Correspondence
Helicobacter pylori and Nonulcer Dyspepsia
N Engl J Med 1999; 340:1508-1511May 13, 1999
- Article
To the Editor:
McColl et al. and Blum et al. (Dec. 24 issue)1,2 reached opposite conclusions regarding the eradication of Helicobacter pylori infection in patients with nonulcer dyspepsia. In an accompanying editorial, Friedman3 concluded that breakthroughs in the treatment of nonulcer dyspepsia will probably result from basic investigations into visceral sensitivity and brain–gut interactions rather than from further examination of the role of H. pylori infection.
Nonulcer dyspepsia is a heterogeneous condition. It is conceivable that the two studies involved somewhat different groups of patients with different sensitivities to antibiotic treatment. Indeed, one subgroup of patients with nonulcer dyspepsia — namely, those with alcoholic gastritis — appears to have a response to such treatment. Studies initiated over 40 years ago revealed that antibiotics eradicate bacterial gastric ammonia production,4 and in patients with alcoholic gastritis, the severity of H. pylori–induced gastric injury is correlated with the level of gastric-juice ammonia, suggesting that ammonia has a pathogenic role in the H. pylori–associated gastric injury.5 Furthermore, in one study, antibiotic therapy was associated with the amelioration of histologic abnormalities and dyspeptic symptoms, including epigastric pain, nausea, vomiting, heartburn, halitosis, burping, postprandial bloating, and flatulence,6 which, with the exception of vomiting, are among the eight most common symptoms in patients with nonulcer dyspepsia. In two studies, all H. pylori–positive patients with nonulcer dyspepsia and alcoholic gastritis had a response to antihelicobacter therapy, whereas controlled abstinence from alcohol had no such effect, nor was there any improvement in the patients who received antacids alone.6,7 Since the difference between the results of the studies by McColl et al. and Blum et al. reflected the outcome in only a relatively small percentage of patients, factors such as an unequal number of patients with alcoholic gastritis in the two studies may have been important.
7 ReferencesCharles S. Lieber, M.D.
Bronx Veterans Affairs Medical Center, Bronx, NY 104681
McColl K ,Murray L ,El-Omar E , et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1869-1874
Full Text | Web of Science | Medline2
Blum AL ,Talley NJ ,O'Morain C , et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1875-1881
Full Text | Web of Science | Medline3
Friedman LS . Helicobacter pylori and nonulcer dyspepsia. N Engl J Med 1998;339:1928-1930
Full Text | Web of Science | Medline4
Lieber CS ,Lefevre A . Ammonia as a source of gastric hypoacidity in patients with uremia. J Clin Invest 1959;38:1271-1277
CrossRef | Web of Science | Medline5
Triebling AT ,Korsten MA ,Dlugosz JW ,Paronetto F ,Lieber CS . Severity of Helicobacter-induced gastric injury correlates with gastric juice ammonia. Dig Dis Sci 1991;36:1089-1096
CrossRef | Web of Science | Medline6
Uppal R ,Lateef SK ,Korsten MA ,Paronetto F ,Lieber CS . Chronic alcoholic gastritis: roles of alcohol and Helicobacter pylori. Arch Intern Med 1991;151:760-764
CrossRef | Web of Science | Medline7
Lieber CS . Gastritis in the alcoholic: relationship to gastric alcohol metabolism and Helicobacter pylori. Addict Biol 1998;3:423-433
CrossRef | Web of Science
To the Editor:
McColl et al. did not address the effect of “eradicating” H. pylori infection on nonulcer dyspepsia but instead addressed the effect of “treating” H. pylori infection. We think that they should have tested the effect of successful eradication on nonulcer dyspepsia, since the infection was not eradicated in at least 12 percent of the patients who received antibiotics and omeprazole (four patients in this group did not have a urea breath test after treatment). It is also noteworthy that 5 percent of the patients in the placebo group had a negative urea breath test one month after treatment — an extraordinarily high percentage for sham eradication.
We suggest that additional analyses of the data reported by McColl et al. and Blum et al. be conducted so that the effect of eradicating H. pylori infection is more explicitly addressed.
Andreas Püspök, M.D.
Georg Oberhuber, M.D.
University of Vienna, 1090 Vienna, AustriaTo the Editor:
It is possible that some of the patients in the study by McColl et al. had duodenitis without discrete duodenal ulceration at the time of endoscopy. This would be in keeping with the high incidence of symptomatic ulcer disease in their placebo group. Patients with duodenal erosions were excluded from the trial by Blum et al. In the Nottingham randomized trial of dyspepsia management, we found that 41 percent of the patients referred for early endoscopy and then classified as having duodenal ulcer disease (22 of 54) had H. pylori–associated duodenitis (confirmed on biopsy) with or without erosions but without discrete ulceration.1 Were duodenal biopsies performed to exclude patients with this manifestation of ulcer disease, as recommended by Talley?2
2 ReferencesRichard F.A. Logan, F.R.C.P.
Robert P.H. Logan, M.R.C.P.
