- Email: [email protected]
Gastric Mucosal Injury by Aspirin
Vol. 51, No. 3 Printed in U.S.A.
GASTROENTEROLOGY
Copyright © 1966 by The Williams & Wilkins Co.
EDITORIALS
GASTRIC MUCOSAL INJURY BY ASPIRIN tinal bleeding is simply the casual attitude of the public toward aspirin, which is usually not regarded as a drug. The patient presenting with a hemorrhage will therefore not bother to mention a history of recent aspirin intake, and many physicians and house officers will forget to inquire into one. vVhen a relationship between gastrointestinal hemorrhage and aspirin intake is investigated carefully and when proper controls are established, a cause-to-effect relationship between aspirin and bleeding can be demonstrated in 1 out of 7 cases. 1 In addition to this type of modern clinical investigation, the world literature is rife with individual case reports of patients with "obscure" and long-standing iron deficiency anemias cured only upon recognition and correction of a habitual ingestion of aspirin. Parenthetically, this habit of regular aspirin consumption is far more widespread than we usually realize. The mild sedative action of the drug makes it an excellent sleeping medication devoid of the aftereffects of barbiturates and unfettered by prescription requirements, so that it is easy to fall into the habit of taking it every night. The practical implication of this should be the careful inquiry into a possible history of aspirin ingestion in any patient presenting with gastrointestinal hemorrhage or an iron deficiency anemia. It is well known that patients with peptic ulcer disease are particularly intolerant to aspirin and are more liable to develop gastrointestinal bleeding as a consequence of aspirin ingestion. The pathological basis for the bleeding manifestations of aspirin-related bleeding in patients with a previously existing peptic ulcer apto be due more often to a superimpears Address requests for reprints to: Dr. Rene 1 M enguy, Department of Surgery, University of posed gastritis than to the chronic ulcer. It Chicago, 950 E. 59th Street, Chicago, Illinois is apparent that hemorrhage is not the only 60637. manifestation of gastric injury by aspirin.
Although the manufacturers of aspirin go to extreme lengths to point out in television commercials that the "other brands" of aspirin may play havoc with the lining of the stomach, the role of this drug in the etiology of gastric disease has drawn little attention from the medical profession. This is surprising since gastric "irritation" was foremost among the side effects of salicylic acid noted following the first account of the treatment of rheumatic fever by salicylic acid in 1876. The gastric distress caused by this drug was almost intolerable, and its sodium salt, sodium salicylate, was soon adopted. This compound has, however, an extremely unpleasant taste in addition to significant gastric side effects, and was later abandoned for the acetyl derivative of salicylic acid, aspirin, the trade name given to the compound by the parent firm of Bayer. When aspirin was substituted for sodium salicylate the incidence of dyspeptic side effects was substanti ally reduced. However, the widespread adoption of aspirin as a household remedy led to the recognition among the lay public of the occasional gastric side effects of this panacea. By contrast with the widespread lay awareness of the relationship between aspirin ingestion and digestive symptoms, the scientific definition of the problem as a distinct entity has lagged. It has been, first of all, difficult to gather the evidence showing that, in fact, aspirin ingestion does injure the stomach. The next question, and one which still remains unanswered, concerns the mechanism of such an action. The reason for the difficulty in proving a cause-to-effect relationship between aspirin ingestion and gastrointes-
430
SeptembeT 1966
EDITORIALS
Recent studies implicate aspmn in more than one-half of a large series of patients with chronic gastric ulcer. 2 Having satisfied ourselves that aspirin ingestion does lead to gastric injury, we must now ask the obvious question: What is the mechanism of this action? Specifically, does aspirin injure the gastric mucosa by a local, "irritating" necrotizing effect of undissolved aspirin particles on the gastric mucosa or is the injury produced by some systemic action of circulating salicylate on the gastric mucosal cells? Here \Ve stumble into a long-standing controversy. Obviously, if the former view were correct, one could prevent the gastric side effects of aspirin by various pharmaceutical manipulations; buffered aspmn tablets, more soluble preparations of aspirin, "enteric-coating" of tablets. It has ahYays seemed to us that the buffering of aspirin tablets is a particularly naive approach to the problem, in view of the weak acidity of aspirin. However, the most damning argument against the theory of a local action of aspirin is the conclusion derived from the experiments reported by several workers: gastric mucosal injury by aspirin does not require contact of .the compound with the gastric mucosa. 