Peptic Ulcer: New Therapies, New Diseases

UCLA CONFERENCE

Peptic Ulcer: New Therapies, New Diseases Moderator: MORTON I. GROSSMAN, M.D.. Ph.D. Discussants: JOHN H. KURATA, Ph.D.; JEROME I. ROTTER, M.D.: JAMES H. MEYER, M.D.; ANDRE ROBERT. M.D., Ph.D,; CHARLES T. RICHARDSON. M.D. HAILE T. DEBAS, M.D.; and DENNIS M, JENSEN. M.D ; Los Angeles. California; and Dallas, Texas Although hospitaiizations and deaths attributable to peptic ulcer have decreased notably during the past decade, it is not certain whether this decrease is because of reduced incidence of new cases or changes in other factors, such as the severity of the disease. Severai genetic traits associated with peptic ulcer have been recognized. Hyperpepsinogenemia I is the most prevalent. Peptic ulcer is a heterogeneous group of disorders with multiple genetic and environmental causes. One manifestation of the diversity of ulcer disease is the variety of physiologic abnormalities seen in patients. The use of endoscopy has enabled more reliable evaluation of new treatments. Histamine H2-receptor antagonists are the dominant mode of treatment, but increasing attention is being given to agents that enhance the resistance of the mucosa to injury, such as prostaglandins. Because of the lower frequency of side effects, proximal gastric vagotomy is gradually replacing truncal vagotomy with drainage. The possibility that endoscopic treatments, such as laser coagulation, may reduce mortality from bleeding ulcers is being investigated. D H . MORTON I, GROSSMAN (Center for Ulcer Research and Education, Veterans Administration Wadsworth Medical Center and UCLA School of Medicine. Los Angeles, California): Since our last conference on peptic ulcer {1), there have been new discoveries about this group of diseases. Epidemiologic studies have shown major time trends, genetic studies have uncovered new markers and have changed our concepts about the basic nature of this disease, new physiologic abnormalities have been recognized, and new medical and surgical treatments have been introduced. The research carried out at the Center for Ulcer Research and Education (CURE) by the discussants and others has played a prominent role in these advances. This conference presents a sampling of the present state of knowledge about ulcer disease; a more comprehensive view will be found in the recent book by the staff of CURE (2).

Time Trends

Dr. John H. Kurata (CURE, Veterans Administration Wadsworth Medical Center and UCLA School of Medicine and Public Health, Los Angeles, California): Dramatic changes in the pattern of peptic ulcer disease are occurring. Hospitalization and mortality for ulcer disease •• An cdiieii iraniLription of an Intertlepartmental Conference arranged by the Dtpariment of Medicine of ihe UCLA School of Medicine; Los Angeles. California • Authors whi) wish Ui cite a seclion of this conference and specifically indicate its .uithiir can use this example of the form of reference: R o n IK JI. Heierogeneity of ulcer disease, pp. 610-5. In; GROSSMAN M l , moderator. Peplic ulcer; new therapies, new diseases. Ann Intem Med. l98l;95:609-27.

Annals Of Internal Medicine. 1981;95:609-627.

have declined in Western countries during the past 20 years (3-7). Moreover, some investigators have speculated that the incidence of peptic ulcer disease may also be decreasing. (Incidence is the number of new cases arising during a given time interval per specified unit of population.) An understanding of these changes is important in ascertaining the causes, the economic impact, and the effects of treatment of peptic ulcer disease. Hospitaiizations for ulcer disease, especially duodenal ulcer disease, have decreased notably during the last two decades (3). From 1970 to 1978. hospitaiizations for duodenal ulcer in the United States dropped by about 43%; for gastric ulcer, about 9% (Figure 1). Deaths due to peptic ulcer are at present declining by about 5% per year (Figure 2) (8). Death rates are dropping in all age groups for men and women. The ratio of men to women for hospitaiizations and deaths has been decreasing during the past few decades, mainly because of a more rapid decrease of these occurrences for men than for women. Although the frequency of ulcer often is said to be increasing in women, it is simply decreasing more slowly in women than in men. These declines in hospitaiizations and mortality, however, may not indicate a true decline in ulcer incidence because these rates might only reflect changes in diagnostic practices, effectiveness of treatment, or severity of disease. Patients with perforations, who represent about 5% of hospitalized cases, provide a firmer index of the incidence of ulcer disease because the rate of perforations per case remains constant and because patients with perforations rarely escape detection and hospitalization. The incidence of perforation of duodenal ulcer does not show a substantial change from 1970 to 1977 (3). Studies that have attempted to measure ulcer incidence directly have produced equivocal results. The best recent study of ulcer incidence was conducted by Bonnevie (911). From 1963 to 1968, Bonnevie recorded the incidence of new cases of peptic ulcer (as diagnosed by roentgenogram, endoscopy, surgery, or necropsy) in all persons over 15 years old living in Copenhagen County, Denmark. He found no decline in the incidence of peptic ulcer disease during this period. Bonnevie repeated his study of Copenhagen County during 1978 and 1979 and found no notable changes in incidence from the earlier study (BONNEVIE O. Unpublished data, 1980). The Health Interview Survey of the National Center for Health Statistics (12, 13) is the only populationbased study of peptic ulcer disease incidence rates in the United States. This survey showed no substantial decline 01981 American College of Physicians