University of Nottingham, Nottingham NG7 2UH, United Kingdom1
Duggan A ,Elliott C ,Logan RPH ,Hawkey C ,Logan RFA . Does “near patient“ H. pylori testing in primary care reduce referral for endoscopy? Results from a randomised trial. Gastroenterology 1998;114:A110-A110 abstract.
CrossRef | Web of Science2
Talley NJ . A critique of therapeutic trials in Helicobacter pylori-positive functional dyspepsia. Gastroenterology 1994;106:1174-1183
Web of Science | Medline
To the Editor:
The 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36)1 is a popular generic measure of health status that is widely used in clinical trials. Unfortunately, in some studies, care has not been taken to apply the measure in the way that its developers intended, as is the case for the study by McColl et al. These authors have incorrectly summed the eight individual scales of the SF-36 survey to obtain a total score ranging from 0 to 800. There is no psychometric evidence to support this method of scoring, and most clinical trials either report the scores on individual scales that are hypothesized to be affected by treatment (e.g., mental health, pain, and vitality) or summarize the eight scores on the scales in the form of two composite scales: one for physical health and one for mental health.2 The authors cite a secondary source for the scoring of this instrument rather than the scoring manual for the instrument itself1; this may have affected their ability to detect a meaningful difference in quality of life between the two treatment groups.
2 ReferencesPatricia A. Ganz, M.D.
UCLA School of Medicine, Los Angeles, CA 90095-6900To the Editor:
In his editorial, Friedman did not mention a likely confounding factor in both studies. Both groups of investigators unknowingly included in their studies patients with peptic ulcer disease, who would have been expected to have improvement after the eradication of H. pylori infection. There were at least four such patients in the study by McColl et al. and seven in the study by Blum et al.
If endoscopy is performed to diagnose dyspepsia as part of a research protocol or in routine clinical practice, it must be done when the patient is having symptoms. Normal findings on endoscopy performed when a patient is asymptomatic cannot be used to rule out peptic ulcer disease. A policy of performing endoscopy only when patients with dyspepsia are symptomatic may be less convenient, but it can be carried out simply by giving patients the instructions for endoscopy and asking them to call when they start to have symptoms so that they can be scheduled for endoscopy as soon as possible.
On the basis of these two studies, it would be unsafe to conclude that the eradication of H. pylori infection has a place in the management of true nonulcer dyspepsia.
Brian B. Scott, M.D.
County Hospital, Lincoln LN2 5QY, United KingdomAuthor/Editor Response
The authors reply:
To the Editor: Several of the correspondents propose explanations for the different conclusions reached in our study and that of Blum et al. However, we believe that the results of the two studies are similar, with each showing a small benefit of eradicating H. pylori infection in patients with nonulcer dyspepsia.
In our study, we found a significant effect of the eradication of H. pylori infection on the proportion of patients who had a resolution of symptoms, with an absolute difference of 14 percent (95 percent confidence interval, 7 to 24 percent) between the active-treatment group and the placebo group. The primary outcome of the study by Blum et al. was also the resolution of symptoms at one year. The difference between the two groups — although not significant — was also in favor of active treatment (an absolute difference of 6.7 percent; 95 percent confidence interval, 2.6 to 16.0 percent). The study by Blum et al. was designed with power to detect a difference of more than 20 percent between the active-treatment and placebo groups and was therefore unlikely to detect the difference of 14 percent that we found.
The editorial by Friedman highlights the fact that the rate of resolution of symptoms in the placebo group was lower in our study than in that by Blum et al. However, in our study, the resolution of symptoms was defined as no or virtually no symptoms over the preceding six months, whereas the definition in the study by Blum et al. was no or minimal symptoms over the preceding week. The far more stringent definition of symptom resolution that we used explains the lower proportion of patients in whom it was achieved. With such different definitions of symptom resolution, it is very misleading to compare the response rates for the placebo groups in the two studies.
We chose a dyspepsia score of less than 2 as indicative of the resolution of symptoms because our previous validation studies had indicated that this was the most appropriate cutoff point. If we were to use a symptom score of less than 3 as indicative of the resolution of symptoms, then this would mean that symptoms resolved in 29.2 percent of the active-treatment group as compared with 17.5 percent of the placebo group (95 percent confidence interval for the difference between active treatment and placebo, 2.3 to 21.1 percent). When trying to detect a subgroup response, it is appropriate to compare the proportion of patients with a cure in the active-treatment group with the proportion in the placebo group rather than to look merely at differences in mean values between the two overall groups.
