The role of Helicobacter pylori infection in non-ulcer dyspepsia

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1 Aliment Pharmacol Ther 1997; 11 (Suppl. 1), The role of Helicobacter pylori infection in non-ulcer dyspepsia S. J. O. VELDHUYZEN VAN ZANTEN Division of Gastroenterology (1), Dalhousie University, Queen Elizabeth II Hospital, Victoria General Hospital Site, Halifax, Nova Scotia, Canada SUMMARY It is currently unclear whether Helicobacter pylori (H. pylori) infection plays a role in patients who fulfil the criteria for non-ulcer dyspepsia. This paper reviews evidence for H. pylori-induced changes in gastric emptying, gastrointestinal motility, gastric acid secretion, and gastric perception in patients with non- ulcer dyspepsia. Problems in study design and execution of non-ulcer dyspepsia treatment trials are discussed. The results of non-ulcer dyspepsia treatment trials which have been performed in H. pylori-positive patients are reviewed. To date none of them has convincingly shown that cure of the H. pylori infection leads to a sustained improvement in symptoms. INTRODUCTION One of the most important current clinical questions in gastroenterology is whether Helicobacter pylori infection often plays a role in patients fulfilling the criteria for nonulcer dyspepsia. Over the years several definitions of non-ulcer dyspepsia, which is referred to as functional dyspepsia, have been proposed. The following working definition will be used, which is in keeping with the Rome criteria for the diagnosis of non-ulcer dyspepsia. Nonulcer dyspepsia is defined as unexplained pain or discomfort which is centred in the upper part of the abdomen. Symptoms have to be chronic and are either persistent or frequently recurring. This review will evaluate the current state of knowledge regarding the effect of H. pylori infection on gastric emptying and gastrointestinal motility, gastric acid secretion, and gastric perception. Subsequently, the study designs used in non-ulcer dyspepsia treatment trials will be critically appraised with special emphasis on outcome measures. Finally, results of non-ulcer dyspepsia treatment trials in H. pylori-positive patients will be analysed to determine whether eradication of the infection leads to a sustained improvement of symptoms. Correspondence to: Dr. S.J.O. Veldhuyzen van Zanten, Division of Gastroenterology, Victoria General Hospital, RC Dickson Centre, Rm 4087, 1278 Tower Road, Halifax, NS B3H 2Y9, Canada. H. PYLORI, GASTRIC MOTILITY AND GASTRIC EMPTYING Although one might suspect that H. pylori-induced inflammation of the gastric mucosa may affect gastric motility, to date no consistent motility abnormalities have been found increased, unchanged and decreased activity have all been reported. The study by Mearin et al. showed some decrease in post-prandial antral motility when H. pylori-positive patients with nonulcer dyspepsia were compared to H. pylori-negative nonulcer dyspepsia patients, but the differences, although statistically significant, were small. It is therefore unclear whether these differences have any clinical relevance. Gastric emptying has been shown to be delayed in some studies but not in others. The study by Tucci et al. investigated four groups: normal controls with and without H. pylori infection, H. pylori-infected non-ulcer dyspepsia patients, and H. pylori-negative non-ulcer dyspepsia patients. No differences were observed in solid gastric emptying when H. pylori-positive non-ulcer dyspepsia patients were compared to non-infected controls. Differences were seen between H. pylori-negative nonulcer dyspepsia patients and normal controls, with the non-ulcer dyspepsia patients having a significant delay in gastric emptying. Interestingly, in the latter group there was an over-representation of young females. Although there was no difference in gastric emptying between 1997 Blackwell Science Ltd 63

