PROGRESS IN GASTROENTEROLOGY

Transcription

1 GASTROENTEROLOGY Copyright 1968 by The Williams &; Wilkins Co. Vol. 54, No.4, Part I of 2 Parts Pr'inted in U.S.A. PROGRESS IN GASTROENTEROLOGY PEPTIC ULCER: A REVIEW OF THE RECENT LITERATURE ON VARIOUS CLINICAL ASPECTS Part I JOSEPH B. KmSNER, M.D., PH.D. Department of Medicine, University of Chicago This current review of peptic ulcer deals almost exclusively with clinical aspects of the problem and excludes the many important studies of gastric secretion in animals and numerous reports on experimental peptic ulcer. The review has been expanded, with the invaluable aid of the literature survey provided by "Gastroenterology Abstracts and Citations." As in preceding reviews, much useful additional information has been published on gastric secretion in man. Particular interest in this category includes the use of gastrin and gastrin-like pentapeptides to measure gastric secretion in man. Interest in gastric secretory inhibitors continues and progress in this area probably will accelerate in the near future. The investigation of tissue resistance remains at a relatively modest level, although considerable attention has been directed to the problem of drug-induced peptic ulceration, particularly the ulcerogenic effects of salicylates. The variants of the Zollinger-Ellison syndrome continue to attract attention. Some evidence is emerging that the humoral effects associated with these tumors are not limited to the gastric secretory mechanism, but also influence pancreatic and biliary secretion, and possibly intestinal transport. Total gastric resection, when the tumor cannot be removed Address requests for reprints to: Joseph B. Kirsner, M.D., Department of Medicine, University of Chicago, 950 East 59th Street, Chicago, Illinois completely, has emerged as the preferred method of surgical treatment. No significantly new trends are apparent in the area of ulcer complications, although percutaneous selective arteriography of the celiac and mesenteric arteries appears to be a useful addition in the diagnosis of massive gastrointestinal hemorrhage. The literature on the medical treatment of peptic ulcer may be characterized as quiescent. Except possibly for the continuing studies on antipeptic agents and carbenoxolone, no completely new therapeutic agents have been described during the past year. Perhaps we can look forward to a new approach in the development of compounds inhibiting gastrin. The articles on gastric freezing include clinical evaluations and also anatomical studies of the histological effects of freezing upon the gastric and duodenal mucosa. The literature on the surgical management of peptic ulcer this year is dominated by numerous reports on the late nutritional and metabolic consequences of gastric resection. Vagotomy and gastroenterostomy, vagotomy and pyloroplasty, and vagotomy and antrectomy ~ o n t iunder n u e evaluation, with generally favorable conclusions. The procedure of vagotomy and pyloroplasty now is being utilized in the surgical management of gastric ulcer, as well as duodenal ulcer. "Selective vagotomy" seems to have attracted limited interest during the past year. The much larger volume of reports on the surgical treatment of peptic ulcer, in comparison

2 612 PROGRESS IN GASTROENTEROLOGY Vol. 54, No.4, Part 1 with the literature on medical therapy, of course, does not reflect the more frequent applicability of medical management. Medical men temporarily may have exhausted their fund of reportable therapeutic results, both positive and negative, although this state surely will not continue indefinitely. Surgeons have a considerable continuing responsibility to observe and report on the consequences of their efforts, especially in the category of gastric resection. The appearance of several unfavorable reports on pyloroplasty may indicate the need for further careful review of patients undergoing this procedure. Considering the enormous amount of clinical material and the tremendous surgical effort represented in the surgical evaluations, this reviewer regrets the comparatively limited and often scientifically uncontrolled approach reflected in these reports. Regrettable also is the apparent scarcity of full medical-surgical cooperation in the management and study of these patients. In general, the clinical trends in peptic ulcer appear approximately the same as in preceding years. The relative paucity of fundamental new studies again is to be noted, but the sustained and perhaps increasing general interest in the ulcer problem remains a source of encouragement. Gastric Secretion in Man Methodology. The clinical usefulness of gastric secretory studies in man has been limited by the considerable fluctuation and nonreproducibility of secretory data, often attributable to technical defects, such as improper location of the nasogastric tube. The ability to properly position a nasogastric tube during gastric analysis was evaluated in 103 patients both before and after correct tube length had been determined fluoroscopically.l Even with knowledge of proper tube length for each patient, placement was satisfactory III only 50% of patients. Occasionally, acid output varies inexplicably despite careful technique. In 1 patient tested with histamine and with gastrin subcutaneously, the tip of the aspiration tube was placed in the most dependent portion of the stomach under fluoroscopic controj.2 Initially, the maximal acid output for 1 hi' was 2 meq. Thirty months later, the maximal secretion was 27 meq. X-rays of the stomach and other studies were normal. This observation recalls similar findings in response to histamine. 3 In the evaluation of achlorhydria, the standard gastric analysis may be misleading because it often fails to detect small quantities of acid secretion. Three of 54 patients with presumed pernicious anemia, tested with modern techniques, were found to secrete acid 4 ; later 2 patients were shown to produce intrinsic factor and therefore did not have pernicious anemia. The 3 patients subsequently had diagnoses made of sprue, nutritional megaloblastic anemia, and juvenile pernicious anemia. H istarnine-stimulated gastric secretion in peptic ulcer. The gastric secretory responses to histamine in patients with peptic ulcer in various countries throughout the world generally yielded similar data. In a study from France 5 involving 330 subjects (including 72 controls without ulcer, 62 with gastric ulcer, 191 with duodenal ulcer, and 5 with gastroduodenal ulcer), the average acid output was higher in patients with duodenal ulcer than in controls, as had been reported frequently. Values were significantly lower in females, whether normal or with peptic ulcer. There was no precise correlation between acid secretion and age, race, familial incidence, clinical findings, or prognosis. However, a report from Copenhagen, Denmark,6 indicated a statistically significant correlation between age and peak acid output in men with duodenal ulcer, the output decreasing by 5 meq per hr for each lo-year increase in age. In women, the acid output fell approximately 2 meq per hr per 10 years, but the statistical significance of this trend was less certain. In a study from India involving 33 patients with duodenal ulcer and 22 controls,1 acid outputs (maximal histamine test) were lower than reported in western subjects, and the basal to maximal acid