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in incidence rate per 1000 persons per year between the 1968 value of 3.0 and the 1975 value of 2,9. Although this survey has been strongly criticized because it is based on "perceived illness," it remains the only study of its kind done in the United States. Two recent studies in the United States reported declines in the number of diagnoses of peptic ulcer disease during several years. Mendeloff (5) reported a 50% decline between 1960 and 1972 in the number of diagnoses of duodenal ulcers among U.S. work force and armed services personnel. Using outpatient data for 1967 through 1973 from a Health Maintenance Organization with over 200 000 members, Vogt and Johnson (7) showed a notable decline in arbitrarily defined "new cases" of duodena! and gastric ulcer. Although both studies strongly suggest a decline in incidence rates, neither study distinguished adequately between new and recurrent cases, an essential feature for establishing true incidence. In summary, indirect measures of peptic ulcer incidence, such as hospitaiizations and mortalities, show a definite decline. However, studies attempting to measure incidence directly have presented inconsistent results. Some possible hypotheses for what is occurring are the following: 1. There is a decline in the iticidence rate of peptic ulcer. The data from the National Center for Health Statistics may be inaccurate because they are based on patient recall. Although Bonnevie's incidence rates are sound, his data are for the Danish population and may not apply to the United States. 2. The increased use of antacids, and now cimetidine, tnay have reduced the serious manifestations of peptic ulcer disease bur not its incidence. Data on sales of antacids show a steady increase during the past two decades

(14), Because consumption of antacids relieves symptoms and promotes healing, it may also prevent progression of the disease and subsequent hospitalization. Although the serious manifestations of peptic ulcer disease are decreasing, incidence rates of peptic ulcer are not. 3. A change in diagnostic practices may have reduced the number of cases identified as peptic uJcer disease but not the "true" incidence rate. With the advent of endoscopy, standards for diagnosis of peptic ulcer by roentgenogram or endoscopy may have become stricter, and cases formerly called peptic ulcer are now diagnosed as something else. In support of this theory, the number of hospitaiizations in the United States for duodenitis/gastritis increased by 24 000 from 1973 to 1977, whereas hospitaiizations for peptic ulcer disease decreased by 19 000 (15, 16). Cases formerly diagnosed as peptic ulcer are now perhaps being diagnosed as duodenitis/gastritis, or perhaps there is a change in the physiologic manifestations of peptic ulcer disease. There are conflicting trends for peptic ulcer, with direct measurements of incidence on the one hand and hospitalization and mortality data on the other. Has the incidence actually remained constant while hospitaiizations and deaths have decreased because of a combination of factors: decreased severity of disease, higher threshold for hospitalization, more successful treatment, and change in diagnostic practices? To answer this question, studies of direct incidence, hospitalization, and mortality must be done in the same population. Heterogeneity

Dr. Jerome I. Rotter (CURE, Los Angeles County Harbor-UCLA Medical Center, Torrance, California, and UCLA School of Medicine, Los Angeles, California): Peptic ulcer has often been considered a continuum.

In Memoriam: Morton I. Grossman, M.D., Ph.D.; 1919-1981 MORTON GROSSMAN died at his home in Santa Monica on 26

May 1981, of eosphageal cancer. In both his scientific and his personal life he set standards for us all. During ihe past several decades Dr. Grossman has been a leading figure in gastrointestinal physiology (1). One central theme of his work was a systematic unraveling of the interaction of hormones and nerves on gastrointestinal function. His masterly reviews molded the evolution of gastroenterology to its present state as an active field with a strong scientific basis. He set "the highest standards of critical insight, rigorous experimental evidence and quantification of expression"(l). Morton Grossman did his undergraduate work at Ohio State University, switching from English literature to biochemistry 610

