acetic acids. Gastroenterology, 49:238-245, 1965. 22. Davenport, H. W., Warner, N. A., and Code, C. F.: Functional significance of the gastric mucosal barrier to sodium. Gastroenterology, 47:142-152,1964. 23. Davies, W. A., and Reed, P. I.: Controlled trial ofduogastrone in duodenal ulcer. Gut, 18:78-83, 1977. 24. Dent, R. 1., James, J. H., and Fischer, J. E.: Hypergastrinemia in patients with renal failure. Surg. Forum. 23:320. 1972. 25. Dockray, G. J., Debus, H. T., Walsh, J. H., et al.: Molecular forms of gastrin in antral mucosa and the serum of dogs. Proc. Soc. Exper. BioI. Med., 149:550-552,1975. 26. Doll, R., Jones, F. A., and Pygott, F. : Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet, 1 :657-662, 1958. 27. Doll, R., and Kellock, T. D.: The separate inheritance of gastric and duodenal ulcers. Ann. Eugen. (Lond.), 16:231-240, 1951. 28. Doll, R., Langman, M. J. S., and Shawdon, H. H.: Treatment of gastric ulcer with carbenoxolone: antagonistic effect of spironolactone. Gut, 9:42-45, 1968. 29. Dragsted, L. R., and Woodward, E. R.: Gastric stasis, a cause of gastric ulcer. Scand. J. Gastroenterol., 6(Suppl.):243-252, 1970. 30. Fisher, R. S., and Cohen, S.: Pyloric sphincter dysfunction in patients with gastric ulcer. New Eng. J. Med., 288:273-276, 1973. 31. Fordtran, J. A.: Reduction of acidity by diet antacids and anticholinergics. In Sleisenger, M. H., and Fordtran, J. S., eds.: Gastrointestinal Disease. Philadelphia, W. B. Saunders Co., 1973, 718-742.
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32. Fordtran, J. S., and Walsh, J. H.: Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer. (Abstract.) Clin. Res., 23:92, 1975. 33. Fung, W. P., Karin, S. M. M., and Tye, C. Y.: Effectofl5 (R) 15 methyl prostaglandin E2 on healing of gastric ulcers. Lancet, 2: 10-11, 1974. 34. Ganguli, P. C., Polak, J. M., Pearse, A. G. E., et al.: Antral gastrin cell hyperplasia in peptic ulcer disease. Lancet, 1 :583-585, 1974. 35. Gregory, I. R. S., and Tracey, H. J.: The constitution and properties of two gastrins extracted from hog antral mucosa. Gut, 5: 103-107, 1964. 36. Gregory, R. A., and Tracey, H. J.: The chemistry of gastrins: Some recent advances. In Thompson, J. C., ed.: International Symposium on Gastrointestinal Hormones. Austin, University of Texas Press, 1975. 37. Ivy, A. C.: The problem of peptic ulcer. J.A.M.A., 132:1053-1059, 1946. 38. Isenberg, J. L., Walsh, J. H., Grossman, M. L.: Zoilinger-Ellison syndrome. Gastroenterology, 65:140-165,1973. 39. Isenberg, J. L., Grossman, M. L., Maxwell, V., et al.: Increased sensitivity to stimulation of acid secretion by pentagastrin in duodenal ulcer. J. Clin. Invest., 55 :330-337, 1975. 40. Ivy, K. J., Den Besten, L., and Clifton, J. A.: Effect of bile salts on ionic movement across the human gastric mucosa. Gastroenterology, 59:683-690,1970. 41. James, 0., and Kenefick, J. S.: Pain in peptic ulcer. Proc. Roy. Soc. Med.,68:10-11, 1975. 42. Jensen, K. G.: Peptic ulcer: Genetic and epidemiological aspects based on twin studies. Copenhagen, Munksgaard Forlag, 1972. 43. Kaye, M., Menta, S., and Showalter, J.: Manometric studies of the human pylorus. Gastroenterology, 70:477-480, 1976. 44. McConnel, R. B.: The Genetics of Gastrointestinal Disorders. London, Oxford University Press, 1966. 45. Meade, T. W., Arie, T. H. D., Brevis, M., et aI.: Recent history of ischaemic heart disease and duodenal ulcer in doctors. Brit. Med. J., 3:701-704,1968. 46. Mendeloff, A. L., and Dunn, J. P.: Vital and health statistics monographs, Chap. 2, Digestive Diseases. Amer. Public Health Assoc., Cambridge, Harvard Univ. Press, 1971. 47. Mirsky, I. A.: Physiologic, psychologic and social determinants in the etiology of duodenal ulcer. Amer. J. Dig. Dis., 3:285-314, 1958. 48. Monson, R. R., and MacMahon, B.: Peptic ulcer in Massachusetts physicians. New Eng. J. Med., 281 :11-15,1969. 49. Nylander, B., and Anderson, S.: Gastric secretory inhibition induced by three methyl analogues of prostaglandin E2 administered intragastricaily to man. Scand. J. Gastroent., 9:751-758,1974. 50. Oi, M., Oshida, K., and Sugimira, S.: The location of gastric ulcer. Gastroenterology, 36:45-52, 1959. 