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Nervous and Hormonal Influences in Peptic Ulcer
Nervous and Hormonal Influences in Peptic Ulcer JOHN M. BEAL, M.D., F.A.C.S. * KIRBY A. MARTIN, M.D.**
THE precise etiology of peptic ulcer remains obscure although the number of experimental and clinical studies which are concerned with this problem increase yearly. Peptic ulceration occurs only in those areas of the gastrointestinal tract that are exposed to acid juice which is produced by the gastric mucosa. It is not surprising that the great majority of studies have been concerned with the factors that alter the production of gastric secretion, principally the acidity and volume of secretion. The direction of study has been partly influenced by the ease with which volume and acid may be measured in contrast to other possible factors. Thus, despite the considerable increase in knowledge of gastric physiology and in the pathogenesis of peptic ulceration, the cause has not been clarified. This suggests that some of the factors other than acid production should be studied more extensively, particularly those which relate to mucosal resistance. It is the purpose of the present paper to discuss some of the factors in the production of peptic ulceration that seem to be pertinent to the surgical treatment. The complex nature of the disease and the voluminous literature make it impossible to include many studies that may seem equally important to the reader. NERVOUS FACTORS
Pavlov demonstrated nearly five decades ago in dogs that sham feeding produced a stimulation and production of gastric juice and that this response was abolished by the division of the vagus nerves. Thestimulation of gastric secretion by the sight, smell, taste or thought of food l
From the Departments of Surgery and Medicine, New York Hospital-Cornell Medical Center, New York, N. Y. This research was aided by grants from the Dr. William Malcolm Fund. * Associate Professor of Clinical Surgery, Cornell University Medical College; Attending Surgeon, The New York Hospital. ** Assistant Professor of Clinical Medicine, Cornell Um·ver6ity Medical College; Assistant Attending Physician, The New York Hospital. 385
388
John M. Beal, Kirby A. Martin
constitutes the cephalic phase of gastric secretion. The secretion which is thus produced is rich in acid, pepsin and mucus. There is a latent period of five to ten minutes after stimulation has occurred and the secretion persists for 30 minutes or longer after stimulation has ceased, although there appears to be considerable variation in the duration of secretion. The cephalic phase is mediated entirely through efferent impulses which are carried by the vagus nerves. Dragsted2 has calculated from animal experiments that the nervous phase is responsible for approximately 45 per cent of the total acid production of the stomach. Gastric juice is secreted at a constant acidity, a view held by Pavlov and confirmed in recent years. Variation in acidity depends upon a variety of neutralizing factors, such as mucus, regurgitated duodenal fluid, food, and saliva, and upon the volume of the secretion. The nervous phase of gastric secretion may be stimulated by hypoglycemia which follows the injection of insulin. In the presence of intaet vagus nerves, the rapid fall of the blood sugar to levels below 50 mg. per 100 ml., sufficient to produce hypoglycemic symptoms, is followed by a significant stimulation of gastric secretion which is rich in pepsin and hydrochloric acid. Complete division of the vagus nerves prevents the gastric secretory response. In the fasting unstimulated state, the stomach continues to secrete gastric juice, at a rate that has been estimated to range from about 30 to 60 cc. per hour. It has been found that patients with duodenal ulcers produce a greater volume of gastric juice which is highly acid than do normal subjects when the stomach is carefully aspirated throughout the night. I vy3 has found that, regardless of the stimulus, the volume and acidity of gastric juice tends to be higher in patients with duodenal ulcers than in normal persons. However, he has also pointed out that the overlap is sufficiently great to indicate that the difference in acid secretion alone cannot account for the presence of an ulcer. Dragstedt has presented extensive evidence that the hypersecretion of gastric juice, both in the fasting state and in response to the ingestion of food, in duodenal ulcer patients is of nervous origin. Complete division of the vagus nerves in man has been found to eliminate this hypersecretion.' It would also appear that complete division of the vagus nerve also significantly diminishes the gastric phase of secretion, as determined by response. to histamine. 5 GASTRIC PHASE
The gastric phase has been estimated by Dragstedt to contribute approximately 45 per cent of the total acid output. 2 Two types of stimuli act directly upon the stomach to produce stimulation of secretion. These are mechanical distention and certain secretagogues. It has been found that the antrum mediates the gastric phase of secretion. Certain foodstuffs, such as lean meat, will stimulate secretion, while a sufficiently low
Nervous and Hormonal Influences in Peptic Ulcer
387