3 - 6 In light of this evidence, one can conclude iYith Grossman et al. 4 that " .. . there is at present no route of administration or dosage form of salicylates of proven safety in these patients." In other words, the aspirin problem does not hold a future for pillrolling. The next step in our inquiry is to determine why circulating salicylate injures the gastric mucosa. Does it do so by raising gastric secretion? Probably not. A number of investigators have studied the action of aspirin on gastric secretion of human subjects and of animals and the consensus of these reports is that aspirin either has no effect on gastric secretion, or, if anything, lowers gastric secretory activity. 6 • 7 In unpublished experiments, we found that the oral administration of aspirin to dogs with Heidenhain pouches appreciably diminished acid secretion from the pouches. Since aspirin does not appear to increase the ulcer-abetting
431
agency of HCl secretion, the next logical step would be to find out whether aspirin might injure the gastric mucosa by interfering with one of the mechanisms responsible for protecting the gastroduodenal mucosa against the action of its own secretions. Of these, the most important, or at least the best known, is the "mucous barrier." The mucous barrier is a thin layer of mucus adherent to the underlying epithelium and continuously renewed by. the secretions from the underlying mucous cells as the superficial coats of the mucous layer are wiped off by peristalsis and intraluminal contents. The glycoprotein nature of mucus renders it relatively re·. sistant to the action of proteolytic enzymes and thereby enhances its protective action. In experiments conducted on both dogs and rats, we found that aspirin, administered so that the compound did not enter into contact with the gastric mucosa, profoundly decreased the rate of mucous secretion and also altered the composition of mucus in such a way as to render it theoretically less efficient as a protective barrier. 8 The effects of :aspirin on mucous secretion were strikingly similar to those that we had previously observed with cortisone. 9 We have postulated that the mechanism of gastric mucosal injury by aspirin is an aspirin-induced impairment of the ability of the gastric mucosa to form this protective layer of mucus. This would render the superficial mucosal cells more liable to damage by intraluminal contents. In turn, the loss of this "barrier" could explain the increased back-diffusion of H+ that DavenporV 0 has observed after gastric• mucosal injury by acetylsalicylic acid applied locally. This may represent the mechanism of the lowered acid secretion produced by aspirin. One must keep in mind, of course, the fact that the decrease in mucus may not be the actual causative factor of gastric mucosal injury, but an important symptom of the causative factor. The production of mucus can be considered as a metabolic product of the superficial mucus-secreting cells. A decreased output of mucus, as well as an alteration in the quality of the mucus secreted, would indicate an impairment of cellular
EDITORIALS
432
metabolism. It is entirely possible then that the altered mucous production represents simply the result of aspirin-induced cellular injury which, in turn, might render the cells more friable, with ensuing appearance of superficial erosions. But whatever its intimate mechanism may be, gastric injury by aspirin is a morbid entity with a great future; the consumption of aspirin in the United States alone has increased from 10 million to 20 million pounds per annum during the last 10 years. Rene Menguy, M.D., Ph.D. Department of Surgery University of Chicago Chicago, Illinois REFERENCES 1. Muir, A., and I. A. Cassar. 1955. Aspirin and ulcer. Brit. M ed. J. 2 : 7-12. 2. D ouglas, R. A., and E. D. Johnston. 1961.
Aspirin and chronic gastric ulcer. M ed. J. Aust. 2: 893-897. 3. Barbour, H. G., and V. C. Dickerson. 1938.
Yol. 51, No.3
Gastric ulceration produced in rats by oral and subcutaneous aspirin . Arch . Int. Pharmacodyn. 58: 78-87. 4. Grossman, M. I., V. K. Matsumoto, and R. J. Lichter. 1961. Fecal blood loss produced by administration of various salicylates. Gastro enterology 40: 383~388 . 5. Dodd, K., A. S. M inot, and J. M . Arena. 193i. Salicylate poisoning; an explanation of the more serious manifestations. Amer. J. Dis. Child. 53: 1435-1446. 6. Lynch, A.; H. Shaw, and G . IV. Milton . 1964. Effect of aspirin on gastric secretion. Gut 5: 230-236 .
7. Winkelman, E. I., and W. H. J . Summerskill. 1961. Gastric secretion in relation to gastrointestinal bleeding from salicylate compounds. Gastroenterology 40 : 56-63. 8. Menguy, R., and Y. F . Masters. 1965. Effects of aspirin on gastric mucous secretion. Surg. Gynec. Obstet. 120 : 92"-98. 9. Menguy, R., and Y. F. Masters. 1963. Effect of cortisone on mucoprotein secretion by gastric antrum of dogs; pathogenesis of steroid ulcer. Surgery 54: 19-28. 10. D avenport, H. IV. 1964. Gastric mucosal injury by fatty and acetylsalicylic acids. Gastroenterology 46 : 245-253.