51. Paffenbarger, R. S., Wing, A. L., and Hyde, R. T.: Chronic disease in former college students. XIII. Early precursors of peptic ulcer. Amer. J. Epidemiol., 1 00: 307-315, 1974. 52. Pearse, A. G. E., Polak, J. M., and Bloom, S. R.: The newer gut hormones: cellular sources, physiology, pathology and clinical aspects. Gastroenterology, 72:746-761, 1977. 53. Pulvertaft, C. N.: Peptic ulcer in town and country. Brit. J. Prev. Soc. Med., 13: 131-138, 1959. 54. Reeder, D. D., Becker, H. D., and Thompson, J E.: Effect of intravenously administered calcium on serum gastrin and gastric secretion in man. Surg. Gynec. Obstet., 138 :847850,1974. 55. Salmon, P. R., Brown, P., Williams, R., et al.: Evaluation of colloidal bismuth (De-Nol) in the treatment of duodenal ulcer emptying endoscopic selection and follow-up. Gut, 15: 189-193, 1974. 56. Samloff, I. M., Liebman, W. M., and Panities, N. M.: Serum group I pepsinogens by radioimmunoassay in control subjects and patients with peptic ulcer. Gastroenterology, 69:83-90, 1975. 57. Schrager, J., Spink, R., Mitra, S.: The antrum in patients with duodenal and gastric ulcers. Gut, 8:497-508, 19f17. 58. Stacher, B., Berner, P., Naske, R., et al.: Effects of hypnotic suggestion of relaxation on basal and betazole-stimulated gastric acid secretion. Gastroenterology, 68 :656-661, 1975. 59. Straus, E., and Yalow, R. S.: Studies on the distribution and degradation of heptade capeptide, big and big-big gastrin. Gastroenterology, 66:936-939, 1974. 60. Sturdevant, R. A. L., Isenberg, J. L., Secrist, D., et aI.: Antacid and placebo produce similar pain relief in duodenal ulcer patients. Gastroenterology, 72: 1-5, 1977. 61. Sun, D. C. H., Shay, H., Dlin, B., et al.: Conditioned secretory response following repeated emotional stress in a case of duodenal ulcer. Gastroenterology, 35: 155-176, 1958.
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62. Thompson, J. C., Reeder, D. D., Viller, H. V., et aL: Natural history and experience with diagnoses and treatment of the Zollinger-Ellison syndrome. Surg. Gynec. Obstet., 140:721, 1975. 63. Valenzuela, J., DeFilippi, C., and Csendes, A.: Manometric studies of the human pyloric sphincter. Effect of cigarette smoking, metoclopramide and atropine. Gastroenterology, 70:481-483, 1976. 64. Vesely, K. T., Kubickova, Z., Dvorakova, M., et al.: Clinical data and characteristics differentiating types of peptic ulcer. Gut, 9 :57-68, 1968. 65. Vinik, A. L., Grant, B. J., and Novis, B.: Gastrins in human antrum, duodenum and peripheral circulation. S. Afr. Med. J., 49:255-260, 1975. 66. Walsh, J. D.: Diet therapy of peptic ulcer disease. Gastroenterology, 72:740-745, 1977. 67. Walsh, J. H., and Grossman, M.: Gastrin. New Eng. J. Med., 292:1324-1334, 13771384,1975. 68. Walsh, J. H., Richardson, C. T., and Fordtran, J. S.: pH dependence of acid secretion and gastrin release in normal and ulcer subjects. J. Clin. Invest., 55 :462-468, 1975. 69. Werther, J. L., Janowitz, H. D., Dyck, W. P., et al.: The effect of bile on electrolyte movement across canine gastric antral and fundic mucosa. Gastroenterology, 59:691697,1970. 70. Wesdrop, R. I. C., and Fischer, J. E.: Plasma gastrin and acid secretion in patients with peptic ulceration. Lancet, 2:857-858, 1968. 71. Wolff, S., and Wolff, H. B.: Human Gastric Function. London, Oxford University Press, 1973. 72. Wormsly, K. G., and Grossman, M. L.: Maximal histolog test in control subjects and in patients with peptic ulcer. Gut, 6:427-435, 1965. 73. Yalow, R. S., and Berson, S. A.: Size and change distinctions between endogenous human plasma gastrin in peripheral blood and heptadecapeptide gastrins. Gastroenterology, 58:609-612, 1970. Department of Medicine 14 East 82nd Street New York, New York 10028
Peptic Ulcer A Medical Perspective
Mark L. Chapman, M.D. *
Up until fairly recently it was not unusual for a lecturer in gastroenterology to tell his students, "we know little more than we did one hundred years ago about the cause and treatment of peptic ulcer disease." Actually, there have been notable and significant advances with regard to etiology, pathogenesis, pathophysiology, and biochemistry of this disease, as well as what might prove to be dramatic advances in medical management.