3 A p r i l ~ PROGRESS IN GASTROENTEROLOGY 613 output ratio in Indians, among both normals and patients, was significantly higher than in western subjects. In a study of 40 male patients with duodenal ulcer from the United States,8 peak acid outputs correlated with both surface area and body weight. Depression was found to be the predominant emotional feature in 8 patients with low basal and low peak outputs, while anxiety predominated in 8 patients with low basal output and high peak outputs. In Great Britain, the maximal acid output in 8 normal subjects and 23 patients with duodenal ulcer was significantly related to the lean body mass. 9 Studies in 8 male patients with duodenal ulcer, in which hexamethonium bromide and atropine sulfate were used, indicated decreased responsiveness to histamine when vagal influence was depressed. 10 Measurement of histamine- and insulinstimulated gastric acid, pepsin, and intrinsic factor in 10 men with duodenal ulcer, before and after vagotomy with Heinecke-Mikulicz pyloroplasty (9 patients) or gastrojejunostomy (1 patient), with a temporary gastrostomy, indicated similar secretory patterns pre- and postoperatively after histamine stimulation, but postoperative responses were smallery After insulin stimulation, however, the secretion patterns were the same for all components studied, with an initial depression followed by a return to basal values. H istalog-stimulated gastric secretion. The applicability of histalog gastric analysis as a clinical or investigative tool has not been established completely because of different population groups studied, varying dosage schedules, and different methods of collecting gastric juice or measuring titration end points. The optimal dose to evoke maximal acid secretion probably is 1. 7 to 2.0 mg per kg body weight. A uniform 100-mg dose provided less than maximal stimulation in patients weighing more than 66 kg, and the relatively high dosage probably subjected those patients weighing less than 66 kg to an increased risk of side effects. 12 Control men secreted 10.7 meq HCl ± 6.0 in the peak 30- min period after 100 mg of histalog. Men with duodenal ulcer secreted 17.5 meq ± 6.6 in the same period. The values for women were 8.4 meq ± 5.8 and 15 meq ± 7.9, respectively. In contrast to basal secretion, differences between means after histalog significantly separated control from ulcer groups. Comparison of the results of the present study with those of a study utilizing histamine suggested a threshold level of acid output of approximately 7 and 14 meq, respectively, for peak 30- and 60-min periods for both men and women, below which duodenal ulcer seemed unlikely. However, while these levels may be necessary for ulceration in patients with normal gastric or duodenal mucosa, lesser amounts may be associated with ulcer formation in patients with antecedent mucosal damage. Although less than observed with histamine, serious side effects occasionally were encountered in patients given histalog in amounts sufficient to evoke maximal secretion. Among 20 men and 10 women, with an age range from 21 to 45 years (26 normal, 3 duodenal ulcer, and 1 gastritis), peak rates of secretion were maintained for 30 to 45 min with histamine and for 45 to 90 min with betazole. 13 During the 1st hr after injection, the mean responses to the 2 compounds were approximately equal. During the 2nd hr after injection, the mean response to betazole exceeded that to histamine. For the full 2-hr period of collection in 26 normal subjects, the mean secretion of HCl after histamine was 44 meq and after betazole, 61.9 meq; this difference was statistically significant. However, in another study, the 1- hr volumes of gastric juice and total HCl secretion after the subcutaneous injection of 0.05 mg per kg body weight of histamine phosphate and 50 mg of betazole (histalog) in 21 patients were approximately the samey A maximal dose of histalog (2.0 mg per kg) was evaluated as a stimulant for clinical testing of gastric secretion in 131 patients. 15 The highest hourly output of gastric secretion in patients with duodenal

4 614 PROGRESS IN GASTROENTEROLOGY Vol. 54, No.4, Part 1 ulcer occurred between 30 and 90 min. Thus, in the evaluation of duodenal ulcer patients, the histalog test should be continued for 90 min. Severe vasomotor collapse was observed in 3 patients, despite the prior administration of benadryl in 2 patients. Significant bleeding from the stomach was noted in 14 patients. The advantages of betazole are effectiveness after oral administration, fewer side effects, and gastric stimulating effect approximating that of histamine. 16 In another study, the stimulating effect of betazole (histalog, 100 mg or 1.5 mg per kg) was compared with that of histamine (0.5 mg subcutaneously) and insulin (0.2 unit per kg intravenously).n The peak 30- min flow caused by betazole was equal to the 2-hr flow produced by histamine and exceeded the gastric secretory response to insulin. Electrolytes in gastric juice. Electrolyte concentrations and interrelationships were measured in histamine-stimulated gastric secretion in 60 patients with a variety of diagnoses, including gastric and duodenal ulcer.18 Ages ranged from 21 to 90 years; both men and women were included. The average concentration of calcium in unstimulated gastric juice was one-third that of serum; the concentration of phosphorus was approximately the same, suggesting different secretory mechanisms. After histamine, the concentrations of calcium and phosphorus decreased, outputs remaining constant. The average concentration of magnesium (0.9 meq per liter) in unstimulated gastric juice was less than that in serum. 19 A positive correlation was observed between magnesium and sodium, but no correlation existed between magnesium and total acid, magnesium and calcium, or between magnesium and phosphorus, either before or after histamine. Measurement of the total nitrogen was a more reliable indicator of proteins secreted or lost with the gastric juice than determination of the proteins themselves. 