With respect to the point raised by Dr. Ganz, there were no significant differences after treatment between the active-treatment and placebo groups with respect to the mean score for any of the eight individual scales in the SF-36 quality-of-life survey.
Several of the correspondents suggest that the patients who had a benefit from treatment to eradicate H. pylori infection may have had duodenal ulcers that were healed at the time of endoscopy. We believe that this suggestion is probably wrong, since there was no association between risk factors for ulcer and the response to treatment.
We included in our study patients whose predominant symptom was heartburn or acid regurgitation suggestive of gastroesophageal reflux disease. In our group of 95 patients with symptoms suggestive of gastroesophageal reflux disease, 20 percent had a resolution of symptoms after active treatment, as compared with 2 percent after placebo (P=0.007), which represented at least as great a benefit of treatment as that in our 171 patients with ulcerlike symptoms (23 percent of whom had a resolution of symptoms after active treatment, as compared with 10 percent after placebo; P=0.02). Blum et al. excluded patients with symptoms suggestive of gastroesophageal reflux disease, presumably on the assumption that they would not benefit from treatment. Future studies should include patients with the full spectrum of upper gastrointestinal symptoms and, in particular, those with heartburn or acid reflux.
Taking the findings of the two studies together, we believe the message is that eradicating H. pylori infection results in a resolution of symptoms in a subgroup of patients with normal endoscopic findings. In addition, it is important to recognize that the benefit is at least as great in patients with symptoms suggestive of gastroesophageal reflux disease.
Kenneth E.L. McColl, M.D.
Lilian S. Murray, Ph.D.
Emad M. El-Omar, M.D.
Western Infirmary, Glasgow G11 6NT, United KingdomAuthor/Editor Response
Dr. Lieber suggests that the apparently disparate results of the two studies may be explained by the enrollment of different groups of patients with different sensitivities to antibiotics. We agree. However, Dr. Lieber's hypothesis that patients with “alcoholic gastritis” (i.e., alcohol-induced gastric damage) may be a subgroup that does not have a response to treatment is not well founded, since the data cited1 were obtained from only 14 patients and the study was not well controlled. Alcohol damage is very unlikely to account for our results; patients with alcoholism were excluded, and none of our patients had the classic finding of alcohol damage, focal subepithelial hemorrhage.2
Drs. Logan and Logan suggest that duodenitis should have been a criterion for exclusion from the study. Since the majority of H. pylori–infected patients have duodenal inflammation on histologic examination,3 this criterion would have excluded most patients from the study and would thus have led to a selection bias. In addition, duodenitis is an ill-defined entity. In an analysis of the response in terms of symptoms in relation to histologic findings, we found no difference between patients with antrum-predominant gastritis (a finding typical in patients with duodenal ulcer) and those with corpus-predominant gastritis (not usually found in patients with duodenal ulcer). If many patients with duodenal ulcer had been inadvertently included, we would have expected more of the patients in the antrum-predominant group to have had a response.
Dr. Scott stresses that endoscopy must be performed while patients are symptomatic in order to rule out peptic ulcer disease. Our patients were symptomatic when they underwent endoscopy on enrollment in the study. Unlike McColl et al., we routinely performed endoscopy in all patients 3 and 12 months after treatment was completed to determine whether ulcers had developed during the study. In the study by McColl et al., very few symptomatic patients underwent repeated endoscopy; ulcers were detected in four of six such patients in the group given omeprazole alone. Both symptomatic and asymptomatic ulcers may have been missed.
Drs. Püspök and Oberhuber suggest that the results might be different if patients cured of infection were compared with those not cured. We reported the rates of symptom relief in both H. pylori–positive and H. pylori–negative patients after antibiotic therapy (31 percent and 26 percent, respectively); the difference was not significant. We have now also compared symptom relief in the patients who remained positive for H. pylori infection after treatment with omeprazole (24 percent) with symptom relief in those who were cured of infection after antibiotic therapy (31 percent). The difference was not significant, confirming the results of our intention-to-treat analysis. A word of caution should be added about the use of these subgroups: since they are based on both treatment and the result of treatment, the groups are no longer randomized.
The response rates in the active-treatment groups in our study (27 percent) and in that of McColl et al. (21 percent) were remarkably similar. In the study by McColl et al., the distributions of the Glasgow Dyspepsia Severity Score in the group of patients who received antibiotics and the group who received omeprazole alone were not strikingly different at 12 months, despite the observation of a significant difference when an arbitrary cutoff score of 0 or 1 was chosen. We conclude that although different populations of patients may have been enrolled in the two studies, the results are, in fact, reasonably similar, and they show that the eradication of H. pylori infection is of little benefit in patients with nonulcer dyspepsia.