EPIDEMIOLOGY
The "Vanishing" Duodenal Ulcer With the development of clinical and radiologic criteria, it was apparent by the 1940's that a duodenal ulcer was a common disorder in work force males. Ivy37 in 1946 projected that duodenal ulcer was developing in the men in the United States at the rate of 150,000 new cases a year in the population over 30, and possibly 15,000 to 20,000 new cases annually in the group under 30. At this rate, one man in 10 in the United States would harbor an ulcer by age 65. In initial British autopsy studies this figure of 10 per cent was exceeded. In a multicentered autopsy study in England in 1956, reviewed by Mendeloff and Dunn,46 the prevalence rate for active duodenal ulcers in men, including those that were fatal, was about 6 per cent. When a study of the living British population was carried out it was concluded that about 7 per cent of the working population of English men had duodenal ulcers. By the 1960's it was apparent that the peptic ulcer "epidemic" had peaked out in the United States and England about 10 to 20 years ago, and is now declining. The recent incidence of duodenal ulcer in men is 1.0 to "Assistant Clinical Professor of Medicine (Gastroenterology), The Mount Sinai School of Medicine of the City University of New York, New York, New York
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3.5 cases per 1000 per year; the incidence in women is 25 to 40 per cent of that in men. 45 , 48, 53 The recent incidence of gastric ulcers in men is about 0.5 per 1000 per year; the incidence in women is 60 to 80 per cent of that in men.7, 45, 48, 53
Predisposing Factors PSYCHOLOGICAL FACTORS. There have been numerous observations on the response to emotional stress in subjects with gastric fistula, including hyperemia, hypersecretion,5 and even scattered bleeding points and erosions. 71 Psychological interviews can produce hypersecretion, as well as a conditioned response to both the time of the interview and even the appearance ofthe psychiatrist without the interview,61 Recently, the suggestion of relaxation by hypnosis on basal and betazole-stimulated secretion of acid was found to result in a significant reduction in acid secretion in unstimulated as well as betazole-stimulated subjects, and in a decrease in gastric motility. 58 In 1958 Mirsky reported that he had been able to predict duodenal ulcer development in 10 of 120 army recruits who had psychological tests revealing intense infantile and oral dependent wishes, and high serum pepsinogen. 47 More recently Samloff and Lieberman56 have been able to demonstrate that patients with duodenal ulcers have increased levels of circulating group I pepsinogens. About 64 per cent of patients with duodenal ulcer have circulating pepsinogen concentrations of 175 ng per ml or higher, while only 8 per cent of normal subjects fall into this range. There is also good correlation between maximal acid output and the circulating pepsinogen level. OTHER ENVIRONMENTAL FACTORS. Aspirin. While chronic ingestion of aspirin seems to increase the incidence of gastric ulcer in women, 14 and certainly in experimental studies aspirin disrupts the gastric mucosa both anatomically and physiologically,21 there is no conclusive evidence that it causes duodenal ulcer disease. Corticosteroids. There is no significant correlation between the use of glucocorticoids and the development of peptic ulcer.l3 Other Drugs. There is no conclusive evidence that other antiinflammatory drugs such as butazolidine, indomethacin, or iboprofen produce peptic ulcers; nor do the rauwolffia alkaloids, despite early allusions to this. 14 Alcohol. While alcohol has been alleged to be ulcerogenic, there is no epidemiologic evidence establishing alcohol as a cause of peptic ulcer. 14 Coffee, Cola and Cigarettes. In a retrospective study of male college students, ingestion of coffee, soft drinks (primarily cola), and cigarettes, individually and commutatively, seems to increase the incidence of duodenal ulcer. Drinking milk seems to decrease the risk; whether it is the drug or the psychological status of the user that increases the risk of ulcer is unclear. 51 Smoking does appear to delay healing of gastric ulcers.26 GENETICS. Peptic ulcer occurs 2 to 2% times as frequently among the living siblings of patients with ulcer as among the general