pH will inhibit the antral or gastric phase of secretion. Alcohol appears to stimulate gastric secretion by direct action upon the gastric antrum. The antrum stimulates gastric secretion through a humoral mechanism. In dogs with Heidenhain pouches, transplantation of the antrum to the colon resulted in an increased secretion of juice from the pouch. Removal of the transplanted antrum was followed by a diminished output of pouch secretion. 6 These physiological and experimental observations have led Dragstedt to implicate the gastric antrum in the pathogenesis of gastric ulcer. It has been noted that the secretion of acid by patients with gastric ulcers in the fasting state or in collected nocturnal secretion was less than that usually found among normal patients. This correlates well with the observation that the antral mucosa is not stimulated when the stomach is empty in the fasting state. It has also been reported that gastric ulcers have developed after vagotomy without an associated drainage procedure, in the treatment of duodenal ulcer. A gastrojejunostomy which is placed high on the gastric wall may also be followed by the development of gastric ulceration. In both instances, stimulation of the antrum has been demonstrated experimentally. While the clinical and experimental evidence affords indirect support to this concept of the antral hyperfunction in the pathogenesis of gastric ulcer, confirmation by means of secretory studies in patients is lacking. This has certain obvious difficulties. It is also strange that pyloric obstruction due to duodenal ulcer, though often longstanding, is seldom associated with gastric ulceration. STRESS
There have been numerous references to the occurrence of acute peptic ulcers following severe burns, trauma and the administration of steroids. It has long been known that individuals with chronic gastric or duodenal ulcerations or individuals with a previous history of peptic ulcer were subject to exacerbation, usually manifested by bleeding or perforation. This problem has been stimulated by the finding that stress results in an increase in the production of corticotrophin by the anterior pituitary with consequent adrenal stimulation. It has been postulated by Gray and others 7 that the administration of ACTH and cortisone results in a hypersecretion of gastric juice and thereby leads to an exacerbation of the peptic ulcer. The mechanism of the production of ulceration of the stomach and duodenum following stress or the administration of steroids remains obscure. In studies on patients who were burned or who were subjected to operation it has been found that gastric secretion is either not stimulated or is reduced. This is of significance because many of the acute exacerbations of peptic ulceration, usually manifested by bleeding, occur within the first 48 hours after trauma. Dragstedt 8 has been unable to
'* 388
John M. Beal, Kirby A. Martin
demonstrate an increase in gastric secretion by the administration of either ACTH or cortisone. Hirschowitz 9 has studied gastric secretion in stressed individuals and has found a marked reduction of the viscosity and the visible mucus content of the gastric juice. Information is lacking in regard to the direct effect of elevated steroid levels upon the mucosa and the resistance of the mucosa under these circumstances. PANCREATIC TUMORS AND ULCER
Recently Zollinger and Ellison!O have directed attention to the occurrence of fulminating peptic ulceration in association with noninsulinproducing islet cell tumors of the pancreas. The ulceration is rapidly progressive, often of atypical location, and recurrence appears despite apparent adequate medical or surgical therapy. In 24 cases recently reviewed by Ellison,!! 14 of the tumors were single and 10 were multiple. Nineteen of these were malignant. The syndrome is associated with excessive gastric secretion. Ellison has reported the acid determinations in one patient in whom a return of the gastric secretion to normal levels was found following the resection of a noninsulin-producing islet cell pancreatic tumor. It would appear from these findings that a humoral factor was involved in the production of the ulcers. However, the atypical location of some of these ulcers, for example, in the jejunum, in areas which are not apparently exposed to gastric juice, raises the question of the existence of an effect upon some mechanisms other than merely hypersecretion of gastric juice. It would also appear that this lesion is a relatively rare, though serious etiologic factor in peptic ulceration. In a 25 year survey of marginal ulceration at The New York Hospital one verified case of islet cell tumor was found in 205 patients with marginal ulcers and this was interestingly enough in a diabetic. More significant, perhaps, is that the existence of this clinical syndrome attests to the complex nature of peptic ulceration from the standpoint of pathogenesis and suggests that a variety of factors may be responsible. The apparent humoral nature of this entity suggests that further search should be made for other humoral factors other than that arising from antral hyperfunction. RECENT EXPERIMENTAL OBSERVATIONS
A wide variety of experiments has been devised to produce experimental ulcer. Recently a new method has been devised in our laboratory which has resulted in the production of both duodenal and gastric ulcers in dogs and which has certain physiological advantages.!2 An intact segment of the duodenum with common bile duct, pancreas and accompanying blood supply has been interposed in continuity at various levels in the more distal portion of the intestinal tract. This permits anastomosis of a proximal segment of duodenum to the more
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Fig. 79. The daily output of hydrochloric acid, expressed as milliequivalents, has been charted. The duodenal segment was transplanted in continuity to the terminal ileum within 25 cm. of the ileocecal valve 23 days after formation of a Heidenhain pouch. The dog expired from perforation of a duodenal ulcer 70 days later. The experimental production of ulcer was not accompanied by a significant elevation of acid production by the pouch.
