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Why duodenal ulcers recur
GASTROENTEROLOGY
SELECTED
1988;94:1508-15
SUMMARIES
ROBERT M. GLICKMAN Selected Summaries Editor Columbia University College of Physicians & Surgeons New York, New York 10032
Thomas A. Brasitus, Chicago, Ill. Richard J. Deckelbaum, New York, N.Y. Serge Erlinger, Paris, France Hans Fromm, Washington, D.C. W. G. M. Hardison, San Diego, Calif. Lucien R. Jacobs, Los Angeles, Calif. Khursheed Jeejeebhoy, Toronto, Canada Martin F. Kagnoff, San Diego, Calif.
WHY DUODENAL
Raymond S. Koff, Framingham, Mass. Robert C. Kurtz, New York, N.Y. Richard P. MacDermott, St. Louis, MO. Arthur M. Magun, New York, N.Y. James McManus, Temple, Tex. Ann Ouyang, Philadelphia, Pa. John H. C. Ranson, New York, N.Y. Melvin Schapiro, Los Angeles, Calif.
ULCERS RECUR
Coglan JG, Humphries H, DooJey C, et al. [Department of Gastroenterology, Adelaide and St. James Hospitals and Trinity College, Dublin) Campylobacter pylori and recurrence of duodenal ulcers-a 12 month follow-up study. Lancet 1987;ii:1109-11. This study examines the recurrence rate of duodenal ulcer disease in relation to the presence or absence of Campylobacter pylori in the gastric antrum. A consecutive group of patients who were found at endoscopy to have a duodenal ulcer were randomly assigned to treatment with either colloidal bismuth subcitrate (32 patients) or cimetidine (34 patients). At the time of diagnosis of the ulcer, 93% of the patients in both treatment groups had evidence of Campylobacter pylori (CP) infection. Campylobacter pylori was documented in three ways: by growth of ureasepositive colonies on culture, by Gram stain, and by hematoxylin and eosin stain of gastric biopsy specimens. At least two of the three methods of identification of the organism were positive in each patient. More than twothirds of the patients in each group smoked. After 6 wk of treatment, endoscopy revealed that 23 patients (72%) of the 32 in the bismuth group and 23 patients (68%) of the 34 in the cimetidine group had healed ulcers. About half the patients in the bismuth group and 83% in the cimetidine-treated group remained CPpositive after treatment. All patients were followed for ~~,irl~“~~ “I nf IbbUIIC,11bb PLIPIIT.TCX~PCI“I nf ,,l,-ov rlironco h7.t nn “YIUUIIbZi UIbrTL UliltiU.TCI. ‘A,t,,iJ, XIIL(1~LU0, “UL II” other therapy, were allowed ad libitum. The patients were examined every 3 mo and if symptoms were not controlled with antacids, endoscopy was performed. If the patients were asymptomatic, endoscopy was performed after 1 yr. The endoscopist was unaware of CP status. Six patients were lost to follow-up and 1 patient refused further endoscopy. Of the remaining 39 patients, 14 remained asymptomatic throughout the year of follow-up, II\ I”
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had severe enough symptoms to warrant early endoscopy. At the end of the 1 yr follow-up, 11 of 21 bismuth-treated patients and 12 of 18 cimetidine-treated patients developed recurrent duodenal ulcer. Almost 80% of the patients
Konrad Schulze-Delrieu, Iowa City, Iowa Helen M. Shields, Boston, Mass. Michael L. Steer, Boston, Mass. Joseph Sweeting, New York, N.Y. Martin H. Ulshen, Chapel Hill, NC. Ernest Urban, Pittsburgh, Pa. Milton M. Weiser, Buffalo, N.Y.
