Peptic Ulcer Disease
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The Course of Peptic Ulcer Disease Julian Katz, MD*
Peptic ulcer disease is a disorder typified by periodic exacerbations and remissions. Although pain usually accompanies the presence of ulceration of the mucosa, peptic ulcers can be present without disturbing and appreciably discernible symptoms. In fact, one might question whether the presence of an ulcer crater without appreciable discomfort and that does not interfere with activities can be considered a disease entity. Patients may have complications of an ulcer, such as bleeding and perforation, without notable preceding symptoms. Clinical trials of antiulcer mediation have utilized serial endoscopic examination to determine the healing of the ulcer crater. 11, 29 These more precise diagnostic examinations have shown that the relief of pain occurs more frequently and earlier than healing of the ulcerated mucosa. The disappearance of symptoms then does not necessarily indicate the actual total healing, the re-epithelization of the ulcer crater. A high frequency of recurrence is present after the healing of an ulcer. 3 Within 1 year, a large number of patients with healed peptic ulcer disease who have not been on any regular antiulcer therapy can be expected to have a recurrence of their ulcer, sometimes without symptoms. 47 This is more often the case with duodenal ulcer than with gastric ulcer, and the natural history of the peptic ulceration associated with gastroesophageal reflux is different.
INCIDENCE Peptic ulcer disease of the stomach and duodenum was considered an uncommon disorder in the 19th century. The disease became more evident during the early 20th century. In the 1940s, at least 10% to 15% of men were said to have a duodenal ulcer. Obviously, precise diagnostic techniques were not available at that time. However, it does seem that people born in the latcr part of the 19th century or in the early 20th century seem to have had a propensity for developing peptic ulcers of the duodenum. The *Clinical Professor of Medicine. Medical College of Pennsylvania; and Adjunct Clinical Professor of Ivledicine, Jefferson Medical College, Philadelphia, Pennsylvania
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decline in incidence of duodenal ulcers may be due to the dying and aging of this group. Perhaps people who were born at the turn of the century were exposed to environmental factors that put them at risk of developing peptic ulcer disease throughout their lives. Although changes in coding of diagnosis, hospitalization practices for ulcer disease, and the greater a';ailability of diagnostic modalities may contribute to the apparent decline in the incidence, most careful observers believe that there has been a definite decline in duodenal ulcer disease. 6 24. 60 The changes in incidence in gastric ulcer disease are influenced by the aging of the population and by the use of ulcerogenic medications. Even before the advent of H2-blocker therapy, when only antacids and diets of questionable scientific merit were available, the occurrence of ulcer complications declined, less operations were performed, and the mortality rate decreased. 6 It is ironic that with the availability of newer, more effective medical therapy, there has been a change in incidence of acid-related disease. 54 The predominance of duodenal ulcer over gastric ulcer in most Western countries has been changing. 60 Geographic studies would indicate that the duodenal ulcer to gastric ulcer ratio is probably influenced more by environmental than ethnic factors. Although gastric ulcer is more common in women and the elderly, recent trends are altering these clinical observations. 6, 24. 2.5. 50 Prepyloric and duodenal ulcer disease probably have similar pathophysiologic mechanisms and can be lumped together, in contrast to ulcers of the proximal gastric body, the acid-secreting portion of the stomach. The acid-secreting mucosa may be thought to be especially resistant to ulceration, but patients with gastric ulcers seem to have a decrease in gastric acid secretion and diminished defensive mechanisms. 12. lb In spite of the changes in occurrence, peptic ulcer is one of the most prevalent gastrointestinal disorders and still is a common, chronic, and recurrent disease. The occurrence of a peptic ulcer actually produces little change in life expectancy. Bleeding, perforation, and obstruction are the major complications and ulcer-related deaths are the result of these complications, often in association with emergency surgery. Less than 2% of ulcer patients under therapy are expected to have a complication during a I-year period. Obviously, the death rate increases sharply with age and with associated severe medical conditions. Even today, gastric ulc~r hospitalization rates have remained steady, but this is because gastric ulcers occur in older patients who are more prone to have complications, associated medical problems, and possible malignant causes for ulceration. As well as a change in the incidence of ulcer disease,60 there has been a perceived change in the type of patient who gets an ulcer. The notion of peptic ulcer being a disease of hard driving, white, middle-aged, middleclass men has been replaced by the fact that peptic ulcer is an equal opportunity offender. Women are achieving comparable rates of affliction, and race, economic status, and psychologic stress are not really evident factors in the acquisition of an ulcer. Although gastric ulcer is recognized as a disease of older people, particularly women, there is now a seeming increase in the age of duodenal ulcer patients. It was assumed that th~ decline in gastric acid secretion associated with the aging process would make duodenal ulcer an infrequent problem in the elderly. The develop-
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ment and use of anti-inflammatory agents certainly contributes to the increase in ulcer disease~H; it is notable that any drug useful for arthritis or other inflammatory process invariably puts the patient at risk for developing gastrointestinal mucosal ulceration. Nevertheless, there seems to be a bimodal incidence of duodenal ulcer that cannot be explained merely by the use of ulcerogenic mediation. Perhaps infection with Helicohacter pylori is altering the incidence of duodenal ulcer disease. The acquisition of H. pylori infection is associated with getting older and is firmly associated with peptic ulcer disease. 1:1 Nevertheless, only a small portion of people with H. pylori infection develop a peptic ulcer. Ulcer disease probably involves heterogeneous mechanisms. 4J H. pylori infection of the gastric mucosa in most situations is necessary for the occurrence of duodenal ulcer disease; probably infection involves scattered gastric cellular nests in the duodenal mucosa. Yet some patients with gastric hypersecretion due to Zollinger-Ellison syndrome do not harbor the organism. In gastric ulcers, H. pylori is always present unless nonsteroidal antiinflammatory agents are implicated as the causative factor. Interestingly, in pernicious anemia in which autoimmune gastritis is thought to be involved, H. pylori is frequently absent. lO Thus, a genetic predisposition, environmental factors, and infection alter the processes of mucosal destruction and repair so that peptic ulcer occurs. 28, 47 There certainly are familial and genetic factors involved in ulcer disease. 15 Duodenal ulcer seems to be two to three times more prevalent in relatives of patients with ulcers. Family studies, twin studies, and genetic marker investigations support the role of genetic factors in peptic ulcer disease. Less frequent are the genetically determined syndromes with multiple endocrine abnormalities. The multiple endocrine neoplasia syndrome 61 consists of tumors or hyperplasia of the parathyroid glands, pituitary, adrenal cortex, pancreatic islets,46 and thyroid, along with peptic ulcer disease and usually an increase in gastric acid secretion. The in-born predisposition to ulcer disease may include an increase in parietal cell mass 27 with higher levels of acid secretion, as well as alterations in the composition of the mucus overlying the mucosa, changes in bicarbonate l6 and prostaglandin protective mechanisms, and other unknown factors. Emotions, stress, and cultural and social factors are surely involved in the course of peptic ulcer disease. 7 To call a disease psychosomatic is merely to pose the problem and in no way answers the question of etiology. Central nervous system mechanisms are involved in the secretion of gastric acid and in altering mucosal protection. When Beaumont in the early 19th century looked through a fistula into the stomach of Alexis St. Martin, he noted that there were changes associated with emotional turmoil and situational stress. Some observers have shown that patients with ulcers do not have different reactions to life stresses than people without ulcers.8 Supposedly, occupations considered stressful and hectic are associated with a greater tendency for ulcer disease. Still, no definite association between stress, occupation, and incidence of peptic ulcer disease has been established by the numerous studies that have been done. The mind does influence gastrointestinal functions, perhaps through neurohumoral pathways, but it has not been fully established that this relationship is important