distal duodenum. When the isolated duodenal segment is transplanted to a new position within 75 cm. or less of the ileocecal valve or into the colon, peptic ulceration has developed uniformly in the intact duodenum or in the stomach, or in both locations. The ulceration usually occurs six to eight weeks after the experimental operation unless the segment is placed into the colon, in which case ulceration occurs within approximately two weeks. When the segment has been interposed in thes mall intestine proximal to the 75 cm. or more level, duodenal or gastric ulceration has not been found although the nutritional status of the dogs has been comparable and evidence of reflux of the biliary and pancreatic secretions has been absent. More recently Heidenhain pouches have been constructed prior to transplantation of the duodenal segment. This has permitted measurement of the volume and acid production of the pouch. Mter the duodenal segment has been interposed into distal ileum or colon, a significant change in the acid secretion, as measured by pouch drainage, has not occurred (Fig. 79, 80). Supportive parenteral fluid therapy has not influenced the pouch secretion. These findings raise certain important questions. The ulcerations occur in the duodenum and/or the stomach and thus not in:mucosa that is
John M. Beal, Kirby A. Martin
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Fig. 80. The acid production by a Heidenhain pouch in a dog has been charted before and after transplantation of the duodenal segment to the proximal colon. Perforation of a duodenal ulcer caused death of the animal 20 days after the operative procedure. Acid production, as measured by pouch secretion, remained low.
unaccustomed to acid peptic juice. The absence of a rise in acid production, as determined by pouch drainage, indicates that hypersecretion is not a factor in the pathogenesis of these ulcers. This suggests that some factor which influences mucosal resistance is involved. This could be either failure to absorb some essential element from the diet in the short intestinal segment, or due to the production of, or the lack of production of some unidentified substance. In our previous reports,12. 13 the essential difference in the two series of dogs (one producing duodenal ulcers and gastric ulcers or both, and the other no ulcers) was the length of the terminal ileum distal to the duodenal insert, draining the bile and pancreatic secretion into the terminal ileum. The acid and pepsin bathed the gastric and duodenal mucosa alike in the two series and were unbuffered by the bile and pancreatic secretion. This simple procedure removes from the experiment the factor of hydrochloric acid, heretofore said to be the principle cause of the ulcers. These ulcers were gastric and duodenal and not marginal on unaccustomed tissue. In the present experiment, further evidence is presented to show that duodenal and gastric ulceration occurs without a significant increase of the hydrochloric acid before or after the ulcer is formed. Some factor other than acid must be responsible for the production of the ulceration. Poor nutrition per se was not an essential factor.