after a job as an assistant in a research laboratory. His concern for effective written communication is evident in all of his publications. He received his M.D., and a Ph.D. in physiology, ai Northwestern as a student of the nationally known gastrointestinal physiologist. Dr. Andrew Ivy. From there he went to the University of Illinois and later to the U.S. Army Medical Nutritional Laboratory. In 1955 Dr, Grossman joined the UCLA School of Medicine and Wadsworth Veterans Administration Hospital. In 1974. Dr. Grossman established the NIH-UCLA-Wadsworth Veterans Administration Center for Ulcer Research and Education (CURE). In a short period CURE became a "focal point of world attention to the problem of peptic ulcer" (1) The central position of CURE is due not only to Dr. Grossman's "scientific distinction, but also to his ability to persuade other distinguished scientists of many different disciplines to work together in fruitful harmony" (1.2). Mort Grossman had a crucial role in the development of Gastroenterology, the journal of the American Gastroenterological Association. He was associated continuously with this journal beginning with his appointment as Assistant to the Editor at Ihe time of the journal's inception in 1940 to the Chairman of the Editorial Board from 1973 to 1978. That it became the preeminent scientific journal in its field was due mainly to

Novambarl981 • AnnBlaotlfilernal Modlclne • Volume 95 • Numbers

the result of an imbalance between the aggressive forces of acid and pepsin and the defensive forces of mucosal resistance. In the continuing search for the single pathophysiologic defect that underlies peptic ulcer, many abnormalities^physiologic, biochemical, immunologic, histologic—have been described (17-19), Each of these abnormalities occurs in some, but not all, patients with ulcer. The solution to this quandary has been the gradual realization that peptic ulcer is not a single disease but a host of disorders with a common clinical manifestation: a hole in the lining of the gastrointestinal tract in areas exposed to acid and pepsin (17-20). This concept of heterogeneity, that peptic ulcer consists of different diseases, has important implications for all aspects of peptic ulcer disease; these distinct diseases may differ in their pathophysiology, genetics, interaction with environmental agents, natural history, and response to therapeutic and preventive measures. Heterogeneity of a common disease can be shown by criteria listed in Table 1 (17-40); advances in all these areas have contributed to our knowledge of ulcer heterogeneity. These approaches are being used increasingly to define the heterogeneity of many common gastrointestinal diseases (18). The evidence for heterogeneity of peptic ulcer has accumulated rapidly during the past several years (17-20). Many lines of evidence for ulcer heterogeneity are genetic. This is not mere happenstance: genetic methods are powerful tools for sorting out distinct disorders from a broad phenotype. We shall present briefiy the evidence for each of these distinct disorders; more extensive recent reviews are available (18, 19). The existence of rare distinct genetic syndromes associated with peptic ulcer is a definitive demonstration of genetic heterogeneity (Table 2) (18, 19. 41, 42). The best known is multiple endocrine adenoma Wermer syn-

his direction (3). His scientific work and contributions to the practice of medicine and gastroenlerology led lo the presidency of the American Gaslroenterological Association (1967-1968). He also received such distinguished awards as the Anniversary Medal of the Swedish Medical Society (1970), the Mayo H. Soley Award of the Western Society for Clinical Research (1973). the Modern Medicine Award for Distinguished Achievement (1976), and the Friedenwald Medal of the American Gastroenterological Association (1978). Perhaps his most lasting and unique contribution to medical science was, in his own words, "in providing a place and atmosphere in which fledgling scientists could develop and grow to independence" (4). His many fellows and associates populate Ihc world of gastroenterology, physiology, and related disciplines. Yet. with typical modesty, he took little credit, insisting [hat their many accomplishments were simply a result of their own abilities. This constant influx of new people and new ideas is exemplified by contrasting this issue's UCLA Conference with that published in the January 1976 issue of Annals of Internal Medicine (5). Except for the director, the entire staff has changed. Morton Grossman was uniquely adept at learning from his many associates and acquaintances in all disciplines, putting it all together, and then pointing out new lines of research to each of ihem. As this UCLA conference illustrates, besides being a

drome, type I, characterized by parathyroid, pancreatic, and pituitary adenomas (43). The pancreatic adenomas may secrete gastrin leading to severe ulcer disease (Zollinger-EIlison syndrome). Until the association of ulcer disease with other endocrine tumors was recognized, the dominant pattern of inheritance elucidated, and the biochemical marker of increased plasma gastrin levels characterized, this specific entity was lost among the many cases of peptic ulcer. Gastrinoma of the pancreas and associated ulcer disease may also occur as a sporadic somatic mutation without familial aggregation and without endocrine tumors in other organs (43). Systemic mastocytosis is another multisystem syndrome complicated by peptic ulcer, in this case because of histamine excess (19). Both dominant and recessive pedigrees have been described. Another rare dominant syndrome consisting of a tetrad of abnormalities—essential tremor, congenital nystagmus, a narcolepsy-like sleep disturbance, and severe duodenal ulceration—has recently been described (44). A distinct form of amyloidosis is also accompanied by duodenal ulcer (45). Other genetic syndromes in which an increased incidence of ulcer has been suggested include alpha-1-antitrypsin deficiency, hyperparathyroidism (this association may be solely through multiple endocrine adenoma syndrome I), cystic fibrosis, carcinoid syndrome, a recently described "stiff-skin syndrome," and pachydermoperiostosis (19, 46). These disorders not only show the existence of genetic heterogeneity but also illustrate that different pathogenetic mechanisms can lead to peptic ulcer. Just as megaloblastic anemia can result from folate or vitamin B12 deficiency, both multiple endocrine adenoma syndrome I and systemic mastocytosis can cause acid hypersecretion leading to duodenal ulcer. In one case it is due to excess gastrin and in another to excess histamine. The existence of these rare disorders