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in the causation of peptic ulcer. Nevertheless, a tried and tested way of producing an experimental ulcer is the restraint model, in which the laboratory animal is tied down without any apparent opportunity for altering the situation: this animal develops an ulcer. There are differences in the types and prevalence of ulcers in different countries. This may involve cultural as well as environmental factors, such as diet and H. pylori infection rates. Certainly, there are differing therapeutic responses to placebo in the treatment of ulcer disease in different countries and among different ethnic groups. Information is incomplete regarding the association between peptic ulcer disease and other diseases. 30, 32 Traditionally, there has been thought to be a relationship between chronic lung disease, chronic renal failure, and cirrhosis. These diseases often involve the use of cigarettes, analgesics, and alcohol. 38 Patients with rheumatoid arthritis·57 probably have a propensity for ulcer disease, particularly gastric ulcer, that is independent of the use of anti-inflammatory agents. Polycythemia, Cushing's disease, and hyperparathyroidism probably increase the occurrence of peptic ulcer disease, and uncommon disorders such as systemic mastocytosis and the ulcer-tremor-nystagmus syndrome are associated with ulcers. 15 Some studies attempt to implicate cigarette smoking as an etiologic factor in peptic ulcer disease ..5, 23, 26 The effect is claimed to be dose dependent. The smoking of cigarettes inhibits the synthesis of prostaglandins, reduces mucosal blood flow, and inhibits pancreatic bicarbonate secretion. Also, acid secretion following stimulation by a gastrin analogue is greater in smokers than in nonsmokers, and nicotine in laboratory animals increases the parietal cell mass. Cigarette smoking adversely affects duodenal ulcer healing; yet stopping cigarette smoking does not particularly have a favorable influence on the long-term course of ulcer disease. The role of dietary factors in p~ptic ulcer disease is a controversial one. 45 Physicians, in the past, have certainly been guilty of various dietary horrors, from the forcing of patients to eat zwieback toast and baby foods to the prescription of diets associated with promotion of atherosclerosis by emphasizing whole milk and cream. Although alcohol can cause gastric mucosal damage, the prohibition of alcohol use does not have a completely documented beneficial basis. Caffeine may increase gastric acid secretion, yet it may be that oils and other components of coffee have greater effects on upper gastrointestinal tract function. Patients with ulcers should probably moderate their use of alcohol and caffeine,38 but the firm evidence to indicate that heavy users of coffee and alcohol are prone to get a peptic ulcer is not really available. A diet rich in fiber, which seems to be good for just about everything, is thought by some to be helpful in preventing peptic ulcer disease. Dietary factors may be more important in gastroesophageal reflux disease. Peptic esophagitis may be influenced by various foods that irritate the esophageal mucosa, decrease the lower esophageal sphincter strength, and retard gastric emptying. 4 . 40 People who use anti-inflammatory drugs are more likely to have problems with peptic ulcer disease. Anti-inflammatory agents are a frequent cause of gastric and duodenal mucosal injury.48 Aspirin has been shown to damage the gastric surface mucosal cells, and anti-inflammatory agents
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impair defensc mechanisms by decreasing mucosal bicarbonate secretion, changing prostaglandin output, and altering other physiologic and anatomic factors. IJ Some of the changes in the incidence and clinical presentation of ulcer disease may be due to the increased use of these agents. However, anti-inflammatory drugs are used quite frequently, and ulcer disease is really not that common a problem in patients who utilize these medications. Aspirin appears to increase duodenal ulcer bleeding, and the use of nonsteroidal anti-inflammatory agents has been incriminated in the complications and alterations of ulcer disease. The association of adrenocorticosteroid therapy and peptic ulcer is controversia!,"'2 but high-dose adrenocorticosteroids are probably causative in some ulcerations of the mucosa of the upper gastrointestinal tract. SYMPTOMS AND COMPLICATIONS Peptic ulcer causes pain, and complications include bleeding, perforation, and obstruction. The pain of peptic ulcer involving the stomach and duodenum is frequently described as annoying, gnawing, burning, aching discomfort usually present in the epigastrium. Duodenal ulcer pain is usually relieved by reduction or neutralization of acid and typically is provoked by fasting and relieved by eating. This pattern is often less consistent in gastric ulcers, and the pain of prepyloric or channel ulcer usually becomes more evident with eating and is occasionally associated with nausea. Gastroesophageal reflux pain typically consists of pyrosis or heartburn and occasionally may be manifest only as nausea upon awakening; the postural effects of sleeping may be the cause of irritation and subsequent nausea. The manifestations of esophageal pain are sometimes unusual; distention of the esophagus in various sites provokes differing locations of discomfort. 20 With all our knowledge of peptic ulcer disease, the cause of ulcer pain is not totally understood. \Vhen the endoscopist cuts, burns, or rubs the gut mucosa, no pain is elicited. When the endoscopist infuses hydrochloric acid over an active symptomatic duodenal ulcer, ulcer pain is elicited in about 40% of the subjects. 12 Acid, therefore, has a definite role in the pathogenesis of the pain, but what about the majority of the patients? Palmer in 1926 suggested a much closer relationship between ulcer, acid, and pain, hut the attractive concept of ulcer pain being due to the irritating effect of acid on the exposed nerve endings in an ulcer crater,6 was not accepted by all. 44 Altered motility with changes in intraluminal pressure can give gut pain, and there may be factors that cause ulcer pain by affecting gastroenteric motility. Duodenal pH varies and it may be that the concentration of acid at the ulcer site is related to the pain. Antacids and placebo can produce similar pain relief in duodenal ulcer patients, 56 but again this may merely indicate that placebo is a good drug. The tenderness elicited by palpation in the upper abdomen of the patient with an active ulcer cannot be readily explained by motility disturbances or acid bathing exposed nerve endings. Serosal irritation and peritoneal inflammation have been mentioned as possible factors. The disassociation of symptoms and the presence of active