2 64 S. J. O. VELDHUYZEN VAN ZANTEN healthy controls and H. pylori-positive non-ulcer dyspepsia patients, the range of emptying times was much wider in H. pylori-positive patients. This raises the possibility that different subgroups may exist among the H. pylori-positive patients. The study by Minocha et al. showed no differences in gastric emptying but faster oral caecal transit time when H. pylori-positive non-ulcer dyspepsia patients were compared to H. pylori-negative non-ulcer dyspepsia patients. H. PYLORI AND ACID SECRETION Currently there is a controversy whether chronic H. pylori infection does lead to alterations in gastric acid secretion. There is agreement that during the initial stages of H. pylori infection a suppression of acid secretion can be found., This decrease in acid secretion is temporary and the period of hypochlorhydria appears to facilitate colonization of H. pylori organisms in the stomach. One has to keep in mind that in most cases of human H. pylori infection the actual time of acquisition is unknown. Therefore, it remains to be determined whether hypochlorhydria occurs in all acute H. pylori infections. Most of the debate on alterations in gastric acid secretion induced by H. pylori centres on patients with duodenal ulcers. There is agreement on the following findings when patients with H. pylori-positive duodenal ulcers are compared to H. pylori-negative controls: there is an elevation of basal acid output, peak acid output, and fasting and meal-stimulated gastrin concentrations. With the exception of one recent study, no changes in pentagastrin-stimulated gastric acid output are seen when H. pylori-positive duodenal ulcer patients are compared to non-infected controls. McColl and co-workers have done several elegant studies demonstrating that intravenous infusion of gastrin-releasing peptide (GRP)-stimulated gastrin release and acid output are increased in both H. pyloripositive non-ulcer dyspepsia patients and H. pyloripositive duodenal ulcers when compared to H. pylori non-infected controls., The increase in serum gastrin concentrations was similar in H. pylori-positive healthy volunteers, H. pylori-positive non-ulcer dyspepsia patients, and H. pylori-positive duodenal ulcer patients (all three groups showed a three-fold increase) when compared to non-infected healthy controls. All three H. pylori-infected groups showed an increase in GRPstimulated acid output but there were differences among the three groups: H. pylori-positive duodenal ulcer patients H. pylori-positive non-ulcer dyspepsia patients H. pylori-positive healthy volunteers. McColl has argued that GRP stimulation mimics the gastric physiology in response to a meal. The controversy centres on the question whether findings after GRP stimulation can be translated to the normal physiological situation that is whether indeed an increase in acid secretion takes place. There is agreement that the increase in both fasting and meal-stimulated gastrin is related to H. pylori-induced antral gastritis, which occurs both in H. pylori-positive duodenal ulcer and non-ulcer dyspepsia patients, but also in infected asymptomatic controls. Interestingly there appears to be a greater density of H. pylori organisms and more severe gastritis in the antrum, but not in the body, when H. pylori-positive, duodenal ulcer patients are compared to H. pylori-infected nonulcer dyspepsia patients. This raises the question whether the severity of inflammation, either as a result of the infection itself or a more vigorous response by the host, dictates clinical outcome. It has been shown that severity of gastritis is a predictor of higher relapse rates in duodenal ulcer patients when H. pylori is not eradicated. If one looks at average ph in the stomach, no significant differences are found between infected and non-infected non-ulcer dyspepsia patients. Whether there is a difference in acid secretion between H. pylori-positive patients who fulfil the criteria for non-ulcer dyspepsia, H. pylori-negative non-ulcer dyspepsia patients, and H. pylori-negative control patients is unclear,, although the debate is much the same as for duodenal ulcers. The mean gastrin levels are increased in H. pyloripositive non-ulcer dyspepsia patients and H. pyloripositive asymptomatic volunteers when compared to H. pylori-negative controls., It may be more important to look at the range of values, which is much wider in H. pylori-infected individuals than for the H. pylori-negative patients. A substantial proportion of H. pylori-positive non-ulcer dyspepsia patients have gastrin levels that are still within the normal range. This raises the possibility that there may be different sub-groups within the nonulcer dyspepsia patients. McColl and co-workers have also described a small sub-group of non-ulcer dyspepsia patients who have inappropriately low gastric acid secretion in response to GRP. These hypochlorhydria patients showed normalization in GRP-stimulated acid secretion following successful cure of the infection.