Nervous and Hormonal Influences in Peptic Ulcer
391
COMMENT
It has long since been suspected clinically, and commented on frequently in the literature, that hydrochloric acid alone cannot account for all the factors in peptic ulceration; however, this concept has received scant attention. On the other hand, the acid theory has gained much momentum from the work of the internist and surgeon alike since the turn of the century. The present status of this disease is disturbing because the great improvement in diagnostic and operative procedures combined with nutritional advancements and newer drug therapy has not been accompanied by a significant rise in the rate of prevention or cure. "The history of the medical treatment (in ulcer) is indeed a record of mistaken estimates, of 'treatments' initially believed effective but later proved useless." 14 A concept that merits serious consideration in relation to peptic ulceration is not so much the cause of ulcer formation but rather the reason for failure to heal once it has formed. The normal stomach will withstand injury well and will heal readily under great latitudes of stress. Hollander15 more than 30 years ago showed (and it has been recently confirmed by Dragstedt 16) that hydrochloric acid secretion in dogs was increased tenfold during lactation, normal before and during pregnancy. It has been observed in our laboratory that free gastric acid mounts to the upper limits and remains there following the surgical stripping of the mucosal lining of the dog's stomach. After approximately three weeks the hydrochloric acid titer returns to normal. Biopsies of the stomach have shown the mucosa to regenerate and heal without significant scar in this blast furnace of hydrochloric acid and pepsin. These observations would suggest that the wide fluctuations observed clinically and experimentally in the hydrochloric acid secretion are physiologic and probably will cause no damage to the gastric or duodenal mucosa if it was normal before. We feel that the condition which determines the onset of peptic ulceration in a setting of stress may be quite different from that which prevents its healing. SUMMARY
Some of the physiologic factors known to be involved in the presence of peptic ulcer have been reviewed. Experimental data have been presented which demonstrates that peptic ulceration in the stomach, duodenum or both may be produced without a significant increase in acid secretion. A defective mucosa is thought to be an important cause of the peptic ulceration. This is the second series of experiments in which we have shown that hydrochloric acid is essential for the development of peptic ulceration but may not be the primary cause.
392
John M. Beal, Kirby A. Martin REFERENCES
1. Pavlov, I. P.: The Work of the Digestive Glands. London, Griffin, 1910. 2. Dragstedt, L. R., Woodward, E. R., Stover, E. H., Oberhelman, H. A. Jr., and Smith, C. A.: Quantitative Studies on Mechanism of Gastric Secretion in Health and Disease. Ann. Surg. 132: 626, 1950. 3. Ivy, A. C., Grossman, M. I. and Bachrach, W. H.: Peptic Ulcer. Philadelphia, BIakiston Co., 1950, p. 693. 4. Dragstedt, L. R. and Woodward, E. R.: Appraisal of Vagotomy for Peptic Ulcer After Seven Years. J.A.M.A. 145: 795, 1951. 5. Oberhelman, H. A. Jr., and Dragstedt, L. R.: Effect of Vagotomy on Gastric Secretory Response to Histamine. Proc. Soc. Expel'. BioI. & Med. 67: 336, 1948. 6. Dragstedt, L. R., Oberhelman, H. A. and Smith, C. A.: Experimental Hyperfunction of Gastric Antrum with Ulcer Formation. Ann. Surg. 134: 332, 1951. 7. Gray, S. J., Benson, J. A., Reifenstein, R. W. and Spiro, H. M.: Chronic Stress and Peptic Ulcer. J.A.M.A. 147: 1529, 1951. 8. Dragstedt, L. R., Ragins, H., Dragstedt, L. R. and Evans, S. 0.: Stress and Duodenal Ulcer. Ann. Surg. 144: 450, 1956. 9. Hirschowitz, B. I., Streeten, D. H. P., Pollard, H. M. and Boldt, H. A.: Role of Gastric Secretions in Activation of Peptic Ulcers by Corticoptropin (ACTH). J.A.M.A. 158: 27, 1955. 10. Zollinger, R. M. and Ellison, E. H.: Primary Peptic Ulcerations of Jejunum Associated with Islet Cell Tumors of Pancreas. Ann. Surg. 142: 709, 1955. 11. Ellison, E. H.: Ulcerogenic Tumor of Pancreas. Surgery 40: 147, 1956. 12. Keefer, E. B. C., Martin, K. A. and Glenn, F.: A New Method of Producing Duodenal and Gastric Ulcers in Dogs. Surgical Forum. Philadelphia, W. B. Saunders Co., IV, 330, 1953. 13. Keefer, E. B. C., Hays, D. M., Martin, K. A., Beal, J. M. and Glenn, F.: Further Studies of Experimental Gastric and Duodenal Ulcers in Dogs. Surgical Forum. Philadelphia, W. B. Saunders Co., V, 288, 1954. 14. Illingworth, C. F. W. Peptic Ulcer. Baltimore, Williams & Wilkins Co., 1953. 15. Hollander, F.: Gastric Hypersecretion Following Parturition in Dogs. Proc. Soc. Exper. BioI. & Med. 27: 303, 1930. 16. McCarthy, J. D., Evans, S. O. and Dragstedt, L. R.: Gastric Secretion in Dogs During Pregnancy and Lactation. Gastroenterology 27: 275 (Sept.) 1954. 525 East 68th Street New York 21, N. Y.