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peptic ulcer seem to be more common in the elderly and particularly in patients who take nonsteroidal anti-inflammatory agents. Patients with asymptomatic ulcers receiving treatment with nonsteroidal anti-inflammatory agents are at much greater risk from hemorrhage, perforation, and other significant complications. 1.48 Careful history taking reveals that the diagnosis of ulcer disease by symptoms alone is not foolproof. Moynihan claimed that most patients with upper gastrointestinal symptoms could be correctly diagnosed solely on the basis of their symptoms. 34 More precise diagnostic techniques have been developed over the past 85 years, and unfortunately we find that well over half of our patients with dyspeptic symptoms cannot be diagnosed by eliciting a typical pattern. 17 The ingestion of food may have only a modest effect on reducing the pain of duodenal ulcer disease in many patients and actually can have little positive and some negative effects on the pain of gastric ulcer. Nocturnal pain correlated best with duodenal ulcer in some studies, but night pain may be part of a more ominous disease process, such as pancreatic cancer. The pain of ulcer disease may not be too disrupting in most ulcer patients who suffer the discomfort of "hunger pangs" or the like for 2 years or so before consulting a physician. 53 The flare-up of ulcer symptoms in the spring and fall has been noted but not completely confirmed. In older people with peptic ulcer disease the symptoms are often variable and vague. Actually, almost one-third of older patients may have not noticed symptoms indicative of ulcer disease. As a matter of fact, most of these patients present first with a significant complication and the prior use of an anti-inflammatory agent is frequently present. 1 Dyspepsia is a term used to describe a symptom complex of epigastric discomfort and fullness, vague nausea, postprandial distention often relieved by eructation, and similar annoying symptoms. There are many causes for this problem other than ulcer disease. 35 Endoscopic evaluation of the upper gastrointestinal tract is the most precise way of making the diagnosis of peptic ulcer disease. A full evaluation, including laboratory studies and diagnostic procedures, is carried out before the diagnosis of functional dyspepsia is made. In appropriate patients, a therapeutic trial with a program directed against peptic ulcer disease is often a first approach. Nonulcer dyspepsia has been studied and H. pylori is probably not the etiologic agent responsible for the problem in most patients. Abnormalities in motility of the stomach and intestine have been sought in patients with functional dyspepsia,42 which is defined as unexplained nausea and abdominal distress. Manometric abnormalities have been found in many of these patients, but the pathogenesis of these alterations in motor function is unknown. Although dyspepsia of unknown cause has been thought to be a stress-related disorder, 58 no obvious association can be well demonstrated. Ulcer disease can occur without symptoms. 21. 39 Endoscopic studies of patients without symptoms and without a history of ulcerogenic drug intake or prior symptomatic ulcer disease have shown an exceedingly low incidence of ulcers. Most asymptomatic duodenal and gastric ulcers occur in patients who have been receiving nonsteroidal anti-inflammatory agents; endoscopic surveys of such patients show that many of these patients have a peptic
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ulcer without symptoms. Asymptomatic ulcers also develop in patients with cstablishcd, but healed, ulcer disease during maintenance therapy with antiulcer therapy, aftcr gastric surgery, and during periods without therapy.'~ If patients are not receiving therapy, they often become symptomatic. However, patients receiving maintenance therapy often do not develop symptoms and complications are rare. The complications of peptic ulcer disease are hemorrhage and, less often, pcrforation and obstruction. [5 The incidence of hemorrhage is not necessarily related to the duration of the ulcer disease, but pati~nts who bleed once have a tendency to manifest hemorrhage again. Complications occur morc commonly in gastric than in duodenal ulcers. Pyloric channel ulcer is associated with a more severe course. Perforation of the peptic ulcer may occur into the abdominal cavity or an adjacent solid organ or may result in a fistula. Acute perforation can be treated medically, but the conventional therapy is surgical. Penetration usually occurs in patients with long duration of peptic ulcer disease. Posterior penetration of a duodenal ulcer into the pancreatic bed results in an alteration of symptoms and may be considered a cause of intractable ulcer disease. Most cases of gastric outlet obstruction are due to benign peptic ulcer disease of the duod~num, pyloric channel, or prepyloric area. [9 Nevertheless, there is concern about the possibility of malignancy, and careful evaluation is in order. The reversible aspects of obstruction can be treated medically, but irreversible cicatrization may require endoscopic balloon dilation or surgical intervention. Currently, there is no firm evidence that the incidence of complications is altered by medical therapy, but it is reasonable to assume that the new medical therapies and the reduction of recurrences will alter the occurrence of complications. Most duodenal ulcers recur if treatment is withdrawn. 47, 55 Even after a year of maintenance therapy, almost half the duodenal ulcers recur and 30% of them occur with symptoms. 5 [ When endoscopic studies are performed every 6 months, 70% to 90% of the patients not treated with medication have eventual recurrence of their ulcers. The healing of duodenal ulcers is retarded by the use of alcohol, the diameter of the ulcer, a history of bleeding, and the presence of prior complications. 49 Interestingly, in one study, smoking, coffee intake, and age did not significantly affect the healing rate. The use of anti-inflammatory drugs and aspirin before the development of an ulcer seem to be factors other than intrinsic considerations that influence the causation of the ulcer and therefore are associated with improved odds of healing. Thus, the dictum "once an ulcer, always an ulcer" is tempered by the presence of reversible precipitating factors. 49, 5.'5 A reduction in the recurrence of ulcers may be possible by the eradication of H. pylori by com bination of treatments; this is an exciting and provocative approach to the problem of the frequent recurrence of ulcer disease. Patients with duodenal ulcers should be treated and when symptoms have abated, no further investigation is needed. However, the patient with a gastric ulcer should be totally assured that the ulcer is benign. If an ulcer does not heal, there is little evidence that changing to another H 2 -antagonist or adding an antimuscarinic agent2 is helpful. Total acid suppression with omepraz~le is indicated for the refractory ulcer;59 whereas maintenance
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therapy with H 2 -blockers reduces but does not eliminate recurrence of ulccrs.l, g, ss Just as ulcers recur spontaneously and without apparent precipitating events, most ulcers heal without treatment. 49, SI After 2 weeks, one-quarter of endoscopically diagnosed ulcers healed without specific therapy; after 4 weeks, two-thirds had disappeared.>l There are probably variations in gastric acid secretion, and the exposure of the ulcerated mucosa to injury changes during the course. In yet to be determined ways, local mucosal defense mechanisms overcome peptic aggressive factors. Newer and exciting approaches are available. The eradication of H. pylori infection in the gastroduodenal mucosa of patients with duodenal ulcer disease substantially reduces the predictable recurrence rate. 41 The role of omeprazole-which inactivates the proton pump of the parietal celJllll.og-in the treatment of ulcer disease is not yet certain. Duodenal and gastric ulcer healing seems to occur more rapidly with omeprazole than with H 2 -blockers. The often poor correlation between the length of symptoms and ulcer healing makes it difficult to determine the appropriate length of therapy. The long-term use of this powerful antiseeretory agent may prevent recurrence, but the safety has not been demonstrated. In any case, all duodenal ulcers, regardless of how they healed, have a tendency to recur at a surprisingly high rate.
SUMMARY Peptic ulcer disease usually has periodic exacerbations and remissions. Pain can disappear without total healing of the ulcer crater and can be absent when an ulcer is present. Changes in the incidence of ulcer disease have been noted in recent years. Genetic predisposition, infection with H. pylori, and the use of anti-inflammatory drugs are involved in causation. Stress; the use of alcohol, tobacco and caffeine; and other diseases have been implicated as etiologic factors. Ulcer pain has a recognizable pattern, but the symptoms can be variable, particularly in older people and in patients taking ulcerogenic medications. The familiar complications of hemorrhage, perforation, and obstruction still occur, and non ulcer dyspepsia has not been fully explained. Duodenal ulcers have a disturbing tendency to return; new therapeutic approaches ofle I' hope.