20 The correlation between protein and electrolytes was poor, in contrast to the good correlation between total nitrogen and electrolytes. 21 In somewhat similar studies from J a pan 22 involving 254 patients, levels of calcium (2 to 2.5 meq per liter) and magnesium (1.5 to 1.9 meq per liter) ions in the gastric juice were almost constant in the basal state, and both decreased to 70 to 80% of the basal level after histamine stimulation. Calcium and magnesium concentrations were low in patients with duodenal ulcer and anemia, and high in persons with gastric cancer and liver disease. Neither calcium nor magnesium concentration in both the gastric juice and blood was significantly affected (in patients and dogs) by the administration of acetazolamide, spironolactone, chlorthalidone, prednisolone, mercurial diuretics, and ouabain. No correlation was found between the change of chloride concentration in the blood (basal level, 100 to 105 meq per liter) and that in the gastric fluid (90 to 100 meq per liter). Chloride concentration in the blood was not significantly affected by histamine, while that in the gastric fluid was increased maximally at 45 min after the injection (10 to 20% increase).23 Blood and gastric fluid chloride concentrations were not altered by the oral administration of 100 mg of spironolactone. Duodenal ph. A composite tube system consisting of one or two intestinal glass electrodes, a reference lead from the Calomel electrode, and a tube opening close to the electrodes for injection of Gastrografin was utilized to study 6 normals, 9 patients with active duodenal ulcer, and 4 patients with "coarse duodenal mucosal folds" and with ulcer symptoms. 24 The tube assembly weighted with a terminal bag of mercury was passed into the stomach; the electrodes, 4 cm apart, were positioned so that one was in the stomach, recording steady ph, and the other in the duodenal bulb, recording fluctuating ph. Duodenal ph was recorded for 12 to 18 hr, particularly between midnight and 8 AM. In the duodenal bulb, wide fluctuations of ph were observed for at least 6 hr after a meal. At night, when gastric emptying was intermittent, the fluctuations in ph continued

5 April 1968 PROGRESS IN GASTROENTEROLOGY for longer periods in patients with duodenal ulcer and patients with coarse duodenal mucosal folds than in normal subjects. Pain was associated with change in ph and did not occur when ph was neutral. Similar studies in 11 normal individuals and 13 patients with duodenal ulcer given a standard meal indicated a steady ph in the antrum and a fluctuating ph in the duodenum. 25 At the base of the bulb, acidity was interrupted by neutrality; beyond the apex, a neutral ph was interrupted by acid; in the middle of the bulb, ph fluctuated approximately evenly between acidity and neutrality. In patients with ulcer, the acidity tended to be high at all sites for a greater proportion of time than in normal subj ects. In both groups of subjects, ph increased from the base of the duodenal bulb to the second part of the duodenum. In the bulb itself, ph increased from the base to the apex. The ph tracings suggested that gastric contents are neutralized in the bulb before reaching the second part of the duodenum, presumably by reflux of alkaline content. In another study, the ph of duodenal bulb contents was recorded with a guarded, in situ glass electrode. Antrocutaneous and duodenocutaneous potential differences were recorded simultaneously from flowing potassium chloride bridges attached to the glass electrode lead. 26 Potential difference patterns were used to position the glass electrode and monitor its location (the reliability of this approach was confirmed by simultaneous cinefluorography). Mean duodenal bulb ph was significantly higher than antral ph in both normal and ulcer subjects. In ulcer patients, mean duodenal bulb ph (2.9) was significantly lower than normal (4.5). Normal subj ects and ulcer patients had similar antral ph values (1.7). There was no significant difference between ulcer and control groups in ph of postbulbar duodenal contents. As in the preceding studies, antral ph was more stable than duodenal bulb ph; postbulbar duodenal ph was higher and more stable than the ph of the duodenal bulb. The hypothesis implicating a humoral inhibition of acid secretion by acidification of the duodenum was tested by (a) transfusing blood from subjects undergoing duodenal acidification to donors with acid secretion stimulated with histamine, (b) studying the effect of duodenal acidification in vagotomized subjects, and (c) examining the gastric acid inhibitory effects of several gastrointestinal hormones. Intravenous infusion of histamine acid phosphate (0.05 to 0.1 flg per kg per min) produced 50% of the maximal total acid output.27 Duodenal acidification with 0.1 N hydrochloric acid rapidly produced a 57% decrease in volume and acid output, but had no effect on acid concentration. Cross-transfusion of 1 pint of blood from a donor with acid inhibition due to duodenal acidification produced in 4 subjects a 51 % inhibition of total acid output of the histamine-stimulated secretion of the recipient. Heparinized or citra ted fresh or blood bank blood, plasma, or saline did not inhibit gastric acid output. Total acid output was unchanged during histamine stimulation following intravenous infusions of secretin (70 to 100 U), pancreozymin (90 to 145 U), or cholecystokinin (75 U). The data were interpreted as suggesting release of an unidentified, acid-inhibiting hormone by duodenal acidification. Insulin-stimulated gastric secretion. Duplicate tests of gastric acid secretion following a standard intravenous dose (0.15 U per kg) of regular insulin were made in 25 subjects, to determine the most reproducible measurement. 28 Because of its similarity to the most reproducible measurement of the augmented histamine test and the desirability of using similar measurements in tests of gastric secretion, the 30-min maximal acid output was recommended as the standard for comparison between insulin tests. The intravenous injection of insulin into normal human subjects and patients with duodenal ulcer inhibited gastric secretion within 14 min, for periods of 15 to 45 min. 29 The degree of gastric inhibition was greater in the ulcer group than in the controls. The character of this inhibitory