THE precise etiology of peptic ulcer remains obscure although the number of experimental and clinical studies which are concerned with this problem increase yearly. Peptic ulceration occurs only in those areas of the gastrointestinal tract that are exposed to acid juice which is produced by the gastric mucosa. It is not surprising that the great majority of studies have been concerned with the factors that alter the production of gastric secretion, principally the acidity and volume of secretion. The direction of study has been partly influenced by the ease with which volume and acid may be measured in contrast to other possible factors. Thus, despite the considerable increase in knowledge of gastric physiology and in the pathogenesis of peptic ulceration, the cause has not been clarified. This suggests that some of the factors other than acid production should be studied more extensively, particularly those which relate to mucosal resistance. It is the purpose of the present paper to discuss some of the factors in the production of peptic ulceration that seem to be pertinent to the surgical treatment. The complex nature of the disease and the voluminous literature make it impossible to include many studies that may seem equally important to the reader. NERVOUS FACTORS
Pavlov demonstrated nearly five decades ago in dogs that sham feeding produced a stimulation and production of gastric juice and that this response was abolished by the division of the vagus nerves. Thestimulation of gastric secretion by the sight, smell, taste or thought of food l
From the Departments of Surgery and Medicine, New York Hospital-Cornell Medical Center, New York, N. Y. This research was aided by grants from the Dr. William Malcolm Fund. * Associate Professor of Clinical Surgery, Cornell University Medical College; Attending Surgeon, The New York Hospital. ** Assistant Professor of Clinical Medicine, Cornell Um·ver6ity Medical College; Assistant Attending Physician, The New York Hospital. 385
388
John M. Beal, Kirby A. Martin
constitutes the cephalic phase of gastric secretion. The secretion which is thus produced is rich in acid, pepsin and mucus. There is a latent period of five to ten minutes after stimulation has occurred and the secretion persists for 30 minutes or longer after stimulation has ceased, although there appears to be considerable variation in the duration of secretion. The cephalic phase is mediated entirely through efferent impulses which are carried by the vagus nerves. Dragsted2 has calculated from animal experiments that the nervous phase is responsible for approximately 45 per cent of the total acid production of the stomach. Gastric juice is secreted at a constant acidity, a view held by Pavlov and confirmed in recent years. Variation in acidity depends upon a variety of neutralizing factors, such as mucus, regurgitated duodenal fluid, food, and saliva, and upon the volume of the secretion. The nervous phase of gastric secretion may be stimulated by hypoglycemia which follows the injection of insulin. In the presence of intaet vagus nerves, the rapid fall of the blood sugar to levels below 50 mg. per 100 ml., sufficient to produce hypoglycemic symptoms, is followed by a significant stimulation of gastric secretion which is rich in pepsin and hydrochloric acid. Complete division of the vagus nerves prevents the gastric secretory response. In the fasting unstimulated state, the stomach continues to secrete gastric juice, at a rate that has been estimated to range from about 30 to 60 cc. per hour. It has been found that patients with duodenal ulcers produce a greater volume of gastric juice which is highly acid than do normal subjects when the stomach is carefully aspirated throughout the night. I vy3 has found that, regardless of the stimulus, the volume and acidity of gastric juice tends to be higher in patients with duodenal ulcers than in normal persons. However, he has also pointed out that the overlap is sufficiently great to indicate that the difference in acid secretion alone cannot account for the presence of an ulcer. Dragstedt has presented extensive evidence that the hypersecretion of gastric juice, both in the fasting state and in response to the ingestion of food, in duodenal ulcer patients is of nervous origin. Complete division of the vagus nerves in man has been found to eliminate this hypersecretion.' It would also appear that complete division of the vagus nerve also significantly diminishes the gastric phase of secretion, as determined by response. to histamine. 5 GASTRIC PHASE
The gastric phase has been estimated by Dragstedt to contribute approximately 45 per cent of the total acid output. 2 Two types of stimuli act directly upon the stomach to produce stimulation of secretion. These are mechanical distention and certain secretagogues. It has been found that the antrum mediates the gastric phase of secretion. Certain foodstuffs, such as lean meat, will stimulate secretion, while a sufficiently low
Nervous and Hormonal Influences in Peptic Ulcer
387