REFERENCES 1. Armstrong Cl', Blower AL: Non-steroidal anti-inflammatory drugs and life-threatening
complications of peptic ulceration. Gut 28:527, 1987 2. Rarhan KD, Thompson M, Bose K, et al: Combined anti-muscarinic and H2 receptor blockade in the healing of refractory duodenal ulcer. A double blind study. Gut 28:1505, 1987 3. Boyd EJ, Penston JG, Johnston DA, et al: Does maintenance therapy keep duodenal ulcers healed? Lancet 1: 1324, 1988 4. Castell DO: The lower esophageal sphincter: Physiologic and clinical aspects. Ann Intern Med S3:390, 1975 5. Doll R, Jones FA, Pygott F: Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet 1:657, 1958
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6. Elashoff J D, Grossman '\II: Trends in hospital admissions and death rates from peptic ulcer in the United States from 1970 to 1978. Gastroenterology 1>4:1558, 1983 7. Ellard K. Beaurepaire J, Jones lVI, et al: Acute and chronic stress in duodenal ulcer disease. Gastroenterology 91:1370, 1986 8. Feldman M, \Valker P, Green JL, et al: Life events, stress, and psychosocial factors in men with peptic ulcer disease. A multidimensional case-controlled study. Gastroenterology 91: 1370, 1986 9. Feldman M, Burton ME: Histamine receptor antagonists: Standard therapy for acidpeptic diseases. 1\ Engl J .\Ied 323:1672, 1990 10. Fong T-L, Dooley CP, Dehesa M, et al: lIelicobacter pylori infections in pernicious anemia: A prospective controlled study. Gastroenterology 100:328, 1991 11. Freston JW: Overview of medical therapy of peptic ulcer disease. Gastroenterol Clin North Am 19(1):121, 1990 12. Graham D, Dyck W, Englert E, et al: Healing of gastric ulcer: Comparison of cimetidine and placebo in the United States. Ann Intern Med 102:573, 198.5 13. Graham DY: Campylobacter pylori and peptic ulcer disease. Gastroenterology 96:615, 1989 14. Graham DY, Smith L: Aspirin and the stomach. Ann Intern Med 104:390, 1986 1.5. Grossman MI (ed): Peptic Ulcer: A Guide for the Practicing Physician. Chicago, Year Book Medical Publishers, 1981 16. Hogan DL, Isenberg JI: Gastroduodenal bicarbonate production. Adv Intern Med 33:385, 1988 17. Horrocks Je, DeDombal FT: Clinical presentation of patients with "dyspepsia." Detailed symptomatic study of 360 patients. Gut 19: 19, 1978 18. Howden C\V, Hunt RH: The relationship between suppression of acidity and gastric ulcer healing rates. Aliment Pharmacol Ther 4:25, 1990 19. Jaffin BW, Kaye :'-iD: The prognosis of gastric outlet obstruction. Ann Surg 201:176, 1985 20. Jones C'\I: Digestive Tract Pain. New York, '\lacmillan, 1938 21. Jorde R, Bostad L, Burhol PG: Asymptomatic gastric ulcer: A follow-up study in patients with previous gastric ulcer. Lancet 1:119, 1986 22. Kang Y, Yap I, Guan R, et al: Acid perfllsion of duodenal ulcer craters and ulcer pain: A controlled double blind study. Gut 27:942, 1986 23. Konnan MC, Hansky J, Eaves EH: Influence of cigarette smoking on healing and relapse in duodenal ulcer disease. Gastroenterology 85:871, 1983 24. Kurata JH: Ulcer epidemiology: An overview and proposed research framework. Gastroenterology 96:569, 1989 2.5. Kurata JH, Haile BM, Elashoff JD: Sex differences in peptic ulcer disease. Gastroenterology 88:96, 1985 26. Lam SK, Hui W'\I, Lau WY, et al: Sucralfate overcomes the adverse effect of cigarette smoking on duodenal ulcer healing and prolongs subsequent remission. Gastroenterology 92:1193, 1987 27. Lam SK, Koo J: Gastrin sensitivity in duodenal ulcer. Gut 26:485, 1985 28. Lam SK: Pathogenesis and pathophvsiology of duodenal ulcer. Clin Gastroenterol 13:447, 1984 29. Lance P, Gazzard BG: Controlled trial of cimetidine for symptomatic treatment of duodenal ulcers. Br '\led J 286:937, 1983 30. Langman MJ, Cooke AR: Gastric and duodenal ulcer and their associated diseases. Lancet 1:680, 1976 31. Lauritsen K, Rune SJ, Bytzer P, et al: Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial. N Engl J .\Ied 312:958, 1985 32. Manson RH.: Duodenal ulcer as a second disease. Gastroenterology.59:712, 1970 33. Martin F, Farley A, Gagnon M, et al: Comparison of the healing capabilities of sucralfate and cimetidine in the short-term treatment of duodenal ulcer: A double-blind randomized trial. Gastroenterology 82:410, 1982 34 . .\Ioynihan BGA: On duodenal ulcer: With notes of 52 operations. Lancet 1:340, 190.5 35. Nyren 0, Adami H-O, Bastes S, et al: Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. :'-i Engl J Med 314:339, 1986 36. Palmer WL: .\lechanism of pain with peptic ulcer: A reply. Am J Med 11):513, 1955 37. Penston JG, \Vormsley KG: Asymptomatic duodenal ulcers-implications of heterogeneity. Aliment Pbarmacol Ther 4:557, 1990
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38. Piper D\V, l\'asery R, McIntosh J, et al: Smoking, alcohol, analgesics, and chronic duodenal ulcer. A controlled study of habits before first symptoms and before diagnosis. Scand J Gastroenterol 19:1015, 1984 39. Pounder H: Silent peptic ulceration: Deadly silence or golden silence? Gastroenterology 96:626, 1989 40. Price SF, Smithson KW, Castell DO: Food sensitivity in reflux esophagitis. Gastroenterology 75:240, 1978 41. Rauws EAJ, Tytgat Gl'iJ: Cure of duodenal ulcer associated with eradication of Helicobacter pyluri. Lancet ,335: 1233, 1990 42. Rees WDW, "filler LT. Malagelada JH: Dyspepsia, antral motor dysfunction and gastric stasis of solids. Gastroenterology 78:360, 1980 43. Rotter JI, Rimoin DL: Peptic ulcer disease: A heterogeneous group of disorders? Gastroenterology 73:604, 1977 44. Huffin JI\I: Mechanisms of ulcer pain and significance. Am J Dig Dis 4:871, 1959 4.5. Rydning A, Berstad A: Dietary aspects of peptic ulcer disease. Scand J Gastroenterol 20(sllppl):29, 1985 4G. Sheppard BC, ;\Iorton JA, Doppman JL, et al: Management of islet cell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 106:1108, 1989 47. Soli AH: Pathogenesis of peptic ulcer disease and implications for treatment. ;\I Engl J Med 322:909, 1990 48. Soli AH (moderator): ;\Ionsteroiclal anti-inflammatory clrugs ancl peptic ulcer disease. Ann Intern Mecl 114:307, 1991 49. Sonnenberg A, Muller Lissner SA, Vogel E, et al: Preclictors of duoclenal ulcer healing and relapse. Gastroenterology 81:1061, 1981 50. Sonnenberg A: Geographic and temporal variations in the occurrence of peptic ulcer disease. Scand J Gastroenterol 20(suppl):11, 1985 51. Sontag SJ: Current status of maintenance therapy in peptic ulcer disease. Am J Gastroenterol 83:607, 1988 52. Spiro H: Is the steroid ulcer a myth? N Engl J Med 309:45, 1983 53. Spiro HM: "loynihan's disease? The diagnosis of duodenal ulcer. N Engl J Med 291:567, 1974 54. Stabile B, Passaro E Jr: Peptic ulcer disease: A disease in evolution. Curl' Proh Surg 21:1, 1984 5,5. Strum WB: Prevention of duodenal ulcer recurrence. Ann Intern Med 105:757, 198G 56. Sturdervant RAL, Isenberg JI, Secrist D, et al: Antacids and placebo produced similar pain relief in duodenal ulcer patients. Gastroenterology 72:1, 1977 57. Sun DC, Roth SH, Mitchell CS, et al: Upper gastrointestinal disease in rheumatoid arthritis. Am J Dig Dis 19:405, 1974 58. Talley NI. ElIard K, Jones M, et al: Suppression of emotions in essential dyspepsia and chronic duodenal ulcer. Scand J Gastroenterol 23:337, 1988 59. Tytgat Gl'iJ, Lamers CBHW, Hameeteman W, et al: Omeprazole in peptic ulcers resistant to histamine H,-receptor antagonists. Aliment Phannacol Ther 1:31, 1987 60. Vogt TM, Johnson RE: Recent changes in the incidence of duodenal and gastric ulcer. Am J Epidemiol 111:713, 1980 61. Wenner P: Endocrine adenomatosis and peptic ulcer in a large kindred: Inherited multiple tumors and mosaic pleiotropism in man. Am J Med 35:205, 1963
Address repdnt requests to Julian Katz, MD The "ledical College of Pennsylvania 3300 Henry Avenue Philadelphia, PA 19129
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The Course of Peptic Ulcer Disease Julian Katz, MD*
Peptic ulcer disease is a disorder typified by periodic exacerbations and remissions. Although pain usually accompanies the presence of ulceration of the mucosa, peptic ulcers can be present without disturbing and appreciably discernible symptoms. In fact, one might question whether the presence of an ulcer crater without appreciable discomfort and that does not interfere with activities can be considered a disease entity. Patients may have complications of an ulcer, such as bleeding and perforation, without notable preceding symptoms. Clinical trials of antiulcer mediation have utilized serial endoscopic examination to determine the healing of the ulcer crater. 11, 29 These more precise diagnostic examinations have shown that the relief of pain occurs more frequently and earlier than healing of the ulcerated mucosa. The disappearance of symptoms then does not necessarily indicate the actual total healing, the re-epithelization of the ulcer crater. A high frequency of recurrence is present after the healing of an ulcer. 3 Within 1 year, a large number of patients with healed peptic ulcer disease who have not been on any regular antiulcer therapy can be expected to have a recurrence of their ulcer, sometimes without symptoms. 47 This is more often the case with duodenal ulcer than with gastric ulcer, and the natural history of the peptic ulceration associated with gastroesophageal reflux is different.