who were CP-positive after the initial 6 wk of either treatment relapsed and only 27% of the patients who were CP-negative after initial treatment relapsed. All patients in whom CP was present after initial treatment had CP present after follow-up endoscopy at the end of the study; 33% of the patients in whom CP was not found after initial treatment developed CP infection. None of the patients who remained CP-negative throughout the year of follow-up developed histologic gastritis, whereas 86% of the patients who were CP-positive after the year of follow-up did have histologic gastritis. Comment. There have been >lOO articles published in the past 2 yr concerning CP and the association of this organism with gastroduodenal inflammation (Gastroenterology 1987;93:371-83). The impressive interest of physicians and investigators in this organism stems from the magnitude of the problem of peptic disease, the frustrations related to patients who have pain despite eradication of the ulcer, high recurrence rates after treatment, and the realization that the mucosal barrier has been an important but poorly defined contributor to the pathogenesis of ulcers. Although current therapies heal -90% of peptic ulcers, recurrence rates after 1 yr approach 80% (Gut 1982;23:239-42). The causes of ulcer recurrence remain unknown (Ann Intern Med 1986;105:757-61). The identification of an organism whose presence may explain ongoing pain, gastritis, and even recurrence of ulceration is a significant finding. There is still much controversy regarding the etiologic role of Campylobacter in peptic disease but a number of conclusions have been generally accepted. The growth and microbiologic characteristics of the organism have been reasonably well defined (J Ciin Pathoi 1965;138:1127-313. The organism can be cuitured from the gastric antrum of large numbers of patients with peptic disease and some studies suggest up to a 50% exposure in the general population (J Med Microbial 1986;22:57-62). When the organism is found in the stomach, it is always associated with gastritis and often, though not always, with peptic ulceration (Med J Aust 1985;142:439-44). Reliable diagnostic methods include culture from gastric mucosa, histologic identification, urease activity, and a breath test after ingestion of [‘%]urea (Gut 1985;26:1183-8, Lancet 1987;i:1174-7). Treatment of the organism with antibiotics and bismuth preparations has shown that it can be eradicated from the mucosa. The current study stems from the observations concerning the treatment of peptic disease with bismuth compounds. Although the mechanism of action of bismuth is not clear, a number of
SELECTED
June 1988
studies have demonstrated that bismuth heals peptic ulcers as efficiently as cimetidine (Gut 1983;24:1148-51; Gut 1980;21:32933). One previous study (Gut 1986;27:106-10) has shown that after duodenal ulcer healing, the recurrence rates of patients initially treated with bismuth were 43% as compared with 78% in the cimetidine-treated group. As bismuth has been shown to be an effective treatment for CP (Br Med J 1986;293:645-9), the possibility that the presence of Campylobacter may influence ulcer recurrence rates was raised and explored in the present study. The protocol in the current study was straightforward. Patients with a duodenal ulcer were treated for 6 wk with either bismuth or cimetidine. The presence or absence of CP was documented at the initial endoscopy and at the 6-wk time point. Patients were followed for 1 yr and underwent endoscopy at the end of the year or sooner if symptoms developed. The key findings were as follows: 93% of the patients were CP-positive at the start of the study; -70% of patients healed their ulcers after 6 wk of treatment with either regimen; the patients receiving bismuth cleared CP much better than the patients receiving cimetidine (50% vs. 83%); and patients who remained CP-positive after ulcer healing had a much higher rate of ulcer relapse than the patients who were CP-negative after ulcer healing (79% vs. 27%, p < 0.01). The allowed ad libitum use of antacids during the period after ulcer healing weakens the conclusions of the study somewhat. Undoubtedly, antacid use can influence duodenal ulcer recurrence rates. As CP infection may be facilitated by the presence of a nonacidic milieu (Lancet 1984;11:525-63, antacid use during the observation period may also contribute to continued CP presence. Recurrence rates and the presence of CP when no therapy is administered need further study. Two-thirds of the patients smoked, and the effect of smoking on CP should also be investigated as ulcer recurrence rates in smokers are increased (Gastroenterology 1983;85:871-4). Healing ulcers in the 1980s has become easy. Many drug regimens have been shown to be well tolerated and effective. The problem is the management of the patient after ulcer healing. No one knows how long to keep otherwise healthy people on maintenance therapy, particularly if they are asymptomatic. Does Campylobacter cause duodenal ulcer recurrence? It remains to be proved. This study suggests a strong association. If ulcer recurrence is clearly related to Campylobacter and if eradication of the
organism effects long-term remissions, most physicians would undoubtedly
revise
current
therapies. A. M. MAGUN, M.D.