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population. 27 In addition, there is a higher rate of concordance for duodenal ulcer among monozygous (three times as often) than among dizygous male twins. 42 Other evidence for genetic factors influencing the development of duodenal ulcer is the fact that subjects of blood group "0" are about 37 per cent more likely to develop duodenal ulcer than people of other groups and that nonsecretors of blood group substances in their saliva are 50 per cent more prone to develop duodenal ulcer. The genes exert their effects independently.44 Phenyl thiocarbamide taste sensitivity is significantly different from controls in duodenal ulcer,64 and there are even studies that correlate the linear build (low mean weight/statue ratio) with both the incidence and the prognosis of peptic ulcer.16
PATHOGENESIS OF DUODENAL ULCER Increased Capacity to Secrete Acid and Pepsin At autopsy studies the stomachs of patients with duodenal ulcer contain 2 billion parietal cells, which is about twice the normal number. 15 In addition, the maximal secretion of the stomach correlates directly with the number of parietal cells in the stomach. The maximal acid secretion in patients with duodenal ulcer is about 40 mEq per hour, which is about twice normal. 72 However, about 50 per cent of patients with peptic ulcer fall into the normal range, which limits secretory studies as a diagnostic test. 3 There appears to be little correlation between severity of ulcer disease and level of acid hypersecretion, and there is little evidence at present to justify a policy of selective surgery, "tailored" to the level of secretion. 4 Increased Responsiveness of the Stomach to Submaximal Stimulation by Agents Promoting Gastric Secretion The stomach secretes maximally for only a few minutes after each meal. If the stomach of patients with duodenal ulcer is more sensitive to submaximal stimulation one would expect increased levels of secretion during intraprandial periods. Isenberg et al. 39 gave graded submaximal doses of pentagastrin to patients with duodenal ulcer and controls and found that the dose required to produce half-maximal secretion is in duodenal ulcer, only one third that required in normals. Surgical removal of the vagus decreases basal and stimulated secretion. It has long been suspected that increased vagal drive, originating high in the central nervous system, leads to hypersecretion of duodenal ulcer. Unfortunately, vagal drive cannot be measured. Gastrin Gastrin, a potent stimulator of gastric secretion, is a peptide horomone secreted by the G cells in the gastric antrum and to a lesser extent in the duodenum. It is released by vagal stimulation, digested protein in the antruin, and distention of the antrum.
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In 1964 Gregory and Tl'acey35 isolated a pure extract of gastrin from hog gastric mucosa consisting of 17 amino acid residues. Yalow and Berson's immunoreactive fractionation resulted in isolation of a large form of gastrin, "big" gastrin, 73 later found to have 34 amino acid residues (G34) as opposed to the 17 amino acids of Gregory and Tracey's "little gastrin" (G17), which in fact is the C terminal fraction of G34. 36 Other immunoreactive gastrins have been identified, one with 13 amino acid residues (G13), or "mini" gastrin, and a very large molecule, "big-big" gastrin.36 In fasting human serum "big" and "big-big" gastrin predominate,59 perhaps because the half-life is related to the size of the molecule. After stimulation the proportion of G17 increases 65 and thus is important because it is a more potent secretogogue. Although G17 made up only 30 per cent of serum gastrin, it accounted for 70 per cent of its acid stimulatory activity.25 It has been postulated that patients with duodenal ulcer may have relatively greater levels of G17 in the fasting state, although the total serum gastrin is normal and antral gastrin content is normal. However, studies have shown an increase in serum gastrin over control levels after a meal in patients with duodenal ulcer,70 and it has been suggested that there is "autonomy" of gastrin release following ingestion of food in patients with duodenal ulcer, although it certainly does not result from a greater number of G cells. It might result from a defect in the feedback inhibition of the release of gastrin.