pH will inhibit the antral or gastric phase of secretion. Alcohol appears to stimulate gastric secretion by direct action upon the gastric antrum. The antrum stimulates gastric secretion through a humoral mechanism. In dogs with Heidenhain pouches, transplantation of the antrum to the colon resulted in an increased secretion of juice from the pouch. Removal of the transplanted antrum was followed by a diminished output of pouch secretion. 6 These physiological and experimental observations have led Dragstedt to implicate the gastric antrum in the pathogenesis of gastric ulcer. It has been noted that the secretion of acid by patients with gastric ulcers in the fasting state or in collected nocturnal secretion was less than that usually found among normal patients. This correlates well with the observation that the antral mucosa is not stimulated when the stomach is empty in the fasting state. It has also been reported that gastric ulcers have developed after vagotomy without an associated drainage procedure, in the treatment of duodenal ulcer. A gastrojejunostomy which is placed high on the gastric wall may also be followed by the development of gastric ulceration. In both instances, stimulation of the antrum has been demonstrated experimentally. While the clinical and experimental evidence affords indirect support to this concept of the antral hyperfunction in the pathogenesis of gastric ulcer, confirmation by means of secretory studies in patients is lacking. This has certain obvious difficulties. It is also strange that pyloric obstruction due to duodenal ulcer, though often longstanding, is seldom associated with gastric ulceration. STRESS
There have been numerous references to the occurrence of acute peptic ulcers following severe burns, trauma and the administration of steroids. It has long been known that individuals with chronic gastric or duodenal ulcerations or individuals with a previous history of peptic ulcer were subject to exacerbation, usually manifested by bleeding or perforation. This problem has been stimulated by the finding that stress results in an increase in the production of corticotrophin by the anterior pituitary with consequent adrenal stimulation. It has been postulated by Gray and others 7 that the administration of ACTH and cortisone results in a hypersecretion of gastric juice and thereby leads to an exacerbation of the peptic ulcer. The mechanism of the production of ulceration of the stomach and duodenum following stress or the administration of steroids remains obscure. In studies on patients who were burned or who were subjected to operation it has been found that gastric secretion is either not stimulated or is reduced. This is of significance because many of the acute exacerbations of peptic ulceration, usually manifested by bleeding, occur within the first 48 hours after trauma. Dragstedt 8 has been unable to
'* 388
John M. Beal, Kirby A. Martin
demonstrate an increase in gastric secretion by the administration of either ACTH or cortisone. Hirschowitz 9 has studied gastric secretion in stressed individuals and has found a marked reduction of the viscosity and the visible mucus content of the gastric juice. Information is lacking in regard to the direct effect of elevated steroid levels upon the mucosa and the resistance of the mucosa under these circumstances. PANCREATIC TUMORS AND ULCER
Recently Zollinger and Ellison!O have directed attention to the occurrence of fulminating peptic ulceration in association with noninsulinproducing islet cell tumors of the pancreas. The ulceration is rapidly progressive, often of atypical location, and recurrence appears despite apparent adequate medical or surgical therapy. In 24 cases recently reviewed by Ellison,!! 14 of the tumors were single and 10 were multiple. Nineteen of these were malignant. The syndrome is associated with excessive gastric secretion. Ellison has reported the acid determinations in one patient in whom a return of the gastric secretion to normal levels was found following the resection of a noninsulin-producing islet cell pancreatic tumor. It would appear from these findings that a humoral factor was involved in the production of the ulcers. However, the atypical location of some of these ulcers, for example, in the jejunum, in areas which are not apparently exposed to gastric juice, raises the question of the existence of an effect upon some mechanisms other than merely hypersecretion of gastric juice. It would also appear that this lesion is a relatively rare, though serious etiologic factor in peptic ulceration. In a 25 year survey of marginal ulceration at The New York Hospital one verified case of islet cell tumor was found in 205 patients with marginal ulcers and this was interestingly enough in a diabetic. More significant, perhaps, is that the existence of this clinical syndrome attests to the complex nature of peptic ulceration from the standpoint of pathogenesis and suggests that a variety of factors may be responsible. The apparent humoral nature of this entity suggests that further search should be made for other humoral factors other than that arising from antral hyperfunction. RECENT EXPERIMENTAL OBSERVATIONS
A wide variety of experiments has been devised to produce experimental ulcer. Recently a new method has been devised in our laboratory which has resulted in the production of both duodenal and gastric ulcers in dogs and which has certain physiological advantages.!2 An intact segment of the duodenum with common bile duct, pancreas and accompanying blood supply has been interposed in continuity at various levels in the more distal portion of the intestinal tract. This permits anastomosis of a proximal segment of duodenum to the more
Nervous and Hormonal Influences in Peptic Ulcer
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Fig. 79. The daily output of hydrochloric acid, expressed as milliequivalents, has been charted. The duodenal segment was transplanted in continuity to the terminal ileum within 25 cm. of the ileocecal valve 23 days after formation of a Heidenhain pouch. The dog expired from perforation of a duodenal ulcer 70 days later. The experimental production of ulcer was not accompanied by a significant elevation of acid production by the pouch.