paramount physiologist and gastroenterologist. he taught surgery to surgeons, statistics to statisticians, epidemiology to epidemiologists, and genetics to geneticists. In the words of Rabbi Hanina. "I have learnt much from my teachers, and from my colleagues more than from my teachers, but from my disciples more than from them all" (6). Morton Grossman was a lifelong student and thus one of our greatest teachers. STAFF OF CENTER FOR ULCER RESEARCH AND EDUCATION

Wadsworth Veterans Administration UCLA School of Medicine; Los Angeles. California BIBLIOGRAPHY

1 GRtGORY RA Presentation of the Friedenwald Medal to Morton Grossman. Gastroenterology. 197g;75:l A-4A. 2. EASIMAN P. FOCUS: VA Research and Development. Peptic Ulcer Disease- Available from D. Robert E. Allen (151F) VA Central Office. 8iO Vermont Avenue. N.W.. Washington DC. 20480. 3 DoNAiDSON RM JR, Si tiSENGER MH. FoRiUBAN JS. Morton Grossman and ihe journal: thirty-five years of working logether. Gas-

troenterology. 197S;74:1331. 4. Remarks of Morion Grossman upon receipt of Julius Friedenwald Medal. 22 May \^7i. Las Vegas, Nevada. 5. GROSS ML G U I H PH. ISKNBERG JI, et al A new luok at peptic ulcer.

Ann Intern Med. l976;84:57-67. 6. Quoted in the name of Rabbi Hanina In ihe Babylonian Talmud Tractate Taanith (7A). London: Soncitio Press; 1938:26. Grossman et al. • Peptic Ulcer

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differences within a disorder that can be consistently related to other clinical features, such as the location of ulcer or the age at onset, can also suggest genetic heterogeneity. In gastric and duodenal ulcers, much evidence that these are separate and distinct disorders has been gathered in this fashion, with location of ulcer used as the dividing criterion and then comparisons made with other features—age of onset, complications, ratio of men to women, acid secretion. One of the earliest definitive pieces of evidence that gastric and duodenal ulcer were separate disorders was the study of Doll and Kellock (24), which showed that the increased familial risk for ulcer was site specific. For example, if the index patient had gastric ulcer, then the prevalence of gastric and not duodenal ulcer was increased among his or her relatives; if the index patient had duodenal ulcer, then the prevalence of duodenal and not gastric ulcer increased in his or her family. Studies of twins supported this separation, as the ulcer location was usually concordant when both members of a twin pair were affected (25). The study of Doll and Kellock (24) also suggested that combined ulcer (gastric plus duodenal) may also segregate independently. This is supported by the epidemiologic studies of Bonnevie (47), which show that the incidence of duodenal and gastric ulcers in the same patient is about 20 times that expected from the relative frequencies of the two disorders in the population. Heterogeneity of duodenal ulcer has also been suggested by using age of onset as a dividing criterion. Childhood duodenal ulcer may be distinct genetically from

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YEAR Figure 1. Estimated hospitalizations (tn thousands) in the United States in which primary diagnoses were duodenal and gastric ulcers. Based on data Irom Hospital Record Study for 1970 to 1978 (3).

also suggests that what we recognize as "common" peplic ulcer may. in fact, comprise several disorders. The marked ethnic variability in the prevalence, and especially in the clinical features of peptic ulcer, constitutes epidemiologic evidence for heterogeneity (18, 19, 21-23). Although duodenal ulcer is usually commoner than gastric ulcer, this ratio varies widely throughout the world; in a few locations, such as in Japan, gastric ulcer occurs more frequently. The absolute incidence elso varies widely; for example, the frequency of duodenal ulcer in Southwest American Indians is one fortieth that in white persons in the United States. The ratio of men to women also varies widely: from over 30:1 in rural Africa and India to about 2:1 or 3:1 in the United States. Most notably, there is extensive ethnic and geographic variation in clinical characteristics, such as age of onset and complications. In Western countries, pyloric stenosis is an infrequent indicator for surgery, whereas in rural India it is the primary indication in 80% of patients with ulcer who undergo surgery (23). The demonstration of clinical, physiologic, or genetic 612

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