GASTROESOPHAGEAL REFLUX: AN INCREASINGLY COMPLEX EVENT Gill RC, Kellow JE, Wingate DL [Gastrointestinal Science Research Unit, London Hospital Medical College, London, United Kingdom) Gastroesophageal reflux and the migrating motor complex. Gut 1987;28:929-34. The factors contributing to gastroesophageal reflux are multiple and growing in number. The primary barrier to reflux continues to be the lower esophageal sphincter (LES), as it appears that reflux occurs when the transsphincteric pressure difference is zero. This can be achieved either by increasing the intragastric pressure or by decreasing the LES pressure to equal intragastric pressure. Recently, the phenomenon of transient LES relaxation has been investigated and appears to play an important role in nocturnal gastroesophageal reflux. In addition, studies in the dog and in humans have indicated that the LES
SUMMARIES
1509
demonstrates cyclic activity concomitant with the interdigestive motor complex, raising another potential component in the control of the LES pressure. Gill, Kellow, and Wingate investigated the correlation between the interdigestive migrating motor complex (MMC) and gastroesophageal reflux in normal volunteers and their findings suggest an increased incidence of gastroesophageal reflux associated with periods of gastric motor activity, related to phases II and III of the interdigestive MMC interval. Five men and 2 women underwent a 24-hr recording of the intraesophageal pH (5 cm above the LES) and the intraluminal pressures from the LES, gastric antrum, and two sites in the duodenum. Recordings started at 8:30 AM. Subjects were seated and awake during the day and supine and “asleep” after 11:30 PM. The recording periods were divided into a diurnal fasting period (8:30 AM to 5:30 PM], a nocturnal fasting period (11:30 PM to 8:30 AM], and a postprandial period (5:30 PM to 8:30 PM). During fasting periods, reflux was noted both during the day and at night. The duration was greater at night than during the day (46 vs. 25 s), but the frequency was less. During the postprandial period reflux was also seen with a frequency greater than during the fasting periods. The authors were unable to identify phase III of the MMC in the gastric recordings, thus periods of gastric motor activity are comprised of a combination of phases II and III, lasting 33 ? 18 min at night and 43 k 2 7 min during the day (p < 0.01). No difference in the amplitude of contractions was noted during the day compared with at night. Episodes of nocturnal and diurnal reflux were of longer duration and more frequent during periods of gastric motor activity than during gastric motor quiescence. At night the duration of reflux during episodes of gastric motor activity was greater than during the day, although not more frequent. During periods of gastric motor quiescence, this difference was not seen. A correlation was seen between gastric motor activity and the increase in duration and number of gastroesophageal reflux episodes. Comment. This interesting paper examines the potential role of yet another factor in influencing gastroesophageal reflux. Although the LES pressure remains the most important barrier to reflux, it is now clear that this pressure is variable over time. Is the MMC another event associated with transient changes in the LES and therefore associated with intermittent reflux? Others have shown that transient inappropriate LES relaxation can occur and is associated with reflux (Gastroenterology 1981;81:376-94, J Clin Invest 1980;65:256-67). This transient relaxation is more frequent at night. In addition, levels of consciousness are tied in with events of gastroesophageal reflux, and esophageal acidification will in itself result in a greater level of consciousness (J Clin Invest 1980;65:256-67, Gastroenterology 1984;86:814-9). Long-term motility studies such as conducted in this study are hard to do and the authors are to be commended. It is a pity that the technique used to examine the LES pressure is suspect as the tube is likely to slip a few millimeters, at least during a long-term recording, making it difficult to differentiate a fall in LES pressure from the tube slipping into the stomach or into the esophagus. I assume that is why no mention is made of the LES pressure, although the recordings shown suggest that reflux is associated with a fall in LES pressure. It is curious that the LES pressure should fall during the gastric motor activity. In animals, the LES pressure increases
SELECTED
1988;94:1508-15
SUMMARIES
ROBERT M. GLICKMAN Selected Summaries Editor Columbia University College of Physicians & Surgeons New York, New York 10032
Thomas A. Brasitus, Chicago, Ill. Richard J. Deckelbaum, New York, N.Y. Serge Erlinger, Paris, France Hans Fromm, Washington, D.C. W. G. M. Hardison, San Diego, Calif. Lucien R. Jacobs, Los Angeles, Calif. Khursheed Jeejeebhoy, Toronto, Canada Martin F. Kagnoff, San Diego, Calif.