distal duodenum. When the isolated duodenal segment is transplanted to a new position within 75 cm. or less of the ileocecal valve or into the colon, peptic ulceration has developed uniformly in the intact duodenum or in the stomach, or in both locations. The ulceration usually occurs six to eight weeks after the experimental operation unless the segment is placed into the colon, in which case ulceration occurs within approximately two weeks. When the segment has been interposed in thes mall intestine proximal to the 75 cm. or more level, duodenal or gastric ulceration has not been found although the nutritional status of the dogs has been comparable and evidence of reflux of the biliary and pancreatic secretions has been absent. More recently Heidenhain pouches have been constructed prior to transplantation of the duodenal segment. This has permitted measurement of the volume and acid production of the pouch. Mter the duodenal segment has been interposed into distal ileum or colon, a significant change in the acid secretion, as measured by pouch drainage, has not occurred (Fig. 79, 80). Supportive parenteral fluid therapy has not influenced the pouch secretion. These findings raise certain important questions. The ulcerations occur in the duodenum and/or the stomach and thus not in:mucosa that is
John M. Beal, Kirby A. Martin
390
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Fig. 80. The acid production by a Heidenhain pouch in a dog has been charted before and after transplantation of the duodenal segment to the proximal colon. Perforation of a duodenal ulcer caused death of the animal 20 days after the operative procedure. Acid production, as measured by pouch secretion, remained low.
unaccustomed to acid peptic juice. The absence of a rise in acid production, as determined by pouch drainage, indicates that hypersecretion is not a factor in the pathogenesis of these ulcers. This suggests that some factor which influences mucosal resistance is involved. This could be either failure to absorb some essential element from the diet in the short intestinal segment, or due to the production of, or the lack of production of some unidentified substance. In our previous reports,12. 13 the essential difference in the two series of dogs (one producing duodenal ulcers and gastric ulcers or both, and the other no ulcers) was the length of the terminal ileum distal to the duodenal insert, draining the bile and pancreatic secretion into the terminal ileum. The acid and pepsin bathed the gastric and duodenal mucosa alike in the two series and were unbuffered by the bile and pancreatic secretion. This simple procedure removes from the experiment the factor of hydrochloric acid, heretofore said to be the principle cause of the ulcers. These ulcers were gastric and duodenal and not marginal on unaccustomed tissue. In the present experiment, further evidence is presented to show that duodenal and gastric ulceration occurs without a significant increase of the hydrochloric acid before or after the ulcer is formed. Some factor other than acid must be responsible for the production of the ulceration. Poor nutrition per se was not an essential factor.