INCIDENCE Peptic ulcer disease of the stomach and duodenum was considered an uncommon disorder in the 19th century. The disease became more evident during the early 20th century. In the 1940s, at least 10% to 15% of men were said to have a duodenal ulcer. Obviously, precise diagnostic techniques were not available at that time. However, it does seem that people born in the latcr part of the 19th century or in the early 20th century seem to have had a propensity for developing peptic ulcers of the duodenum. The *Clinical Professor of Medicine. Medical College of Pennsylvania; and Adjunct Clinical Professor of Ivledicine, Jefferson Medical College, Philadelphia, Pennsylvania
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decline in incidence of duodenal ulcers may be due to the dying and aging of this group. Perhaps people who were born at the turn of the century were exposed to environmental factors that put them at risk of developing peptic ulcer disease throughout their lives. Although changes in coding of diagnosis, hospitalization practices for ulcer disease, and the greater a';ailability of diagnostic modalities may contribute to the apparent decline in the incidence, most careful observers believe that there has been a definite decline in duodenal ulcer disease. 6 24. 60 The changes in incidence in gastric ulcer disease are influenced by the aging of the population and by the use of ulcerogenic medications. Even before the advent of H2-blocker therapy, when only antacids and diets of questionable scientific merit were available, the occurrence of ulcer complications declined, less operations were performed, and the mortality rate decreased. 6 It is ironic that with the availability of newer, more effective medical therapy, there has been a change in incidence of acid-related disease. 54 The predominance of duodenal ulcer over gastric ulcer in most Western countries has been changing. 60 Geographic studies would indicate that the duodenal ulcer to gastric ulcer ratio is probably influenced more by environmental than ethnic factors. Although gastric ulcer is more common in women and the elderly, recent trends are altering these clinical observations. 6, 24. 2.5. 50 Prepyloric and duodenal ulcer disease probably have similar pathophysiologic mechanisms and can be lumped together, in contrast to ulcers of the proximal gastric body, the acid-secreting portion of the stomach. The acid-secreting mucosa may be thought to be especially resistant to ulceration, but patients with gastric ulcers seem to have a decrease in gastric acid secretion and diminished defensive mechanisms. 12. lb In spite of the changes in occurrence, peptic ulcer is one of the most prevalent gastrointestinal disorders and still is a common, chronic, and recurrent disease. The occurrence of a peptic ulcer actually produces little change in life expectancy. Bleeding, perforation, and obstruction are the major complications and ulcer-related deaths are the result of these complications, often in association with emergency surgery. Less than 2% of ulcer patients under therapy are expected to have a complication during a I-year period. Obviously, the death rate increases sharply with age and with associated severe medical conditions. Even today, gastric ulc~r hospitalization rates have remained steady, but this is because gastric ulcers occur in older patients who are more prone to have complications, associated medical problems, and possible malignant causes for ulceration. As well as a change in the incidence of ulcer disease,60 there has been a perceived change in the type of patient who gets an ulcer. The notion of peptic ulcer being a disease of hard driving, white, middle-aged, middleclass men has been replaced by the fact that peptic ulcer is an equal opportunity offender. Women are achieving comparable rates of affliction, and race, economic status, and psychologic stress are not really evident factors in the acquisition of an ulcer. Although gastric ulcer is recognized as a disease of older people, particularly women, there is now a seeming increase in the age of duodenal ulcer patients. It was assumed that th~ decline in gastric acid secretion associated with the aging process would make duodenal ulcer an infrequent problem in the elderly. The develop-
TIlE COCRSE OF PEPTIC CLCEH DISEASE
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ment and use of anti-inflammatory agents certainly contributes to the increase in ulcer disease~H; it is notable that any drug useful for arthritis or other inflammatory process invariably puts the patient at risk for developing gastrointestinal mucosal ulceration. Nevertheless, there seems to be a bimodal incidence of duodenal ulcer that cannot be explained merely by the use of ulcerogenic mediation. Perhaps infection with Helicohacter pylori is altering the incidence of duodenal ulcer disease. The acquisition of H. pylori infection is associated with getting older and is firmly associated with peptic ulcer disease. 1:1 Nevertheless, only a small portion of people with H. pylori infection develop a peptic ulcer. Ulcer disease probably involves heterogeneous mechanisms. 4J H. pylori infection of the gastric mucosa in most situations is necessary for the occurrence of duodenal ulcer disease; probably infection involves scattered gastric cellular nests in the duodenal mucosa. Yet some patients with gastric hypersecretion due to Zollinger-Ellison syndrome do not harbor the organism. In gastric ulcers, H. pylori is always present unless nonsteroidal antiinflammatory agents are implicated as the causative factor. Interestingly, in pernicious anemia in which autoimmune gastritis is thought to be involved, H. pylori is frequently absent. lO Thus, a genetic predisposition, environmental factors, and infection alter the processes of mucosal destruction and repair so that peptic ulcer occurs. 28, 47 There certainly are familial and genetic factors involved in ulcer disease. 15 Duodenal ulcer seems to be two to three times more prevalent in relatives of patients with ulcers. Family studies, twin studies, and genetic marker investigations support the role of genetic factors in peptic ulcer disease. Less frequent are the genetically determined syndromes with multiple endocrine abnormalities. The multiple endocrine neoplasia syndrome 61 consists of tumors or hyperplasia of the parathyroid glands, pituitary, adrenal cortex, pancreatic islets,46 and thyroid, along with peptic ulcer disease and usually an increase in gastric acid secretion. The in-born predisposition to ulcer disease may include an increase in parietal cell mass 27 with higher levels of acid secretion, as well as alterations in the composition of the mucus overlying the mucosa, changes in bicarbonate l6 and prostaglandin protective mechanisms, and other unknown factors. Emotions, stress, and cultural and social factors are surely involved in the course of peptic ulcer disease. 7 To call a disease psychosomatic is merely to pose the problem and in no way answers the question of etiology. Central nervous system mechanisms are involved in the secretion of gastric acid and in altering mucosal protection. When Beaumont in the early 19th century looked through a fistula into the stomach of Alexis St. Martin, he noted that there were changes associated with emotional turmoil and situational stress. Some observers have shown that patients with ulcers do not have different reactions to life stresses than people without ulcers.8 Supposedly, occupations considered stressful and hectic are associated with a greater tendency for ulcer disease. Still, no definite association between stress, occupation, and incidence of peptic ulcer disease has been established by the numerous studies that have been done. The mind does influence gastrointestinal functions, perhaps through neurohumoral pathways, but it has not been fully established that this relationship is important
834
JULIAN KATZ