Defective Inhibition of Gastrin Release of gastrin is inhibited by the very acidity it stimulated. Antral acidification is one of the most potent inhibitors of the release of gastrin. The hypothesis that the G cells of patients with duodenal ulcer may not be as sensitive to acid inhibition has been tested by perfusing the stomachs of patients with duodenal ulcer and controls, and simultaneously measuring acid secretion and intragastric pH and serum gastrin; at a pH of 2.5, release of gastrin is almost completely inhibited in normal subjects, but is moderately inhibited in patients with duodenal ulcer.68 Hormonal regulation may be a principal mechanism in inhibition of gastrin. Gastrointestinal polypeptide-secreting cells all originate from the neural crest and possess similar staining characteristics (amino-precursor uptake and decarboxylation) from which the acronymous title APUD has been derived. 52 Four peptides of the secretin family (secretin, glucagon, GIP, and VIP) all inhibit stimulated release of gastrin and acid secretion. 52 Although most studies deal with pharmacologic doses of these polypeptides, and their true physiologic activity with regard to acid secretion is unknown, it is conceivable that a defect in release of some of these pep tides may be responsible for impaired inhibition of gastrin release in duodenal ulcer. Abnormal Gastric Emptying In an elegant study using a standard steak, water, and bread meal, Fordtran32 found that patients with ulcer have markedly increased gastric emptying so that there is a rapid loss of the buffering capacity of the meal.
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In addition there was concomitant increase in acid secretion rate because of the acid-stimulating effect of protein, which was higher in ulcer patients. Fordtran postulated that the rapid buffer emptying, acid hypersecretion, and increased parietal cell responsiveness could all be manifestations of a single underlying abnormality, e.g., increased vagal tone or a defect in hormonal inhibition of gastric motility and secretion by duodenal factors. U sing a peptide meal, Cano and Isenberg8 found that patients with duodenal ulcer have a greatly increased acid load during the second half hour after a meal. Some of the patients had an increased acid load by virtue of rapid emptying of buffer, although the secretory response to a meal remained normal. Duodenal Defense and Acid Neutralization Acid entering the duodenum is neutralized by both pancreatic secretion of bicarbonate and absorption of acid. Patients with duodenal ulcer do not have pancreatic insufficiency. Chapman et al. l1 found that there was decreased gastric permeability to acid in those with duodenal ulcer, with a possible resultant increase in acid load delivered to the duodenum. Mechanisms of resistance of the duodenum remain poorly understood, particularly with reference to blood supply and intrinsic cellular defenses to damage. Naturally Occurring Experiments in Duodenal Ulcer ZOLLINGER-ELLISON SYNDROME. This is now known to be due to a non-beta islet cell tumor of the pancreas which secretes gastrin, although extrapancreatic tumor is occasionally found in the wall of the duodenum and rarely in extragastrointestinallocations. The tumor is malignant 60 per cent of the time and produces fulminant or recurrent ulcer disease, the ulcer being in atypical locations (postbulbar, jejunal) less than 25 per cent of the time. There is concomitant massive hypersecretion of acid, hypergastrinemia, and diarrhea 70 per cent ofthe time. About 20 per cent of the time the syndrome exists with other endocrine adenomas, and sometimes as part of the multiple endocrine neoplasia syndrome (Type I M.E.N.), where other associated adenomas include those of pancreas, pituitary, and adrenal glands. Patients with this disease will have markedly elevated serum gastrin levels and acid hypersecretion. Rarely the disease is due to diffuse 38 hyperplasia of pancreatic islet cells rather than tumor. THE RETAINED ANTRUM. When the antrum is inadvertently left in, after subtotal gastrectomy and gastrojejunostomy, it becomes isolated from the acid stream and release of gastrin is no longer inhibited by low pH leading to hypergastrinemia, hypersecretion, and ulcer.67 HYPERPLASIA OF ANTRAL GASTRIN CELLS. There are some patients with clinical features of the syndrome but in whom there is no islet cell tumor or hyperplasia, but hyperplasia of G cells in the antrum. 34 RENAL DISEASE. While other hypergastrinemic syndromes are due to excessive production of gastrin, elevated serum gastrin in renal failure is due to lack of renal24 inactivation. Although patients with renal