6 616 PROGRESS IN GASTROENTEROLOGY Vol. 54, No.4, Part 1 effect was not altered by gastric antrectomy, bilateral thoracolumbar sympathectomy, pancreatitis, or endocrine dysfunction (bilateral adrenalectomy, total thyroidectomy, bilateral orchiectomy, bilateral oophorectomy, and diabetes mellitus). Other secretory tests. The effect of nicotinic acid (100 mg) on gastric secretion resembled that obtained with histamine (0.5 mg), as revealed in a study on 62 patients (duodenal and gastric ulcers and nonulcer diseases). 30 A radiotelemetering system and a capsule with glass electrode, 9.5 by 25 mm in size, developed for measuring gastrointestinal ph,31 was reported to have an accuracy within 0.1 ph, a long battery life, and easy operability. In clinical trials, the ph ranged from 1.5 to 2.5 in the stomach, 5 to 6 in the duodenal bulb, 6 to 7 in the duodenum, 7 to 8 in the small intestine, and 6 to 8 in the large intestine. Gastrin. Early observations on Edkins' hypothesis of the gastric secretory hormone, gastrin, were reviewed by Grossman,32 who concluded that acetylcholine released by nerves is the mediator for all forms of gastrin release, both from vagal impulses and from local stimuli. Gregory and T racy33 described recent developments leading to the biochemical identification of the gastrin molecule and emphasized the current need to study the metabolism of gastrin in blood and tissues. A substituted derivative, structurally related to gastrin, the pentapeptide lei 50123, was tested for its action on gastric secretion in man, as compared with gastrin and histamine. 34 In 2 subjects, the maximal responses calculated from doseresponse curves following the subcutaneous injection of gastrin or pentapeptide were similar to those obtained in earlier studies and were independent of the nature of the stimulant or the route through which it was administered. In terms of the dose eliciting half the maximal response (ED50), gastrin was 30 times more potent on a molar basis than the pentapeptide and 240 times more potent than histamine. The response to 6 p.g per kg of the pentapeptide and to 40 p.g per kg of histamine acid phosphate administered subcutaneously were similar. No side effects were encountered at doses up to and including 6 p.g per kg of the pentapeptide. Two subj ects tested with doses above 8 and up to 13 p.g per kg reported a sinking abdominal sensation lasting around 10 min. Seven individuals, tested with doses of gastrin II and histamine, produced similar near maximal outputs of acid. 35 The outputs of pepsin after gastrin, although lower, were correlated with the corresponding outputs after histamine. A peak stimulation of gastric output was obtainable (generally within 30 min) in 17 to 29 volunteers given lei (0.01 to 0.1 p.g per kg per min by constant intravenous infusion).36 Upon termination of the infusion, acid output returned to basal levels within 15 min. After priming of the pancreas with secretin (1.0 to 6.0 units per kg per hr, constant intravenous infusion), the pentapeptide stimulated bicarbonate and enzyme output of the pancreas, usually within 20 min but at somewhat higher doses. With these increases, there was a greater influx of bile and sodium chloride into the duodenum. Abdominal cramps, nausea, and vomiting occurred m 3 of 16 subjects who received 0.1 p.g of the peptide, and hypotension developed in 3 of 6 subjects given 6 p.g per kg subcutaneously. Studies in 13 normal medical students and 23 patients with duodenal ulcer, given the pentapeptide intravenously at a constant rate in a dose range of to 0.3 p.g per kg per min, indicated that the acidsecreting cells of patients with duodenal ulcer are not more sensitive to lower dose rates of the pentapeptide and are not stimulated maximally more easily than the parietal cells of normal subjects. 37 In another study, lei was a more effective stimulant of gastric secretion in man than histamine and produced a maximal acid output at 1.2 p.g per kg per hr by constant intravenous infusion or at 6 p.g per kg by subcutaneous injection. 3s Administration of atropine or vagotomy with pyloroplasty reduced the response to the pentapeptide approximately 2-fold more than the response to histamine, sug-

7 April 1968 PROGRESS IN GASTROENTEROLOGY 617 gesting that cholinergic innervation plays an important role in the effect of pentapeptide on gastric secretion. Gastrin in doses of 2 p.g per kg body weight was injected subcutaneously in 10 subjects, two times in each, with an interval of 1 hr to 4 days between tests. 39 A highly significant correlation in acid output between the two series of tests was noted (r = 0.945). Gastric juice was aspirated for 1 hr before and after the injection of gastrin (2 p.g per kg) in 10 subjects on 10 occasions. 40 Concentrations of total acid, potassium, and magnesium increased after gastrin; concentrations of sodium, calcium, and phosphorus decreased, resembling the findings reported for histamine and other stimulants. Serum electrolytes were unchanged after gastrin administration. 41 The patterns of electrolyte and acid secretion in gastric content were very similar to those following histamine. These and other secretory studies thus indicate that the maximal response to pentagastrin is achieved at doses of 6 p.g per kg body weight subcutaneously or 6 p.g per kg body weight per hr by intravenous infusion. 42 In individuals with and without duodenal ulcer, acid responses as great as those to maximal doses of histamine were obtained with pentagastrin, and the results were sufficiently reproducible for clinical applicability. Transient vasomotor symptoms or mild nausea or both, or abdominal discomfort were experienced with pentagastrin, but the side effects were less frequent and less severe than those from histamine. It seems possible now that a single subcutaneous dose of pentagastrin can be used instead of histamine in assessing maximal acid response. However, according to Wormsley43 the intravenous dose rate required to elicit maximal secretion may differ by a factor of up to 100 in different subjects. "Depending, therefore, on the level of the dose rate evoking a maximal gastric response, up to a lo-fold increase in dosage may be necessary to confirm the absolute maximal acid output." In 18 patients who had undergone vagotomy and drainage, the mean acid output was greater after the injection of pentagastrin than after maximal histamine stimulation. 44 Propantheline effectively reduced the acid response to the pentagastrin after complete vagtomy. Both the increased acid output after stimulation with pentagastrin and the reduction after propantheline resulted largely from changes in the volume of secretion. These findings suggest that in man the parietal cells after vagotomy respond more readily to gastrin-like stimulants than to histamme. In doses of 0.25 to 0.5 p.g per kg body weight intravenously over 3 min, ICI apparently increased activity of the colon and rectum. 