in the causation of peptic ulcer. Nevertheless, a tried and tested way of producing an experimental ulcer is the restraint model, in which the laboratory animal is tied down without any apparent opportunity for altering the situation: this animal develops an ulcer. There are differences in the types and prevalence of ulcers in different countries. This may involve cultural as well as environmental factors, such as diet and H. pylori infection rates. Certainly, there are differing therapeutic responses to placebo in the treatment of ulcer disease in different countries and among different ethnic groups. Information is incomplete regarding the association between peptic ulcer disease and other diseases. 30, 32 Traditionally, there has been thought to be a relationship between chronic lung disease, chronic renal failure, and cirrhosis. These diseases often involve the use of cigarettes, analgesics, and alcohol. 38 Patients with rheumatoid arthritis·57 probably have a propensity for ulcer disease, particularly gastric ulcer, that is independent of the use of anti-inflammatory agents. Polycythemia, Cushing's disease, and hyperparathyroidism probably increase the occurrence of peptic ulcer disease, and uncommon disorders such as systemic mastocytosis and the ulcer-tremor-nystagmus syndrome are associated with ulcers. 15 Some studies attempt to implicate cigarette smoking as an etiologic factor in peptic ulcer disease ..5, 23, 26 The effect is claimed to be dose dependent. The smoking of cigarettes inhibits the synthesis of prostaglandins, reduces mucosal blood flow, and inhibits pancreatic bicarbonate secretion. Also, acid secretion following stimulation by a gastrin analogue is greater in smokers than in nonsmokers, and nicotine in laboratory animals increases the parietal cell mass. Cigarette smoking adversely affects duodenal ulcer healing; yet stopping cigarette smoking does not particularly have a favorable influence on the long-term course of ulcer disease. The role of dietary factors in p~ptic ulcer disease is a controversial one. 45 Physicians, in the past, have certainly been guilty of various dietary horrors, from the forcing of patients to eat zwieback toast and baby foods to the prescription of diets associated with promotion of atherosclerosis by emphasizing whole milk and cream. Although alcohol can cause gastric mucosal damage, the prohibition of alcohol use does not have a completely documented beneficial basis. Caffeine may increase gastric acid secretion, yet it may be that oils and other components of coffee have greater effects on upper gastrointestinal tract function. Patients with ulcers should probably moderate their use of alcohol and caffeine,38 but the firm evidence to indicate that heavy users of coffee and alcohol are prone to get a peptic ulcer is not really available. A diet rich in fiber, which seems to be good for just about everything, is thought by some to be helpful in preventing peptic ulcer disease. Dietary factors may be more important in gastroesophageal reflux disease. Peptic esophagitis may be influenced by various foods that irritate the esophageal mucosa, decrease the lower esophageal sphincter strength, and retard gastric emptying. 4 . 40 People who use anti-inflammatory drugs are more likely to have problems with peptic ulcer disease. Anti-inflammatory agents are a frequent cause of gastric and duodenal mucosal injury.48 Aspirin has been shown to damage the gastric surface mucosal cells, and anti-inflammatory agents
TIlE COl'HSE OF PEPTIC
C LCEH
DISEASE
835
impair defensc mechanisms by decreasing mucosal bicarbonate secretion, changing prostaglandin output, and altering other physiologic and anatomic factors. IJ Some of the changes in the incidence and clinical presentation of ulcer disease may be due to the increased use of these agents. However, anti-inflammatory drugs are used quite frequently, and ulcer disease is really not that common a problem in patients who utilize these medications. Aspirin appears to increase duodenal ulcer bleeding, and the use of nonsteroidal anti-inflammatory agents has been incriminated in the complications and alterations of ulcer disease. The association of adrenocorticosteroid therapy and peptic ulcer is controversia!,"'2 but high-dose adrenocorticosteroids are probably causative in some ulcerations of the mucosa of the upper gastrointestinal tract. SYMPTOMS AND COMPLICATIONS Peptic ulcer causes pain, and complications include bleeding, perforation, and obstruction. The pain of peptic ulcer involving the stomach and duodenum is frequently described as annoying, gnawing, burning, aching discomfort usually present in the epigastrium. Duodenal ulcer pain is usually relieved by reduction or neutralization of acid and typically is provoked by fasting and relieved by eating. This pattern is often less consistent in gastric ulcers, and the pain of prepyloric or channel ulcer usually becomes more evident with eating and is occasionally associated with nausea. Gastroesophageal reflux pain typically consists of pyrosis or heartburn and occasionally may be manifest only as nausea upon awakening; the postural effects of sleeping may be the cause of irritation and subsequent nausea. The manifestations of esophageal pain are sometimes unusual; distention of the esophagus in various sites provokes differing locations of discomfort. 20 With all our knowledge of peptic ulcer disease, the cause of ulcer pain is not totally understood. \Vhen the endoscopist cuts, burns, or rubs the gut mucosa, no pain is elicited. When the endoscopist infuses hydrochloric acid over an active symptomatic duodenal ulcer, ulcer pain is elicited in about 40% of the subjects. 12 Acid, therefore, has a definite role in the pathogenesis of the pain, but what about the majority of the patients? Palmer in 1926 suggested a much closer relationship between ulcer, acid, and pain, hut the attractive concept of ulcer pain being due to the irritating effect of acid on the exposed nerve endings in an ulcer crater,6 was not accepted by all. 44 Altered motility with changes in intraluminal pressure can give gut pain, and there may be factors that cause ulcer pain by affecting gastroenteric motility. Duodenal pH varies and it may be that the concentration of acid at the ulcer site is related to the pain. Antacids and placebo can produce similar pain relief in duodenal ulcer patients, 56 but again this may merely indicate that placebo is a good drug. The tenderness elicited by palpation in the upper abdomen of the patient with an active ulcer cannot be readily explained by motility disturbances or acid bathing exposed nerve endings. Serosal irritation and peritoneal inflammation have been mentioned as possible factors. The disassociation of symptoms and the presence of active
836
JULlA]\; KATZ
peptic ulcer seem to be more common in the elderly and particularly in patients who take nonsteroidal anti-inflammatory agents. Patients with asymptomatic ulcers receiving treatment with nonsteroidal anti-inflammatory agents are at much greater risk from hemorrhage, perforation, and other significant complications. 1.48 Careful history taking reveals that the diagnosis of ulcer disease by symptoms alone is not foolproof. Moynihan claimed that most patients with upper gastrointestinal symptoms could be correctly diagnosed solely on the basis of their symptoms. 34 More precise diagnostic techniques have been developed over the past 85 years, and unfortunately we find that well over half of our patients with dyspeptic symptoms cannot be diagnosed by eliciting a typical pattern. 17 The ingestion of food may have only a modest effect on reducing the pain of duodenal ulcer disease in many patients and actually can have little positive and some negative effects on the pain of gastric ulcer. Nocturnal pain correlated best with duodenal ulcer in some studies, but night pain may be part of a more ominous disease process, such as pancreatic cancer. The pain of ulcer disease may not be too disrupting in most ulcer patients who suffer the discomfort of "hunger pangs" or the like for 2 years or so before consulting a physician. 