Nervous and Hormonal Influences in Peptic Ulcer
391
COMMENT
It has long since been suspected clinically, and commented on frequently in the literature, that hydrochloric acid alone cannot account for all the factors in peptic ulceration; however, this concept has received scant attention. On the other hand, the acid theory has gained much momentum from the work of the internist and surgeon alike since the turn of the century. The present status of this disease is disturbing because the great improvement in diagnostic and operative procedures combined with nutritional advancements and newer drug therapy has not been accompanied by a significant rise in the rate of prevention or cure. "The history of the medical treatment (in ulcer) is indeed a record of mistaken estimates, of 'treatments' initially believed effective but later proved useless." 14 A concept that merits serious consideration in relation to peptic ulceration is not so much the cause of ulcer formation but rather the reason for failure to heal once it has formed. The normal stomach will withstand injury well and will heal readily under great latitudes of stress. Hollander15 more than 30 years ago showed (and it has been recently confirmed by Dragstedt 16) that hydrochloric acid secretion in dogs was increased tenfold during lactation, normal before and during pregnancy. It has been observed in our laboratory that free gastric acid mounts to the upper limits and remains there following the surgical stripping of the mucosal lining of the dog's stomach. After approximately three weeks the hydrochloric acid titer returns to normal. Biopsies of the stomach have shown the mucosa to regenerate and heal without significant scar in this blast furnace of hydrochloric acid and pepsin. These observations would suggest that the wide fluctuations observed clinically and experimentally in the hydrochloric acid secretion are physiologic and probably will cause no damage to the gastric or duodenal mucosa if it was normal before. We feel that the condition which determines the onset of peptic ulceration in a setting of stress may be quite different from that which prevents its healing. SUMMARY
Some of the physiologic factors known to be involved in the presence of peptic ulcer have been reviewed. Experimental data have been presented which demonstrates that peptic ulceration in the stomach, duodenum or both may be produced without a significant increase in acid secretion. A defective mucosa is thought to be an important cause of the peptic ulceration. This is the second series of experiments in which we have shown that hydrochloric acid is essential for the development of peptic ulceration but may not be the primary cause.
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John M. Beal, Kirby A. Martin REFERENCES
1. Pavlov, I. P.: The Work of the Digestive Glands. London, Griffin, 1910. 2. Dragstedt, L. R., Woodward, E. R., Stover, E. H., Oberhelman, H. A. Jr., and Smith, C. A.: Quantitative Studies on Mechanism of Gastric Secretion in Health and Disease. Ann. Surg. 132: 626, 1950. 3. Ivy, A. C., Grossman, M. I. and Bachrach, W. H.: Peptic Ulcer. Philadelphia, BIakiston Co., 1950, p. 693. 4. Dragstedt, L. R. and Woodward, E. R.: Appraisal of Vagotomy for Peptic Ulcer After Seven Years. J.A.M.A. 145: 795, 1951. 5. Oberhelman, H. A. Jr., and Dragstedt, L. R.: Effect of Vagotomy on Gastric Secretory Response to Histamine. Proc. Soc. Expel'. BioI. & Med. 67: 336, 1948. 6. Dragstedt, L. R., Oberhelman, H. A. and Smith, C. A.: Experimental Hyperfunction of Gastric Antrum with Ulcer Formation. Ann. Surg. 134: 332, 1951. 7. Gray, S. J., Benson, J. A., Reifenstein, R. W. and Spiro, H. M.: Chronic Stress and Peptic Ulcer. J.A.M.A. 147: 1529, 1951. 8. Dragstedt, L. R., Ragins, H., Dragstedt, L. R. and Evans, S. 0.: Stress and Duodenal Ulcer. Ann. Surg. 144: 450, 1956. 9. Hirschowitz, B. I., Streeten, D. H. P., Pollard, H. M. and Boldt, H. A.: Role of Gastric Secretions in Activation of Peptic Ulcers by Corticoptropin (ACTH). J.A.M.A. 158: 27, 1955. 10. Zollinger, R. M. and Ellison, E. H.: Primary Peptic Ulcerations of Jejunum Associated with Islet Cell Tumors of Pancreas. Ann. Surg. 142: 709, 1955. 11. Ellison, E. H.: Ulcerogenic Tumor of Pancreas. Surgery 40: 147, 1956. 12. Keefer, E. B. C., Martin, K. A. and Glenn, F.: A New Method of Producing Duodenal and Gastric Ulcers in Dogs. Surgical Forum. Philadelphia, W. B. Saunders Co., IV, 330, 1953. 13. Keefer, E. B. C., Hays, D. M., Martin, K. A., Beal, J. M. and Glenn, F.: Further Studies of Experimental Gastric and Duodenal Ulcers in Dogs. Surgical Forum. Philadelphia, W. B. Saunders Co., V, 288, 1954. 14. Illingworth, C. F. W. Peptic Ulcer. Baltimore, Williams & Wilkins Co., 1953. 15. Hollander, F.: Gastric Hypersecretion Following Parturition in Dogs. Proc. Soc. Exper. BioI. & Med. 27: 303, 1930. 16. McCarthy, J. D., Evans, S. O. and Dragstedt, L. R.: Gastric Secretion in Dogs During Pregnancy and Lactation. Gastroenterology 27: 275 (Sept.) 1954. 525 East 68th Street New York 21, N. Y.