GASTROENTEROLOGY
Copyright © 1966 by The Williams & Wilkins Co.
EDITORIALS
GASTRIC MUCOSAL INJURY BY ASPIRIN tinal bleeding is simply the casual attitude of the public toward aspirin, which is usually not regarded as a drug. The patient presenting with a hemorrhage will therefore not bother to mention a history of recent aspirin intake, and many physicians and house officers will forget to inquire into one. vVhen a relationship between gastrointestinal hemorrhage and aspirin intake is investigated carefully and when proper controls are established, a cause-to-effect relationship between aspirin and bleeding can be demonstrated in 1 out of 7 cases. 1 In addition to this type of modern clinical investigation, the world literature is rife with individual case reports of patients with "obscure" and long-standing iron deficiency anemias cured only upon recognition and correction of a habitual ingestion of aspirin. Parenthetically, this habit of regular aspirin consumption is far more widespread than we usually realize. The mild sedative action of the drug makes it an excellent sleeping medication devoid of the aftereffects of barbiturates and unfettered by prescription requirements, so that it is easy to fall into the habit of taking it every night. The practical implication of this should be the careful inquiry into a possible history of aspirin ingestion in any patient presenting with gastrointestinal hemorrhage or an iron deficiency anemia. It is well known that patients with peptic ulcer disease are particularly intolerant to aspirin and are more liable to develop gastrointestinal bleeding as a consequence of aspirin ingestion. The pathological basis for the bleeding manifestations of aspirin-related bleeding in patients with a previously existing peptic ulcer apto be due more often to a superimpears Address requests for reprints to: Dr. Rene 1 M enguy, Department of Surgery, University of posed gastritis than to the chronic ulcer. It Chicago, 950 E. 59th Street, Chicago, Illinois is apparent that hemorrhage is not the only 60637. manifestation of gastric injury by aspirin.
Although the manufacturers of aspirin go to extreme lengths to point out in television commercials that the "other brands" of aspirin may play havoc with the lining of the stomach, the role of this drug in the etiology of gastric disease has drawn little attention from the medical profession. This is surprising since gastric "irritation" was foremost among the side effects of salicylic acid noted following the first account of the treatment of rheumatic fever by salicylic acid in 1876. The gastric distress caused by this drug was almost intolerable, and its sodium salt, sodium salicylate, was soon adopted. This compound has, however, an extremely unpleasant taste in addition to significant gastric side effects, and was later abandoned for the acetyl derivative of salicylic acid, aspirin, the trade name given to the compound by the parent firm of Bayer. When aspirin was substituted for sodium salicylate the incidence of dyspeptic side effects was substanti ally reduced. However, the widespread adoption of aspirin as a household remedy led to the recognition among the lay public of the occasional gastric side effects of this panacea. By contrast with the widespread lay awareness of the relationship between aspirin ingestion and digestive symptoms, the scientific definition of the problem as a distinct entity has lagged. It has been, first of all, difficult to gather the evidence showing that, in fact, aspirin ingestion does injure the stomach. The next question, and one which still remains unanswered, concerns the mechanism of such an action. The reason for the difficulty in proving a cause-to-effect relationship between aspirin ingestion and gastrointes-
430
SeptembeT 1966
EDITORIALS
Recent studies implicate aspmn in more than one-half of a large series of patients with chronic gastric ulcer. 2 Having satisfied ourselves that aspirin ingestion does lead to gastric injury, we must now ask the obvious question: What is the mechanism of this action? Specifically, does aspirin injure the gastric mucosa by a local, "irritating" necrotizing effect of undissolved aspirin particles on the gastric mucosa or is the injury produced by some systemic action of circulating salicylate on the gastric mucosal cells? Here \Ve stumble into a long-standing controversy. Obviously, if the former view were correct, one could prevent the gastric side effects of aspirin by various pharmaceutical manipulations; buffered aspmn tablets, more soluble preparations of aspirin, "enteric-coating" of tablets. It has ahYays seemed to us that the buffering of aspirin tablets is a particularly naive approach to the problem, in view of the weak acidity of aspirin. However, the most damning argument against the theory of a local action of aspirin is the conclusion derived from the experiments reported by several workers: gastric mucosal injury by aspirin does not require contact of .the compound with the gastric mucosa. 