53 The flare-up of ulcer symptoms in the spring and fall has been noted but not completely confirmed. In older people with peptic ulcer disease the symptoms are often variable and vague. Actually, almost one-third of older patients may have not noticed symptoms indicative of ulcer disease. As a matter of fact, most of these patients present first with a significant complication and the prior use of an anti-inflammatory agent is frequently present. 1 Dyspepsia is a term used to describe a symptom complex of epigastric discomfort and fullness, vague nausea, postprandial distention often relieved by eructation, and similar annoying symptoms. There are many causes for this problem other than ulcer disease. 35 Endoscopic evaluation of the upper gastrointestinal tract is the most precise way of making the diagnosis of peptic ulcer disease. A full evaluation, including laboratory studies and diagnostic procedures, is carried out before the diagnosis of functional dyspepsia is made. In appropriate patients, a therapeutic trial with a program directed against peptic ulcer disease is often a first approach. Nonulcer dyspepsia has been studied and H. pylori is probably not the etiologic agent responsible for the problem in most patients. Abnormalities in motility of the stomach and intestine have been sought in patients with functional dyspepsia,42 which is defined as unexplained nausea and abdominal distress. Manometric abnormalities have been found in many of these patients, but the pathogenesis of these alterations in motor function is unknown. Although dyspepsia of unknown cause has been thought to be a stress-related disorder, 58 no obvious association can be well demonstrated. Ulcer disease can occur without symptoms. 21. 39 Endoscopic studies of patients without symptoms and without a history of ulcerogenic drug intake or prior symptomatic ulcer disease have shown an exceedingly low incidence of ulcers. Most asymptomatic duodenal and gastric ulcers occur in patients who have been receiving nonsteroidal anti-inflammatory agents; endoscopic surveys of such patients show that many of these patients have a peptic
TilE COl'nSE OF PEPTIC CLCEH DISEASE
837
ulcer without symptoms. Asymptomatic ulcers also develop in patients with cstablishcd, but healed, ulcer disease during maintenance therapy with antiulcer therapy, aftcr gastric surgery, and during periods without therapy.'~ If patients are not receiving therapy, they often become symptomatic. However, patients receiving maintenance therapy often do not develop symptoms and complications are rare. The complications of peptic ulcer disease are hemorrhage and, less often, pcrforation and obstruction. [5 The incidence of hemorrhage is not necessarily related to the duration of the ulcer disease, but pati~nts who bleed once have a tendency to manifest hemorrhage again. Complications occur morc commonly in gastric than in duodenal ulcers. Pyloric channel ulcer is associated with a more severe course. Perforation of the peptic ulcer may occur into the abdominal cavity or an adjacent solid organ or may result in a fistula. Acute perforation can be treated medically, but the conventional therapy is surgical. Penetration usually occurs in patients with long duration of peptic ulcer disease. Posterior penetration of a duodenal ulcer into the pancreatic bed results in an alteration of symptoms and may be considered a cause of intractable ulcer disease. Most cases of gastric outlet obstruction are due to benign peptic ulcer disease of the duod~num, pyloric channel, or prepyloric area. [9 Nevertheless, there is concern about the possibility of malignancy, and careful evaluation is in order. The reversible aspects of obstruction can be treated medically, but irreversible cicatrization may require endoscopic balloon dilation or surgical intervention. Currently, there is no firm evidence that the incidence of complications is altered by medical therapy, but it is reasonable to assume that the new medical therapies and the reduction of recurrences will alter the occurrence of complications. Most duodenal ulcers recur if treatment is withdrawn. 47, 55 Even after a year of maintenance therapy, almost half the duodenal ulcers recur and 30% of them occur with symptoms. 5 [ When endoscopic studies are performed every 6 months, 70% to 90% of the patients not treated with medication have eventual recurrence of their ulcers. The healing of duodenal ulcers is retarded by the use of alcohol, the diameter of the ulcer, a history of bleeding, and the presence of prior complications. 49 Interestingly, in one study, smoking, coffee intake, and age did not significantly affect the healing rate. The use of anti-inflammatory drugs and aspirin before the development of an ulcer seem to be factors other than intrinsic considerations that influence the causation of the ulcer and therefore are associated with improved odds of healing. Thus, the dictum "once an ulcer, always an ulcer" is tempered by the presence of reversible precipitating factors. 49, 5.'5 A reduction in the recurrence of ulcers may be possible by the eradication of H. pylori by com bination of treatments; this is an exciting and provocative approach to the problem of the frequent recurrence of ulcer disease. Patients with duodenal ulcers should be treated and when symptoms have abated, no further investigation is needed. However, the patient with a gastric ulcer should be totally assured that the ulcer is benign. If an ulcer does not heal, there is little evidence that changing to another H 2 -antagonist or adding an antimuscarinic agent2 is helpful. Total acid suppression with omepraz~le is indicated for the refractory ulcer;59 whereas maintenance
838
JULlAN KATZ
therapy with H 2 -blockers reduces but does not eliminate recurrence of ulccrs.l, g, ss Just as ulcers recur spontaneously and without apparent precipitating events, most ulcers heal without treatment. 49, SI After 2 weeks, one-quarter of endoscopically diagnosed ulcers healed without specific therapy; after 4 weeks, two-thirds had disappeared.>l There are probably variations in gastric acid secretion, and the exposure of the ulcerated mucosa to injury changes during the course. In yet to be determined ways, local mucosal defense mechanisms overcome peptic aggressive factors. Newer and exciting approaches are available. The eradication of H. pylori infection in the gastroduodenal mucosa of patients with duodenal ulcer disease substantially reduces the predictable recurrence rate. 41 The role of omeprazole-which inactivates the proton pump of the parietal celJllll.og-in the treatment of ulcer disease is not yet certain. Duodenal and gastric ulcer healing seems to occur more rapidly with omeprazole than with H 2 -blockers. The often poor correlation between the length of symptoms and ulcer healing makes it difficult to determine the appropriate length of therapy. The long-term use of this powerful antiseeretory agent may prevent recurrence, but the safety has not been demonstrated. In any case, all duodenal ulcers, regardless of how they healed, have a tendency to recur at a surprisingly high rate.
SUMMARY Peptic ulcer disease usually has periodic exacerbations and remissions. Pain can disappear without total healing of the ulcer crater and can be absent when an ulcer is present. Changes in the incidence of ulcer disease have been noted in recent years. Genetic predisposition, infection with H. pylori, and the use of anti-inflammatory drugs are involved in causation. Stress; the use of alcohol, tobacco and caffeine; and other diseases have been implicated as etiologic factors. Ulcer pain has a recognizable pattern, but the symptoms can be variable, particularly in older people and in patients taking ulcerogenic medications. The familiar complications of hemorrhage, perforation, and obstruction still occur, and non ulcer dyspepsia has not been fully explained. Duodenal ulcers have a disturbing tendency to return; new therapeutic approaches ofle I' hope.