45 Subcutaneous doses of 1 to 4 p.g per kg body weight had no constant effect. In view of these demonstrations of the powerful gastric secretory effects of gastrin and gastrin-like preparations, the induction of peptic ulcer in animals given gastrin extracts was to be expected. The continuous intravenous injection of porcine gastrin extract or pure porcine gastrin II to conscious, intact cats resulted in the development of erosions or ulcers in the proximal duodenum, often with gross bleeding. 46 The administration of gastrin extract for 96 hr resulted in duodenal ulcers, with perforation and with hemorrhage. Small erosions or ulcerations of the pyloric gland area or the oxyntic gland area of the stomach were noted occasionally. Similarly, hog gastrin, in an aqueous gelatin suspension subcutaneously, induced a sustained release of gastrin and a prolonged increase in gastric acid secretion in dogs with Heidenhain pouches. 47 When this preparation of gastrin-gelatin mixture equivalent to 35 g of hog antral mucosa per kg of body weight every 12 hr was administered to guinea pigs, duodenal ulcers developed within 14 days in threefourths of 35 animals. "Antigastrin." 2-Phenyl-2- (2-pyridyl) thioacetamide (antigastrin) specifically inhibited the gastric acid secretory responses to both pure gastrin II and the synthetic gastrin-like pentapeptide, pentagastrin,48 and had no effect on responses to histamine or to methacholine. The effec-

8 618 PROGRESS IN GASTROENTEROLOGY Vol. 54, No.4, Parti tive dose of antigastrin approximated 10 mg. The intravenous injection of the antigastrin compound depressed the meal responses of denervated Heidenhain pouches more completely than those of vagally innervated pouches. Since the meal response of the Heidenhain pouch probably is mediated almost wholly by gastrin release (whereas the control of acid secretion in the innervated pouch contains both vagal and gastrin components), this difference in the inhibitor behavior of the two pouches is further support for a specific activity against gastrin-stimulated acid secretion. Gastrin secretion in newborn infants. In newborn infants, the volume, ph, total acidity, chloride content, and pepsin activity of the gastric content varied independently of one another.49 Pneumonia and bronchitis, compromising respiratory function, were characterized by decreased acidity. Infants with acyanotic congenital heart disease showed significantly decreased pepsin content and increased chloride concentration, despite normal acidity. Infants with short gut after bowel resection displayed significant increases in gastric acidity and volume of secretion. In a group of 65 full term, healthy infants, studied at intervals during the first 24 hr of life, the gastric ph averaged 6.0 immediately after birth.50 By 2 hr of age, the ph had fallen to 3.5, and thereafter ranged between 2.5 and 3.5 for the first 24 hr. Babies delivered by Cesarean section, in contrast to vaginal deliveries, had a more alkaline initial ph, averaging 7.5. However, when the stomach was washed with sodium chloride solution immediately after birth, strongly acid gastric juice was secreted immediately. From this observation the initial alkalinity of the stomach was attributed to retained amniotic fluid. There was no correlation between gastric ph in the newborn with obstetric drugs and anesthesia, including pentobarbital, promethazine, hydroxyzine hydrochloride, succinylcholine, ethylene anesthesia, and nerve conduction block. Studies of the maximal gastric secretion after histalog stimulation (1.7 mg per kg subcutaneously) III 50 normal newborn infants, 3 to 37 hr after birth, indicated that gastric secretion was considerably less in the newborn than in adults, in proportion to body weight, probably because of the reduced number of gastric secretory cells. 51 In contrast, premature infants had lower rates of gastric acid output and a higher incidence of achlorhydria. The larger parietal cell mass and transient increase in gastric acid secretion in the full term normal infant may be related to hormonal stimulation in the third trimester of pregnancy, supplemented by increased activity of vagal tone shortly after birth. Gastric secretion (maximal histamine test) was measured in 10 children, with an average age of 21 months (range 11 to 30) and average body weight of 11.8 kg (range 8 to 13.9), without gastrointestinal disease. 52 Volume, acid, and intrinsic factor secretion were increased after histamine, but the secretory pattern of pepsin was difficult to assess. In general, secretory patterns paralleled those in healthy adults. Examination of total stomach specimens, obtained within 4 hr of autopsy from 4 newborn infants (ages 2 to 16 hr), indicated that the parietal cell mass was 2 to 3 times larger than that of the normal adult. 53 The parietal cell mass was highest in the corpus (maximal in the midportion), decreased in density in the incisura and cardia, and was absent in the prepyloric-antral region. Hypercalcemia and gastric secretionparathyroid extract. Among 61 patients with primary hyperparathyroidism, 15 (24.5%) had a peptic ulcer of the stomach, duodenum, or jejunum (demonstrated by X-ray, surgery, or autopsy).54 Ulcer symptomatology was elicited in 27 patients (44.2%). The pylorus and prepyloric part of the stomach were involved most frequently. Complications (perforation, hemorrhage, stenosis) occurred in 10 of 15 (75%) with proven ulcer. Family histories of peptic ulcer wer elicited in 9 of 15 (60%) with proven ulcer, in 7 of 12 (58%) with ulcer symptomatology, and in 12 of 34 (35%) without ulcer symptomatology. After the elimination

9 April 1968 PROGRESS IN GASTROENTEROLOGY 619 of parathyroid hyperfunction, ulcer symptomatology regressed in 11 of the 15 patients. Basal gastric secretion was increased in a woman with hyperparathyroidism, who had developed two large duodenal ulcers, one of which had penetrated, producing a subphrenic abscess. Gastric secretion decreased during the year after removal of several parathyroid adenomas and could be increased again by the artificial induction of hypercalcemia. 55 This observation coincides with the pronounced stimulation of gastric acid, pepsin, and volume of secretion noted during the intravenous administration of calcium salts. In the latter experiments, following the induction of hypercalcemia in 24 peptic ulcer patients by the intravenous administration of calcium hexonate, acid output rose to 12.2 meq per hr, a rate 29% of the peak response to histalog. 