3 THE ROLE OF H. PYLORI INFECTION IN NON-ULCER DYSPEPSIA 65 The real question is whether the changes in gastric acid secretion, ph, gastrin levels, or inflammation in the antrum and body in H. pylori-positive patients with nonulcer dyspepsia have any correlation with the non-ulcer dyspepsia symptoms that patients are complaining of. Even in patients with an active duodenal ulcer, there is a poor correlation between symptoms and the presence of active ulceration., Furthermore, there is no good explanation why many individuals infected with H. pylori remain asymptomatic and others go on to develop nonulcer dyspepsia symptoms. H. PYLORI AND GASTRIC PERCEPTION The point prevalence of dyspepsia in the general population is 25% and the annual incidence varies between 1.6% and 8%. Up to 5% of all consultations in primary care are for dyspepsia. Many patients with chronic dyspepsia never consult a physician. The reasons for encounters with the physician will not be discussed here although what determines healthcare-seeking behaviours in non-ulcer dyspepsia patients is an important but difficult area of research. Most studies that investigate the relationship between H. pylori and non-ulcer dyspepsia have been conducted in GI clinics and academic centres, which in all likelihood see a very different population compared to the one served by family physicians. Does H. pylori infection indeed play a role in altered gastric perception? Mearin and co-workers have reported a small but detailed study in which three groups of patients were compared: H. pylori-positive non-ulcer dyspepsia patients (n 27), H. pylori-negative non-ulcer dyspepsia patients (n 22), and uninfected asymptomatic controls (n 12). No differences in severity of symptoms were found between H. pylori-positive and negative patients. Using a special gastroduodenal sleeve catheter, which was placed across the gastroduodenal junction, motility, gastrointestinal pressure activity, and subjective perception to graded increases in volume of an intragastrically positioned balloon were measured. All three groups showed a similar relationship between increases in balloon volume and change in intragastric pressure. When the balloon volume was gradually increased no differences were seen among H. pyloripositive and H. pylori-negative non-ulcer dyspepsia in their recording of abdominal discomfort. However, the results in the two non-ulcer dyspepsia groups were markedly different when compared to healthy controls. Both groups of non-ulcer dyspepsia patients complained of more abdominal discomfort for a given balloon volume. These data support the concept that altered visceral gastric perception plays a role in at least a sub-set of nonulcer dyspepsia patients. The study also investigated differences in both fasting and post-prandial motility. No differences were found among the three groups in the fasting state. For recording of post-prandial activity a somewhat complicated score the motility index, which incorporated the number of propagated waves and their amplitude was calculated. Using this motility index no differences were found among H. pylori-negative nonulcer dyspepsia patients and healthy controls. A lower motility score was obtained in the H. pylori-positive nonulcer dyspepsia patients. Whether this antral hypomotility has any clinical relevance, such as a correlation with symptoms, remains to be seen. Looking at the range of motility index scores, one of the striking features is the wider range of values seen in the H. pylori-infected group compared to the non-infected non-ulcer dyspepsia patients. This once again raises the possibility that different sub-groups may exist among patients with nonulcer dyspepsia. DYSPEPSIA SUB-GROUPS Recently, there has been an interest in dividing non-ulcer dyspepsia into sub-groups. Based on symptomatology, four dyspepsia sub-groups have been proposed: ulcerlike dyspepsia, reflux-like dyspepsia, dysmotility-like dyspepsia, and unclassifiable dyspepsia. Although the dyspepsia sub-groups are intuitively attractive as they coincide with beliefs about underlying pathophysiology (e.g. disturbed motility), to date there is no evidence that dyspepsia sub-groups truly exist. Recent data suggested that based on symptoms alone it is impossible to subdivide patients into sub-groups because significant overlap among the sub-groups is present. However, there is one recent study which suggests that H. pylori-positive patients with ulcer-like dyspepsia may respond better to treatment than those with reflux and dysmotility-like dyspepsia. H. PYLORI PREVALENCE AND SEVERITY OF SYMPTOMS Studies vary in their definition of non-ulcer dyspepsia making true comparisons somewhat difficult. One review suggested that the prevalence of H. pylori infection may be increased in non-ulcer dyspepsia patients compared to