WHY DUODENAL
Raymond S. Koff, Framingham, Mass. Robert C. Kurtz, New York, N.Y. Richard P. MacDermott, St. Louis, MO. Arthur M. Magun, New York, N.Y. James McManus, Temple, Tex. Ann Ouyang, Philadelphia, Pa. John H. C. Ranson, New York, N.Y. Melvin Schapiro, Los Angeles, Calif.
ULCERS RECUR
Coglan JG, Humphries H, DooJey C, et al. [Department of Gastroenterology, Adelaide and St. James Hospitals and Trinity College, Dublin) Campylobacter pylori and recurrence of duodenal ulcers-a 12 month follow-up study. Lancet 1987;ii:1109-11. This study examines the recurrence rate of duodenal ulcer disease in relation to the presence or absence of Campylobacter pylori in the gastric antrum. A consecutive group of patients who were found at endoscopy to have a duodenal ulcer were randomly assigned to treatment with either colloidal bismuth subcitrate (32 patients) or cimetidine (34 patients). At the time of diagnosis of the ulcer, 93% of the patients in both treatment groups had evidence of Campylobacter pylori (CP) infection. Campylobacter pylori was documented in three ways: by growth of ureasepositive colonies on culture, by Gram stain, and by hematoxylin and eosin stain of gastric biopsy specimens. At least two of the three methods of identification of the organism were positive in each patient. More than twothirds of the patients in each group smoked. After 6 wk of treatment, endoscopy revealed that 23 patients (72%) of the 32 in the bismuth group and 23 patients (68%) of the 34 in the cimetidine group had healed ulcers. About half the patients in the bismuth group and 83% in the cimetidine-treated group remained CPpositive after treatment. All patients were followed for ~~,irl~“~~ “I nf IbbUIIC,11bb PLIPIIT.TCX~PCI“I nf ,,l,-ov rlironco h7.t nn “YIUUIIbZi UIbrTL UliltiU.TCI. ‘A,t,,iJ, XIIL(1~LU0, “UL II” other therapy, were allowed ad libitum. The patients were examined every 3 mo and if symptoms were not controlled with antacids, endoscopy was performed. If the patients were asymptomatic, endoscopy was performed after 1 yr. The endoscopist was unaware of CP status. Six patients were lost to follow-up and 1 patient refused further endoscopy. Of the remaining 39 patients, 14 remained asymptomatic throughout the year of follow-up, II\ I”
hurl llYY
minnr llllll”I
cxrmntnmc YJ”‘ yL”“‘Y
rnntmllorl Y”IILL”IIUU
xuith onto&Jr 111L11 YIILUULUY,
onJ YllU
7 r
had severe enough symptoms to warrant early endoscopy. At the end of the 1 yr follow-up, 11 of 21 bismuth-treated patients and 12 of 18 cimetidine-treated patients developed recurrent duodenal ulcer. Almost 80% of the patients
Konrad Schulze-Delrieu, Iowa City, Iowa Helen M. Shields, Boston, Mass. Michael L. Steer, Boston, Mass. Joseph Sweeting, New York, N.Y. Martin H. Ulshen, Chapel Hill, NC. Ernest Urban, Pittsburgh, Pa. Milton M. Weiser, Buffalo, N.Y.