56 Pepsin output rose to a rate 43% of the peak histalog response. Hypercalcemia failed to produce a significant alteration in the peak response to histalog. The injection of atropine or pentolinium abolished the effect of hypercalcemia on spontaneous gastric secretion, as did the concomitant induction of hypermagnesemia. Maximal gastric acid secretion was determined in 8 patients (3 with duodenal ulcer, 1 with gastric ulcer, 2 with alcoholic gastritis, and 2 without gastrointestinal disease) following the administration of betazole (1.5 mg per kg).57 On some days basal secretion was collected for 1 hr, after which an infusion of either saline or calcium gluconate (15 mg per kg of calcium gluconate over 4 hr) was given; serum calcium was measured every 60 min. Gastric acid increased during calcium infusion in all 8 subj ects; the peak calciumstimulated acid secretion was 30% of the peak response to betazole. In 6 of 8 subjects, acid secretion continued for 2 hr or more following cessation of the calcium infusion. In 1 patient, calcium chloride had a similar influence. The increased acid secretion presumably was mediated either through the release of gastrin or through an increased cholinergic effect facilitated by the hypercalcemia. These findings in man are III contrast to experiments in dogs with denervated Heidenhain pouches, in which hypercalcemia was induced by the infusion of 50 to 70 ml of 10% CaCl 2 during 1 hr.58 The highest serum calcium concentration attained was between 17.0 and 18.2 mg per 100 ml; after cessation of the infusion, the hypercalcemia continued for another 2 hr. In no instance, did the elevated serum calcium increase gastric secretion. On the contrary, basal secretion and pepsin concentration decreased. When the serum calcium levels returned to normal, the basal pouch secretion returned to control values. The infusion of 5% levulose (500 ml per hr) resulted in a 5- to 6-fold increase in volume secreted by the pouch. The effects of (a) food, (b) gastrin, (c) gastrin tetrapeptide, (d) prostigmine, and (e) histamine upon gastric secretion were tested during periods of normal calcium blood levels and hypercalcemia. Hypercalcemia blocked the effects of all of these substances, with the exception of histamine, the effect of which was practically the same as that obtained when the serum calcium was normal. Histamine- and intubation-induced gastric secretion was studied in 15 subjects following the intramuscular administration of parathyroid extract (45 U per day X 5).59 Gastric secretion in patients with normal or hypoacidity was unchanged. However, among 8 hyperacid patients, gastric secretion decreased substantially in 6; no change in calcium blood levels was observed in this group. Histological and histochemical studies were performed on gastric mucosa obtained from 3 men treated for 5 consecutive days with 45 U per day of parathyroid extract, and from 25 rats treated for 20 or 5 consecutive days with 45 U per day of parathyroid extract.60 Among the treated animals, no changes in either gastric morphology or histology were observed. Likewise, no morphological, histological, or histochemical changes were observed in the gastric mucosa of the men. Gastric secretion after portacaval shunt. Gastric hypersecretion, with a gastric ulcer, was noted in a patient with cirrhosis

10 620 PROGRESS IN GASTROENTEROLOGY Vol. 54, No.4, Part 1 of the liver and esophageal varices treated by a portacaval shunt. 6! The blood histamine level was increased, but in several other patients with portacaval shunt it was not. This clinical observation recalls the increased acid secretion from canine Heidenhain pouches after shunting of the venous drainage from the colon around the liver. 62 These findings support the hypothesis of a gastric secretory stimulant in portal blood, probably originating in both the colon and small bowel. Similar observations were made in dogs with Heidenhain pouches that were rendered cirrhotic by treatment with carbon tetrachloride, prior to establishment of a portacaval anastomosis and return to normal diet. 63 Each dog served as its own control for measurements of gastric secretion prior to liver damage, following development of cirrhosis, and after creation of the shunt. Statistically significant increases of gastric secretion followed the induction of liver cirrhosis, and these levels were increased further by 200% to more than 500% following the shunt. This second increase was accompanied by increased liver parenchymal damage, confirmed at necropsy. Following the observation of 2 patients with portacaval shunt complicated by encephalopathy, dog studies suggested that decrease in gastric acid secretion could influence ammonia production by permitting bacterial overgrowth. 64 In a third case, a man with a shunt subsequent to vagotomy had severe hepatic encephalopathy if he ate more than 30 g of protein per! day. Acidification of the small intestine by the infusion of hydrochloric acid into the jejunum lowered the production of ammonia after gastric administered proteose peptone solution and decreased the quantities of urease and amino acid oxidase in the jejunum. Apparently, achlorhydria, by facilitating overgrowth of the intestinal batcerial flora, enhances the development of encephalopathy after portacaval shunt. Gastric secretion after intestinal resection. Gastric hypersecretion following small bowel resection in man previously has received only brief mention. Repeated gastric aspiration in a man following a massive bowel resection for multiple arterial occlusions of mesenteric vessels revealed gastric hypersecretion, with a daily volume of 2 to 4 liters containing 200 to 500 meq of hydrogen ion. 65 This hypersecretion resulted in gross biochemical abnormalities, including hypochloremic alkalosis. The hypersecretion of gastric acid after extensive intestinal resection was confirmed in dogs with Heidenhain pouches. The degree of hypersecretion increased as the amount of resected intestine was increased. Lower small intestinal resection was followed by a greater increase in secretion than removal of an equal amount of upper small intestine. 66 Explanation or resection of the gastric antrum abolished this hypersecretion. The results suggested loss of an inhibitor substance rather than the acquisition of a secretory stimulant. Similar experiments demonstrated the prompt development of gastric hypersecretion following 75% distal small intestine resection (from the ligament of Treitz to approximately 3 inches proximal to the ileocecal valve) with j ejunoileal anastomosis. 67 The acid hypersecretion was not attributable to anemia, electrolyte imbalance, quantitative changes of food intake, or morphological changes in the liver or pancreas. However, the number of gastric mucosal parietal cells increased substantially. Gastric hypersecretion also may develop after colectomy with ileoproctostomy in dogs, even after antrectomy. The increases in secretion could not be accounted for on the basis of gastric retention, measurable impairment of liver function, or abnormal serum electrolytes. 6s Gastric mucosa in relation to gastric secretion. Augmented histamine tests and gastric biopsies were performed on 83 patients and 13 healthy normals. 69 Gastritis was demonstrated in 65 of 66 subjects with an acid response less than 10 meq per hr. Of 30 subjects with acid outputs exceeding 10 meq per hr, 3 had severe atrophic gastritis and 7 had mild atrophic gastritis or gastric atrophy. Similar findings were noted in a group