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failure have a high incidence of peptic ulcer, no correlation between serum gastrin, gastric secretion, and peptic ulcer in renal failure has been demonstrated. THERAPY. It is very rare to find a solitary nonmetastasizing pancreatic turn or in the Zollinger-Ellison syndrome so that surgical treatment is total gastrectomy. 38 DIFFERENTIATING HYPERGASTRINEMIC STATES. "OXO" meat broth will produce a significant rise in serum gastrin in antral hyperplasia but not in the Zollinger-Ellison syndrome. 67 The hypergastrinemic response to an infusion of serum calcium in Zollinger-Ellison is more than double that seen in patients with duodenal ulcer. 54 After stimulation with secretin, patients with retained antrum and G cell hyperplasia of the antrum usually have a decreased serum gastrin level, while in gastrinoma there is a doubling of basal gastrin. 62
PATHOGENESIS OF GASTRIC ULCER The concept that all gastric ulcers are due to poor gastric emptying, secondary to pyloric stenosis, with distention of antrum, excessive release of gastrin, and ulcer production, 29 is highly unlikely. Patients with gastric ulcer have normal emptying and low acid secretion, and those with low acid secretion have high serum gastrin because there is less acid to inhibit antral gastrin release. Gastric ulcers may be due to an abnormality in the gastric mucosa. Breaking the Gastric Mucosal Barrier It is now well documented that the gastric surface epithelium is relatively impermeable to certain ions. In the oxyntic gland area, this barrier to ionic migration markedly restricts the rate of back diffusion of hydrogen ion from the gastric lumen to blood, and there is concomitant limitation of sodium ion movement in the opposite direction. 22 In the pyloric gland area, there is greater net flux across the mucosa of hydrogen, sodium, and potassium ions than in the oxyntic gland area, but it still offers a significant barrier to their free diffusion. This is referred to as the gastric mucosal barrier. The remarkable resistance of the normal gastric mucosa to damage by hydrogen ions appears to be related to this impermeability to ions. Davenport and his colleagues have found that non-ionized and fatsoluble substances such as acetic acid, propionic acid, acetylsalicylic acid, ethanol, and eugenol, when applied to mucosa of the oxyntic gland area, result in increased transmucosal flux of hydrogen, sodium, and potassium ions. Similar changes were noted with dog bile, sodium, taurocholate, deacyl sulfate, urea lysolecithin, digitonin, and phospholipase A.17-20 It was found that human bile disrupted the gastric mucosal barrier in both oxyntic and pyloric gland area pouches 69 and in the human stomach. 40 The increased rate of penetration of hydrogen ion into the mucosa with impaired barrier function has been thought to cause bleeding and
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ulceration via the mechanism of local histamine release with vasodilation, tissue damage, and bulk flow of intestinal fluid. Pyloric Sphincter Incompetence and Dysfunction and Gastric Ulcer GASTRITIS. Attempts have been made to study the behavior of the gastric mucosal barrier in normal and abnormal human stomachs. These studies, which utilized instilled acid loads and glycine buffers after stimulation with pentagastrin, found that some patients with gastric ulcer and atrophic gastritis absorbed more hydrogen ion through the mucosa and put out more sodium ion into the lumen than normal control subjects. lO • 11 Schrager et al. 57 have demonstrated that diffuse inflammatory and epithelial changes are nearly always present in the mucosa of patients with gastric ulcer. These changes are severe and are limited, for the most part, to the pyloric gland area mucosa. They are present in areas remote from the ulceration itself and may persist after the ulcer is healed. Nearly all gastric ulcers occur in the pyloric gland area mucosa (or at least the "alkaline area of mucosa") and the pyloric gland area may occupy an unusually large proportion of the total gastric lining in the gastric ulcer disease. 