3 - 6 In light of this evidence, one can conclude iYith Grossman et al. 4 that " .. . there is at present no route of administration or dosage form of salicylates of proven safety in these patients." In other words, the aspirin problem does not hold a future for pillrolling. The next step in our inquiry is to determine why circulating salicylate injures the gastric mucosa. Does it do so by raising gastric secretion? Probably not. A number of investigators have studied the action of aspirin on gastric secretion of human subjects and of animals and the consensus of these reports is that aspirin either has no effect on gastric secretion, or, if anything, lowers gastric secretory activity. 6 • 7 In unpublished experiments, we found that the oral administration of aspirin to dogs with Heidenhain pouches appreciably diminished acid secretion from the pouches. Since aspirin does not appear to increase the ulcer-abetting
431
agency of HCl secretion, the next logical step would be to find out whether aspirin might injure the gastric mucosa by interfering with one of the mechanisms responsible for protecting the gastroduodenal mucosa against the action of its own secretions. Of these, the most important, or at least the best known, is the "mucous barrier." The mucous barrier is a thin layer of mucus adherent to the underlying epithelium and continuously renewed by. the secretions from the underlying mucous cells as the superficial coats of the mucous layer are wiped off by peristalsis and intraluminal contents. The glycoprotein nature of mucus renders it relatively re·. sistant to the action of proteolytic enzymes and thereby enhances its protective action. In experiments conducted on both dogs and rats, we found that aspirin, administered so that the compound did not enter into contact with the gastric mucosa, profoundly decreased the rate of mucous secretion and also altered the composition of mucus in such a way as to render it theoretically less efficient as a protective barrier. 8 The effects of :aspirin on mucous secretion were strikingly similar to those that we had previously observed with cortisone. 9 We have postulated that the mechanism of gastric mucosal injury by aspirin is an aspirin-induced impairment of the ability of the gastric mucosa to form this protective layer of mucus. This would render the superficial mucosal cells more liable to damage by intraluminal contents. In turn, the loss of this "barrier" could explain the increased back-diffusion of H+ that DavenporV 0 has observed after gastric• mucosal injury by acetylsalicylic acid applied locally. This may represent the mechanism of the lowered acid secretion produced by aspirin. One must keep in mind, of course, the fact that the decrease in mucus may not be the actual causative factor of gastric mucosal injury, but an important symptom of the causative factor. The production of mucus can be considered as a metabolic product of the superficial mucus-secreting cells. A decreased output of mucus, as well as an alteration in the quality of the mucus secreted, would indicate an impairment of cellular
EDITORIALS
432
metabolism. It is entirely possible then that the altered mucous production represents simply the result of aspirin-induced cellular injury which, in turn, might render the cells more friable, with ensuing appearance of superficial erosions. But whatever its intimate mechanism may be, gastric injury by aspirin is a morbid entity with a great future; the consumption of aspirin in the United States alone has increased from 10 million to 20 million pounds per annum during the last 10 years. Rene Menguy, M.D., Ph.D. Department of Surgery University of Chicago Chicago, Illinois REFERENCES 1. Muir, A., and I. A. Cassar. 1955. Aspirin and ulcer. Brit. M ed. J. 2 : 7-12. 2. D ouglas, R. A., and E. D. Johnston. 1961.
Aspirin and chronic gastric ulcer. M ed. J. Aust. 2: 893-897. 3. Barbour, H. G., and V. C. Dickerson. 1938.
Yol. 51, No.3
Gastric ulceration produced in rats by oral and subcutaneous aspirin . Arch . Int. Pharmacodyn. 58: 78-87. 4. Grossman, M. I., V. K. Matsumoto, and R. J. Lichter. 1961. Fecal blood loss produced by administration of various salicylates. Gastro enterology 40: 383~388 . 5. Dodd, K., A. S. M inot, and J. M . Arena. 193i. Salicylate poisoning; an explanation of the more serious manifestations. Amer. J. Dis. Child. 53: 1435-1446. 6. Lynch, A.; H. Shaw, and G . IV. Milton . 1964. Effect of aspirin on gastric secretion. Gut 5: 230-236 .
7. Winkelman, E. I., and W. H. J . Summerskill. 1961. Gastric secretion in relation to gastrointestinal bleeding from salicylate compounds. Gastroenterology 40 : 56-63. 8. Menguy, R., and Y. F . Masters. 1965. Effects of aspirin on gastric mucous secretion. Surg. Gynec. Obstet. 120 : 92"-98. 9. Menguy, R., and Y. F. Masters. 1963. Effect of cortisone on mucoprotein secretion by gastric antrum of dogs; pathogenesis of steroid ulcer. Surgery 54: 19-28. 10. D avenport, H. IV. 1964. Gastric mucosal injury by fatty and acetylsalicylic acids. Gastroenterology 46 : 245-253.