who were CP-positive after the initial 6 wk of either treatment relapsed and only 27% of the patients who were CP-negative after initial treatment relapsed. All patients in whom CP was present after initial treatment had CP present after follow-up endoscopy at the end of the study; 33% of the patients in whom CP was not found after initial treatment developed CP infection. None of the patients who remained CP-negative throughout the year of follow-up developed histologic gastritis, whereas 86% of the patients who were CP-positive after the year of follow-up did have histologic gastritis. Comment. There have been >lOO articles published in the past 2 yr concerning CP and the association of this organism with gastroduodenal inflammation (Gastroenterology 1987;93:371-83). The impressive interest of physicians and investigators in this organism stems from the magnitude of the problem of peptic disease, the frustrations related to patients who have pain despite eradication of the ulcer, high recurrence rates after treatment, and the realization that the mucosal barrier has been an important but poorly defined contributor to the pathogenesis of ulcers. Although current therapies heal -90% of peptic ulcers, recurrence rates after 1 yr approach 80% (Gut 1982;23:239-42). The causes of ulcer recurrence remain unknown (Ann Intern Med 1986;105:757-61). The identification of an organism whose presence may explain ongoing pain, gastritis, and even recurrence of ulceration is a significant finding. There is still much controversy regarding the etiologic role of Campylobacter in peptic disease but a number of conclusions have been generally accepted. The growth and microbiologic characteristics of the organism have been reasonably well defined (J Ciin Pathoi 1965;138:1127-313. The organism can be cuitured from the gastric antrum of large numbers of patients with peptic disease and some studies suggest up to a 50% exposure in the general population (J Med Microbial 1986;22:57-62). When the organism is found in the stomach, it is always associated with gastritis and often, though not always, with peptic ulceration (Med J Aust 1985;142:439-44). Reliable diagnostic methods include culture from gastric mucosa, histologic identification, urease activity, and a breath test after ingestion of [‘%]urea (Gut 1985;26:1183-8, Lancet 1987;i:1174-7). Treatment of the organism with antibiotics and bismuth preparations has shown that it can be eradicated from the mucosa. The current study stems from the observations concerning the treatment of peptic disease with bismuth compounds. Although the mechanism of action of bismuth is not clear, a number of
SELECTED
June 1988
studies have demonstrated that bismuth heals peptic ulcers as efficiently as cimetidine (Gut 1983;24:1148-51; Gut 1980;21:32933). One previous study (Gut 1986;27:106-10) has shown that after duodenal ulcer healing, the recurrence rates of patients initially treated with bismuth were 43% as compared with 78% in the cimetidine-treated group. As bismuth has been shown to be an effective treatment for CP (Br Med J 1986;293:645-9), the possibility that the presence of Campylobacter may influence ulcer recurrence rates was raised and explored in the present study. The protocol in the current study was straightforward. Patients with a duodenal ulcer were treated for 6 wk with either bismuth or cimetidine. The presence or absence of CP was documented at the initial endoscopy and at the 6-wk time point. Patients were followed for 1 yr and underwent endoscopy at the end of the year or sooner if symptoms developed. The key findings were as follows: 93% of the patients were CP-positive at the start of the study; -70% of patients healed their ulcers after 6 wk of treatment with either regimen; the patients receiving bismuth cleared CP much better than the patients receiving cimetidine (50% vs. 83%); and patients who remained CP-positive after ulcer healing had a much higher rate of ulcer relapse than the patients who were CP-negative after ulcer healing (79% vs. 27%, p < 0.01). The allowed ad libitum use of antacids during the period after ulcer healing weakens the conclusions of the study somewhat. Undoubtedly, antacid use can influence duodenal ulcer recurrence rates. As CP infection may be facilitated by the presence of a nonacidic milieu (Lancet 1984;11:525-63, antacid use during the observation period may also contribute to continued CP presence. Recurrence rates and the presence of CP when no therapy is administered need further study. Two-thirds of the patients smoked, and the effect of smoking on CP should also be investigated as ulcer recurrence rates in smokers are increased (Gastroenterology 1983;85:871-4). Healing ulcers in the 1980s has become easy. Many drug regimens have been shown to be well tolerated and effective. The problem is the management of the patient after ulcer healing. No one knows how long to keep otherwise healthy people on maintenance therapy, particularly if they are asymptomatic. Does Campylobacter cause duodenal ulcer recurrence? It remains to be proved. This study suggests a strong association. If ulcer recurrence is clearly related to Campylobacter and if eradication of the
organism effects long-term remissions, most physicians would undoubtedly
revise
current
therapies. A. M. MAGUN, M.D.