50 BILE REFLUX AND PYLORIC DYSFUNCTION. Beaumont,5 from his study of Alexis St. Martin in 1833, stated that "Bile is never found in the gastric lumen in a state of health." Increased bile acid reflux in patients with gastric ulcer has been demonstrated via many techniques. It is possible that excessive bile reflux from duodenum into stomach, in the presence of acid secretion, might lead to damage of the gastric mucosal barrier and to chronic inflammatory and metaplastic changes seen in human gastric ulcer and ultimately to chronic peptic ulcer itself. While some investigators report no evidence of a pyloric sphincter or high pressure zone,43 Valenzuela et al. 63 report that patients with gastric ulcer have a lower basal sphincter pressure than normal individuals or patients with duodenal ulcer. Fisher and Cohen30 reported that in patients with gastric ulcer, pyloric sphincter pressure did not increase in response to secretin, cholecystokinin, intraduodenal amino acids, or fat. Cigarette smoking, which has been shown to increase bile reflux, decreases resting sphincter pressure. 63
THERAPY The goals of therapy in peptic ulcer are to relieve pain, promote healing, and prevent complications. Diet At least five studies 66 since 1942 have demonstrated that slightly modified or regular diets produce radiologic evidence of healing as well as relief of symptoms, just as effectively as the strict or bland "peptic ulcer diet." Frequent feedings are stimulants of acid secretion. Milk, which only transiently neutralizes gastric acid, also stimulates acid secretion
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and is followed by a rise in gastric acidity.31 No studies show that frequent feedings or milk are effective forms oftherapy. Despite this, a bland diet was used for in-hospital therapy in 77 per cent of hospitals in a recent survey, and frequent milk in over 50 per cent. 66
Antacids Antacids have been used in the past occasionally as part of a regular progr'am for treatment of ulcer, and more frequently on an as needed basis for relief of ulcer pain. Few gastroenterologists will deny that antacids relieve pain, and early uncontrolled studies reported relief of pain in 80 per cent of subjects. There are, however, studies where introduction of acid failed to produce pain and at least one study where ulcer pain was relieved with 200 ml of 0.1 N hydrochloric acid in 18 of 42 subjects. 4 In a recent double-blind controlled study, antacid and placebo produced similar relief of pain in patients with duodenal ulcer. 60 Despite this disquieting information, there is certainly a physiologic rationale for the use of antacids. Peptic ulcer does not develop in the absence of acid and the activity of pepsin decreases with decrease in acidity. Experimental ulcer formation is inhibited by antacids, and acidreducing operations cure peptic ulcer. Although it is relatively impossible to maintain an intragastric pH above 3.5, the average level of maximal activity of pepsins, one must remember that pH changes logarithmically, and changes at very low levels do not accurately reflect neutralization; e.g., a change in pH from 1.3 to 1.6 represents 50 per cent neutralization, from 1.3 to 2.3, 90 per cent, and from 1.3 to 3.3, 99 per cent. Minor changes in pH make major changes in the amount of hydrogen ion available for mucosal damage. PHARMACOLOGY. Antacids act either by chemical neutralization (sodium bicarbonate, calcium carbonate, or magnesium hydroxide) or by absorption (aluminum hydroxide gels). Fordtran31 has shown that in the fasting state, antacids have only a transient intragastric buffering effect of 15 to 20 minutes. The optimally effective dose is that given 1 hour after a meal, as they then have a prolonged effect of some 3 to 4 hours. Another dose some 3 hours after a meal will continue to prolong the buffering effect. A recent report has demonstrated promotion of ulcer healing using this regimen. The in vitro and in vivo buffering effects of antacids vary, some being very potent and others much weaker, so one should be familiar with potency. Optimal buffering differs in different patients. The hypersecretor (MAO of greater than 25 mEq per hour) requires about 80 to 160 mEq of buffer (equivalent to 30 to 60 cc of Mylanta or Maalox) and in the hypersecretor, such as the patient with gastric ulcer, 40 to 80 mEq of buffer (15 to 30 cc of Mylanta or Maalox) will suffice. Since magnesium can produce diarrhea, the antacids containing magnesium can be alternated with equivalent amounts of aluminium hydroxide gel (40 to 80 cc in hypersecretors), which is constipating. 3 ! The calcium carbonate antacids, which are very potent, are now in disfavor because calcium is absorbed in acid milieu and can produce an increase in serum gastrin and acid secretion. There is evidence that there can be significant hypercalcemia and impaired renal function as well as increased ulcer pain and delay in healing with their use.