3 ReferencesAndré L. Blum, M.D.
Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, SwitzerlandNicholas J. Talley, M.D.
University of Sydney, Penrith, NSW 2751, AustraliaManfred Stolte, M.D.
Klinikum Bayreuth, 95440 Bayreuth, Germany1
Uppal R ,Lateef SK ,Korsten M ,Paronetto F ,Lieber CS . Chronic alcoholic gastritis: roles of ethanol and Helicobacter pylori. Arch Intern Med 1991;151:760-764
CrossRef | Web of Science | Medline2
Laine L ,Marin-Sorensen M ,Weinstein WM . Campylobacter pylori in alcoholic hemorrhagic “gastritis.“ Dig Dis Sci 1989;34:677-680
CrossRef | Web of Science | Medline3
Caselli M ,Gaudio M ,Chiamenti CM , et al. Histologic findings and Helicobacter pylori in duodenal biopsies. J Clin Gastroenterol 1998;26:74-80
CrossRef | Web of Science | Medline
Author/Editor Response
Lieber suggests that in patients with gastropathy caused by both alcohol consumption and H. pylori infection, dyspepsia is likely to resolve after the eradication of H. pylori infection. However, his hypothesis is based on a nonrandomized, unblinded, and essentially uncontrolled study of only 14 patients who were reassessed with the use of an unvalidated “total dyspepsia score” only several weeks after the completion of therapy.1 More rigorous clinical testing of this hypothesis is required. Moreover, a distinction should be made between alcoholic gastropathy, which is characterized histologically by subepithelial hemorrhages and erosions but generally not by inflammation, and H. pylori gastritis, a truly inflammatory process.2
Scott reiterates the possibility, mentioned in my editorial, that some patients with nonulcer dyspepsia and H. pylori infection in fact have peptic ulcer disease in endoscopic remission. However, his assertion that the detection of an ulcer requires that endoscopy be performed when the patient is symptomatic is a common misconception. In fact, symptoms of peptic ulcer lack both specificity and sensitivity for the endoscopic diagnosis of an ulcer.3 For example, endoscopy reveals clinically silent peptic ulcers in 1 to 3 percent of asymptomatic adult subjects,4 and 20 percent of patients with complicated ulcers (e.g., bleeding or perforation) have no history of dyspepsia.5 It is the absence of a correlation between dyspepsia and endoscopic detection of ulcers that makes the management of nonulcer dyspepsia so challenging.
5 ReferencesLawrence S. Friedman, M.D.
Massachusetts General Hospital, Boston, MA 021141
Uppal R ,Lateef SK ,Korsten M ,Paronetto F ,Lieber CS . Chronic alcoholic gastritis: roles of alcohol and Helicobacter pylori. Arch Intern Med 1991;151:760-764
CrossRef | Web of Science | Medline2
Weinstein WM. Other types of gastritis and gastropathies, including Ménétrier's disease. In: Feldman M, Sleisenger MH, Scharschmidt BF, eds. Sleisenger & Fordtran's gastrointestinal and liver disease: pathophysiology/diagnosis/management. 6th ed. Vol. 1. Philadelphia: W.B. Saunders, 1998:711-32.
3
Soll AH. Peptic ulcer and its complications. In: Feldman M, Sleisenger MH, Scharschmidt BF, eds. Sleisenger & Fordtran's gastrointestinal and liver disease: pathophysiology/diagnosis/management. 6th ed. Vol. 1. Philadelphia: W.B. Saunders, 1998:620-78.
4
Kuipers EJ ,Thijs JC ,Festen HP . The prevalence of Helicobacter pylori in peptic ulcer disease. Aliment Pharmacol Ther 1995;9:Suppl 2:59-69
Web of Science | Medline5
Pounder R . Silent peptic ulceration: deadly silence or golden silence? Gastroenterology 1989;96:626-631
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- Citing Articles (1)
Citing Articles
1
Luiz E. Mazzoleni, Guilherme B. Sander, Eduardo A. Ott, Sérgio G. S. Barros, Carlos F. Francesconi, Carisi A. Polanczyk, André C. Wortmann, Alexandro L. Theil, Leandro G. Fritscher, Luis F Rivero, André Cartell, Maria I. A. Edelweiss, Diego M. Uchôa, João C. Prolla. (2006) Clinical Outcomes of Eradication of Helicobacter pylori in Nonulcer Dyspepsia in a Population with a High Prevalence of Infection: Results of a 12-Month Randomized, Double Blind, Placebo-Controlled Study. Digestive Diseases and Sciences 51:1, 89-98
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