4 66 S. J. O. VELDHUYZEN VAN ZANTEN normal controls, but this was disputed in another review., On the other hand a methodologically strong study by Bernersen et al. found no correlation between symptoms of dyspepsia and presence of H. pylori infection. No consistent differences in symptom severity or frequency of symptoms have been seen when H. pyloripositive dyspepsia patients are compared to H. pylorinegative patients.,, From a clinical point of view the most important unresolved question at the moment is whether cure of H. pylori infection leads to a sustained improvement over time in patients who fulfil the criteria for non-ulcer dyspepsia. In order to determine whether H. pylori eradication improves dyspepsia symptoms the first question one has to ask is whether reliable outcome measures exist. These measures must be able to carefully document the severity of symptoms but more importantly must also be able to detect a change (hopefully an improvement) in symptom severity. OUTCOME MEASURES IN NON-ULCER DYSPEPSIA Unfortunately most trials published on effectiveness of treatment in non-ulcer dyspepsia do not stand up to critical appraisal and thus far the same is true for nonulcer dyspepsia studies examining the role of H. pylori infection., Recently a systematic overview was published which carefully examined the trial methodology and use of outcome measures in non-ulcer dyspepsia studies. Fiftytwo randomized double-blind placebo controlled studies were retrieved which had a sample size of at least 20 patients. Thirty-six of the studies used a parallel design; 16, a crossover format. The large majority of studies were done in specialized GI centres with only 8% of studies reporting entry at the level of the family physician. The average treatment duration in most studies was short. The duration of treatment was 4 weeks or less in 44 studies. Only four studies had a treatment duration of 8 weeks or longer. Only seven studies had a follow-up after treatment, which is surprising for a chronic condition such as non-ulcer dyspepsia. With regard to individual symptoms, 94% of studies looked at severity of epigastric pain discomfort. The frequency of other symptoms studied was nausea 73%, heartburn 56%, abdominal bloating distention 48%, and excessive burping and belching 35%. In addition 37% of studies used a global assessment as an outcome measure. A further 27% of studies looked at a global assessment after treatment to try and detect whether patients had improved, deteriorated, or stayed the same. Overall 65% of studies used categorical (interval) scales. A weakness of many studies was the use of relatively insensitive scales. Nineteen studies used 4-point interval (so-called Likert) scales. An example of a 4-point interval scale in one which, for example, measures the severity of a symptom from 1 no problem to 4 a very severe problem. Because in non-ulcer dyspepsia symptoms often are not at the severe end of the spectrum, a 4-point scale is in effect reduced to a two-point scale. This may make it difficult to show a difference. Studies using 5- or 7-point scales are better able to pick up small differences as a result of treatment should such differences indeed be present. Only five studies used a 5- or 7-point scale. One of the reasons that it is mandatory to include a placebo arm in non-ulcer dyspepsia studies is the high placebo response. In the 52 studies, this varied from 13% to 73%. The exact placebo response, however, could not be determined in 20 studies. This systematic review makes clear that there is a current lack of consensus among investigators about study design in this area. Very little attention has been paid to the importance of validated outcome measures. Only five of the 52 studies used outcome measures which had been previously validated. Furthermore, a comprehensive assessment of overall quality of life was not performed in these patients. VALIDATED OUTCOME MEASURES USED TO DATE An in-depth review of validated outcome measures used in non-ulcer dyspepsia studies is beyond the scope of this article. When subjective endpoints are used to determine a change in health status the outcome measures should fulfil four requirements : i) the range of symptoms included should be important for the disease process; the measurements should ii) be reproducible (producing similar results when repeated in subjects who have not changed); iii) be able to detect change (responsive) and iv) if a change is detected it should reflect a real change in general health status. The ability to detect a clinically important change (either improvement or deterioration) in health status, assuming that such a change indeed took place, is referred to as responsiveness. The validity of a detected change can be constructed by comparison with other outcome measures if they are available. Unfortunately, no well-accepted objective outcome measurements are available for functional dyspepsia. Establishing the four attributes ideally requires a separate

5 THE ROLE OF H. PYLORI INFECTION IN NON-ULCER DYSPEPSIA 67 study to demonstrate that the instruments to be used meet the requirements. Nyren and co-workers were among the first to attempt to validate outcome measures in non-ulcer dyspepsia. They used a multidimensional score which assessed the duration and intensity of epigastric pain. The strength of this approach is that it uses a single outcome measure and therefore does not suffer from problems with multiple comparisons. The scale was successfully used in a study of 159 non-ulcer dyspepsia patients which did not show a difference in symptom relief when placebo, antacids, and cimetidine were compared. A Scandinavian group recently reported development of a new scale, the gastrointestinal system rating scale (GSRS)., This questionnaire includes 