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The other antacids also have complications, which include diarrhea with magnesium, magnesium toxicity in renal failure, and constipation and hypophosphatemia with the aluminum hydroxide gels. The tablet form of antacid is not as effective as the liquid form. Antisecretory Drugs ANTICHOLINERGICS. Anticholinergic drugs can inhibit secretion by 30 to 50 per cent at 1 to 2 hours after oral administration with the effect lasting 4 to 5 hours. They are therefore prescribed 1 hour before each meal and at bedtime. 31 The effective dose level varies in different patients, and all the anticholinergics produce side-effects. Use is prohibited in glaucoma, urinary retention, gastric retention, and sometimes in arrhythmias. The side-effects almost obviate performing double blind control studies and to say the least there is a great deal of data, mostly conflicting, concerning efficacy in relief of pain as well as promotion of healing and prevention of complications. From a purely physiologic point of view, their use in patients with duodenal ulcer might be justified. HISTAMINE (H 2) ANTAGONISTS. Conventional antihistamines will antagonize the action of histamine on smooth muscle in the gut and bronchus, but not the stimulation of gastric secretion, the former being mediated by Hi receptors. 1 Black et al. 6 described the properties of an H2 receptor antagonist, burimamide. These properties include inhibition of secretion induced by histamine, pentagastrin, and insulin hypoglycemia. A more potent oral compound was introduced, metiamide, which profoundly decreased nocturnal acid secretion and meal-stimulated secretion up to 80 per cent in both normal individuals and those with duodenal ulcer.6 In a multicenter double-blind trial in 68 patients with endoscopically proven duodenal ulcer,' healing was significantly greater in the patients receiving metiamide (67 per cent) compared with those receiving placebo (25 per cent). Transient granulocytopenia occurred in 7 patients receiving the drug, and was readily reversible in 6, but 1 died. The toxicity was thought to be due to thiourea moiety in the molecule. 9 Cimetadine which substitutes a cyanoguanidine for the thiourea is as potent as metiamide and diminishes 24 hour intragastric hydrogen ion concentration when given in four 300 to 400 mg divided oral doses. After 6 weeks of continuous treatment with cimetadine the effect of the drug on basal and pentagastrin-induced secretion is not diminished. There is permanent inhibition while the patient is on the drug, with rapid return of secretion when off the drug. Six week double blind endoscopic studies have shown complete healing in 80 to 90 per cent of patients with duodenal ulcer, a significant difference when compared to placebo-treated controls.2 There have also been reports that treatment results in some rapid healing of gastric ulcers.49 It is highly effective in controlling the Zollinger-Ellison syndrome medically49 lPld its role in the treatment of gastrointestinal hemorrhage, erosive gastritis and reflux esophagitis appears promising in early trials. The H2 receptor antagonists have raised intriguing questions about the role of histamine in the control of gastric secretion. There is still
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debate as to whether histamine serves as the final common pathway in the mediation of secretion or whether the effects can be explained by some form of interaction between the parietal cell receptors. Although it appears that the drug will prove valuable during acute exacerbations of duodenal ulcer, it remains to be seen whether or not chronic administration is safe, before there is a major effect on the role of surgery in management of the disease. PROSTAGLANDINS. The prostaglandins are naturally occurring unsaturated hydroxy fatty acids which may play a role as messengers in enzyme activated effector organs, and inhibit adenyl cyclase release or action, leading to accumulation of cyclic AMP which has been shown in some studies to inhibit gastric secretion. Prostaglandin E 2, which is present in human gastric mucosa and is rapidly inactivated, is effective only in large doses via intravenous administration. 49 The synthetic analogue (methylesters), such as 15 (R) 15-methyl prostaglandin E2 methylester, is not rapidly inactivated and is an extremely potent inhibitor of acid secretion when administered orally, and 16,16 dimethyl prostaglandin E2 caused about 80 per cent inhibition of pentagastrin-stimulated acid secretion. 49 The adverse side-effect is diarrhea, but good inhibition can be obtained without the diarrheogenic effects. Early clinical trials have shown beneficial effect in healing of gastric ulcers.33
Mucosal Protective Agents Carbenoxolone sodium, a triterpene derived from glycyrrhizic acid after extraction from licorice roots, has been shown in numerous studies to increase the gastric ulcer healing rate in ambulant working patients. 28 The drug appears to have a manifold action, decreasing the rate of extrusion of epithelial cells and enhancing intracellular and surface production of mucin. Evidently mucosal contact is necessary and therefore it has been used in capsule form with regard to duodenal ulcer (Duogastrone). Double-blind controlled studies have shown improvement in rate of healing and symptoms; however, some studies do not report a beneficial response. 12 ,23 Carbenoxolone resembles aldosterone and side-effects include hypokalemia, fluid retention, and hypertension. COLLOIDAL BISMUTH. This has been thought to produce an adherent and impervious bismuth protein complex on the ulcer surface, insulating it against digestion. De-Nol (colloidal tripotassium dicitrate bismutrate) has been found in a randomized double-blind study to promote healing of gastric and duodenal ulcers. 55
Summary A host of other drugs are in the process being tested, but lack of studies make their mention superfluous. It remains to be seen whether any drug will materially affect the long term course of peptic ulcer and militate against complications requiring surgical intervention.
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