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complications of peptic ulceration. Gut 28:527, 1987 2. Rarhan KD, Thompson M, Bose K, et al: Combined anti-muscarinic and H2 receptor blockade in the healing of refractory duodenal ulcer. A double blind study. Gut 28:1505, 1987 3. Boyd EJ, Penston JG, Johnston DA, et al: Does maintenance therapy keep duodenal ulcers healed? Lancet 1: 1324, 1988 4. Castell DO: The lower esophageal sphincter: Physiologic and clinical aspects. Ann Intern Med S3:390, 1975 5. Doll R, Jones FA, Pygott F: Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet 1:657, 1958
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6. Elashoff J D, Grossman '\II: Trends in hospital admissions and death rates from peptic ulcer in the United States from 1970 to 1978. Gastroenterology 1>4:1558, 1983 7. Ellard K. Beaurepaire J, Jones lVI, et al: Acute and chronic stress in duodenal ulcer disease. Gastroenterology 91:1370, 1986 8. Feldman M, \Valker P, Green JL, et al: Life events, stress, and psychosocial factors in men with peptic ulcer disease. A multidimensional case-controlled study. Gastroenterology 91: 1370, 1986 9. Feldman M, Burton ME: Histamine receptor antagonists: Standard therapy for acidpeptic diseases. 1\ Engl J .\Ied 323:1672, 1990 10. Fong T-L, Dooley CP, Dehesa M, et al: lIelicobacter pylori infections in pernicious anemia: A prospective controlled study. Gastroenterology 100:328, 1991 11. Freston JW: Overview of medical therapy of peptic ulcer disease. Gastroenterol Clin North Am 19(1):121, 1990 12. Graham D, Dyck W, Englert E, et al: Healing of gastric ulcer: Comparison of cimetidine and placebo in the United States. Ann Intern Med 102:573, 198.5 13. Graham DY: Campylobacter pylori and peptic ulcer disease. Gastroenterology 96:615, 1989 14. Graham DY, Smith L: Aspirin and the stomach. Ann Intern Med 104:390, 1986 1.5. Grossman MI (ed): Peptic Ulcer: A Guide for the Practicing Physician. Chicago, Year Book Medical Publishers, 1981 16. Hogan DL, Isenberg JI: Gastroduodenal bicarbonate production. Adv Intern Med 33:385, 1988 17. Horrocks Je, DeDombal FT: Clinical presentation of patients with "dyspepsia." Detailed symptomatic study of 360 patients. Gut 19: 19, 1978 18. Howden C\V, Hunt RH: The relationship between suppression of acidity and gastric ulcer healing rates. Aliment Pharmacol Ther 4:25, 1990 19. Jaffin BW, Kaye :'-iD: The prognosis of gastric outlet obstruction. Ann Surg 201:176, 1985 20. Jones C'\I: Digestive Tract Pain. New York, '\lacmillan, 1938 21. Jorde R, Bostad L, Burhol PG: Asymptomatic gastric ulcer: A follow-up study in patients with previous gastric ulcer. Lancet 1:119, 1986 22. Kang Y, Yap I, Guan R, et al: Acid perfllsion of duodenal ulcer craters and ulcer pain: A controlled double blind study. Gut 27:942, 1986 23. Konnan MC, Hansky J, Eaves EH: Influence of cigarette smoking on healing and relapse in duodenal ulcer disease. Gastroenterology 85:871, 1983 24. Kurata JH: Ulcer epidemiology: An overview and proposed research framework. Gastroenterology 96:569, 1989 2.5. Kurata JH, Haile BM, Elashoff JD: Sex differences in peptic ulcer disease. Gastroenterology 88:96, 1985 26. Lam SK, Hui W'\I, Lau WY, et al: Sucralfate overcomes the adverse effect of cigarette smoking on duodenal ulcer healing and prolongs subsequent remission. Gastroenterology 92:1193, 1987 27. Lam SK, Koo J: Gastrin sensitivity in duodenal ulcer. Gut 26:485, 1985 28. Lam SK: Pathogenesis and pathophvsiology of duodenal ulcer. Clin Gastroenterol 13:447, 1984 29. Lance P, Gazzard BG: Controlled trial of cimetidine for symptomatic treatment of duodenal ulcers. Br '\led J 286:937, 1983 30. Langman MJ, Cooke AR: Gastric and duodenal ulcer and their associated diseases. Lancet 1:680, 1976 31. Lauritsen K, Rune SJ, Bytzer P, et al: Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial. N Engl J .\Ied 312:958, 1985 32. Manson RH.: Duodenal ulcer as a second disease. Gastroenterology.59:712, 1970 33. Martin F, Farley A, Gagnon M, et al: Comparison of the healing capabilities of sucralfate and cimetidine in the short-term treatment of duodenal ulcer: A double-blind randomized trial. Gastroenterology 82:410, 1982 34 . .\Ioynihan BGA: On duodenal ulcer: With notes of 52 operations. Lancet 1:340, 190.5 35. Nyren 0, Adami H-O, Bastes S, et al: Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. :'-i Engl J Med 314:339, 1986 36. Palmer WL: .\lechanism of pain with peptic ulcer: A reply. Am J Med 11):513, 1955 37. Penston JG, \Vormsley KG: Asymptomatic duodenal ulcers-implications of heterogeneity. Aliment Pbarmacol Ther 4:557, 1990
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38. Piper D\V, l\'asery R, McIntosh J, et al: Smoking, alcohol, analgesics, and chronic duodenal ulcer. A controlled study of habits before first symptoms and before diagnosis. Scand J Gastroenterol 19:1015, 1984 39. Pounder H: Silent peptic ulceration: Deadly silence or golden silence? Gastroenterology 96:626, 1989 40. Price SF, Smithson KW, Castell DO: Food sensitivity in reflux esophagitis. Gastroenterology 75:240, 1978 41. Rauws EAJ, Tytgat Gl'iJ: Cure of duodenal ulcer associated with eradication of Helicobacter pyluri. Lancet ,335: 1233, 1990 42. Rees WDW, "filler LT. Malagelada JH: Dyspepsia, antral motor dysfunction and gastric stasis of solids. Gastroenterology 78:360, 1980 43. Rotter JI, Rimoin DL: Peptic ulcer disease: A heterogeneous group of disorders? Gastroenterology 73:604, 1977 44. Huffin JI\I: Mechanisms of ulcer pain and significance. Am J Dig Dis 4:871, 1959 4.5. Rydning A, Berstad A: Dietary aspects of peptic ulcer disease. Scand J Gastroenterol 20(sllppl):29, 1985 4G. Sheppard BC, ;\Iorton JA, Doppman JL, et al: Management of islet cell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 106:1108, 1989 47. Soli AH: Pathogenesis of peptic ulcer disease and implications for treatment. ;\I Engl J Med 322:909, 1990 48. Soli AH (moderator): ;\Ionsteroiclal anti-inflammatory clrugs ancl peptic ulcer disease. Ann Intern Mecl 114:307, 1991 49. Sonnenberg A, Muller Lissner SA, Vogel E, et al: Preclictors of duoclenal ulcer healing and relapse. Gastroenterology 81:1061, 1981 50. Sonnenberg A: Geographic and temporal variations in the occurrence of peptic ulcer disease. Scand J Gastroenterol 20(suppl):11, 1985 51. Sontag SJ: Current status of maintenance therapy in peptic ulcer disease. Am J Gastroenterol 83:607, 1988 52. Spiro H: Is the steroid ulcer a myth? N Engl J Med 309:45, 1983 53. Spiro HM: "loynihan's disease? The diagnosis of duodenal ulcer. N Engl J Med 291:567, 1974 54. Stabile B, Passaro E Jr: Peptic ulcer disease: A disease in evolution. Curl' Proh Surg 21:1, 1984 5,5. Strum WB: Prevention of duodenal ulcer recurrence. Ann Intern Med 105:757, 198G 56. Sturdervant RAL, Isenberg JI, Secrist D, et al: Antacids and placebo produced similar pain relief in duodenal ulcer patients. Gastroenterology 72:1, 1977 57. Sun DC, Roth SH, Mitchell CS, et al: Upper gastrointestinal disease in rheumatoid arthritis. Am J Dig Dis 19:405, 1974 58. Talley NI. ElIard K, Jones M, et al: Suppression of emotions in essential dyspepsia and chronic duodenal ulcer. Scand J Gastroenterol 23:337, 1988 59. Tytgat Gl'iJ, Lamers CBHW, Hameeteman W, et al: Omeprazole in peptic ulcers resistant to histamine H,-receptor antagonists. Aliment Phannacol Ther 1:31, 1987 60. Vogt TM, Johnson RE: Recent changes in the incidence of duodenal and gastric ulcer. Am J Epidemiol 111:713, 1980 61. Wenner P: Endocrine adenomatosis and peptic ulcer in a large kindred: Inherited multiple tumors and mosaic pleiotropism in man. Am J Med 35:205, 1963
Address repdnt requests to Julian Katz, MD The "ledical College of Pennsylvania 3300 Henry Avenue Philadelphia, PA 19129