11 April 1968 PROGRESS IN GASTROENTEROLOGY 621 of 86 patients with various gastric diseases, studied in Czechoslovakia. 70 Superficial gastritis usually improved in patients with a normal gastric secretion but progressed toward atrophy in patients with low secretory output. Similar findings were reported from Germany71; pronounced gastritis and atrophic gastritis in the region of the corpus were associated with decreased volume and acidity. Gastric secretion (maximal histamine) and mucosal histology also were studied in 81 patients, divided into four groups: normal, superficial gastritis, gastritis with atrophy, and gastric atrophy.72 Patients with superficial gastritis and little apparent glandular atrophy had decreased weight of gastric juice solids and diminished outputs of acid and proteolytic enzyme activity; the output of hexose and vitamin B 12 -binding materials was similar to that of patients with normal gastric mucosa. With more severe mucosal lesions, including atrophy, gastric secretion and the output of hexose and vitamin B 12 - binding materials decreased further. Patients with gastritis and atrophy secreted very small amounts of acid and proteolytic enzymes. Patients with complete glandular atrophy secreted small volumes of concentrated juice, lacking in acid and proteolytic enzyme activity, yet containing small amounts of vitamin B 12 -binding materials and high concentrations of hexose. Vitamin B12 absorption was normal in all patients except those with gastric atrophy, even though patients with gastritis and partial glandular atrophy produced very little vitamin B 12 -binding materials. The effects of prednisolone on gastric mucosal histology, gastric secretion of acid and intrinsic factor, vitamin B12 absorption, and the serum titers of antibody to intrinsic factor and to gastric parietal cell cytoplasm were studied in 6 patients with pernicious anemia, 1 with latent pernicious anemia, and in 1 patient with atrophic gastritis. 73 Prednisolone enhanced vitamin B12 absorption in 4 patients with pernicious anemia and in the individual with latent pernicious anemia; absorption remained normal in the patient with atrophic gastritis. In 5 patientb (3 with pernicious anemia, 1 with latent pernicious anemia, and 1 with atrophic gastritis), gastric glands containing parietal and chief cells were identified in mucosal biopsies during steroid therapy. The reappearance of parietal cells was associated with acid secretion in 3 patients and with intrinsic factor secretion in each of t he 5 patients. The serum titers of parietal cell antibody remained constant in 7 patients during steroid therapy; in 1 patients who received the highest daily dose of prednisolone (40 mg), the titer of this antibody decreased. The titers of intrinsic factor antibody decreased in 2 patients. This study thus indicates that the atrophic gastric mucosa in patients with pernicious anemia retains its potential to regenerate parietal cells. Regeneration was observed in patients with the higher titers of parietal cell antibody and did not occur in patients with low titers who also exhibited extensive intestinal metaplasia. The persistently high titers of gastric parietal cell antibody in patients with pernicious anemia may be in response to the release of antigen from degenerating cells in atrophic gastric glands. In 18 patients with pernicious anemia in remission given prednisone for 6 weeks, intrinsic factor production increased substantially in 7.74 Normal gastric glands containing parietal cells were noted in the atrophic mucosa in 9 patients. These effects were independent of the titers of gastric antibodies, suggesting a secondary role for gastric antibodies in pernicious anemia. Study of the gastric mucosal epithelium from patients with duodenal ulcer and other patients undergoing aspiration biopsy indicated both in the fundus and in the pyloric glands a large content of neutral mucopolysaccharides, a moderate nucleic acid content, and a small protein content; acid mucopolysaccharides were absent. 75 Increased numbers of parietal and chief cells were found in gastric biopsies of patients with active duodenal ulcer.76 In patients with chronic pyloric obstruction due to duodenal ulcer, benign gastric ulcer, or gastric carcinoma, biopsies demonstrated increased mucous neck

12 622 PROGRESS IN GASTROENTEROLOGY Vol. 54, No.4, Part 1 cells and decreased chief cells. There appeared to be no precise relationship between gastric acid secretion and the number of parietal cells. Gastric secretory inhibitors. The effects of heparin on the gastric secretory response to histamine (0.02 mg per kg subcutaneously) and insulin (10 to 15 U intravenously) were compared in 68 paired control studies in 63 patients (31 with duodenal ulcer, and 32 control patients).77 Heparin suppressed both the volume of secretion and concentration of acid in control and ulcer patients; insulin and histamine stimulated volume and concentration. Heparin intravenously also suppressed gastric secretion in dogs. 78 Its inhibitory effect was most impressive against the physiological stimulus of food, but it also significantly diminished the response to a variety of stimuli, suggesting a site of action near the end organ, the parietal cell. Sensors for detecting ph and electrical potential difference between skin and bowel lumen were withdrawn from the duodenum into the stomach of human subj ects before and after the administration of betazole hydrochloride (histalog) or secretin. 79 The decrease in gastric ph caused by betazole hydrochloride usually was reflected by an accompanying decrease in ph of the bulbar portion of the duodenum, but not in the postbulbar portion of the duodenum. Injection of secretin increased ph from the postbulbar part of the duodenum to the gastric antrum. In dogs, at least some degree of endogenous inhibition of gastrin- and histamine-induced Heidenhain pouch secretion was exerted by the antrum. so A number of substances (gastrones) found in gastrointestinal mucous secretions inhibit acid secretion when injected intravenously in experimental animals. Experiments utilizing the isolated rat gastric mucosa preparation indicated that the inhibitory action in the intact animal is exerted at a more proximal site than the parietal cel1. 