15 items which are graded on a 7-point Likert scale. It consists of three dimensions: dyspeptic symptoms, indigestion symptoms (such as abdominal distention and increased flatus), and bowel dysfunction. A Canadian study validated the use of Likert scales for measurement of the severity of eight gastrointestinal symptoms common in functional dyspepsia. These outcome measures, measured on a 7-point scale, were successfully used in a small clinical trial of patients with non-ulcer dyspepsia who were H. pylori-positive. Patients were randomized to either triple therapy aimed at curing the H. pylori infection or placebo. Patients were followed-up 4 weeks after treatment was finished and 6 months later. Although symptoms improved in patients over time, no statistically significant (and clinically important) differences were found when placebo-treated patients were compared to patients treated with active therapy. No differences were seen in global assessment of dyspepsia severity and global assessment of overall quality of life among the two groups. This study does not prove that H. pylori does not play a role in non-ulcer dyspepsia as the study sample size (n 49) was small. Furthermore, all patients were enroled in a GI clinic. It is certainly possible that one would get different results if patients with new onset dyspepsia were enroled from family practise offices. What the study does show is that it is feasible to do methodologically sound studies in nonulcer dyspepsia patients. As has been reviewed elsewhere most non-ulcer dyspepsia treatment trials in H. pylori non-ulcer dyspepsia patients do not stand up to critical appraisal. One study, however, has highlighted the importance of long-term follow up in these patients. Patchett et al. assigned 90 H. pylori-positive non-ulcer dyspepsia patients to three different treatment regimens. Some of the treatment combinations had low efficacy in curing the H. pylori infection. The overall eradication rate was 49%. The mean symptom scores did improve when patients were re-evaluated 4 weeks after treatment had been completed. However, no differences were seen among the three treatment arms nor when patients in whom H. pylori had been successfully cured were compared to those who had a persistent infection. A weakness of this study was that no placebo group was included. Seventyfive of the 90 enroled patients were subsequently reevaluated 1 year later. In those patients in whom H. pylori was cured symptom scores remained low. In contrast, patients with persistent infection had a recrudescence of their symptoms and also required more additional visits to the physicians. A problem with this study is that this part of the study was not blinded. Both physicians and patients were aware of their H. pylori status. As it may take up to 6 months before the histological inflammation in the mucosa returns to normal, this study certainly highlights the need for longterm follow-up in these patients, if one assumes that the mucosal inflammation is associated with the presence of symptoms. A recent study suggests that there may be some long-term improvement in successfully treated H. pylori-positive non-ulcer dyspepsia patients, but this was not observed in another study. Several large H. pylori-positive non-ulcer dyspepsia studies are underway and hopefully they will resolve the question whether H. pylori infection plays a role in non-ulcer dyspepsia. CONCLUSIONS Currently, it is unclear whether H. pylori infection plays a role in causing symptoms in patients fulfilling the criteria for non-ulcer dyspepsia. To date no consistent abnormalities have been documented in either gastric emptying or gastrointestinal motility which would help explain the symptoms of non-ulcer dyspepsia. There is agreement that H. pylori infection does cause changes in gastric physiology. The most important one appears to be hypergastrinaemia induced by antral inflammation. Abnormalities in GRP-stimulated acid are seen which resolve following cure of the infection. Most clinical treatment trials in H. pylori-positive non-ulcer dyspepsia patients do not stand up to critical appraisal. Data from a meta-analysis made clear that most non-ulcer dyspepsia trials suffer from sub-optimal study design. Methodologically sound studies are possible and hopefully the

6 68 S. J. O. VELDHUYZEN VAN ZANTEN studies which are currently under way will help to solve the question whether cure of the H. pylori infection leads to a sustained improvement in symptoms. Long-term follow-up for at least 6 12 months in these patients is required. ACKNOWLEDGEMENT Dr Veldhuyzen van Zanten holds a Career Award from the Pharmaceutical Manufacturers Association of Canada Medical Research Council. REFERENCES 1 Talley NJ, Colin-Jones D, Koch KL, et al. Functional dyspepsia: A classification with guidelines for diagnosis and management. Gastroenterology Intl 1991; 4: Minocha A, Mokshagundam S, Gallo SH, Rahal PS. Alterations in upper gastrointestinal motility in H. pylori non-ulcer dyspepsia. Am J Gastroenterol 1994; 89: Pieramico O, Distchuneit H, Malfertheiner P. Gastrointestinal motility in patients with non-ulcer dyspepsia: A role for Helicobacter pylori infection? Am J Gastroenterol 1993; 88: Mearin F, de Ribot X, Balboa A, et al. 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