GASTROESOPHAGEAL REFLUX: AN INCREASINGLY COMPLEX EVENT Gill RC, Kellow JE, Wingate DL [Gastrointestinal Science Research Unit, London Hospital Medical College, London, United Kingdom) Gastroesophageal reflux and the migrating motor complex. Gut 1987;28:929-34. The factors contributing to gastroesophageal reflux are multiple and growing in number. The primary barrier to reflux continues to be the lower esophageal sphincter (LES), as it appears that reflux occurs when the transsphincteric pressure difference is zero. This can be achieved either by increasing the intragastric pressure or by decreasing the LES pressure to equal intragastric pressure. Recently, the phenomenon of transient LES relaxation has been investigated and appears to play an important role in nocturnal gastroesophageal reflux. In addition, studies in the dog and in humans have indicated that the LES
SUMMARIES
1509
demonstrates cyclic activity concomitant with the interdigestive motor complex, raising another potential component in the control of the LES pressure. Gill, Kellow, and Wingate investigated the correlation between the interdigestive migrating motor complex (MMC) and gastroesophageal reflux in normal volunteers and their findings suggest an increased incidence of gastroesophageal reflux associated with periods of gastric motor activity, related to phases II and III of the interdigestive MMC interval. Five men and 2 women underwent a 24-hr recording of the intraesophageal pH (5 cm above the LES) and the intraluminal pressures from the LES, gastric antrum, and two sites in the duodenum. Recordings started at 8:30 AM. Subjects were seated and awake during the day and supine and “asleep” after 11:30 PM. The recording periods were divided into a diurnal fasting period (8:30 AM to 5:30 PM], a nocturnal fasting period (11:30 PM to 8:30 AM], and a postprandial period (5:30 PM to 8:30 PM). During fasting periods, reflux was noted both during the day and at night. The duration was greater at night than during the day (46 vs. 25 s), but the frequency was less. During the postprandial period reflux was also seen with a frequency greater than during the fasting periods. The authors were unable to identify phase III of the MMC in the gastric recordings, thus periods of gastric motor activity are comprised of a combination of phases II and III, lasting 33 ? 18 min at night and 43 k 2 7 min during the day (p < 0.01). No difference in the amplitude of contractions was noted during the day compared with at night. Episodes of nocturnal and diurnal reflux were of longer duration and more frequent during periods of gastric motor activity than during gastric motor quiescence. At night the duration of reflux during episodes of gastric motor activity was greater than during the day, although not more frequent. During periods of gastric motor quiescence, this difference was not seen. A correlation was seen between gastric motor activity and the increase in duration and number of gastroesophageal reflux episodes. Comment. This interesting paper examines the potential role of yet another factor in influencing gastroesophageal reflux. Although the LES pressure remains the most important barrier to reflux, it is now clear that this pressure is variable over time. Is the MMC another event associated with transient changes in the LES and therefore associated with intermittent reflux? Others have shown that transient inappropriate LES relaxation can occur and is associated with reflux (Gastroenterology 1981;81:376-94, J Clin Invest 1980;65:256-67). This transient relaxation is more frequent at night. In addition, levels of consciousness are tied in with events of gastroesophageal reflux, and esophageal acidification will in itself result in a greater level of consciousness (J Clin Invest 1980;65:256-67, Gastroenterology 1984;86:814-9). Long-term motility studies such as conducted in this study are hard to do and the authors are to be commended. It is a pity that the technique used to examine the LES pressure is suspect as the tube is likely to slip a few millimeters, at least during a long-term recording, making it difficult to differentiate a fall in LES pressure from the tube slipping into the stomach or into the esophagus. I assume that is why no mention is made of the LES pressure, although the recordings shown suggest that reflux is associated with a fall in LES pressure. It is curious that the LES pressure should fall during the gastric motor activity. In animals, the LES pressure increases