81 Other experiments indicated that gastrone (from antral gastric juice) did not damage the luminal-mucosal barrier to absorption. s2 A gastrone-like substance inhi biting gastric secretion also was obtained from the thoracic duct of dogs.83 The capacity of human gastric juice to inhibit gastric secretion when administered intravenously to dogs or rats was described as early as Subsequent investigations showed a similar effect of human saliva. The nature of the gastric secretory-inhibiting substances in human gastric juice and in human saliva remains unknown. In further studies of this problem, saliva and secretion from the ducts of parotid, submaxillary, and sublingual glands were collected from healthy fasting subj ects. The samples of saliva were dialyzed and lyophilized; the material was dissolved in a phosphate buffer and administered intravenously to anesthetized animals. 84 The amount of gastric inhibitory substance in a measured sample of saliva or glandular secretion was estimated by the percentage of inhibition of gastric secretion as compared with that of the controls. The concentration of gastric inhibitory substance in whole human saliva appeared to depend predominantly upon the secretion from the sublingual glands. Since the active ingredient in the gastric juice has been termed gastric inhibitory substance, the name "sialogastrone" was suggested for the inhibitory substance in the saliva. This term thus would distinguish the inhibitor in saliva from other inhibitors in the gastric juice, in intestinal secretion, and in urine. In further studies,85 the gastric inhibitory activity of lyophilized human saliva varied indirectly with the rate of secretory flow. Inhibition of gastric secretion was greatest when saliva was administered intravenously; moderate inhibition followed intramuscular injection; and intrajejunal administration failed to influence gastric secretion. The inhibitory substance was not destroyed by mild acid hydrolysis or enzymatic proteolysis of saliva. Chromatographic separation of fractions of lyophilized human saliva showed that the inhibitory substance was a large molecular glycopeptide. Stress Ulcer Curling's ulcer. Since Curling's86 initial description of acute ulceration of the duo-

13 April 1968 PROGRESS IN GASTROEN TEROLOGY 623 denum in 10 patients with extensive thermal injury, mostly children and young people, many similar cases have been reported from all parts of the world. In a series of 193 instances of Curling's ulcer, bleeding was the most common presenting symptom. Gastric ulcers were more common than duodenal,87 In 20 cases of Curling's ulcer treated surgically, the survival rate was 45%. In an attempt to explain the mechanism of ulcers associated with burns, operations upon the brain, other surgical procedures, trauma, and various diseases, hypovolemia was induced in rabbits by the removal of blood. The gastric mucosa became pale as a consequence of general vasoconstriction, and this was followed by the development of small, sharply defined areas in which anoxic tissue lesions, with capillary injury and hemorrhages, developed during the period of shock. 88 Since burns decrease gastric mucous production in animals, loss of this protective factor may contribute to gastroduodenal ulceration after thermal injury.89 Stress ulcer. The incidence of acute ulcers of the upper gastrointestinal tract ranges from 1 to 6%.90 In patients with intracranial tumors, the incidence may be 2-fold greater. Frequent acute ulcerations of the upper gastrointestinal tract are noted also among patients with extensive burns, after neurosurgical operations, and in patients with poliomyelitis. In at least 80%, the principal manifestation is massive gastrointestinal bleeding; perforation is the dominant clinical manifestation in approximately 15%. While acid secretion and lowered tissue resistance are involved in the pathogenesis of the lesions, neurophysiological factors seem important. Eighty-eight patients with acute gastroduodenal ulceration after trauma, surgery, or severe illness were noted among 1500 patients with peptic ulcer (6%).91 Fifty-one of the 88 patients died, a mortality of 58%. Autopsy study indicated that acute stress ulceration is usually present in the form of a single ulcer, either gastric or duodenal. Early gastric resection for hemorrhage and simple closure for perforation are recommended. Of 19 patients with stress ulcer after surgery, 14 were treated conservatively and 5 by operation.92 Seven patients were cured,while 12 died, either from ulcer complications or the underlying disease. Partial gastrectomy with vagotomy is indicated for the complication of gastrointestinal bleeding 93 ; vagotomy and py 101'0- plasty may be less effective. Since 1935, 338 patients with postoperative gastroduodenal ulceration have been reported. 94 Among 14 cases, there were 6 with acute ulcerations complicating cardiovascular surgery (all males, between 4 and 9 years of age). In 116 patients the ulcers were precisely localized; 44% were in the stomach, 44% in the duodenum, and 12% were diffuse. Severe, acute ulceration complicated surgical intervention at a rate of approximately 1 to 3% of the patients; but the percentage is much higher with cardiac, urinary, or abdominal surgery. In 91% of the patients, the acute ulceration appeared within the 10th postoperative day and it was more frequent in both adolescent and aged patients. Among 157 patients, 79% were male. For the 338 patients, the over-all mortality rate was 36.5%. Drug-induced Gastric Injury Salicylate injury to gastric mucosa. Study of gastrectomy specimens obtained after the administration of repeated doses of aspirin confirmed its erosive effect ; the previously reported inconsistencies in the incidence of hemorrhagic lesions were largely a function of dosage. More than 70% of 226 subjects lost more than 2 ml of blood per day of treatment with aspirin.so The rate of exfoliation of gastric epithelial cells was increased by aspirin in such individuals. Fecal blood loss was measured in 53 hospitalized patients who had received red cells labeled with Cr51.96 In 11 patients receiving aspirin, the daily fecal blood loss rose from 0.7 ml per day to 3.5 ml per day. Gastrointestinal bleeding was slight after the administration of mefenamic acid. Among various nonnarcotic analgesic agents tested in Pavlov pouch dogs, only aspirin in suspensions at ph 3.0 produced significant bleeding. 97 The same drug in solution, as well as salicylic acid, sali-